It's my pleasure today to discuss with you the results of the MOMENTUM study as presented at EHA 2022. So, the MOMENTUM study is an incredibly important study in the development of a drug called Momelotinib, a JAK inhibitor that differentiates itself from other inhibitors that are already approved for the treatment of patients with myelofibrosis.
A key off-target effect on a molecule called ACVR1, also known as ALK2, It does have the kind of canonical JAK inhibition of JAK2 that we see with other JAK inhibitors. But again, the standout feature is this off-target effect on ACVR1/ALK2 CVR. What that does is it's a master regulator of iron metabolism in our body and actually affects hepcidin levels.
It can lower hepcidin levels, thus treating the inflammatory component of anemia. Anemia is an incredibly important problem in patients with myelofibrosis. It is a diagnostic criterion as well as a prognostic criterion for patients with this disease. And there is some retrospective analysis suggesting that if we could impact disease-related anemia and improve it, patients could have better overall survival in addition to better quality of life and potentially better resource utilization.
So, in this trial, the MOMENTUM study, momelotinib as a JAK inhibitor slash ACVR1 inhibitor was pitted against Danazol in anemic patients with myelofibrosis previously treated with JAK inhibitors. These patients also had to be symptomatic and have enlarged spleens. The top line results were previously released in a press release from the company.
But in these abstracts, we have much more detail on the outcomes for the primary endpoint of this study. The primary endpoint of the study was an improvement in symptom burden at week 24. Additional key secondary endpoints included spleen vine responses at week 24, as well as transfusion independence at week 24. So, taking that last point is key because Danazol was selected as a comparator arm because it is used to treat anemia in myelofibrosis patients as recommended by the NCCN and ESMO guidelines.
So, in those results, the Momelotinib arm outperformed the Danazol arm in terms of transfusion independence at week 24. Moreover, Momelotinib was able to shrink spleens as well as improve symptoms in patients to a much greater degree as compared to Danazol. I think that is really the key take-home point from this study. The top-line total study results were presented by Dr. Verstovsek, and the special subset of patients with thrombocytopenia were presented by Dr. Verstovsek at this year's EHA meeting in two separate abstracts. And the reason that we focused on patients with lower platelet counts is that Earlier Momelotinib trials, as well as this trial, did include patients with thrombocytopenia.
In fact, we included patients with a platelet count as low as 25,000. Therefore, severe thrombocytopenia was included in this study, and a fair number of patients did have severe thrombocytopenia. And I think that's really important to note because Currently available Ruxolitinib and Fedratinib have limits on how much we can use them in clinical oncology and what doses because of thrombocytopenia.
Of course, there is the approved Pacritinib that can be safely given to patients with platelet counts of less than 50,000. So as more and more JAK inhibitors come into clinical use every day in the clinic, I think it's going to be really important how we try to separate these things out and which patient populations have data that supports the use of these drugs as well.
And again, these were a lot of the top-line results from this momelotinib study, but the work going forward would really be on identifying the best populations for each of these JAK inhibitors. Now that we have almost an embarrassment of riches in the number of JAK inhibitors approved, the next step for this particular drug is really regulatory approval.
This was a registration and the data is being further cleaned up and correlated and is being put together for regulatory submission to the FDA for hopefully regulatory approval sometime in the year 2023. The quicker we can get momelotinib to our patients, the better.
Is one of the "myeloproliferative neoplasms (MPNs)," a type of blood cancer in which bone marrow cells that make blood cells grow and behave improperly.
Transfusions of blood If you have severe anemia, regular blood transfusions can boost your red blood cell count and alleviate symptoms like exhaustion and weakness. Medication can sometimes help improve anemia in patients with myelofibrosis.
Despite the lack of a unified definition, transfusion dependence (TD) is typically defined as patients who require regular platelet and/or red blood cell (RBC) transfusions more frequently than every 8 weeks due to a consistently low count.
Aaron T. Gerds, MD, MS from the Cleveland Clinic, Dr. Aaron Gerds earned his bachelor's degree in biology and chemistry with honors from Hope College in Holland, Michigan. Following that, he earned his M.D. from Loyola University Chicago Stritch School of Medicine. Dr. Gerds completed his Internal Medicine residency at Loyola University Hospital, where he also served as head resident. While examining clinical trial results under the tutelage of Dr. Patrick Stiff, he became interested in hematology for the first time. During his residency, he decided to pursue a master's degree in clinical research methodologies and epidemiology. Dr. Gerds then moved to Seattle to finish his hematology/oncology fellowship at the University of Washington's Fred Hutchinson Cancer Research Center. He received the ASBMT's New Investigator Award during his fellowship. Dr. Gerds subspecialized in treating patients with myeloproliferative neoplasms (MPNs) such as polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis (MF), myelodysplastic syndromes (MDS), and chronic myelomonocytic leukemia (CMML), with a special emphasis on allogeneic hematopoietic cell transplantation Dr. Gerds is also an active member of the American Society of Hematology, having participated in the Advocacy Leadership Institute, Clinical Research Training Institute, and Test Materials Development Committee. Dr. Gerds, an Assistant Professor of Medicine (Hematology and Medical Oncology) at the Cleveland Clinic Taussig Cancer Institute, is the principal investigator for a number of clinical trials for the treatment of MPNs, and her research is focused on identifying novel therapeutics for these patients.
Momelotinib, a new oral ACVR1/ALK2 and JAK1/2 inhibitor, demonstrated clinical activity in the SIMPLIFY trials for MF symptoms, RBC transfusion requirements (anemia), and spleen volume.
This pivotal phase 3 research compared Momelotinib to Danazol on major symptoms, anemia, and spleen volume endpoints at 24 weeks in MF patients previously treated with a JAK inhibitor (JAKi) (wks), looking at the total symptom score.
Eligibility requirements include - Primary or post-ET/PV MF; DIPSS high risk, Int-2, or Int-1; MF Symptom Assessment Form Total Symptom Score (MFSAF TSS) 10; hemoglobin (Hgb) 10 g/dL; prior JAKi for 90 days, or 28 days if RBC transfusions 4 units in 8 wks or Gr 3/4 thrombocytopenia, anemia in patients with myelofibrosis, or hematoma; palp TSS (22 vs 22), palpable spleen (12 cm vs 12 cm), and RBC units transfused (0, 1-4, and 5+) stratification The JAKi taper and washout took 21 days. Randomization - Momelotinib 200 mg QD + Danazol placebo or Danazol 600 mg QD plus Momelotinib placebo for 24 weeks, followed by open-label Momelotinib. Assessments: The patient kept a daily eDiary and had his spleen volume measured with an MRI or CT. TSS response (50 percent reduction from baseline [BL]) rate was the primary goal at week 24. Secondary objectives were RBC TI rate, splenic response rate (SRR; 25% reduction in volume from BL), change from BL in TSS, SRR (35 % reduction from BL), and rate of zero transfusions since BL, all examined sequentially at wk 24. All participants provided informed consent.
The 24-week randomized treatment (RT) phase was completed by 94 of 130 (72%) Momelotinib patients and 38 of 65 (58%) Danazol patients. Hgb levels were 8.1 (Momelotinib) and 7.9 (Danazol) g/dL, and platelets were 97 (Momelotinib) and 94 (Danazol) x109/L, respectively. BL TI was 13% (Momelotinib) and 15% (LMB) (Danazol). The mean spleen volume in BL patients was 2367 (Momelotinib) and 2288 (Danazol) cm3. Prior JAK inhibitor was treated with ruxolitinib in 195 patients treated (100%) and fedratinib in 9 patients (5%); the mean duration of prior JAK inhibitor was 134 weeks. All of the primary and key secondary endpoints were met (Table). The most common grade 3 treatment-emergent adverse events (TEAEs) in the RT phase of the research were thrombocytopenia (Momelotinib, 22%; Danazol, 12%). (Momelotinib, 8 percent ; Danazol, 11 percent ). Gr 3 infections occurred in 15% of Momelotinib patients and 17% of Danazol patients. Peripheral neuropathy (PN) occurred in 5% of Momelotinib (all Gr 2) and 2% of Danazol (Gr 2) Pts during the RT phase, with no patients discontinuing study medication due to PN. Overall, TEAEs caused study drug discontinuation in 18% of Momelotinib and 23% of Danazol patients, with significant TEAEs observed in 35% of Momelotinib and 40% of Danazol patients during the RT phase. Momelotinib vs Danazol showed a trend toward improved overall survival up to week 24 (HR=0.506, p=0.0719).
Momelotinib was superior to Danazol in symptomatic and anemic MF patients for symptom responses, transfusion requirements, and spleen responses, with comparable safety and good survival. Momelotinib may fill a crucial unmet need, especially in patients with myelofibrosis with anemia. NCT04173494.
MOMENTUM is a randomized, double-blind Phase 3 clinical trial comparing momelotinib to danazol (n=180; 2:1) in symptomatic, anemic patients who have previously received treatment with an authorized JAK inhibitor. The study's goal is to confirm [in a statistically significant way] momelotinib's distinctive advantages on all three hallmarks of myelofibrosis (MF): symptoms, anemia, and splenomegaly in patients with myelofibrosis.
The MFSAF Total Symptom Score (TSS) response rate at Week 24 is the study's primary goal. Secondary objectives were anemia benefit and splenic response rate confirmation.
Danazol was chosen as an appropriate therapy comparator since it has been shown to improve anemia in myelofibrosis patients, as suggested by NCCN and ESMO guidelines. Patients will be randomly assigned to either momelotinib or danazol. Patients on danazol will be able to switch to momelotinib after 24 weeks of treatment. For confirmed symptomatic splenic progression, an early cross-over to momelotinib is available.
Dr. Srdan Verstovsek, Chief, Section for Myeloproliferative Neoplasms, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, and Dr. Ruben Mesa, Director of the Mays Cancer Center, home to UT Health San Antonio MD Anderson Cancer Center, are the study's co-Chief Investigators. Dr. Verstovsek and Dr. Mesa are both world-renowned clinician scientists in the field of myeloproliferative neoplasms. Most investigational and authorized medications for the treatment of myelofibrosis have been developed by Drs. Verstovsek and Mesa. Dr. Verstovsek and Dr. Mesa, in particular, have been involved in the development of momelotinib as consultants and clinical investigators since 2011.
18 years old.
A PMF diagnosis has been verified, according to the World Health Organization.
World Health Organization (WHO) 2016 standards, or Post-PV/ET MF in accordance with
Myeloproliferative Neoplasms Research and Treatment (MRT) International Working Group (IWG-MRT criteria).
Symptomatic, defined as a TSS of 10 units as determined by a single MFSAF v4.0 evaluation prior to Day BL1.
Anemia is defined as a Hgb level of less than 10 g/dL during the screening or baseline period.
Previously treated for 90 days with an authorized JAK inhibitor for PMF or Post-PV/ET MF, or 28 days if JAK inhibitor therapy is complicated by an RBC transfusion requirement of 4 units every 8 weeks, or Grade 3/4 AEs of thrombocytopenia, anemia, or hematoma.
Baseline splenomegaly is defined as having a palpable spleen at 5 cm, below the left costal margin, or with a volume of 450 cm3 on imaging (ultrasound, MRI, or CT are acceptable) at any point before randomization.
DIPSS or DIPSS-plus defines high risk, intermediate-2, or intermediate-1 risk MF.
There are no plans for an allogeneic stem cell transplant.
Acceptable laboratory evaluations:
The absolute neutrophil count (ANC) was 0.75 109/L.
PLT (platelet count): 25 109/L (without requirement for platelet transfusion).
Peripheral blast count is 10%.
Alanine aminotransferase/serum glutamic-oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase/serum glutamic-pyruvic transaminase (ALT/SGPT) 3 ULN ( 5 ULN if liver is involved by extramedullary hematopoiesis as judged by the investigator or if related to iron chelator therapy started within
Cockcroft-Gault calculated creatinine clearance (CCr) of 30 mL/min.
2.0 ULN for direct bilirubin.
Use the following approved therapies within the time frames specified:
Prior momelotinib treatment is possible at any moment.
Approved JAK inhibitor medication (e.g., fedratinib or ruxolitinib) must be started within one week of the first day of Baseline.
Active anti-MF therapy should begin no later than one week before the first day of Baseline.
Potent inducers of Cytochrome P450 3A4 (CYP3A4) within 1 week of Randomization
Within 4 weeks of Randomization, the investigational medication (including investigational JAK inhibitors) was administered.
ESA (erythropoiesis stimulating agent) within 4 weeks of Randomization
Danazol was administered within three months of the randomization.
Irradiation of the spleen within three months of the randomization.
Current medication includes simvastatin, atorvastatin, lovastatin, or rosuvastatin.
Prostate cancer history, with the exception of localized prostate cancer treated surgically or with radiotherapy with curative aim and deemed cured.
PSA concentrations more than 4 ng/mL.
Unsuitable for spleen volume measurements due to prior splenectomy or reluctant or unable to have an MRI or CT scan as required by protocol.
Any of the following (criteria a through k):
Active uncontrolled infection (subjects receiving outpatient antibacterial and/or antiviral therapy for infection that is under control or as infection prophylaxis may be included in the experiment).
Significant active or persistent bleeding incident grade 2 according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0, within 4 weeks of Randomization.
Unstable angina pectoris within the last 6 months.
Symptomatic congestive heart failure within the previous 6 months of Randomization.
Uncontrollable heart arrhythmia within 6 months of randomization
Unless attributed to a bundle branch block, the QTcF interval is greater than 500 msec.
Thrombosis is currently progressing despite treatment.
Porphyria has a long history.
Child-Pugh score of ten
Psychiatric illness, social position, or any other condition that, in the opinion of the investigator or sponsor, may impede compliance with trial conditions or may interfere with the interpretation of study data.
Failure or reluctance to adhere to protocol limits on MF therapy and other drugs prior to and during trial treatment.
Subjects having a past or concurrent malignancy whose natural history or treatment has a considerable potential to interfere with the investigational regimen's safety or efficacy assessment.
Anemia caused by iron, vitamin B12, or folate deficits, autoimmune or genetic hemolytic anemia, gastrointestinal hemorrhage, or thalassemia.
The HIV status is known to be positive.
Acute or chronic viral hepatitis A, B, or C infection, or hepatitis B or C carrier (testing required for hepatitis B and C).
Unresolved non hematological toxicity from prior therapy that are greater than Grade 1 according to CTCAE v5.0.
Peripheral neuropathy, grade 2 according to CTCAE v5.0.
Women who are pregnant or breastfeeding.
Additional criteria for inclusion or exclusion may apply.
Aaron T. Gerds, MD, Cleveland Clinic - OncologyTube Interview, May 18, 2022
Sierra Oncology, Inc. - MOMENTUM Clinical Trial - Sierra Oncology Trials, February 11, 2022
ClinicalTrials.gov - A Study of Momelotinib Versus Danazol in Symptomatic and Anemic Myelofibrosis Patients (MOMENTUM). ClinicalTrials.gov, February 11, 2022
65% risk reduction of event-free survival in the Lisocabtagene Maraleucel arm.
10.1 months (95% confidence interval: 6.1, not evaluable) estimated median event-free survival compared to 2.3 months (95% confidence interval: 2.2, 4.3).
59% risk reduction in progression-free survival in the Lisocabtagene Maraleucel arm compared to standard of care.
Lisocabtagene Maraleucel is not approved to treat people with primary central nervous system lymphoma.
Hazard ratio (HR) of 0.34 (95% CI:0.22, 0.52; p-value0.0001), event-free survival was substantially longer in the Lisocabtagene Maraleucel arm.
45% (95% CI: 29, 59) and 24% (95% CI: 14, 35) in the usual treatment predicted 1-year event-free survival in the Lisocabtagene Maraleucel arm.
The suggested dose of lisocabtagene maraleucel for second-line therapy is 90 to 110 106 CAR-positive T cells with a 1:1 CD4:CD8 ratio.
Cytokine release syndrome occurred in 45% of patients (Grade 3 or higher, 1.3%) in investigations with Lisocabtagene Maraleucel as second-line therapy for large B-cell lymphoma, while neurologic toxicities occurred in 27% (Grade 3, 7%).
184 patients were randomly assigned to either a single infusion of Lisocabtagene Maraleucel after fludarabine and cyclophosphamide lymphodepleting chemotherapy or second-line standard therapy, which included three cycles of chemoimmunotherapy followed by high-dose therapy and autologous HSCT in patients who achieved CR or partial response (PR).
33% to 38% of serious adverse events occurred in patients.
So, as the community here is very well aware, patients with large B-cell lymphoma whose diseases are primary refractory LBCL, meaning they have never responded to frontline chemotherapy (systemic therapy) or relapsed within 12 months of initial chemo and immunotherapy, have exceptionally poor outcomes. Salvage immunochemotherapy followed by high-dose chemotherapy and hematopoietic stem cell transplantation has been the standard of care.
Second-line treatment for transplant-eligible, high-risk, large B-cell lymphoma for nearly three decades. Unfortunately, though, only about a quarter of these transplant-eligible patients with relapse-refractory disease achieve durable long-term remission. So, clearly, this is an unmet need. And this is where the pivotal Phase III TRANSFORM study was uniquely designed.
Whereas in Lisocabtagene Maraleucel, a CAR T construct was designed to challenge the current standard of care and thus address this unmet need. So, the TRANSFORM study enrolled patients whose disease was primary refractory LBCL or relapsed 12 months or less after frontline chemotherapy and compared Lisocabtagene Maraleucel with the standard of care, which consisted of 3 cycles of salvage immunochemotherapy followed by high-dose chemo and hematopoietic stem cell transplantation.
The primary endpoint of this study was event-free survival, and the key secondary endpoints will be complete response rate progression, free survival, and overall survival. Nearly 75% of patients in both arms did not have a response to first-line treatment or had primary refractory disease. The study met its primary endpoint with the superiority of Lisocabtagene Maraleucel over the standard of care.
Lisocabtagene Maraleucel demonstrated a 65% risk reduction of event-free survival events with the median EF. Or event-free survival of 10.1 months, compared with only 2.3 months in the standard of care arm, a higher percentage of patients achieved a complete response with Lisocabtagene Maraleucel compared with standard of care Lisocabtagene Maraleucel, thus led to a 59% risk reduction of progression-free survival compared to standard of care.
Overall survival data at this point is certainly immature for this analysis, but it's extremely interesting to see that the curves are showing a trend favoring mature data, which continues to be awaited and will be presented very shortly at the next few meetings. Lisocabtagene Maraleucel also showed an extremely manageable safety profile with very low rates of severe cytokine release syndrome and neurological events.
No new safety signals were observed with Lisocabtagene Maraleucel in the second line setting. And with regards to the low incidence of grade 3 CAR T-cell therapy toxicities that we talked about, which are CRS and neurologic toxicities events, it is extremely important to also remember that there were absolutely no grade 4 or grade 5 events that were reported.
Overall, these adverse events were manageable with treatments as per standard practice. So overall, this study, which compared with the standard of care, Lisocabtagene Maraleucel demonstrated a highly statistically significant and clinically meaningful improvement in terms of the primary, as well as key secondary endpoints. It reduced the risk of EFS by 65% achieved the 29, 27% higher complete response rate.
And it reduced the risk of progression-free survival events by 59%. No new safety signals will be observed with Lisocabtagene Maraleucel in the second line setting grade 3 CRS and neurological events, which generally low with no grade 4 or 5 events that were reported. Thus Lisocabtagene Maraleucel showed superiority over auto transplant as a new standard of care in the second-line treatment for patients with relapse refractory Large B-Cell Lymphoma.
What are the most common questions that my colleagues asked me about this study? I think it's important to remember that these patients are extremely high risk. Especially as the overall outcomes for these patients remain exceptionally poor. Thus, it's really important to get them to a CAR T center.
The minute the patients get identified with primary refractory disease or a disease that relapses within 12 months of treatment. Important to also remember that within the study, besides just Diffuse Large B-Cell Lymphoma NOS, high-grade B-Cell lymphoma with double. Gene rearrangements, T-cell Rich B-Cell Lymphoma, primary media style, B-Cell Lymphoma, Follicular Lymphoma grade 3B as well as Transformed Lymphomas from indolent lymphoma histologies were also included.
Patients with CNS involvement were also included. In terms of some of the other questions that my colleagues pose, where was this infusion given? So, yes, there were sometimes patients admitted to the hospital, but there was also a cohort of patients within this study where Lisocabtagene Maraleucel could be administered in an outpatient setting.
With regards to toxicities, a lot of colleagues ask me, how was the construct tolerated in this transplant-eligible population? The cohort construct with lysis with the Lisocabtagene Maraleucel was exceptionally well tolerated. There were no grade 4 or grade 5 cytokine release syndrome or neurological events that were reported.
I do believe that this data will affect clinicians as of today. And it's really important to highlight that Breyanzi or Lisocabtagene Maraleucel is now approved for patients with high risk relapsed Large B-Cell Lymphoma were transplant eligible in the second-line setting, as well as based on the pilot study that looked at second-line options for relapsed, diffused, Large B-Cell Lymphoma patients.
This study Lisocabtagene Maraleucel is now approved for transplant-ineligible patients in the second line setting.
So thus, as you can see, it has definitely challenged the age-old standard of autotransplant. So, it will absolutely affect clinicians in terms of their daily practice because when they do see patients with primary refractory A Large B-Cell Lymphoma or Large B-Cell Lymphoma that have relapsed within 12 months of frontline, chemo, immunotherapy, or patients who are transplant ineligible, who have relapsed after frontline chemo, immunotherapy.
At this point in time, CAR T-cell therapy with Lisocabtagene Maraleucel is now FDA approved. It's thus really important for them to refer these patients to the CAR T center sites so as to expeditiously walk these patients and be able to get them CAR T-cell therapy.
In terms of the next step for this research, obviously, it is heartening to see that after a very long time. We now have something better as compared to autotransplant. Something that is definitely more efficacious in terms of toxicity, but absolutely manageable. So, in terms of the next steps for research, I would say that it is.
It is probably going to be helpful to see how CAR T-cell therapy compares to auto transplant in patients who have a relapse of diffused Large B-Cell Lymphoma. That's more than AR. Would CAR T-cell therapy beat auto transplant in that setting? Given how efficacious CAR T-cell therapy is and just how oncology research evolves as it keeps being brought into the earlier settings, it would be interesting to see what CAR T-cell therapy would do for patients in the frontline setting.
So, I think these are some of the next steps that we all, as clinical investigators, are really curious to see and excited to see what this field of CAR T-cell therapy unravels for our patients with Large B-Cell Lymphoma, as well as many other subtypes of Lymphoma, like relapsed or refractory LBCL.
So, with regards to this data, what else do medical oncologists and hematologists need to know about this data? I think there are a few things that I do need to highlight based on the transform study, which is a positive study. It is important to remember that patients with high-risk relapse, Large B-Cell Lymphoma, meaning patients who have relapsed after.
Frontline chemotherapy within 12 months, or having just not responded to frontline chemoimmunotherapy, Lisocabtagene Maraleucel was statistically significant, clinically meaningful, and superior compared to an autotransplant. Thus, at this point, it remains the standard of care. It is the new standard of care for patients in the second-line setting who are transplanted.
It is also important to remember that based on the pilot data, which showed some excellent, which showed excellent efficacy and manageable safety for patients who are transplant ineligible with relapse or refractory Large B-Cell Lymphoma, as their outcomes are exceptionally poor. What they did demonstrate in the pilot study.
Was with Lisocabtagene Maraleucel, this cohort of patients had an excellent response rate as well as durability with regards to remission and a very manageable toxicity profile. So, it's really important to highlight that it's pertinent that medical oncologists and hematologists in the community identify these patients and refer them to the CAR T-cell therapy site soon.
It is important to highlight that this is an extremely efficacious and manageable (with regards to toxicity) construct. Even if there is a question about eligibility, it never hurts to send them over to CAR T-cell therapy sites to assess if they could be potential candidates to get Lisocabtagene Maraleucel, given how efficacious and tolerable it is.
It could be given in the outpatient setting. Thus, it definitely plays a huge role with regards to the quality of life for our patients, as it's obviously much, much better preferred to stay in the outpatient setting versus being admitted to the inpatient setting for days. It is important to highlight that with regards to subtypes of lymphoma, diffuse, Large B-Cell Lymphoma, High-Grade B-Cell Lymphoma, and T-cell Rich B-Cell Lymphoma.
Primary Media Cell B-Cell Lymphoma, Follicular Lymphoma grade 3B, and Large B-Cell Lymphoma with CNS involvement. There were also subtypes that were included in the transform study. And I think at this point in time, stay tuned for more updates with regards to the primary analysis of this study. As crossover was permitted, and despite that, the overall survival data at this point, albeit immature, looks like it is favoring license.
So, I would say these would be the key themes to highlight in terms of what I believe medical oncologists and hematologists should know about this data.
Manali Kamdar, MD, MBBS, is an Associate Professor at the University of Colorado Denver. In this video, she speaks about FDA approves lisocabtagene maraleucel for second-line treatment of large B-cell lymphoma.
On June 24, 2022, the Food and Drug Administration approved lisocabtagene maraleucel (Breyanzi, Juno Therapeutics, Inc., a Bristol-Myers Squibb Company) for adult patients with large B-cell lymphoma (LBCL) who have refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy; or to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy. It is not approved to treat people with primary central nervous system lymphoma. This FDA approval of Lisocabtagene Maraleucel for relapsed or refractory LBCL, is a big step forward.
TRANSFORM (NCT03575351), a randomized, open-label, multicenter trial in adult patients with primary resistant LBCL or relapse within 12 months of attaining a complete response (CR) to first-line therapy, was used to assess efficacy. Patients had not yet been treated for relapsed or refractory lymphoma and were candidates for autologous HSCT. A total of 184 patients were randomly assigned to either a single infusion of lisocabtagene maraleucel after fludarabine and cyclophosphamide lymphodepleting chemotherapy or second-line standard therapy, which included three cycles of chemoimmunotherapy followed by high-dose therapy and autologous HSCT in patients who achieved CR or partial response (PR).
An independent review group chose the primary efficacy metric to be event-free survival (EFS) (IRC). With a hazard ratio (HR) of 0.34 (95 percent CI:0.22, 0.52; p-value0.0001), EFS was substantially longer in the lisocabtagene maraleucel arm. The predicted 1-year EFS in the lisocabtagene maraleucel arm was 45 percent (95 percent CI: 29, 59) and 24 percent (95 percent CI: 14, 35) in the usual treatment arm. The estimated median EFS was 10.1 months (95 percent confidence interval: 6.1, not evaluable) and 2.3 months (95 percent confidence interval: 2.2, 4.3), respectively. Patients assigned to standard therapy obtained autologous HSCT as intended in 47 percent of cases, with lack of response to chemotherapy being the most common reason for not obtaining HSCT. The IRC-assessed progression-free survival in the lisocabtagene maraleucel arm was likewise significantly longer, with an HR of 0.41 (95% CI: 0.25, 0.66; p-value 0.0001).
PILOT (NCT03483103), a single-arm, open-label, multicenter trial in transplant-ineligible patients with relapsed or refractory LBCL after one line of chemoimmunotherapy, was also investigated for efficacy. Patients who were ineligible for high-dose therapy and HSCT due to organ function or age were enrolled in the research, but had appropriate organ function for CAR-T cell therapy. Efficacy was measured by an IRC based on CR rate and duration of response (DOR). 61 (82 percent) of 74 patients who underwent leukapheresis (median age, 73 years) received lisocabtagene maraleucel, with 54 percent (95 percent CI: 41, 67) achieving CR. The median DOR in individuals who obtained CR was not reached (95 percent CI: 11.2 months, not reached) and 2.1 months (95 percent CI: 1.4, 2.3) in patients with a best response of PR. The CR rate was 46% among all leukapheresed patients (95% CI: 34, 58).
Because of the potential for catastrophic or life-threatening cytokine release syndrome (CRS) and neurologic toxicities, the FDA authorized lisocabtagene maraleucel with a Risk Evaluation and Mitigation Strategy. CRS occurred in 45 percent of patients (Grade 3 or higher, 1.3 percent) in investigations with lisocabtagene maraleucel as second-line therapy for LBCL, while neurologic toxicities occurred in 27 percent (Grade 3, 7 percent ). Serious adverse events occurred in 33% to 38% of the individuals.
Hematopoietic cell transplantation (also known as bone marrow or stem cell transplantation) is a method of cancer treatment (and a few other conditions as well). Understanding stem cell transplantation will be aided by a study of normal bone marrow activity.
Hematopoietic stem cell function: bone marrow is the soft, spongy interior of several of the body's bigger bones. The marrow is responsible for the production of all blood cells, including red blood cells, white blood cells (of various types), and platelets. In the bone marrow, all immune system cells are produced. All of these cells arise from a type of bone marrow cell known as a "hematopoietic stem cell."
The body may control the development of hematopoietic stem cells into the blood components required at any given time. The bone marrow produces millions of different cells per hour, making this a tremendously busy process. The majority of stem cells remain in the bone marrow until they mature into distinct blood cells, which are then released into the bloodstream to serve specialized roles such as carrying oxygen, protecting against infection, and aiding in blood clotting. However, small amounts of stem cells can be discovered in circulating blood, allowing them to be collected under particular conditions. Many techniques can be used to enhance the number of hematopoietic stem cells in the blood prior to collection.
Hematopoietic cell transplantation: Chemotherapy and radiation, two of the most powerful cancer treatments, are toxic to the bone marrow. In general, the larger the dose, the more harmful the effects on the bone marrow.
You will be given very high doses of chemotherapy or radiation therapy during hematopoietic cell transplantation, which is meant to target cancer cells that may be resistant to more typical doses of chemotherapy. Regrettably, this also destroys normal cells in the bone marrow, including stem cells. You must have a good supply of stem cells reintroduced or transplanted after the procedure. The transplanted cells then restart the bone marrow's blood cell manufacturing process. In rare cases, lower doses of radiation or chemotherapy that do not fully destroy the bone marrow may be employed.
The cells to be transplanted can be obtained from the bone marrow (referred to as a bone marrow harvest), the bloodstream (referred to as a peripheral blood stem cell collection, which requires you to take medication to increase the number of hematopoietic stem cells in your blood), or, in rare cases, blood obtained from the umbilical cord after the birth of a normal newborn (which is stored in umbilical cord blood banks).
Hematopoietic cell transplantation is classified into two types: autologous and allogeneic.
Autologous transplantation: In autologous transplantation, your own hematopoietic stem cells are extracted prior to the administration of high-dose chemotherapy or radiation, and they are then frozen for future use. Following the completion of your chemotherapy or radiation, the collected cells are frozen and returned to you.
Allogeneic transplantation: entails receiving hematopoietic stem cells from a donor, ideally a brother or sister with a similar genetic makeup. If you do not have a genetically comparable sibling, an unrelated person may be substituted. In some cases, a parent or kid who is only half-matched can be used; this is referred to as a haploidentical transplant. Umbilical cord blood may also be used in umbilical cord blood transplants in some cases.
Myeloablative transplant: A myeloablative transplant involves the use of extremely high doses of chemotherapy or radiation prior to transplanting autologous or allogeneic hematopoietic stem cells.
Non-myeloablative transplant: A non-myeloablative transplant, also known as a reduced intensity transplant, permits you to receive less rigorous chemotherapy before receiving allogeneic hematopoietic stem cell transplantation. This technique may be suggested for a number of reasons, including your age, disease kind, other medical conditions, or previous therapies.
What is the best sort of hematopoietic stem cell transplantation? — Your doctor will decide whether allogeneic or autologous transplantation is ideal for you based on a variety of variables, including the underlying condition, your age, overall health, and the availability of a compatible donor. Because different types of transplantation have varying dangers, this is a complex decision that frequently incorporates your perspectives. Because you are given cells from your own body, autologous transplantation is associated with fewer major adverse effects. However, in the treatment of certain types of cancer, an autologous transplant may be less beneficial than an allogeneic transplant.
UpToDate - Patient education: Hematopoietic cell transplantation (bone marrow transplantation) (Beyond the Basics). UpToDate Article, May 6, 2022
For more in-depth information on Manali Kamdar, MD, study on lisocabtagene maraleucel for large B-cell lymphoma, click here.
A new maintenance option is available for AML, but are you proficient in identifying eligible patients? Dr. DiNardo and Dr. Roboz present 3 cases with particular attention to and discussion of risks of relapse in AML, the role of maintenance therapy, and shared decision-making to engage patients in discussions surrounding maintenance therapy.
Claim credit: https://www.achlcme.org/aml-maintenance-therapy-onctube
So, I presented the interim analysis of the second part of the FLARE trial, which is a randomized phase 3 trial in previous stances, CLL patients which the total trial we recruit just under 1500 patient. What we presented here was the first interim analysis of comparison of Ibrutinib (I) and venetoclax (V) compared to Ibrutinib (I) monotherapy where half the patients had reached 2 years.
That was 2,274 patients randomized. So, we analyze over five total that comparison and setting MRD. First of all, we showed that the treatment well tolerated, there were no. Significant tissues with adding the venetoclax (V) to Ibrutinib (I). We saw slightly more neutropenia, slightly more diarrhea but nothing that was dose limiting or treatment limiting and tumor syndrome was only a very small portion and unmanageable.
The primary endpoint of this past the trial was MRD eradication using in blood and marrow, but maybe marrow 10 minus 10,000. And what we showed was that in the Ibrutinib (I) no patients achieved MRD eradication and in the hyper at 2 years, 71 total, 1% just over a patients achieve node to the blood.
And 65% in the marrow, about 43% had stopped treatment in two years and others will stop at later on we, we guide therapy by MRD early patient. In addition, the complete remission rate was higher for the with just under 60% of patients achieving negativity with I compared to only 8% with alone.
We don't have survival that we expect that to be next year, we're seeing continuing increasing depth of remission with subsequent continuous therapy in flare. We can continue the therapy for up to six years to go and respond. And we also showed similar to some of the phase 2 trials that patients.
For features with chemotherapy IGHG only mutated for example, were more likely to have an MRD negative emission than those who were mutated. So almost 80% of patients with unmutated disease were MRD negative by 2 years. And likewise, 11 deletions more patients achieved naivety with 11 to disease.
Without percent negativity in 2 years, so really by encouraging results, indicating that we can use this combination. Safely and that we will stop the majority of patients where under negativity and we anticipate we to prolonged survivals, progression free survivals without all that data won't be out until next year.
So, I think the most common questions asked, include whether the combination of I plus that is safe. Which we demonstrated earlier say, were also asked about the use of MRD to define duration of therapy. And this is one of the trials which uniquely does that. And I think it's clear that if we use MRD to guide therapy, then we're going to get the most out of the accommodations of who won some patients.
If we use a fixation treatment will still be MRD positive who would be negative with further treatment.
The further question that's often asked is about the poorest features. So, the I unmutated and why we would see a higher response rate and allocation rate would the unmutated rather than mutated, which is for chemotherapy, the wrong way around. And the reason I think is because IGHV unmutated disease is very dependent on BSO receptor signaling and, the targets the BSO receptor pathways.
So, I think specifically like, such as ibrutinib (I) is likely to see a better response rate, the combination of has been studied in a number of other trials, one other phase three trial, which will probably lead to the approval of the combination in re in, in certain bodies. And so, I think the combination of will be available and our data from FLAIR, especially when we have the additional data, which we see next year, which will be.
A large dataset will reinforce the use of this combination for the poorest patients. And so, I think, will it impact routine practice, but probably not just yet. So, in our population, I think we need approval of the combination first and I'm not sure where that's planned for.
But probably in the next 12 months, we'll see approvals coming through, and I think this data becomes important.
So, this is the only the second in FLAIR. We have we expect next year to see the definitive comparison with progression survival as employed for I+V compared to FCR which is a key endpoint of the trial. And also, a building on this combination. I, in terms of MRD and progression through survival. So, I think in the next 12 to 18 months, we should see data emerging from this trial, which include survival outcomes.
And if they show an advantage in favor of the combination and then it'll. It will be treatment changing and we'll change the way we treat patients globally.
This is an early readout of a combination of a large phase trial. And we will show further data in future, but it's important. We get long term data cause the outcomes are so good. For CLL, I think we'll lead it. We're moving towards using IGHD mutations data on (inaudible) to define the type of we're using CLL.
As things stand at the moment, the evidence suggests that we should be using and mutated patients. I mutated. Whereas, for the other patients, unmutated probably 17 (inaudible). If we want to stop therapy, a combination of Ibrutinib (I) is more logical. And so I think we're waiting for obviously more mature data.
But I think it's encouraging that we will be using a biological map cause to define a clear choice.
Professor Peter Hillmen, MD, he leads the Experimental Hematology section in LICAP and the Translational Hematology Research group. He is a Professor of Experimental Hematology and Honorary Consultant Hematologist at Leeds Teaching Hospitals NHS Trust at University of Leeds. In this interview, he speaks about the EHA 2022 Abstract - The Combination Of Ibrutinib Plus Venetoclax Results In A High Rate Of Mrd Negativity In Previously Untreated Cll: The Results Of The Planned Interim Analysis Of The Phase III Ncri FLAIR Trial.
Ibrutinib (I) and venetoclax (V) both enhance CLL outcomes. I rarely eliminates measurable residual disease (MRD), whereas V (alone or in combination with anti-CD20) can eliminate MRD, allowing for time-limited therapy. Small studies imply that I and V work together, as I+V resulted in MRD negative in many patients (pts).
The major goal was to compare the rates of MRD eradication between I and I+V. Secondary goals included IWCLL overall response rate (ORR), complete response rate (CR), and safety.
FLAIR (ISRCTN01844152), a phase III, randomized, controlled trial for previously untreated CLL that meets IWCLL criteria and requires therapy. Pts over 75 years old or with a 17p del of more than 20% were excluded. FLAIR was updated in July 2017 to include two additional arms, I monotherapy and I+V. I was prescribed 420mg each day. For I+V, V was added after two months of I, with the dose gradually increasing to 400mg/day over five weeks. MRD established the duration of therapy (DOT), with treatment lasting up to 6 years. MRD was measured centrally using flow cytometry, and MRD negativity was defined as 1 CLL cell in 10,000 leucocytes (IWCLL criteria). MRD was measured in peripheral blood (PB) and bone marrow (BM) at 9 months, 12 months, and subsequently 6 months. When PB was MRD negative, this was repeated three months later, and then three months later in both PB and BM. If both PB and BM were negative, the time to MRD negativity was computed (treatment start to first MRD negative PB), and the DOT was double that. The earliest therapy may be discontinued was two years after randomization. When 50% of points in the I and I+V arms had reached 2 years post-randomization, a formal interim analysis was done, and a p-value of 0.005 was statistically significant.
523 points were assigned to I or I+V. We present an interim analysis of the first 274 points (I [n=138] and I+V [n=136]) reached two years after randomization from 83 UK centers between 13/07/17 and 15/03/19. 72.3 % were male, the median age was 63 years (34.3 % were over 65 years old), and 40.9 % were Binet C. IGHV was available for 256 (93.4 %) patients, with 48.2 % IGHV unmutated (98 % homology to germline), 45.3 % IGHV mutated, and 9.1 % Subset 2. Hierarchical FISH testing found 16.1% 11q del, 19% trisomy 12, 21.9 % normal, and 36.9% 13q del, with 6.2 % failing. For all variables, the arms were well-balanced. MRD negative was reached in BM in 89/136 (65.4 %) and PB in 97/136 (71.3 %) within 24 months in the I+V arm compared to no points in the I arm (p0.0001). Within 24 months, MRD negative for I+V in BM was 51/64 (79.7%) for IGHV unmutated and 31/55 (56.4%) for IGHV mutated. At 9 months, 49/136 (36%) I+V patients were MRD negative in BM and 56/136 (41.2%) negative in PB, compared to 0/138 with I (p0.0001). ORR at 9 months in 120/136 (88.2%) I+V points and 119/138 (86.2%) I points (p=0.6157). At 9 months, CR was found in 81/136 (59.6%) of I+V cases and 11/138 (8%) of I cases (p0.0001). At any time, the I+V CR was 93.4 %. At 24 months, 54/136 (39.7 %) of the patients ceased I+V because they met the MRD stopping criterion.
Ibrutinib with venetoclax is a safe and effective combination that results in a high rate of MRD negative in blood (71.9%) and marrow (65.4%) in the first two years of treatment.
Median age was 73 years (range, 48-90 years), with 81% aged >65 years; 97% had ≥1 comorbidity at the start of IRd therapy.
Efficacy data after an additional 11 months of follow-up (data cut-off: May 4, 2021) showed that iCT to IRd improved responses.
Overall response rate (ORR) had improved from 65% (CR 9%, VGPR 25%, PR 32%), at the end of 3 cycles of V-based induction, to 78% (molecular CR [mCR] 1%, stringent CR [sCR] 3%, CR 32%, VGPR 25%, PR 17%) following iCT to IRd.
At a median follow-up of 18.5 months, the 18-month PFS rate was 84%. The safety profile of IRd was consistent with previous clinical studies.
Grade ≥3 treatment-emergent adverse events (TEAEs) were reported in 64% of patients and treatment-related serious TEAEs in 12% (including 4 on-study deaths), while 16% of TEAEs led to study drug discontinuation.
Here we have analyzed updated data for this patient subset with an additional 11 months of follow-up to further evaluate efficacy and safety, and to determine reasons for premature (within 4 cycles of IRd) discontinuation.
Sixty-eight patients (67%) had completed or discontinued the study since first patient enrolment on November 15, 2017.
Among these patients, 14 (21%) discontinued within 2 cycles of IRd and 27 (40%) discontinued within 4 cycles.
With longer follow-up, use of iCT from V-based induction to IRd to achieve long-term PI-based therapy in NDMM patients demonstrates efficacy via improved response rates and acceptable PFS in this real-world setting.
Over 80% of US MM-6 patients were aged >65 years and most had ≥1 comorbidity prior to study entry.
The rate of patients discontinuing within 4 cycles of iCT (7 cycles of PI-based therapy in total) is concerning because these patients may not receive the full benefit of long-term PI-based treatment.
To date, the majority of premature discontinuations were reported as being due to patient request (44%) followed by TEAEs (30%).
Dosing - 4 mg ixazomib + 25 mg lenalidomide + 40 mg dexamethasone.
For up to 3 years, all participants are requested to take ixazomib 4 mg on Days 1, 8, and 15, lenalidomide 25 mg on Days 1 through 21, and dexamethasone 40 mg on Days 1, 8, 15, and 22 in 28-day cycles until progression or intolerable toxicity.
The treatment phase of this trial is expected to last up to 78 months, including a 42-month enrolment period and a 36-month IRD treatment term (39 cycles) with ixazomib and/or lenalidomide and/or dexamethasone for the final subject recruited.
This is a review of a combination clinical trial including Dexamethasone, Ixazomib, and Lenalidomide from the European Hematology Association (EHA). The abstract of interest is a little bit unusual in its design. A previous trial has been conducted called "MM-6." And that was a little bit unique in that we studied newly diagnosed multiple myeloma patients, and they could have received any Velcade based induction, whether it was a double or a triplet.
After three cycles, if they had stable responding disease, they were then switched to an all-oral triplet combination, which consisted of Ixazomib, Lenalidomide, and Dexamethasone, otherwise known as IRD. And we've previously published on this group showing the feasibility and potential benefits of an in-class transition.
We studied around 100 patients in that single-arm study. However, this abstract is a little bit different in that what we did was we took the 6 databases and then we also started to do matched para-analysis with a large myeloma registry known as INSIGHT MM: a large, global, prospective, non-interventional, real-world study of patients with multiple myeloma.
We matched patients with those who were in treatment phase in the United States, and they were treated with a slightly different regimen where there was parental Velcade given as a subcutaneous injection. So, this was not an all-oral dosing schedule. One of our aims was to see if with all oral regimens we could improve compliance, adherence, and keep people on clinical trial therapy longer.
Myeloma has become a maintenance treatment disease, so what we did was match pair analysis with some of the increased risk I've alluded to. Using the six data points with the in-class transition, we showed, when compared to the INSIGHT MM registry, a higher overall response rate and a longer duration of therapy.
This was somewhat nice and added some validity to the in-class transition approach and, more importantly, the ability to stay on a prolonged all-oral maintenance treatment with Ixazomib, lenalidomide, and dexamethasone. And while this is preliminary data, I think it's encouraging and may pave the way for future class transitions in multiple myeloma treatment.
There's a tremendous number of multiple myeloma drugs being developed into a lot of new treatments, some of which are CAR-T cell specific antibodies, antibody drug conjugate molecules with novel mechanisms of action, some of which are oral, some of which are not. I think this approach provides some good evidence that in class transition, and even using all oral regimens like Ixazomib, lenalidomide, and dexamethasone will really help people stay on maintenance treatment longer and hopefully improve our overall outcome in multiple myeloma and decrease missed dose.
So, although the study design is a bit unusual, it really demonstrates the value of an all-oral regimen, especially in the COVID era. Interestingly, when we designed 6, INSIGHT MM was already up and running. COVID changed a lot of things. A lot of them are now very difficult to analyze. but in the MM-6 trial, COVID was something that played very well with the study because it was an all-oral regimen and patients didn't really have to go to the physician's office frequently. They could stay at home, practice isolation, and monitor themselves for adverse reactions while staying away from COVID. The data analysis is still in progress. So, I think overall, this showed that using the in-class transition and avoiding parental medication increased our response rates and duration of maintenance treatment.
The next step for the MM-6 Trial research would be to design a successor study with some in-class transitions. I know we're looking at the feasibility of doing that, but certainly the concept of in-class transition will be here to stay. And it's how we exploit that in myeloma. And then, obviously, with the insight database and that registry, now closed for a little bit. All that data and insight will start to mature and will be the foundation for a lot of future analyses. I don't know that we'll be able to quite do this same comparison between a registry and a retrospective study, while it has some shortcomings as an eye opener in terms of response rates and duration of therapy.
I think that the clinical trials data overall speaks for itself. As providers become more comfortable with all oral regimens and doing final dose reduction and dose adjustments, toxicities, and then importantly, really measuring patients’ quality of life while watching for new or worsening symptoms. Multiple myeloma patients are on therapy for a very long time, hopefully using Ixazomib, lenalidomide, and dexamethasone, and all the medicines get to minimal residual disease negativity, which is really our goal.
If you remain minimal residual disease negative for a long period of time, at some point you may be able to stop therapy for multiple myeloma, following symptoms, of course. So, this database can, in part, serve as a small part of the foundation for achieving minimal residual disease negativity in newly diagnosed patients. Although that wasn't really our primary endpoint, I think that's everybody's goal at the end of the day.
Long-term PI based treatment duration can enhance results in multiple myeloma across treatment settings. However, there are a variety of physical, geographical, and/or socioeconomic challenges to long-term parenteral PI therapy in community practice. The US MM-6 research (NCT03173092) is looking at in-class transition (iCT) from parenteral bortezomib (V)-based induction to all-oral ixazomib-based therapy with ixazomib, lenalidomide, and dexamethasone (IRd) in a heterogeneous community population in the United States. The study's goal is to extend the length of PI-based treatment while maintaining quality of life and enhancing outcomes. We previously presented promising efficacy and safety data for the first 101 MM-6 patients in the United States (Girnius Blood 2020). We reviewed updated data for this patient subset with an additional 11 months of follow-up to assess effectiveness and safety, as well as causes for premature (within 4 cycles of IRd) discontinuation.
Transplant-ineligible/transplant-delayed (24 months) Patients with Newly Diagnosed Multiple Myeloma at community sites in the United States who had achieved stable disease or better after three cycles of Velcade based induction were given xazomib, Lenalidomide, and Dexamethasone (ixazomib 4 mg, days 1, 8, 15; lenalidomide 25 mg, days 1-21; dexamethasone 40 mg, days 1, 8, 15, 22) for up to 39 28-day cycles, or until progressive disease or unacceptable toxicity. The primary goal is to achieve 2-year diesease progression-free survival (PFS). The rates of partial response (PR), very good partial response (VGPR), and complete response (CR), as well as the length of therapy, are important secondary endpoints. For the current study, sites with patients who had stopped using US MM-6 trial were contacted for extra information.
As of June 1, 2020, 101 individuals had been registered and treated at 21 sites. The median age was 73 years (range, 48-90 years), with 81% older than 65 years and 97% having at least one comorbidity at the commencement of ixazomib, lenalidomide, and dexamethasone therapy. After a further 11 months of follow-up (data cut-off: May 4, 2021), efficacy data showed that iCT to Ixazomib Lenalidomide Dexamethasone improved response and disease progression. Following iCT to IRd, the overall response rate (ORR) increased from 65% (CR 9%, very good partial response 25%, PR 32%) at the end of three cycles of V-based induction to 78% (molecular CR [mCR] 1%, stringent CR [sCR] 3%, CR 32%, VGPR 25%, PR 17%). At the most recent data cut-off, 33 patients (33%) were still on therapy; the median duration of ixazomib, lenalidomide, and dexamethasone was 11.7 months, and the overall median duration of therapy (for all PI-based therapy, including Velcade based induction) was 14.6 months. The 18-month PFS rate was 84% at a median follow-up of 18.5 months. Ixazomib Lenalidomide Dexamethasone safety profile was similar to earlier clinical trials. Treatment-emergent adverse events (TEAEs) of grade 3 were documented in 64% of patients, and treatment-related significant TEAEs in 12% of patients (including 4 on-study deaths), with 16% of TEAEs leading to study drug cessation. Since the first patient's enrolment on November 15, 2017, 68 patients (67%) either completed or discontinued the trial. 14 (21%) of these patients ceased ixazomib, lenalidomide, and dexamethasone within two cycles, and 27 (40%) discontinued within four cycles.
In this real-world situation, the use of iCT from Velcade based induction to Ixazomib Lenalidomide Dexamethasone to achieve long-term PI-based therapy in Newly Diagnosed Multiple Myeloma patients reveals efficacy via enhanced response rates and acceptable progression-free survival with longer follow-up. Over 80% of MM-6 patients in the United States were over the age of 65, and the majority had at least one comorbidity prior to study entry. The rate of patients discontinuing iCT after four cycles (seven cycles of PI-based therapy total) is problematic since these patients may not benefit fully from long-term PI-based treatment. To date, the bulk of early discontinuations (44%) have been attributed to patient requests, followed by TEAEs (30%). The planned US MM7 iCT oncology research in relapsed or refractory MM will address expanded site education and improved patient follow-up to reduce premature discontinuations.
An all-oral regimen triplicate of Ixazomib, Lenalidomide, and Dexamethasone can be taken at home.
Ixazomib is used in conjunction with lenalidomide (Revlimid) and dexamethasone to treat multiple myeloma (bone marrow plasma cell cancer) that has progressed despite treatment with other chemotherapy drugs. Ixazomib belongs to a class of drugs known as proteasome inhibitors. It works by assisting in the death of cancer cells.
Lenalidomide is an oral medication used to treat multiple myeloma. It belongs to a class of medications known as immunomodulatory drugs (IMiDs), which fight against cancer cells in part by enhancing immune system function.
Multiple myeloma is a type of plasma cell malignancy. Plasma cells are present in bone marrow and play a vital role in the immune system. The immune system is made up of various cell types that collaborate to fight infections and other disorders. Lymphocytes (lymph cells) are a type of white blood cell that includes T cells and B cells in the immune system. Lymphocytes can be found in various parts of the body, including lymph nodes, bone marrow, the intestines, and the circulation.
When B cells respond to an infection, they develop into plasma cells. Plasma cells produce antibodies (also known as immunoglobulins), which aid the body in attacking and killing infections. Plasma cells are mostly present in bone marrow. The soft tissue inside bones is known as bone marrow. Other blood cells, such as red cells, white cells, and platelets, live in normal bone marrow in addition to plasma cells.
Multiple myeloma is a malignant condition in which plasma cells grow uncontrollably. Plasma cells produce an aberrant protein (antibody) recognized by several names such as monoclonal immunoglobulin, monoclonal protein (M-protein), M-spike, or paraprotein.
Robert M. Rifkin, MD, FACP - Rocky Mountain cancer Centers
Dr. Rifkin is a board-certified medical oncologist and hematologist specializing in malignant and benign hematology, treating cancer and blood disorders. He has an advanced sub-specialty expertise in coagulation disorders, multiple myeloma and biosimilars. Dr. Rifkin practices evidence-based medicine and follows National Comprehensive Cancer Network (NCCN) guidelines for cancer treatment.
American Cancer Society - What Is Multiple Myeloma? American Cancer Society, February 28, 2018.
ASH Publications - Extended Characterization of Newly Diagnosed Multiple Myeloma (NDMM) Patients with In-Class Transition (iCT) from Parenteral Bortezomib to Oral Ixazomib Proteasome Inhibitor (PI) Therapy in the Community-Based United States (US) MM-6 Study: Updated Efficacy and Safety, and Reasons for Premature Discontinuation. ASH Publications, November 6, 2021.
Some of the leading causes of liver cancer, which is called Hepatocellular Carcinoma, we call it. Oftentimes, just because HCC is a bit of a multiple, we just refer to it as HCC. You hear me talking about the treatment of Hepatocellular Carcinoma (HCC), one of the leading causes of HCC development. In the Western world, particularly if we look at the US or look at parts of Europe, the leading cause would be something called NASH.
NASH is another liver disease. NASH stands for nonalcoholic steatohepatitis. Again, another mouthful. There are lots of acronyms in this world that we live in. NASH is a serious disease and is characterized by a number of different findings, namely fatty liver, as well as liver fibrosis, and also inflammation. And so, it's kind of a perfect storm of those things that can ultimately lead to HCC. And I guess one of the things that I, we're probably familiar with the terminology or the term called cirrhosis, or some people say cirrhosis liver, which is a little bit redundant, but anyway, cirrhosis. This is probably one of the most powerful risk factors that can lead to HCC. This is all intertwined, and so what Hepion has done is developed a drug called Rencofilstat, and Rencofilstat is a drug that has multiple modes of action, or multiple things that it can do. And along the pathway of addressing the disease of liver disease, we can address fatty liver, NASH, and the HCC components. We're trying to hit all three of these things with one molecule. So that really lays out what I was trying to do here. And then a relative of HCC.
Hepatocellular carcinoma is the most common form of liver cancer, accounting for 85% to 90% of all cases.
The randomization of the NASH F3 subjects will be performed in a 1:1:1 ratio between rencofilstat 75 mg, rencofilstat 150 mg, and rencofilstat 225 mg.
Prior to dosing, subjects can have a light breakfast, avoiding high-fat meals. In the follow-up phase, the investigational product (IP) will be discontinued, followed by 14 days of safety follow-up.
DSI change from baseline score of subjects taking rencofilstat (75 mg, 150 mg, 225 mg), determined using the HepQuant SHUNT Test, on Day 60 and Day 120.
The percent of subjects taking rencofilstat (75 mg, 150 mg, 225 mg) that have experienced treatment-emergent adverse events, serious adverse events, adverse events of special interest, and physical and laboratory abnormalities.
Rencofilstat binds to Cyclophilin A, which blocks the binding of Cyclophilin A to specific receptors on inflammatory cells, decreasing the infiltration of the cells into the tissue and production of harmful inflammatory molecules, resulting in reduced inflammatory damage to the liver.
Rencofilstat blocks the actions of Cyclophilin B, an important regulator of collagen production in stellate cells. This leads to a reduction in collagen secretions and fibrotic scarring, a primary goal in the treatment of NASH.
Rencofilstat binds to Cyclophilin D, which prevents or reverses the formation of pores in the mitochondrial membrane that cause mitochondria to rupture, allowing mitochondria to resume normal energy production and enabling the survival of liver cells.
Having orphan drug approval by the FDA is a big deal for us. It's big for a lot of companies that have a drug that addresses an unmet medical need. And you'll hear a lot of companies talk about how they have a drug to meet an unmet medical need. There are certain diseases like Hepatocellular Carcinoma (HCC), which is one of those diseases. There truly is an unmet medical need. There's not a lot out there. That satisfactorily addresses the disease. And the other part of that equation when it comes to orphan drug status is that it's a disease that doesn't occur that frequently. Hence the name, orphan. According to the FDA, it must be a disease that afflicts 200,000 or fewer people in the population, and HCC falls into that category. Having an orphan drug approval for Rencofilstat and HCC is a big thing for us because it allows us to have a constant line of communication with the FDA. It can also give us some tax incentives. We could also look at getting some market exclusivity because once the drug gets approved, we'll have some protection on the commercial. And it allows us to have interaction with the FDA when it comes to protocol development. There are a lot of advantages to having this orphan drug approval and future clinical trials.
Hepion Pharmaceuticals, Inc., a clinical mid-stage biopharmaceutical company focused on AI-driven therapeutic drug development for the overall treatment of non-alcoholic steatohepatitis ("NASH") and HCC, announced today that the U.S. Food and Drug Administration ("FDA") has granted Orphan Drug Designation to rencofilstat, a liver-targeting, orally administered, novel cyclophilin inhibitor.
The most frequent type of liver cancer, accounting for 85-90 percent of all occurrences, is HCC. HCC is caused by NASH, viral hepatitis infection, and alcohol intake. Over 800,000 individuals died from liver cancer worldwide in 2020, ranking second only to lung cancer among all cancer-related deaths. 1 The high mortality rate is partly owing to the fact that only about half of all people diagnosed with HCC in affluent nations receive a diagnosis early enough to benefit from treatment intervention. Furthermore, recurrence rates are significant, and effective treatment choices are scarce.
“Orphan Drug Designation for Rencofilstat in HCC represents a significant milestone for Hepion and its recognition by the FDA of the potential for rencofilstat to address a significant unmet medical need for patients suffering from this aggressive cancer,” “In addition to two Phase 2 studies in patients with NASH, we remain on track to initiate patient enrollment in a Phase 2a study of rencofilstat in HCC in the third quarter of 2022.” said Robert Foster, PharmD, PhD, Hepion’s CEO.
The FDA's Orphan Drug Designation program grants orphan designation to medicines or biologics used to prevent, diagnose, or cure diseases that afflict fewer than 200,000 people in the United States. Orphan Drug Designation entitles sponsors of medications to specific benefits, including tax subsidies for eligible clinical trials, prescription drug user-fee exemptions, and potential seven-year marketing exclusivity upon FDA approval.
Dr. Foster is the CEO of Hepion Pharmaceuticals, which has offices in Edison, New Jersey, and Edmonton, Canada. He is also an Adjunct Professor at the University of Alberta's Faculty of Pharmacy and Pharmaceutical Sciences and a Board member of Transcriptome Sciences Inc. He previously served on the Alberta Economic Development Authority's Board of Directors, as a member of the Alberta Premier's Advisory Council on Health, as an Advisory Board Member of the University of Alberta's Industry Liaison Office, as Co-Chair and Board Member of BioAlberta, and as a member of the Alberta Science and Research Authority's Board of Management.
Dr. Foster started working on cyclophilin medication development in 1988 and has over 30 years of pharmaceutical and biotech experience. He was the CEO and Founder of Ciclofilin Pharmaceuticals Inc. before joining Hepion in 2016. Prior to that, he formed Isotechnika Pharma Inc. (TSX:ISA) in 1993 and served as its Chairman and CEO for nearly two decades. Dr. Foster discovered voclosporin, an immunosuppressive medication used to treat autoimmune illnesses while working at Isotechnika.
Dr. Foster negotiated a USD $215 million licence agreement for voclosporin for kidney transplant immunosuppression with Hoffman-La Roche in 2002, which was Canada's largest at the time (Basel, Switzerland). Later, once Isotechnika bought Aurinia Pharma (NASDAQ:AUPH), he became its founding CEO and then CSO. In January 2021, the FDA authorized voclosporin (LupkynisTM) for the treatment of lupus nephritis. Voclosporin has been licensed for the treatment of lupus nephritis in the EU, Japan, the United Kingdom, Russia, Switzerland, Norway, Belarus, Iceland, Liechtenstein, and Ukraine by Otsuka Pharmaceutical Co., Ltd.
In addition to pharmaceutical discovery and development, Dr. Foster created and received regulatory approval for Helikit, a commercially accessible 13C urea breath test for the detection of H. pylori, a bacteria that can cause peptic ulcers. In 2009, Dr. Foster sold Helikit. It still generates multimillion-dollar annual sales in Canada and other nations today.
Dr. Foster has undergraduate degrees in Science (Chemistry) and Pharmacy, as well as a PharmD and a Ph.D. in Pharmaceutical Sciences. From 1988 to 1997, Dr. Foster was a tenured Associate Professor in the Faculty of Pharmacy and Pharmaceutical Sciences at the University of Alberta. Dr. Foster worked as a Medical Staff, Scientific and Research Associate in the Department of Laboratory Medicine at the Walter C. Mackenzie Health Sciences Centre from 1990 to 1994.
Dr. Foster (Hepion's CEO) has over 200 papers, abstracts, and book chapters on drug analysis, development, and pharmacokinetics to his credit, and he has received numerous accolades for both pharmaceutical research and education. In 2002, he was awarded one of Alberta's 50 Most Influential People, and in 2003, Isotechnika was designated both Alberta Venture's third fastest growing company and Profit Magazine's top 100 fastest growing Canadian company. Dr. Foster previously held the position of Division Chairman of Pharmacy Practice at the University of Alberta and has worked as a consultant for a number of pharmaceutical companies. Dr. Foster is listed as an inventor on about 170 patents.
The company's lead drug candidate is a potent inhibitor of cyclophilins, which are implicated in numerous disease processes. Rencofilstat is now in clinical trials for the treatment of NASH, with the potential to play a significant role in the whole treatment of liver disease, from triggering events to end-stage disease. It has been proven in nonclinical investigations to reduce liver fibrosis and hepatocellular carcinoma tumor burden in experimental models of NASH, as well as antiviral activity against HBV, HCV, and HDV via many mechanisms. Rencofilstat was given Fast Track status by the US Food and Drug Administration ("FDA") in November 2021 for the treatment of NASH. In December 2021, the FDA approved Hepion's investigational new drug (IND) application for rencofilstat for the treatment of HCC. Rencofilstat was designated an orphan drug in June 2022 for the treatment of HCC.
AI-POWRTM stands for Artificial Intelligence - Precision Medicine; Omics (including genomes, proteomics, metabolomics, transcriptomics, and lipidomics); World Database Access; and Response and clinical outcomes. Hepion intends to apply AI-POWRTM to assist in determining which NASH patients may respond best to Rencofilstat, potentially decreasing development timelines and boosting the delta between placebo and treatment groups. Hepion hopes to use AI-POWRTM to find other potential indications for rencofilstat to expand the company's footprint in the cyclophilin inhibition therapeutic arena, in addition to driving its ongoing NASH clinical development program.
Liver fibrosis is the abnormal accumulation of extracellular matrix proteins, such as collagen, that occurs in the majority of chronic liver disorders.
Hepion Pharmaceuticals press release - Hepion Pharmaceuticals Receives FDA Orphan Drug Status Designation for Rencofilstat for the Treatment of Hepatocellular Carcinoma - Hepion Pharmaceuticals Press Release, June 20, 2022
Hepion Pharmaceuticals - Robert Foster, B.Sc. (Pharm), Pharm.D., Ph.D., Chief Executive Officer - Hepion Pharmaceuticals Biography, 2022
I'm going to discuss today our work or an overview first of our approach to treatment, which is to target 1313 interaction, rather than a protein or an Interact or interaction of 2 proteins as generally or at least historically we think about therapy. And the paper I was invited to discuss is it's a protocol we published recently. In cells SAR protocols, and it's called Synthesis of Labeled Epichaperome Probes and assessment in visualizing pathologic protein interaction networks in tumor-bearing mice.
So, as I mentioned, and at least in the context perhaps of cancer treatment chemotherapy, as we know, it's been historically the way of treatment. And as we have started to understand more about the drivers of cancer, we move to the targeted approach. And initially.
We knew how to inhibit. So, there has been an explosion in kinase inhibitor. So even the first successful inhibitor, the BCR inhibitor. Yeah. It's kind of inhibitor. As we moved again, to understand more about the proteins involved and how they interact we moved into disrupting protein interaction, and now the big way is to actually degrade proteins.
And it's a very fashionable way to try to develop new treatments. But we actually know, although perhaps our human mind, it thinks more as a one protein or one individual. We are not the one individual that just has proteins are not one protein. We exist in a, sorry, we exist in a society.
We exist as a group of interactions, whether those are a group of our colleagues, our family society as a whole, who is, are shaping us and we are shaping them. And it's this interaction network. That's really defining our word, our function our it's developing who we are and. Become, and that's exactly the same for proteins.
It's becoming more and more understand that also in disease and of course in cancer as well proteins are shaped and are in their significance and in their oncogenic behavior. They're interactive partners and these interactive partners are can be contact and tissue dependent, meaning a one protein such as Raf Kinase Inhibitor (RKIP) different interactions and different contexts.
And it's really this really the network of these interactions that will defining how to target the protein or how the protein's really influencing the cell or the phenotype as a whole in disease. So, in this context, disease is a really a severity of perturbation of these complex networks or molecular interaction in a cell.
So, how can you target such complexity? It's not much discussed because it's very difficult to really approach something like that, therapeutically and what we believe. So, in this context, you can think as disease is really. As I said a dysfunction in this protein interaction network study it's created not by one driver.
We like to think in cancer is genetics, but it's actually, as we will know it's a combination of factors, whether it's from aging environment, whether it's like a cell environment or the environment as a whole. What. Other diseases or comorbidities that we may have with the genetics and other factors that combine shape or negatively impact the cell is an environment creating disease or phenotype by restructuring this big networks of the proteins in How we can really address this complexity is for discovery. We published not long ago. First in in nature is that. The restructuring of protein networks in disease has a helper. And this helper comes from a restructuring of a large protein family which is called the chaperone or molecular chaperones.
And we all know about chaperones that they fold. They interact dynamically with all sorts of proteins to help them fold or they work in aggregation, disaggregation. This is. What we, we are talking about. What we're talking about is a restructuring of these members of the chaperone family into scaffolding platforms, we term Epichaperome Probes.
So, what these are, these a Epichaperome Probes platforms do not fault. What they do is the reorganize protein interactions at the protein level and disease to regulate. The need of the cell under the pathologic process. Whatever that is. So, we have shown these appearing cancer, the Alzheimer disease of Parkinson.
So, there's a mechanism of pathologic transformation through buying of protein interaction networks through the formation of these scaffolding platforms called epi. So why is this important? It's important because now you can think about a way to actually address targeting protein interaction.
You can target protein interaction by actually targeting the mediators of these alteration in protein network, destruction, meaning Epichaperome Probes. So, if there is a way that you can actually. Target these, detect these you can create both therapeutics and diagnostics for treatment and emerging or detection of these transformations in disease.
The paper that we are in in discussing is really detailing how we created not only drugs to target this dysfunction, but also small molecules that we can use to detect these dysfunctions in protein interaction networks. That, excuse me. I'm mediated by these Epichaperome Probes. And the paper describes the synthesis of these radio labeled agents.
There are small molecules that have attached, and I done 124. Which can be used in positive and emission tomography to visualize tissues tumors that are afflicted by these changes that are driven by epi formation. And we have shown the use of these probes in a variety of settings from obviously to clinical, but also to all the way to clinical level.
And here, I'm going to show you this, an example in the application of these probes are detecting tumors that have this transformation mechanism. So, the alteration and protein interaction networks that are driven by these Epichaperome Probes this is patient. This is an Alzheimer patient. You can clearly see the presence, the anatomical presence.
And quantification through these imaging probes of specific lesion in the brain of this patient that very well aligned to disease known to manifest. You can also see another example here of a lung cancer patient is by the way, was a metastatic, triple negative breast cancer patient.
And these be published as you can see in the journals that I'm mentioning here. And these 2 probes add to another probe we develop, which is from hematologic malignancies. So, this is a as these are imaging agent, these are flow cytometry based agent that can detect these changes in subpopulations they're specific to the specific hematological malignancy.
And again, this was Also published and also its application to clinic published recently in the MPJ position, oncology paper in 2021. You asked me Stephanie what are the questions people are asking is us. And one of the major one that we are receiving is how can you actually differentiate?
How can you create these agents that can differentiate these Epichaperome Probes, which are only affection in the human body and are specific to these tissues undergoing the disease process. From this very abundant family of Epichaperome Probes. Epichaperome Probes, if you might know as I'm showing here, the one of the most abundant proteins in humans, and there are 10% of tall (inaudible) mass in a human.
Which, and if you count for one of them, for example, HSP90, that really amounts to hundreds of grams of protein in any human. So how can you make these small molecules that can differentiate one from the chap ones from the Epichaperome Probes. So, you only want target the epi chaplains. And one of the issues here is also, and I think the question is coming because as you may know, Epichaperome inhibitors, such as HS dose have been tried extensively on oncology.
And have had issues with perhaps lack of efficacy or toxicity. So, there was a bias in the field or in, in the oncology field on this topic. So how can you differentiate an Epichaperome binding agent from a chap binding agent? And we have shoulders in an extensive study, which was published last year in nature communications that you can create a molecule that can differentiate this really abundant family from the small faction Epichaperome by modulating the kinetic activity of these agents.
So, what does kinetic activity mean means that if this firm binds here, it exists very rapidly. And has no effect. However, if it binds to the epi gets stuck and it stay there. So that's why you can actually really use them to emerge these lesions. And here we are showing one of these strokes that I just mentioned, how it can detect only, you can see the red only in this brain tumor, but not in the normal brain anywhere that's around, which has, as I said, grams of the Epichaperome. So, the study really takes you from synthesis to testing in animals, to proof of principle in human patients, obviously in a clinical study setting. So, another question we are receiving is how can you implement or why do you wanna implement these agents to a clinic?
For several reason one is you can detect this tumor. So, what does, what is good that tells you. Well, it's, it really tells you that level of therapeutic vulnerability to the agents that target Epichaperome, because we have shown and published extensively that the higher the app Epichaperome levels, the higher, the number of proteins hired a number of proteins that are being negatively.
How therefore the higher, the number of a band protein food interaction less was the more vulnerable the cell to the, a Epichaperome therapy. And we have in addition to extensive preclinical evidence, we have shown in a in a pilot study. Where this is a metastatic breast cancer study which patients at baseline.
So, before they ran on Epichaperome therapy combination with the bra vaccine, they were image with these agents and emission tomography agents. And you can see some patients. The tumor lit up, meaning they're really high in this protein for detection network dysfunctions that are modulated by Epichaperome. You can see this patient went on therapy.
Clearly see how the tumor went down, both by cat scan and FDG patients who had. Negative Epichaperome level at the baseline, right? So, these tumors have lot of Epichaperome, but not Epichaperome, not these dysfunction protein for intervention networks that are mediated by Epichaperome and clear no signal on, on this post emission tomography, clearly mission demography, clearly, no response.
So, we could actually show in the small study that those patients who actually. To stay longer therapy benefited longer from this therapy were those that had higher Epichaperome level, higher dysfunction in this protein network. So, it's a way of stratifying selecting patients for this therapy.
What other users are for this? Obviously in addition to that you can actually derive target engagement measurements so you can understand what is the dose and the schedule you need to treat specific patient. Using this assay, we could actually derive that those that you need to give to these patients for treatment.
So, you don't, so it's an approach, not by maximum to. But maximum saturated those up to target, then you can gain from using these emerging agents and lastly what you can also we have learned from this is that using these app Epichaperome Probes problems, you can control how 1313 networks behave and manifest in the context of tumors.
So, we have recently published that you can modulate with these inhibitors the protein interaction networks in a way that you make them very vulnerable to current therapy. So, in this paper, what we show is that by using these Epichaperome Probes inhibitors, we can bring the tumor to a state that is highly vulnerable, to already known therapy.
And we show through a principle in pancreatic cancer. These cancer were there, as we all know, don't respond to, for example MAC inhibitors, although RAS Kinase it's a known known driver activated pathway in these tumors. However, if these tumors were in MAC inhibitors were applied to these tumor, After we drove them into this epi mediated state of vulnerability, they became very responsive to the MAC inhibitor.
Gabriela Chiosis, Ph.D., Researcher at Memorial Sloan Kettering Cancer Center. In this video, she speaks about the Synthesis of 124I-labeled epichaperome probes and assessment in visualizing pathologic protein-protein interaction networks in tumor-bearing mice.
Epichaperomes are pathologic scaffolding linked with disease that are made up of firmly bonded chaperones and co-chaperones. They enable precision therapy by detecting and targeting faulty protein-protein interaction networks rather than a single protein. This technique discusses the manufacture and characterization of two 124I-labeled epichaperome probes, [124I]-PU-H71 and [124I]-PU-AD, which have both been used in clinical trials. It details how to utilize these reagents to visualize and quantify epichaperome-positivity in tumor-bearing mice using positron emission tomography.
The FRESCO-2 trial was a Phase 3 clinical trial that has been specifically created for patients that were previously treated with surgically unresectable metastatic colorectal cancer therapy. It was basically a 2:1 randomization for patients that had received prior standard chemotherapy and previously treated metastatic colorectal with Regorafenibor and Lonsurf. Patients may have been exposed to Regorafenib or Lonsurf or both of the drugs and the primary endpoint was overall survival.
Just to keep things in perspective for patients, we tend to give standard chemotherapy to most metastatic colorectal cancer patients, which may be Oxaliplatin based, Irinotecan based and then if appropriate anti-EGFR therapy based if they're RAS wild type. Then after those standard treatments there are two oral agents that are currently FDA approved, Regorafenib and Lonsurf, which are approved as single agents by the FDA in previously treated metastatic colorectal setting. The purpose of the FRESCO randomized clinical trial was to consider providing a clinical trial tested option for patients with metastatic colorectal that were seeking additional treatment options, if they were in that situation.
The design was basically a 2:1 randomization versus placebo controlled. Some people may feel that's inappropriate, but if you really think about it, as I mentioned earlier, if you have been exposed to both drugs in the past, with Regorafenib and Lonsurf, you were still allowed to participate. The reason it was compared to placebo is that there is no other treatment after you've had Regorafenib and Lonsurf so it's the most appropriate setting. So it was a 2:1 randomization with the primary endpoint being overall survival.
I think I mentioned that earlier but you must have received at least two standard lines of therapy, Oxaliplatin, Irinotecan and anti-EGFR therapy. If your RAS wild type was considered the standard of care and once again if you had, you could have had Regorafenib, Lonsurf and/or both.
Provide written informed consent;
Age ≥18 years;
Histologically and/or cytologically documented metastatic colorectal adenocarcinoma. RAS, BRAF, and microsatellite instability microsatellite instability (MSI)/mismatch repair (MMR) status for each patient must be documented, according to country level guidelines;
Subjects must have progressed on or been intolerant to treatment with either trifluridine/tipiracil (TAS-102) or regorafenib. Subjects are considered intolerant to TAS-102 or regorafenib if they have received at least 1 dose of either agents and were discontinued from therapy for reasons other than disease progression. Subjects who have been treated with both TAS-102 and regorafenib are permitted. Subjects must also have been previously treated with standard approved therapies: fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and, if RAS wild-type, an anti-EGFR therapy;
Subjects with microsatellite-high (MSI-H) or mismatch repair deficient (dMMR) tumors must have been treated with immune checkpoint inhibitors if approved and available in the subject's country unless the patient is ineligible for treatment with a checkpoint inhibitor;
Subjects who received oxaliplatin in the adjuvant setting and developed metastatic disease during or within 6 months of completing adjuvant therapy are considered eligible without receiving oxaliplatin in the metastatic setting. Subjects who developed metastatic disease more than 6 months after completion of oxaliplatin-containing adjuvant treatment must be treated with oxaliplatin-based therapy in the metastatic setting to be eligible;
Body weight ≥40kg;
Eastern Cooperative Oncology Group (ECOG) performance status of 0-1;
Have measurable disease according to RECIST Version 1.1, assessed locally. Tumors that were treated with radiotherapy are not measurable per RECIST Version 1.1, unless there has been documented progression of those lesions;
Expected survival >12 weeks.
For female subjects of childbearing potential and male subjects with partners of childbearing potential, agreement to use a highly effective form(s) of contraception, that results in a low failure rate (<1% per year) when used consistently and correctly, starting during the screening period, continuing throughout the entire study period, and for 90 days after taking the last dose of study drug. Such methods include: oral hormonal contraception (combined estrogen/ progestogen, or progestogen-only) associated with inhibition of ovulation, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal ligation, vasectomized partner, or true sexual abstinence in line with the preferred and usual lifestyle of the subject. Highly effective contraception should always be combined with an additional barrier method (eg, diaphragm, with spermicide). The same criteria are applicable to male subjects involved in this clinical trial if they have a partner of childbirth potential, and male subjects must always use a condom.
Subjects with BRAF-mutant tumors must have been treated with a BRAF inhibitor if approved and available in the subject's home country unless the patient is ineligible for treatment with a BRAF inhibitor.
Absolute neutrophil count (ANC) <1.5×109/L, platelet count <100×109/L, or hemoglobin <9.0 g/dL. Blood transfusion within 1 week prior to enrollment for the purpose of increasing the likelihood of eligibility is not allowed;
Serum total bilirubin >1.5 × the upper limit of normal (ULN). Patients with Gilbert syndrome, bilirubin <2 X ULN, and normal AST/ALT are eligible;
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5 × ULN in patients without hepatic metastases; ALT or AST >5 × ULN in patients with hepatic metastases;
Serum creatinine >1.5 × ULN or creatinine clearance <60 mL/min. Creatinine clearance can either be measured in a 24-hour urine collection or estimated by the Cockroft-Gault equation.
Urine dipstick protein ≥2+ or 24-hour urine protein ≥1.0 g/24-h. Subjects with greater than 2+ proteinuria by dipstick must undergo a 24-hour urine collection to assess urine protein level;
Uncontrolled hypertension, defined as: systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg despite optimal medical management;
International Normalized Ratio (INR) >1.5 x ULN or activated partial thromboplastin time (aPTT) >1.5 × ULN, unless the patient is currently receiving or intended to receive anticoagulants for prophylactic purposes;
History of, or active gastric/duodenal ulcer or ulcerative colitis, active hemorrhage of an unresected gastrointestinal tumor, history of perforation or fistulas; or any other condition that could, in the investigator's judgment, result in gastrointestinal hemorrhage or perforation; within the 6 months prior to screening;
History or presence of hemorrhage from any other site (eg, hemoptysis or hematemesis) within 2 months prior to screening;
History of a thromboembolic event, including deep vein thrombosis (DVT), pulmonary embolism (PE), or arterial embolism within 6 months prior to screening.
Stroke and/or transient ischemic attack within 12 months prior to screening;
Clinically significant cardiovascular disease, including but not limited to acute myocardial infarction or coronary artery bypass surgery within 6 months prior to enrollment, severe or unstable angina pectoris, New York Heart Association Class III/IV congestive heart failure, ventricular arrhythmias requiring treatment, or left ventricular ejection fraction (LVEF) <50% by echocardiogram;
Mean corrected QT interval using the Fridericia method (QTcF) >480 msec or any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in a first-degree relative.
Concomitant medications with a known risk of causing QT prolongation and/or Torsades de Pointes.
Systemic anti-neoplastic therapies (except for those described in Exclusion 18) or any investigational therapy within 4 weeks prior to the first dose of study drug, including chemotherapy, radical radiotherapy, hormonotherapy, biotherapy and immunotherapy;
Systemic small molecule targeted therapies (eg, tyrosine kinase inhibitors) within 5 half-lives or 4 weeks (whichever is shorter) prior to the first dose of study drug;
Palliative radiotherapy for bone metastasis/lesion within 2 weeks prior to the initiation of study drug;
Brachytherapy (i.e., implantation of radioactive seeds) within 60 days prior to the first dose of study drug.
Use of strong inducers or inhibitors of CYP3A4 within 2 weeks (or 5 half-lives, whichever is longer) before the first dose of study drug;
Surgery or invasive procedure (i.e., a procedure that includes a biopsy; central venous catheter placement is allowed) within 60 days prior to the first dose of study drug or unhealed surgical incision;
Any unresolved toxicities from a previous antitumor treatment greater than CTCAE v5.0 Grade 1 (except for alopecia or neurotoxicity grade≤2);
Known human immunodeficiency virus (HIV) infection;
Known history of active viral hepatitis. For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with HCV infection who are currently on treatment are eligible if they have an undetectable HCV viral load.
Clinically uncontrolled active infection requiring IV antibiotics;
Tumor invasion of a large vascular structure, eg, pulmonary artery, superior or inferior vena cava;
Women who are pregnant or lactating;
Brain metastases and/or spinal cord compression untreated with surgery and/or radiotherapy, and without clinical imaging evidence of stable disease for 14 days or longer; patients requiring steroids within 4 weeks prior to start of study treatment are excluded;
Other malignancy, except for non-melanoma skin cancer, in situ cervical ca or bladder ca (Tis and T1) that have been adequately treated during the 5 years prior to screening;
Inability to take medication orally, dysphagia or an active gastric ulcer resulting from previous surgery (eg, gastric bypass) or a severe gastrointestinal disease, or any other condition that investigators believe may affect absorption of the investigational product;
Other disease, metabolic disorder, physical examination anomaly, abnormal laboratory result, or any other condition (e.g., current alcohol or drug abuse) that investigators suspect may prohibit use of the investigational product, affect interpretation of study results, or put the patient at undue risk of harm based on the investigator's assessment;
Known hypersensitivity to fruquintinib (or placebo) or any of its inactive ingredients including the azo dyes Tartrazine - FD&C Yellow 5 and Sunset yellow FCF - FD&C Yellow 6;
Subjects who have received prior fruquintinib;
Live vaccine <28days before the first dose of study drug(s). Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. Intranasal vaccines are live vaccines and are not allowed.
The study protocol (Supplement 1) was approved by the independent ethics committee/institutional review board of each participating center. This study was conducted in accordance with the Declaration of Helsinki16 and Guidelines for Good Clinical Practice, as well as the local laws and regulations of China. An independent data analysis monitoring committee, comprising 3 oncologists and 1 statistician, ensured the overall integrity of the trial and safety of the participants.
Unavailable at Publication Date
I think the most interesting aspect of this trial is #1 It's important to understand the mechanism action of this drug, is basically an oral tyrosine kinase inhibitor of the VEGF family, or the vascular endothelial growth factor family. Clinicians are very familiar with Bevacizumab, which specifically blocks one component of the VEGF pathway and then Regorafenibor as many of you are aware as a tyrosine kinase inhibitor that blocks multiple pathways. This is specifically focused on the VEGF pathway and it blocks receptors 1, 2 and 3. Also the potential benefit for a patient treated metastatic colorectal cancer is obviously it's an oral agent versus Bevacizumab. And it would allow another option for patients with metastatic colorectal cancer that are seeking new options. We have not had a new drug approved for standard micro-satellite stable patients without any specific targetable mutations and a disease control rate.
Fruquintinib is a generalized drug that would be, if the data is significant in regards to the primary endpoint of overall survival, once again, we know that we've fulfilled that primary endpoint to what degree we, I can't share that with you at this time but once again this would be another option for patients with metastatic colorectal cancer and we really want to continue to provide multiple options for patients whenever possible. Especially for surgically unresectable patients.
Patients receiving fruquintinib were randomized in a 2:1 ratio to receive either fruquintinib, 5 mg (n = 278) or placebo (n = 138) orally, once daily for 21 days, followed by 7 days off in 28-day cycles, until disease progression, intolerable toxicity, or study withdrawal.
Unavailable at Publication Date
I think it's extremely important to recognize that this trial has fulfilled their primary endpoint of overall survival, and as mentioned in the press release as well as for median overall survival. If Fruquintinib is eventually approved it will provide another option for metastatic colorectal cancer patients and it is an oral agent, which is obviously advantageous for many patients. It makes it more convenient for patient care, but I suspect moving forward and I would hope that you will start seeing Fruquintinib in combination with other drugs and obviously further drug development. So I think it's just really important to keep in mind that this is a new drug that is very promising. At least based upon the data that we have shared thus far in regards to overall survival and progression free survival. And we look forward to sharing this information with others in the near future.
Today announces that the pivotal global Phase 3 FRESCO-2 trial evaluating the investigational use of fruquintinib met its primary endpoint of overall survival (“OS”) in patients with advanced, refractory metastatic colorectal cancer (“CRC”).
The FRESCO-2 study was a multi-regional clinical trial conducted in the U.S., Europe, Japan and Australia that investigated fruquintinib plus best supportive care (“BSC”) vs placebo plus BSC in patients with metastatic CRC who had progressed on standard chemotherapy and relevant biologic agents and who had progressed on, or were intolerant to, TAS-102 and/or regorafenib. In addition to OS, a statistically-significant improvement in progression-free survival (“PFS”), a key secondary endpoint, was observed. The safety profile of fruquintinib in FRESCO-2 was consistent with previously reported studies. Full results will be submitted for presentation at an upcoming medical meeting.
“We are very happy to see the positive outcomes of the FRESCO-2 study which offers a potential new treatment for patients with advanced metastatic colorectal cancer, where the unmet need is very high and patients have limited treatment options,” said Dr Marek Kania, Executive Vice President, Managing Director and Chief Medical Officer of HUTCHMED International. “Results from the global FRESCO-2 study supplement findings from the original FRESCO study that led to the marketing approval and commercialization of fruquintinib in China. We would like to thank the patients, their families, and the healthcare professionals who participated in this study and helped achieve this important milestone.”
Fruquintinib is a highly selective and potent oral inhibitor of VEGFR-1, -2 and -3. VEGFR inhibitors play a pivotal role in blocking tumor angiogenesis. Fruquintinib was designed to improve kinase selectivity to minimize off-target toxicities, improve tolerability and provide more consistent target coverage. The generally good tolerability in patients to date, along with fruquintinib’s low potential for drug-drug interaction based on preclinical assessment, suggests that it may also be highly suitable for combinations with other anti-cancer therapies.
The safety and efficacy of fruquintinib for the following investigational uses have not been established and there is no guarantee that it will receive health authority approval or become commercially available in any country for the uses being investigated:
Gastric Cancer (“GC”) in China: The FRUTIGA study is a randomized, double-blind, Phase III trial evaluating the efficacy and safety of fruquintinib combined with paclitaxel for the treatment of patients with advanced gastric or esophagogastric junction (“GEJ”) adenocarcinoma who did not respond to first-line standard chemotherapy. Approximately 700 patients have received either fruquintinib combined with paclitaxel or placebo combined with paclitaxel. The co-primary efficacy endpoints are OS and PFS (clinicaltrials.gov identifier: NCT03223376).
Cathy Eng, MD, FACP, FASCO, is a Professor of Medicine, Hematology, and Oncology and the Co-Director of the Gastrointestinal Cancer Research Program. In July 2019, she joined the Vanderbilt-Ingram Cancer Center faculty.
Her primary clinical research interests include clinical trials using novel medications to treat colorectal, anal, and appendiceal malignancies. She is particularly interested in young colorectal cancer patients and the role of immunotherapy in HPV-related malignancies. She has numerous papers in these GI malignancies.
Dr. Eng has held numerous leadership positions for ASCO, ASCO GI, ECOG, and the NCI Rectal/Anal Task Force on a national level. She was recently appointed Vice-Chair of the SWOG GI Committee and the NCI GI Steering Committee.
JAMA Network - Effect of Fruquintinib vs Placebo on Overall Survival in Patients With Previously Treated Metastatic Colorectal Cancer. Jama Network Original Investigation, June 26, 2018
Clinical Trials.gov - A Study of Efficacy and Safety of Fruquintinib (HMPL-013) in Patients With Metastatic Colorectal Cancer (FRESCO-2). ClinicalTrials.gov, March 25, 2022
GlobeNewswire - HUTCHMED Announces that Fruquintinib Global Phase III FRESCO-2 Study Has Met Its Primary Endpoint in Metastatic Colorectal Cancer. GlobeNewswire Press Release, August 07, 2022