Jorge Cortes, MD, Director at the Georgia Cancer Center discusses U.S. FDA Approves Supplemental New Drug Application for Takeda’s ICLUSIG® (ponatinib) for Adult Patients with Resistant or Intolerant Chronic-Phase CML.


CAMBRIDGE, Mass. & OSAKA, Japan—(BUSINESS WIRE)—Takeda Pharmaceutical Company Limited (TSE:4502/NYSE: TAK) announced today that the United States has announced The supplemental New Drug Application (sNDA) for ICLUSIG® (ponatinib) has been approved by the Food and Drug Administration (FDA) in adult patients with chronic phase (CP) chronic myeloid leukemia (CML) with resistance or aversion to at least two prior kinase inhibitors. The revised label provides an integrated, response-based ICLUSIG dosing regimen in CP-CML with a starting daily dose of 45 mg and a dose reduction to 15 mg after achieving ~1% BCR-ABL1IS. By providing efficacy and reducing the risk of adverse events (AEs), like arterial occlusive events, this dosing regimen aims to optimize the gain risk (AOEs).

The sNDA approval is based on data from the OPTIC (Optimizing Ponatinib Care In CML) Phase 2 trial and on five-year data from the PACE (Ponatinib Ph+ ALL and CML Evaluation) Phase 2 trial.


The OPTIC trial included patients with CP-CML whose disease was highly resistant to their immediate prior TKI, most of whom (65%) did not respond to immediate prior therapy to a response greater than complete hematological response (CHR). At 12 months, 42 percent of 88 patients using the newly approved response-based dosing regimen (45 mg to 15 mg) achieved ~1 percent BCR-ABL1IS, the primary OPTIC endpoint, and 73 percent of these patients preserved their response at a median follow-up period of 28.5 months. In these patients, 13% had an AOE of any stage, 7% had a grade 3 or higher experience. Risk factors such as uncontrolled hypertension or diabetes should be monitored, and patients with an active or substantial history of clinically significant, uncontrolled cardiovascular disease should be treated with caution.

Prof. Dan Aderka of the Sheba Medical Center discusses the Optimal Sequence of Targeted Agents for All RAS & BRAF Patient Sub-types; Latest Data Update and Clinical Experience.

https://virtualgi2020.com/congress-program/

Helene Rundqvist of the Karolinska Institutet speaks about Cytotoxic T-cells mediate exercise-induced reductions in tumor growth.


An abstract:
Exercise has a large spectrum of structural impacts. Repeated exertion decreases malignant tumor growth in animal models, and exercise can improve outcomes for cancer patients clinically. Like the cellular agents involved, the etiology of the impact of exercise on tumor development is unknown. We show here that exercise-induced reduction of tumor growth in mice is dependent on CD8+ T cells, and that metabolites produced in skeletal muscle and excreted in plasma in both mice and humans at high levels during exercise enhance the effector profile of CD8+ T cells. We observed that activated murine CD8+ T cells alter their central carbon metabolism in response to in vivo exercise and that when transferred to tumor-bearing untrained animals, immune cells from trained mice are more potent antitumor effector cells. These data show that through exercise, CD8+ T cells are metabolically altered in a way that increases their antitumor efficacy.

IN SUMMARY:
Nearly all tissues in the body are affected by exercise, and scientists have found that being physically active can minimize the risk of many forms of cancer and boost cancer patients' outcomes. However, how exercise exerts its beneficial effects is still unclear. The tendency of cancer cells to evade immune system detection, which in some cases can prevent the body from destroying tumor cells, is one of the hallmarks of cancer.


Mice have been used by Rundqvist et al. to study how exercise helps the immune system function against the progression of tumors. They found that tumor growth was decreased when mice exercised, and this decrease in growth depended on the levels circulating in the blood of a particular type of immune cell, the CD8+ T cell. In addition, Rundqvist et al. found that through molecules that muscles released into the blood during exercise, CD8+ T cells were made more effective. After vigorous exercise, isolating immune cells revealed that these super-effective CD8+ T cells alter how they use molecules after exertion for energy production. First, immune cells from regularly exercised mice were transferred to non-exercised mice, where they were more successful than immune cells from untrained mice against tumor cells.

Larysa Sanchez, MD from Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute speaks about the ASH 2020 Abstract - 3242 Real-World Treatment Patterns and Outcomes of Proteasome Inhibitor (PI: Bortezomib [V], Carfilzomib [K], or Ixazomib [I])-Lenalidomide/Dexamethasone (Rd)-Triplets By Prior Lenalidomide-Exposure in Patients with Relapsed/Refractory Multiple Myeloma (RRMM) Engaged in Routine Care in the United States (US)


REFERENCE:
The most frequently used triplet combination regimens in patients (pts) with RRMM in the US are PIs paired with a Rd backbone. The hallmark research supporting the effectiveness of these regimens were primarily in pts without prior exposure to lenalidomide (R).1,2 Real-world studies have shown that R-based regimens are increasingly used in the front-line environment.3-5 Therefore, real-world treatment trends in pts with prior R exposure and comparative real-world efficacy of PI-Rd triplets with RRMM nee in this population

AND METHODS:
In Optum's de-identified national electronic health records database, a retrospective cohort of RRMM pts initiating IRd, KRd, or VRd in line of therapy (LOT) al 2 was followed from 7/2007-9/2018. Between 1/2014 and 9/2018, RRMM pts were identified as those initiating LOT ⁇ 2 and were listed in any previous LOT as having or not having prior exposure to R (R-exposed; no-prior-R). The first implementation of the I-/K-/or V-Rd was the index regimen. In accordance with the NCCN MM Guidelines, LOTs were identified by an algorithm developed with MM specialists to proxy the definition of LOT in RCTs &.6 Baseline data included: CRAB (hypercalcemia, renal failure, anemia, and bone lesions); high-risk cytogenetics (defined as del[17p], 1q21 benefit, t[4;14], or t[14;16]); Charlson Comorbidity Index (CCI) score; and adjusted frailty score using age and age. The median length of therapy (DOT) and time-to-next-treatment (TTNT) (a PFS proxy; defined as the time from the beginning of the index regimen to subsequent LOT or death) were calculated using Kaplan-Meier methods and compared using proportional hazard models of covariate-adjusted Cox (FIGURE). Observations at the time of follow-up failure (f/u)/end of the study period (9/30/2018) were censored.

RESULTATIONS:
Of the 650 pts included, R-exposed was 397 (IRd, n=112; KRd, n=115; VRd, n=170); no-prior-R was 253 (IRd, n=29; KRd, n=62; VRd, n=162). Overall, R-exposed pts were treated in later LOTs (LOT2: 55% v 78%) and had a longer median time from diagnosis to LOT index (26.7 v 13.4 months) than no-prior-R pts; this varied between cohorts of therapy (TABLE). In R-exposed pts, more pts earned KRd than IRd (75 percent & 23 percent) or VRd (74 percent & 16 percent) with symptomatic relapse (approximately 1 CRAB symptom, 87 percent) or high-risk cytogenetics (30 percent) (TABLE). More IRd-treated pts were ~75 years old: 42% (IRd) v 36% (VRd) / 21% (KRd). 35.3 percent of those receiving VRd in LOT ⁇ 2 had previous V-IMID-based therapy in R-exposed pts and 53.5 percent had IMID-based therapy in LOT1 (i.e. IMID without PI or monoclonal antibody); >98 percent of LOT1 IMID use was R across categories. 56.5 percent of those receiving KRd had prior V-IMID-based therapy in R-exposed pts and 16.5 percent had IMID-based therapy in LOT1; 29.5 percent and 43.8 percent had prior V-IMID-based and IMID-based therapy in LOT1 in IRd pts in LOT ⁇ 2. Median TTNT for R-exposed pts: 12.3 months (IRd), 7.8 months (KRd), and 13.9 months (VRd) (P=0.50); median TTNT for TTNTLOT stratified: 0.84 (IRd v KRd), 0.96 (IRd v VRd), 1.15 (KRd v VRd), and median DOT regimen: 8.4 months (IRd), 7.5 months (KRd), and 9.5 months (VRd) (P=0.75) in an unadjusted analysis, at a median f/u of 11, 11.9, and 14.8 months for I-, K-, and V-Rd. HRs for stratified TTNTLOT is important for IRd v KRd (HR=0.33) and KRd v VRd (HR=1.62) (P<0.01, both) at no-prior-R pts; IRd v VRd (HR=0.53; P=0.11). There were no major variations in the modified study for R-exposed pts for TTNT (FIGURE) or DOT regimen PI-Rd regimens. Adjusted HR for TTNT was important for I- v K-Rd (HR=0.36; P=0.03) for no-prior-R pts and significant for I- v V-Rd (HR=0.34; P=0.03) for regimen DOT.

CONCLUSIONS SECTIONS:
In this real-world research, after prior VRd or Rd in the front-line, the majority of pts obtained a PI-Rd combination. The PI-Rd triplets were comparable in TTNT in R-exposed pts treated in LOTs ⁇ 2 after control for baseline characteristics, including prior PI-exposure. For I-v K-Rd in pts with no-prior-R, TTNT was slightly longer, but this is constrained by small sample sizes. Published studies suggest that individualized therapy recommendations may enhance real-world performance, such as IRd v KRd in fragile pts associated with significantly longer TTNT exposure.6 In our study, prior-R exposure does not appear to affect the relative efficacy of the PI-triplet regimen in LOTs. Understanding real-world care trends and corresponding PI-Rd efficacy in consequent LOTs are crucial to improving RRMM pt management with the growing use of R in earlier LOTs.

D. Ross Camidge, M.D., Ph.D. from CU Anschutz Medical Campus, with final thoughts from Andrew Koustenis from Verastem Oncology, speaks about Verastem Oncology Initiates Phase 2 Registration-Directed Trial of VS-6766 and Defactinib in Recurrent Low-Grade Serous Ovarian Cancer.


BOSTON—(COMPANY WIRE)—Nov. Verastem, Inc. (Nasdaq: VSTM) (also known as Verastem Oncology), a biopharmaceutical company dedicated to advancing new medicines for cancer patients, today announced the start of a Phase 2 registration-directed clinical trial in patients with recurrent low-grade serous ovarian cancer of VS-6766, its RAF/MEK inhibitor, and defactinib, its FAK inhibitor (LGSOC).

The Phase 2 (GOG3052) study is a multicenter, parallel, randomized, open-label, adaptive, two-part multicenter trial assessing the efficacy and safety of VS-6766 alone and in combination with defactinib in patients with recurrent LGSOC.1 The first part of the study will determine the optimal regimen of either VS-6766 monotherapy or defactinib in patients with recurrent LGSOC randomized therapy. Based on objective response rate data, the determination of which regimen to take forward into the expansion phase of the trial will be made. The study's expansion process will analyze the effectiveness and safety parameters of the selected regimen. In the United States, trial enrollment is ongoing with European sites to follow. You can find more information about this research here at ClinicalTrialsgov (NCT04625270). The Company has previously announced its fruitful meeting in Q3 2020 with the Food and Drug Administration (FDA) and the support of the FDA for LGSOC's growth plan and adaptive trial design by the Company.

Professor Udai Banerji, Deputy Director of Drug Production at the Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust led the launch of the trial following the recent outcomes of two clinical trials. The first, a Phase 1 study published in The Lancet Oncology, showed that VS-6766 could be successful against a variety of types of KRAS-mutated tumors, including lung and gynecological cancers.3 The second, a Phase 1/2 study presented at the Annual Meeting 2020 of the American Association for Cancer Research (AACR), showed that the combination of an inhibitor of RAF/MEK and FAK could be advantageous for KRAS patients.


Low-Grade Serous Ovarian Cancer Around (LGSOC)
Low-grade serous ovarian cancer (LGSOC) is a high mortality rate, recurrent, chemotherapy-resistant cancer.2 It constitutes 5-10% of serous ovarian cancers and 6-8% of all ovarian cancers.2 An estimated 6,000 patients are living with this disease in the U.S. and 80,000 worldwide.5 LGSOC is most commonly diagnosed in women between the ages of 45-55.2 LGSOC has a median of 45-55 years. The quality of treatment for this condition is chemotherapy.


About VS-6766-666
The oral small-molecule inhibitor of the RAF/MEK signaling pathway is VS-6766. VS-6766 blocks both MEK kinase activity and the ability of RAF to phosphorylate MEK, in contrast to other MEK inhibitors in development. This unusual mechanism allows MEK signaling to be blocked by VS-6766 without the compensatory activation of MEK, which seems to limit the effectiveness of other inhibitors.


About Defactinib and Defactinib
Defactinib (VS-6063) is an oral FAK and PYK2 small molecule inhibitor currently being investigated as a possible combination therapy for different solid tumors. In the US, EU, and Australia, the Company has secured the Orphan Drug status for defactinib for ovarian cancer. The effect of FAK inhibition on improving immune response by reducing immunosuppressive cells, increasing cytotoxic T cells, and reducing stromal density, which enables tumor-killing immune cells to reach the tumor, has been identified in preclinical research by Verastem Oncology scientists and collaborators at world-renowned research institutions.


About the VS-6766/Defactinib Combination
In ~30 percent of all human cancers, RAS mutant tumors have traditionally posed a challenging treatment challenge and are often associated with a substantially worse prognosis.9 Resistance to single agents, 10 tolerable combination regimens with MEK inhibitors, and new RAS inhibitors are the difficulties associated with finding new treatment strategies for these types of cancers.


In patients with KRAS mutant tumors, the combination of VS-6766 and defactinib was found to be clinically active. The combination of VS-6766 and defactinib is being tested in patients with LGSOC, KRAS mutant NSCLC and colorectal cancer in an ongoing investigator-initiated Step 1/2 FRAME trial. At the 2nd Annual RAS-Targeted Drug Development Summit in September 2020, updated data from this study showed a 56 percent overall response rate and a long period of therapy among patients with KRAS-G12 mt LGSOC.10 Verastem will also further explore the function of VS-676 based on the observation of higher response rates seen in NSCLC patients with KRAS-G12V mutations in the study.

Robert M. Rifkin, MD of the Rocky Mountain Cancer Center speaks about the ASH 2020 Abstract - 551 The Phase 3 TOURMALINE-MM2 Trial: Oral Ixazomib, Lenalidomide, and Dexamethasone (IRd) Vs Placebo-Rd for Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma (NDMM).


Context
In transplant-ineligible NDMM patients, continuous Rd-based regimens are among the standards of treatment. These patients are diverse, ranging from healthy 70-plus-year-olds to elderly and/or vulnerable patients with low-performance status, requiring individual patient environments to be tailored to care. The continuous or higher cumulative dose use of proteasome inhibitors (PIs) contributes to improved long-term outcomes; however, long-term administration of injectable PIs can present difficulties associated with the burden of treatment and tolerability. For patients who do not want to or can not drive to the clinic regularly, an all-oral PI-Rd triplet can be useful. With predictable, manageable toxicities, the oral PI ixazomib is ideal for continuous dosing. In transplant-ineligible NDMM patients, the multicenter, double-blind, placebo-controlled TOURMALINE-MM2 analysis compared IRd versus placebo-Rd.


Methodology
Adult transplant-unqualified NDMM patients were randomized (1:1) to ixazomib 4 mg (n=351) or placebo-matched (n=354) on days 1, 8, and 15 of the 28-day periods, plus 25 mg of lenalidomide on days 1-21 (10 mg for patients with renal impairment), and 40 mg of dexamethasone on days 1, 8, 15, and 22 (20 mg for patients >75 years). Dexamethasone was discontinued after 18 cycles and treatment with ixazomib 3 mg and lenalidomide 10 mg continued until development or toxicity occurred. Randomization was stratified at the screening by age (<75 vs 75 years), stage of the International Staging System (ISS) (I or II vs III), and Brief Pain Inventory-Short Form (BPI-SF) worst pain score (<4 vs ⁇ 4). An Independent Review Committee (IRC) determined progression-free survival (PFS) was the primary endpoint; main secondary endpoints included overall survival (OS), complete response (CR) rate, and pain response rate. Complete response rate (ORR), time to response (TTR), time to progression (TTP), and protection were additional secondary endpoints. The sample size was calculated to provide OS power of 80 percent and PFS power of 92 percent. Intention-to-treat (ITT) populations (alpha=0.04) and 3 prespecified parallel subgroups (total alpha=0.01) were tested for PFS, including patients with extended high-risk cytogenetics [t(4;14), t(14;16), del(17p), amp(1q21)], patients <75 years of age, and patients with creatinine clearance (CrCl) >60 mL/min. For PFS, we record data from the final study.



Outcomes
In the IRd vs placebo-Rd arms, the median age at the data cutoff (Dec 2, 2019) was 73 vs 74 years (43 percent vs 44 percent ⁇ 75 years), 16 percent vs 17 percent had ISS stage III MM, and 54 percent of patients in each arm had the worst BPI-SF pain score of ⁇ 4. There was a strong positive trend in PFS favoring IRd at a median follow-up of 53.3 vs 55.8 months; with 169 vs 209 patients having advanced or died in the IRd vs placebo-Rd arms, the median PFS was 35.3 vs 21.8 months (hazard ratio [HR] 0.830; p=0.073; Figure). The median PFS is shown in the table in the three prespecified subgroups of patients with extended high-risk cytogenetics, patients <75 years of age, and patients with CrCl >60 mL/min. ORRs were comparable between weapons, but with IRd vs placebo-Rd, the response depth was greater (Table). In the table, the median TTR and TTP are shown for IRd and placebo-Rd. Median OS was not obtained in either arm (HR 0.998) after a median follow-up of ~58 months, and in the IRd and placebo-Rd arms, respectively, 136 and 148 patients died. For the most part, treatment-emergent adverse effects (TEAEs) is grade 1/2. With IRd vs placebo-Rd, 88% vs. 81% of patients had grade 3 TEAEs; neutropenia (17% vs. 27%), rash (17% vs. 7%), thrombocytopenia (13% vs. 5%), and diarrhea (10% vs. 2%) were the most common grade 3 incidents (about 5% difference); 66% vs. 62% had extreme TEAEs, 35% vs. 27% had TEAEs resuscitated



Findings
The addition of ixazomib to Rd led to a clinically important, obvious positive trend in PFS, with a median increase of 13.5 months in patients with transplant-ineligible NDMM. Improvements were also observed in the TTP and CR rates. IRd increased the low PFS associated with extended high-risk cytogenetics vs. placebo-Rd in line with TOURMALINE-MM1 (Avet-Loiseau Blood 2017). Protection results were generally consistent with ixazomib/well-characterized, IRd's tolerable, and manageable toxicity profile. For those patients who could benefit from an all-oral triplet combination, IRd is a viable treatment option.

Maximilian Merz, MD from Roswell Park Comprehensive Cancer Center speaks about 722 Spatiotemporal Assessment of Immunogenomic Heterogeneity in Multiple Myeloma.


Introducing:
In multiple myeloma, care and immune-mediated procedures are associated with clonal evolution (MM). In this research, whole-exome sequencing (WES) and single-cell RNA sequencing (scRNA-seq) were performed on plasma cells (PC) from iliac crest (BM) bone marrow aspirates and corresponding osteolytic lesions (OL) to investigate spatial heterogeneity in newly diagnosed (NDMM) and relapsed/refractory MMM patients (RRMM). To examine the immunogenomic landscape surrounding malignant PCs, next-generation flow (NGF) and T-cell receptor sequencing (TCRseq) were performed.


Methodology:
In a prospective trial, in addition to the standard BM sampling, 18 patients (NDMM: n=10; RRMM: n=8) consented to an OL imaging-guided biopsy. Thirty-seven distinct sites were biopsied upon inclusion. During treatment, follow-up samples were collected from 5 patients in remission. PCs were subjected to WES and scRNA-seq after CD138+ selection (Chromium, 10x genomics). TCRseq on the CD138- fraction was performed using multiplex PCR (ImmunoSEQ, Adaptive Biotechnologies). Cell Ranger (v3.1.0) and the Seurat R toolkit (v3.1) have been used for scRNA-seq data analyses. ImmunoSEQ ANALYZER (v3.0) and Immunarch R toolkit data were analyzed for TCRseq (v0.6.6.). NGF was performed to study T-, B-, NK- and dendritic cell subsets (DC).



Outcomes:
In contrast to random BM, median PC infiltration was greater in OL (50.0 percent vs 12.5 percent, p=0.041). WES revealed more mutations in RRMM compared to NDMM (median; range: 189;120-523 vs 71;23-136, p<0.001). Based on WES mutational profiles, 4 out of 18 patients demonstrated branching evolution in OL-isolated PCs. Three of the 4 patients had RRMM and a previous history of solitary plasmacytoma was found in one patient with NDMM. In 3 of the 4 patients with branching evolution, PCs were obtained from OL with an adjacent extramedullary disease (EMD). Among site-specific mutations, two distinct BRAF mutations were found in one patient: V600E in the BM and G469R in the OL. The OL was found to have an extra NRAS mutation (G12D). Resistance to BRAF inhibitors is caused by BRAF G469R and NRAS G12D, but this patient was naive to the BRAF inhibitors. Chromosomal aberrations, including site-specific chromothripsis of chromosome 1 in a patient with RRMM, often reflected clonal evolution. ScRNA-seq of more than 150,000 PCs from 10 patients and 21 separate locations reported numerous clones, including in patients with no spatially divergent clones as observed by WES. Differential expression of BM-associated genes (CXCR4), malignant transformation (Jun/Fos, CD27, CD79a), apoptosis (BCL-2), bone disease (DKK1) and LAMP-5 is detected by distinct PC clones. ScRNA-seq demonstrated the emergence of a PC clone characterized by overexpression of Interferon-induced genes (ISG15, IFI27, IFI44L) in a patient with NDMM in remission after induction therapy relative to the initially predominant PC clones. Next, we examined immune cell spatiotemporal variations. Median TCR richness estimation using the abundance-based estimator (Chao1) showed significantly lower values relative to NDMM (389341; 50318-525082, p<0.001) and nine healthy individuals (460278; 138326-696419, p<0.001) in patients with RRMM (120444; 57706-212744). As indicated by Simpson's D, no substantial differences were observed for TCR clonality. Although longitudinal monitoring of TCR clones at primary diagnosis showed no clonal expansion after treatment, induction therapy restored sample richness to levels of healthy individuals in patients with NDMM (p=0.61). A strong concordance of TCR repertoires from OL and random BM with Morisita indices ranging from 0.80 to 0.95 in 90 percent of patients was demonstrated by overlap review. Important site-specific expansion of TCR clones was nevertheless observed. In accordance with TCRseq, more regulatory T-cells (p=0.048) and less myeloid DC (p=0.024), Th9 cells, and CD8 effector memory T-cells compared to NDMM were shown by NGF in the BM of patients with RRMM.





The Conclusion:
The first prospective clinical trial to examine spatiotemporal immunogenomic heterogeneity in multiple myeloma as evaluated by the non-PC compartment's WES and scRNA-seq of PC and NGF and TCRseq is recorded. In particular, in patients with RRMM and/or EMD, we show spatial evolution and reduced TCR diversity. In contrast to WES, ScRNA-seq adds another layer of complexity and helps to define how PC develops an immune suppressive niche for BM.

Eunice S. Wang, MD of Roswell Park Comprehensive Cancer Center discusses the ASH 2020 abstract - 27 Phase 3, Multicenter, Open-Label Study of Gilteritinib, Gilteritinib Plus Azacitidine, or Azacitidine Alone in Newly Diagnosed FLT3 Mutated (FLT3mut+) Acute Myeloid Leukemia (AML) Patients Ineligible for Intensive Induction Chemotherapy.


Context:
In patients with FLT3-mutated (FLT3mut+) relapsed/refractory acute myeloid leukemia (AML), including internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations, Gilteritinib is an oral FMS-like tyrosine kinase 3 (FLT3) inhibitor that has demonstrated efficacy with favorable tolerability. Tumor growth and induced apoptosis and differentiation of FLT3 ITD AML cell lines and patient blasts in vitro were inhibited by combining FLT3 inhibition with azacitidine (AZA). Furthermore, in murine AML xenograft models with FLT3 ITD, the combination of gilteritinib with AZA showed synergy over either treatment alone. An ongoing, open-label, phase 3, randomized trial investigating gilteritinib plus AZA vs AZA alone in newly diagnosed (ND) FLT3mut+ AML adults who were unable to undergo intensive induction chemotherapy is identified (NCT02752035).

Methodology:
This research involves ND FLT3mut+ (ITD or TKD [D835/I836]) AML patients who are (a) ⁇ 65 years old and considered ineligible by the investigator for intensive induction chemotherapy, or (b) ⁇ 18-64 years old with unique comorbidities that cause intensive induction chemotherapy ineligibility. The study started with a Safety Cohort in which patients received 80 mg/d of oral gilteritinib as the initial dose on days 1 to 28 (or 120 mg/d as the next dose level) plus 75 mg/m2/d of AZA on days 1 to 7. A randomization cohort was followed where ~250 patients are expected to be randomized 2:1 to receive oral gilteritinib on Days 1-28 plus AZA 75 mg/m2/d SC/IV on Days 1-7 (Arm AC) or AZA alone, given in 28-day cycles (Arm C) until there is a lack of efficacy, inappropriate toxicity, or a discontinuation case. A gilteritinib-alone treatment arm (Arm A) that was withdrawn was included in an earlier protocol version. The key endpoint is absolute survival (OS). Event-free survival (EFS; primary secondary endpoint), best response, remission rates (complete remission [CR], incomplete hematologic recovery [CRi], partial hematologic remission [CRp], composite CR [CRc; a total of CR, CRi, and CRp]) and duration, transfusion and maintenance rates, leukemia-free survival, patient-reported fatigue, and protection and safety are secondary endpoints. When ~70 and 140 deaths are observed, respectively, one interim and one final review are scheduled. Using the stratified log-rank test, OS and EFS will be evaluated with age strata ( ⁇ 75 vs <75 years), cytogenetic risk (favorable or intermediate vs unfavorable or secondary AML) and FLT3 mutation status (low allelic ratio FLT3 TKD vs FLT3 ITD [<0.5] vs FLT3 ITD high allelic ratio [ ⁇ 0.5]).

Outcomes:
Table 1 describes the features of all patients involved in the Protection and Randomization Cohorts as of 29 June 2020. Fifteen patients were enrolled in the Protection Cohort. 14 patients died and 1 patient failed to undergo care (Figure). The median period of treatment (range) was 6 cycles (<1–34); 40 percent (n=6/15) received >12 treatment cycles. A CRc of 67 percent (n=10/15) was observed overall (Figure). Based on these results, for the Randomization Cohort, a 120 mg daily dose of gilteritinib plus AZA was adopted. As of 29 June 2020, 136 patients were randomized, 114 in Arm AC or C and 22 in Arm A, respectively (now closed). The median (range) period of treatment was 4 (<1–31) cycles, with ~6 treatment cycles being received by 40 percent (n=54/136). A total of 83 (61 percent) patients died in the Randomization Cohort.

Findings:
The research is continuing and no new safety signals have been found to date associated with gilteritinib 120 mg daily plus AZA in the study. The Safety Cohort of gilteritinib 80-120 mg plus AZA shows a CRc rate of 67 percent in mature remission results. In patients with ND FLT3mut+, AML found unfit for intensive chemotherapy, gilteritinib 120 mg/d plus AZA vs AZA alone continues to be randomized to receive 2:1 for initial treatment.

Aung Naing, MD, FACP MD Anderson speaks about Strategies for improving the management of immune-related adverse events.

You can download the IO Tox Management below -
IOS -
https://apps.apple.com/us/app/io-tox-management/id1514006592

Android -
https://play.google.com/store/apps/details?id=com.projectronin.iotoxman&hl=en_US&gl=US

You can find the full Abstract through the link below -
https://jitc.bmj.com/content/8/2/e001754.full



Instract
Durable and drastic responses in many difficult-to-treat malignancies have been observed with the advent of immunotherapeutic agents, outlining a path to overcoming cancer. Immune checkpoint inhibitors (ICPi) are a class of immunotherapy agents that, by reinvigorating the suppressed immune system, attack tumor cells. However, unbridled T-cell activity disrupts immune homeostasis and, in a large proportion of patients, causes a unique spectrum of side effects termed immune-related adverse events (irAEs). These irAEs vary from the side effects that conventional chemotherapeutic agents create. Life-threatening and fatal incidents have been recorded, but the majority of irAEs are manageable with corticosteroids and other immunosuppressive agents. Management of irAEs has been difficult for patients, clinicians, and healthcare providers alike, in the absence of predictive biomarkers to classify patients at risk for irAEs and a systematic method to diagnose, report and treat irAEs. The incidence of irAEs would inevitably increase with the growing use of ICP is for the treatment of different cancers. There is a compelling need to implement strategies, both in community settings and in cancer centers, to handle irAEs effectively. To this end, we propose several strategies in this paper, such as providing patient education, harmonizing the guidelines for irAE management, standardizing irAE reporting, improving the selection of immunosuppressive agents, conducting preclinical, clinical, and translational studies to better understand irAEs, including high-risk patients, integrating diagnostic tools to personalize irAE management.