FRESCO-2 Trial Meets Endpoints: Metastatic Colorectal Cancer

FRESCO-2 Trial Met Primary Endpoints in Patients With Metastatic Colorectal announced HUTCHMED from the Fruquintinib Global Phase III Trial

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 cancer that were seeking additional treatment options, if they were in that situation.

FRESCO-2 Trial Design and Treatment.

The design was basically a 2:1 randomization versus randomized double blind 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.

Patient Eligibility for the Fruquintinib Clinical Trial

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.

Additional Eligibility Information from ClinicalTrailGov.com

Inclusion Criteria:

• 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 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.

Exclusion Criteria: from ClinicalTrailGov.com

• 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 FRESCO-2 Trial treatment are excluded;

• Other malignancy, except for non-melanoma skin cancer, in situ cervical cancer or bladder cancer (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.

Statistical Methods used in the FRESCO-2 trial? from JAMAnetwork.com

The FRESCO-2 Trial 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 clinical trial and safety of the participants.

Key Data or Results from The FRESCO-2 Trial?

Unavailable at Publication Date

What is the most interesting aspects of this trial that oncologists should know?

I think the most interesting aspect of this clinical 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.

Were There Any Interventions in the Fruquintinib trial? from JAMAnetwork.com

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.

Were There Any Adverse Events in the FRESCO-2 trial?

Unavailable at Publication Date

Conclusions and Highlights for Oncologists

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.

Fruquintinib HUTCHMED August 8th, 2022 Press Release Data and Quotes

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 refractory advanced, refractory metastatic colorectal cancer ("CRC").

The FRESCO-2 Trial 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 trial 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 phase III FRESCO-2 trial supplement findings from the original FRESCO-2 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."

About Fruquintinib: from August 8th, 2022 Press Release

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.

About Fruquintinib Development Beyond CRC Monotherapy; From August 8th, 2022 Press Release

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).

Author Credentials and Affiliations

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 metastatic 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.

References

1. 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

2. 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

3. 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