Shots:
- Did you know that more than 80 % of Low-grade Serous Ovarian Cancer (LGSOC) patients experience recurrence?
- The US FDA recently approved Verastem Oncology’s Avmapki Fakzynja Co-Pack, as the first ever treatment of patients with KRAS-mutated recurrent LGSOC
- In an illuminating dialogue exchange with PharmaShots, John Hayslip, CMO at Verastem Oncology, provides a detailed overview of how this combination therapy addresses the unmet needs of patients with KRAS-mutated recurrent LGSOC.
Saurabh: What are the most common or severe adverse effects which were observed during clinical trials?
John: Verastem Oncology evaluated the safety of Avmapki and Fakzynja, in combination, in 57 patients with KRAS-mutated recurrent LGSOC. Possible serious side effects with Avmapki Fakzynja Co-Pack include ocular disorders, skin toxicities (rash), hepatotoxicity, rhabdomyolysis, and fetal harm when administered during pregnancy. The most common side effects, including laboratory changes, of Avmapki Fakzynja Co-Pack include increased levels of an enzyme in the blood (CPK), nausea, fatigue, abnormal liver test (AST), and rash.
Saurabh: What were the key clinical endpoints which were met in the trials which supported the FDA approval of your drug?
John: The accelerated approval of Avmapki Fakzynja Co-Pack is based on the Phase 2 RAMP 201 clinical trial, which evaluated the combination of Avmapki and Fakzynja in 57 adult patients with measurable KRAS-mutated recurrent LGSOC. The major efficacy outcome measure was overall response rate (ORR) assessed by blinded independent review committee (BIRC) according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. An additional efficacy outcome measure was duration of response (DOR).
In the study, Avmapki and Fakzynja, in combination, showed in patients with a KRAS mutation a confirmed ORR by BICR of 44% (25/57; 95% CI: 31-58) with a tolerability profile that only led to a 14% discontinuation rate, which supported patients’ ability to stay on treatment. The median DOR ranged from 3.3 to 31.1 months in the KRAS mutant population.
Saurabh: How does this drug therapy address the unmet needs of patients who are suffering from LGSOC and don’t have multiple therapeutic options?
John: Low-grade Serous Ovarian Cancer or LGSOC is a rare ovarian cancer that is insidious and persistent, with more than 80% of patients experiencing recurrence. There are approximately 6,000 to 8,000 women with LGSOC living in the U.S., and 1,000 to 2,000 cases are diagnosed each year. LGSOC is most commonly diagnosed in women between the ages of 20 to 30 and 50 to 60. The RAS/MAPK pathway is a primary driver of tumor growth: mutations that activate the pathway, including mutations in the KRAS gene, are found in many cancers.
Prior to Verastem Oncology’s approval, there were no FDA-approved treatments specifically for KRAS-mutated recurrent LGSOC, a rare and distinct ovarian cancer that differs from high-grade serous ovarian cancer in both its biology and how it responds to treatment.
Saurabh: What is the next plan for Avmapki -Fakzynja Co-Pack in terms of label expansion now that it has got FDA approval? Do you think it can be a valuable addition to the company’s oncology portfolio?
John: Verastem’s initial focus is to make Avmapki Fakzynja Co-Pack available to the patients who will benefit as fast as possible.
Part of the potential market expansion opportunities include leveraging data from the ongoing RAMP 301 clinical study to expand the Avmapki Fakzynja Co-Pack indication to include LGSOC without KRAS mutations. Our Phase 3 RAMP 301 trial is ongoing and actively enrolling patients with recurrent LGSOC regardless of KRAS status who have received at one line of platinum-based chemotherapy. This study may serve as both the confirmatory trial for the initial KRAS mutant indication and potentially support an expansion to a broader indication that includes LGSOC without KRAS mutations.
Saurabh: What is your Market access strategy for this therapy? Also do you have any plans to pursue regulatory approvals outside US to tap into international markets?
John: In the United States, about half of patients with LGSOC are commercially insured and 45% are on Medicare. There are very few patients with Medicaid or who are uninsured.
Verastem anticipates that some insured patients, for instance those with employer-sponsored insurance, may face standard “new-to-market-blocks” for the first 6-12 months prior to their insurance plan making a formulary decision. Payers typically provide an appeals process to allow for medical exceptions. These exceptions are commonly granted for new cancer therapies. For Medicare patients, we expect routine coverage to be in place within 90 days as the therapy will be considered part of a protected class under Medicare Part D. Until then, Medicare should cover the therapy through the expedited exceptions process.
Verastem is committed to ensuring that insurance and affordability challenges do not become barriers for patients who need Avmapki Fakzynja Co-Pack. We have developed a comprehensive set of support services through our Verastem Cares Program to help people manage through these standard processes. Our best-in-class programs include:
- A Quick Start program that will allow eligible patients to begin immediate access to Avmapki Fakzynja Co-Pack therapy if there are any coverage delays with the insurer.
- Verastem has implemented a zero-dollar copay card program for commercially insured programs and will establish a patient assistance program that will provide free medicine to eligible patients.
- Verastem will distribute the Avmapki Fakzynja Co-Pack via a limited distribution network with two independent, oncology-focused specialty pharmacies to fulfill prescriptions and support the patient community with their complementary and comprehensive services.
Verastem believes these efforts will remove real and perceived barriers and allow for rapid access to the Avmapki Fakzynja Co-Pack treatment and timely reimbursement.
Saurabh: What sets this combination therapy apart from other existing or previously tested treatments in low-grade ovarian cancer?
John: Patients have been typically treated with surgery and off-label use of chemotherapy, endocrine therapy, and some patients may have received MEK-only inhibitors for treatment of recurrent LGSOC. For most patients, those options provide poor to moderate rates of response and are frequently discontinued due to toxicity and poor tolerability. As a result, many patients cycle from one treatment option to the next and often without achieving a substantial tumor response. The Avmapki Fakzynja Co-Pack is the first therapy approved by FDA specifically for the treatment of patients with KRAS-mutated recurrent LGSOC. Having options is important for patients and options designed specifically for their condition are a hallmark of
Saurabh: How well do you think will be the adaption of the therapy in current treatment guidelines and by practicing clinical oncologists?
John: Verastem believes the current treatment options leave room for significant improvement. Prescribers have told us that having a treatment for recurrent LGSOC that improves various efficacy outcomes, such as overall response rate (ORR) and meaningful disease control rate with favorable tolerability and good access, would be beneficial for patients.
Recognizing the limitations of comparing across different studies, the response rate and the tolerability observed in RAMP 201 are encouraging when considering what has been reported for chemotherapy, endocrine therapy, or MEK-only inhibitors. Based on the results from the full RAMP 201 study, the Company has submitted to NCCN for their consideration the inclusion of avutometinib and defactinib based on the entire patient population enrolled in the RAMP 201 trial.
About the Author:
John Hayslip
Dr. Hayslip joined Verastem Oncology as the Chief Medical Officer in April 2024. Dr. Hayslip has more than 25 years of oncology and research and development experience across industry and academia, most recently serving as the chief medical officer at I-MAB Biopharma. Prior to that, Dr. Hayslip was the vice president of clinical development at Nektar Therapeutics and led clinical development activities for multiple therapies while at AbbVie Oncology. Prior to joining AbbVie Oncology, Dr. Hayslip led numerous cancer research studies while at the University of Kentucky’s Markey Cancer Center.
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