5 Key Conclusions: VS-6766 as therapy for RAS

Single agent VS-6766 or VS-6766 plus defactinib in KRAS-mutant non-small-cell lung cancer: the RAMP-202 phase II trial

VS-6766 and Defactinib Combination Trial

In ~30% of all human cancerous cells, 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 kinase activity, 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 defactinib is being tested in patients with low grade serous ovarian cancer, 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. 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.

What Is VS-6766 and What Does it Mean for Non-Small Cell Lung Cancer Cells?

This is a discussion about a breakthrough therapy designation clinical trial involving two drugs. So, the Dual RAF/MEK Inhibitors, which is a combination Rapidly Accelerated Fibrosarcoma (RAF) inhibitor and then it’s being used in combination with a drug called Defactinib, which is a FAK inhibitor.

What is 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 an Orphan Drug status for defactinib for ovarian cancer. The effect of a selective FAK inhibitor 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.

Why was this study done in lung cancer?

I had been looking through the abstracts from AACR earlier in 2020, and I came across this early phase clinical trial with this combination showing fairly dramatic responses in patients with ovarian cancer, but there seemed to be a signal suggesting that many of the patients who were responding had a specific KRAS mutation called G12V.

I’m a thoracic oncologist and G12V is the second most common KRAS mutation in lung cancer. We’ve seen over the last couple of years that a different class of drug called G12C inhibitors has shown activity so I was pretty excited. I was thinking maybe this is going to be treatment options for this other thing. I’d worked G12C inhibitors before so, I didn’t wait for them to contact me. I reached out to them and said, “Hey guys, have you thought about developing this in lung cancer?” And that’s how the Verastem oncology’s strategy began.

The role of KRAS status in this trial.

One of the things is we have started to understand that KRAS, which is an elephant in the room in lung cancer, is the single most common class of mutations in lung cancer cells, but there have not been drugs for it until recently. KRAS has become actionable, not by having one drug for everybody, but by recognizing that there’s heterogeneity, even in KRAS, so KRAS G12C inhibitors have shown activity with response rates ranging from 30 to 50%, KRS and G12V do not have a magic bullet yet and so the idea that there may be a drug or combination of drugs that’s specifically active in G12V was very exciting for me because these patients have an unmet need. They represent somewhere between six and 7% of lung cancer cases. That’s more common. and rearrange lung cancer, for example. So if we could certainly add to that long list of actionable molecular subtypes of lung cancer, that really moves the field.

How well tolerated in the VS-6766 Combo in lung cancer?

What we really want to find out from vs-6766 in combination is obviously how well tolerated it is in our lung cancer patient population. But importantly, what we want to do is show that it’s active that patients with a G12V or some of the other KRAS mutations, because they’re going to be explored too, will actually have their cancer shrink. I’ll take prolonged stabilization. It’s better to have cancer. That’s not moving one, that’s moving, but we’d really like to see potential clinical value. And that’s the primary endpoint of the trial, the response. One of the things about lung cancer is it’s an incredibly common disease and yet their participation in clinical trials has traditionally been rather poor nationally in the United States. Only about 2% of lung cancer patients go on clinical trials in some of the. Better National Cancer Institute designated cancer centers.

It’s maybe about 20% in our center. It’s been about 40% for many years and that’s not because we’re in the business of pushing clinical oncology trials on patients to try and increase treatment options. It’s because we try and use our skills to try and pick the winners early in the drug development process and use the clinical trials as a means of getting our patients access to the best treatments. So, I think when you go into them and say, This isn’t just some pet science project, but you say, We really think there’s potential for a breakthrough therapy designation. This might work. I think patients are very keen to go on studies they want to be part of breakthrough therapy designation. I think with any study, the thing that people want to know when they’re thinking about sending their patients in is, what is the treatment schedule? How much of an inconvenience is it going to be? Especially during this time of COVID, fewer visits and shorter visits become important.

Risk Factors: What Are the Common Side Effects of These Trials?

The second thing is, what’s the price adverse events are we going to be paying? What are the risk factors? So, we know some of the side effects from this drug and drug combination include a rash and can include nausea, but we can modify that by being very proactive about managing these symptoms and side effects from the get go. And then finally, and this is the one that everybody really wants to know, is it going to work now? If we 100% knew, we wouldn’t need to do the study, but we have preliminary or interim data evidence in various tumor cell types that it might work. And so, we’re really going to be looking very hard to see if we can replicate the same signal transducer in lung cancer.

In non-small cell lung cancer, we already have, amazingly enough, something like seven or eight different molecularly specific subtypes of non-small cell lung cancer that have a targeted therapy that you would prioritize over standard chemotherapy or radiotherapy or immunotherapy. What this study holds the promise of is adding KRAS G12V to that list and that’s a huge, and indeed I would say transformative advance if you are a patient who has that molecular abnormality at the moment, there is nothing specifically directed against G12V. We know from the G12C story, that there’s a very interesting picture emerging. Some people respond beautifully, some people don’t respond at all. So even amongst G12C there’s heterogeneity and some people. Briefly and then progress again, suggesting there’s a feedback loop or required resistance.

The drug, the combination RAFT what they calling vertical inhibition. Two points in that inhibit critical signaling pathways, we hope, will have activity against G12V. The theory is supposed to work against one of the feedback loops. So we’re hoping that either one or the combination of these two drugs together is really going to get G12V into the public consciousness and is going to say, “This is something which is actionable and it’s not just going to be a flash in the pan.” It’s going to actually cause shrinkage and have a durable duration of benefit.

What is low-grade serous ovarian cancer?

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

Inclusion Criteria for VS-6766:

• LGSOC (Low-grade serous ovarian carcinoma) has been established histologically (ovarian, peritoneal)

• Part KRAS mutation, KRAS wild type

• LGSOC (Low-grade serous ovarian carcinoma) progression or recurrence following at least one previous systemic therapy for metastatic illness.

• Measurable sickness as defined by RECIST 1.1

• A performance status for the Eastern Cooperative Group (ECOG) 1.

• Organ function that is adequate

• Adequate recovery from previous therapies’ toxicity

• Agreement to adopt a very effective contraceptive technique

Exclusion Criteria for VS-6766:

• Within 4 weeks of the first dosage of study medication, systemic anti-cancer therapy was initiated.

• High-grade serous ovarian cancer or another histology coexisting

• Prior malignancy history with recurrence within 3 years of enrollment

• Major surgery in four weeks

• Symptomatic brain metastases that necessitate the use of steroids or other treatments

• SARS-Cov2 infection (clinical signs) 28 days before starting study therapy

• Grade 4 toxicity was attributed to the MEK inhibitor in subjects who had already been exposed to MEK.

• Active skin disorder requiring systemic therapy in the last year

• Rhabdomyolysis history

• Ocular diseases that occur concurrently

• Concurrent heart disease or severe pulmonary obstructive disease

• Patients who are unable to swallow oral drugs

Author Credentials and Affliations

D. Ross Camidge, M.D., Ph.D. from CU Anschutz Medical Campus, with final thoughts from Andrew Koustenis from Verastem Oncology, speaks about the Verastem Oncology Initiates Phase 2 Registration-Directed Trial of VS-6766 in combination with Defactinib (which is a FAK inhibitor) in Recurrent Low Grade Serous Ovarian Cancer.

From Verastem Oncology Press Release

Verastem, Inc. (also known as Verastem Oncology), a development stage biopharmaceutical company dedicated to advancing new medicines for cancer patients, today announced the start of the recommended Phase 2 registration-directed clinical trial in patients with recurrent low grade serous ovarian cancer (in gynaecological oncological trial groups) of VS-6766, its RAF/MEK inhibitors, 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 preliminary efficacy and safety of VS-6766 alone and in combination with defactinib in patients with recurrent LGSOC 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 successful 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.

My name is Andrew Koustenis, and I am the global program leader for the clinical trial at Verastem Oncology. We at Verastem Oncology’s views are very excited to be following the signal that we saw in a frame study with the initiation of our phase 2 registration directed trial for those patients with current KRAS mutated non-small cell lung cancer, with a particular focus on the G12V variant. This study, which we now call the RAMP202 study, RAMP standing for RATH and MET program, is an opportunity for us to evaluate pharmacologic blockade, specifically vertical pharmacologic blockade of both RATH and MET inhibition. We hope this trial will improve outcomes for patients with recurrent non-small cell lung cancer with S KRAS mutation, but we believe they have a high unmet medical need. We have initiated this trial recently in the United States and will be doing so very shortly in Europe. And I also would like to thank Dr. Mage and his colleagues at the University of Colorado for collaborating and partnering with Verastem Oncology for the initiation and conduct of this important study.

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 trials. The first, a Phase 1 study published in The Lancet Oncology, showed that VS6766 could be successful against a variety of types of KRAS-mutated tumors, including lung and gynecological cancers. The second, a Phase 1, Phase 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 a selective FAK inhibitor could be advantageous for KRAS patients.

Professor Udai Banerji was quoted, "Cancers caused by the commonly mutated KRAS gene continue to represent an important area of unmet need. When we develop cancer drugs, we often have to walk a narrow path between on one hand effectively shrinking the tumour and on the other hand managing side effects. We need to think out of the box and use innovative intermittent schedules as a way of delivering effective and tolerable drugs.” Professor Udai Banerji also stated, "Our study shows that this new drug is safe for patients taken twice a week, and we have seen multiple promising responses in patients with KRAS-mutated tumours. We are conducting further studies combining this drug with other novel treatments, and hope we can open the door to new options for patients with a hard-to-treat group of cancers."

References

1. Professor Udai Banerji – New drug for difficult-to-drug cancer mutation could be key treatment for a range of cancers, including low grade serous ovarian cancer. ICR The Institute of Cancer Research, archive, November, 2020