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The last time I mentioned Verastem (NASDAQ:VSTM) was in a prior Seeking Alpha article entitled “Verastem: Potential Accelerated Approval Filing In H1 2024“. In this article I noted that the company was gearing up to initiate the rolling submission of avutometinib and defactinib to the FDA for the treatment of patients with low grade serous ovarian cancer [LGSOC]. It is still on track to do this, with a possible expected commercial launch happening in 2025. However, this isn’t the only catalyst for investors to keep an eye on this year. The company might be able to expand the use of these combination drugs [avutometinib + defactinib] to treat other patient populations. One such catalyst would be an initial data readout from the ongoing RAMP-205 trial, which is using this avutometinib combination plus standard of care [SOC] chemotherapy for the treatment of frontline metastatic pancreatic cancer.
Such initial clinical data is expected to be released in the 1st half of 2024. There is another data readout, which is expected to happen during this same time period, which is what I want to focus in on. It is expected that results from two other ongoing studies, RAMP-203 and RAMP-204, are to also be released in the 1st half of 2024. Both of these involve a combination of avutometinib, adagrasib, sotorasib and defactinib or combination thereof for the treatment of patients with relapsed/refractory non-small cell lung cancer [NSCLC] with the KRAS G12C mutation. Prior data was encouraging in RAMP-203, so much so, that the FDA decided to give avutometinib in combination with LUMAKRAS [sotorasib] FDA Fast Track Designation.
Defactinib Combinations For KRAS Mutant Non-Small Cell Lung Cancer Shaping UP
As I highlighted above, Verastem is gearing up to release results from two phase 1 studies, which are RAMP-203 and RAMP-204, respectively. Both of these studies are advancing different combinations with avutometinib for the treatment of patients with KRAS G12C mutant non-small cell lung cancer. Non-small cell lung cancer [NSCLC] is a type of disorder characterized as the growth of malignant cells on the lung. It is said that about 80% to 85% of lung cancer patients have NSCLC. However, for the case of this company, the goal is to specifically target such patients with the KRAS G12C mutant type. The global non-small cell lung cancer market is expected to reach $38.8 billion by 2030. This is a large global market of course; however, this is going to be slightly reduced because of the focus on only patients with this specific mutation type. It is said that KRAS G12C mutation occurs in approximately 13% of these NSCLC patients. However, the beauty is that defactinib [RAF/MEK] clamp inhibitor can be applied towards the targeting of many aspects of the RAS pathway. Thus, is applying defactinib towards other indications beyond LGSOC and NSCLC, such as: Pancreatic ductal adenocarcinoma, relapsed/refractory colorectal cancer [CRC], breast cancer, melanoma, and a few others. The fact is that about one-third of all human cancers are driven by mutation of RAS. Speaking of pancreatic cancer, this is one of the catalysts I noted above, with a data readout expected in the 1st half of 2024. That is, it is expected that initial safety and efficacy results from the RAMP-205 study, using avutometinib and defactinib in combination with SOC gemcitabine and nap-paclitaxel for the treatment of patients with frontline metastatic pancreatic cancer, will be released then. The two RAMP trials, using defactinib combinations are deployed as follows:
- RAMP-203 – avutometinib + sotorasib [LUMAKRAS] + defactinib for the treatment of patients with KRAS G12C-mutant non-small cell lung cancer who have not been previously treated with a KRAS G12C inhibitor [first-line setting]
- RAMP-204 – avutometinib + adagrasib [KRAZATI] for treatment of patients with G12C mutant non-small cell lung cancer who have been given prior G12C inhibitor therapy and experienced disease progression
The RAMP-204 study data, using avutometinib + adagrasib for treatment of patients with G12C mutant NSCLC that have progressed on prior treatment, is expected to have initial safety and recommended dose data released. However, as I noted directly above, Verastem had already released positive data from the ongoing RAMP-203 study. Such clinical data was presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in October of 2023. As a matter of fact, it was noted that there were some decent responses observed for patients who took the avutometinib + sotorasib combination. Across two patient populations, the following was observed:
- 1 out of 7 patients [14.3%] KRAS G12C inhibitor resistant NSCLC response
- 2 out of 5 patients [40%] KRAS G12C inhibitor naive NSCLC response
Overall the response across both, thus, was 25% or 3 out of 12 patients. The goal is to provide an update on this phase 1/2 RAMP-203 study in the 1st half of 2024. The newly released data is going to include the expansion portion of the trial, which is also treating patients who are KRAS G12C inhibitor naive [first-line] and previously treated patients. This data is actually very good, so much so, that the FDA has decided to give the avutometinib combination Fast Track Designation. This would be with respect to the combination of avutometinib + sotorasib [LUMAKRAS] for the treatment of KRAS G12C patients who had at least received only one prior systemic therapy and who have not yet been treated with another type of KRAS G12C inhibitor therapy.
Financials
According to the 10-Q SEC Filing, Verastem had cash, cash equivalents and investments of $165.7 million as of September 30th 2023. It is expected that the cash on hand that it has will be enough to fund its operations for at least 12 months from the date of the 10-Q SEC Filing, which was filed on November 8th of 2023. The thing is that this biotech does at least have some financial transactions in place to carry it forward. The first of which would be with respect to the Oxford Finance LLC Credit Facility. This entails a multiple of opportunities, such as the receiving of: up to $150 million available in a series of term loans, $40 million term loans outstanding and about $110 million remaining with achievement of pre-defined milestones or at lenders discretion. It had also established a deal with the offloading of COPIKTRA. Based on this, it expects to receive regulatory and commercial milestone payments of up to $95 million, along with other financial transactions expected. Whether it chooses to use the term loans or obtain them based on milestones/lender’s approval remains to be seen. If it is not possible to obtain these payments, then it will likely have to obtain funding by other means.
Risks To Business
There are several risks that investors should be aware of before investing in Verastem Oncology. The first risk to consider would be with respect to initiation of the rolling New Drug Application [NDA] submission of Avutometinib and defactinib for the treatment of patients with recurrent low-grade serous ovarian cancer [LGSOC]. Even upon initiation of such a submission, there is no assurance that the FDA will ultimately accept the entire regulatory application in its entirety. Not only that, but even if it does accept the NDA submission of Avutometinib + defactinib for LGSOC, it will still have to review it for U.S. marketing approval. There is no guarantee that Verastem will receive regulatory approval for these drugs to treat this patient population.
A second risk to consider would be with respect to the advancement of the two ongoing studies known as RAMP-203 and RAMP-204. Both of these trials are exploring the use of avutometinib in combination with other KRAS G12C inhibitors like LUMAKRAS from Amgen and KRAZATI from Bristol-Myers Squibb for the treatment of patients with KRAS G12C mutant non-small cell lung cancer [NSCLC]. Data from both of these studies are expected to be released mid-year and success in either one of these studies could boost shareholder value. On the flip side, there is no guarantee that either of these combinations will produce superior efficacy over their counterparts given alone as monotherapies.
A third risk to consider would be with respect to the advancement of avutometinib and defactinib in combination with standard of care [SOC] gemcitabine and nab-paclitaxel for the treatment of patients with 1st-line metastatic pancreatic cancer. The hope is that adding both of these clinical candidates from Verastem’s pipeline to SOC helps improve overall-survival for these patients. Pancreatic cancer is very difficult to treat and there is no guarantee that positive results from the ongoing RAMP 2025 study will be achieved.
The fourth and final risk to consider would be with respect to the financial position that this biotech is in. That’s because as I stated above, it only has enough cash to fund its operations for at least the next 12 months. It could receive cash with respect to the loan it made, for non-dilutive funding. Except such a loan is under certain milestones being met and then the other portion is only given at lenders discretion. Thus, it is quite possible that it might need to raise cash by using another financial instrument instead.
Conclusion
Verastem has made sufficient progress in advancing the use of its drugs avutometinib + defactinib for the treatment of patients with relapsed/refractory LGSOC. That’s because it is gearing up to submit a rolling NDA submission to the FDA for both of these drugs for the treatment of this patient population. Should the NDA submission go well, then it expects that the combination of these drugs will reach the market for LGSOC in 2025. A good thing about this company is its flexibility in combining either avutometinib or defactinib with a variety of other drugs to treat patients with specific types of cancer. For example, avutometinib is being explored in two different studies with two different types of KRAS G12C inhibitors, which are LUMAKRAS and KRAZATI respectively.
Both of these studies are targeting NSCLC patients with the KRAS G12C tumor mutation. One-third of human cancers are driven by the RAS pathway mutation, thus there might be an opportunity to expand the use of these drugs towards treating other solid tumors with this mutation pathway. Another catalyst to keep an eye on would be the advancement of a phase 2 study using avutometinib + defactinib + gemcitabine/nab-paclitaxel for the treatment of patients with pancreatic cancer. With results from this mid-stage trial expected in the 1st half of 2024, this is another study which might prove the ability for both avutometinib + defactinib to work well in synergy with each other in solid tumors. I believe that Verastem remains a buy rating with all of the upcoming catalysts on the way. This would be with respect to the rolling NDA submission for LGSOC described directly above and the release of results from RAMP-203 and RAMP-204. Both of these catalysts are expected during this period and I believe that investors could benefit from any potential gains made here.
