Verastem, Inc. (NASDAQ: VSTM) is focused on developing cancer treatments targeting the RAS/MAPK pathway. The company's lead therapy combines Avutometinib and Defactinib, offering complementary mechanisms of action to disrupt malignant cell growth and metastasis. The primary indication is for recurrent low-grade serous ovarian cancer (LGSOC), with a rolling NDA submission expected to be finalized by the second half of 2024. Verastem is also investigating potential applications in metastatic pancreatic cancer and mKRAS G12C non-small cell lung cancer (NSCLC).
Avutometinib and Defactinib: Targeting Cancer Pathways
Verastem's pipeline is led by the combination of Avutometinib and Defactinib for recurrent LGSOC. Avutometinib targets the RAS/MAPK pathway, while Defactinib inhibits focal adhesion kinase (FAK), which is linked to cancer cell metastasis and immune evasion. This dual mechanism aims to provide a more comprehensive anti-cancer treatment.
The RAMP 201 Phase 2 registration-directed trial is expected to provide mature data to finalize the rolling NDA in 2H2024. Additionally, the RAMP 301 Phase 3 trial is actively enrolling patients.
Expanding Applications: NSCLC and Pancreatic Cancer
The combination of Avutometinib and Defactinib, with or without KRAS G12C inhibitors, is in Phase 2 development for KRAS G12C mutant non-small cell lung cancer (mKRAS G12C NSCLC). This approach aims to overcome resistance to KRAS G12C inhibitors.
Verastem's RAMP 203 trial is a collaboration with Amgen, while RAMP 204 involves a partnership with Bristol-Myers Squibb (formerly Mirati Therapeutics) to investigate Avutometinib in combination with Adagrasib, a KRAS G12C inhibitor. Initial interim data from RAMP 204 is expected in 2H2024.
The FDA has granted Fast Track Designation for the combination of Avutometinib and Sotorasib for patients with mKRAS G12C NSCLC who have received prior systemic treatment and were not previously administered a KRAS G12C inhibitor.
Clinical Trial Data and Safety Profile
Interim results from the RAMP 201 trial showed an overall response rate (ORR) of 45%, with an ORR of 60% in KRAS-mutated patients. Furthermore, 86% of patients showed tumor regression. For context, current LGSOC treatments typically have ORRs ranging from 0% to 26%.
While 19 grade 3 or higher treatment-emergent adverse events (TEAEs) were reported in 12 patients, including nausea, diarrhea, and dermatitis, the discontinuation rate was relatively low at 9%.
Financial Position and Market Opportunity
Verastem's investor presentation estimates the incident market opportunity for LGSOC at $270 million for KRAS mutant and $300 million for KRAS wild-type, with a prevalent TAM as high as $1.7 billion for KRAS mutant and $1.1 billion for KRAS wild-type.
As of Q2 2024, Verastem had $83.4 million in cash and equivalents against $40.8 million in financial debt. Pro forma, the cash balance is $144.5 million, including proceeds from a capital raise and a milestone payment from COPIKTRA sales. The company's estimated yearly cash burn is $110.4 million, providing a cash runway through the anticipated FDA approval decision by 1H2025.
Investment Considerations
Verastem's combination therapy represents a promising late-stage treatment for LGSOC, a condition with significant unmet needs. FDA approval would be a major milestone for the company, potentially unlocking substantial market opportunities. However, regulatory delays or rejection could lead to significant shareholder losses.
