Pipeline

We’re Recognizing Potential and Urgently Delivering on New Possibilities

VS-6766

Dual RAF/MEK Inhibitor

VS-6766 is a dual RAF/MEK inhibitor that offers more complete vertical blockade of the RAS pathway in a single molecule and is thought to be the only vertical blocker of the RAS pathway in clinical development.

Defactinib (VS-6063)

Selective FAK Inhibitor

Defactinib (VS-6063) is a best-in-class selective FAK inhibitor that has been studied as a monotherapy and in combination in patients with solid tumors.

VS-6766 + Defactinib

Trial Name/Tumor Type Preclinical Phase 1 Phase 2 Phase 3 Market

RAMP-201

KRAS mt/wt LGSOC

Phase 2

RAMP-202

KRAS mt G12V NSCLC

Phase 2

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Advanced LGSOC

Phase 1

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Advanced KRAS mt NSCLC (all variants)

Phase 1

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Advanced CRC

Phase 1

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Advanced KRAS-G12V mt NSCLC

Phase 1

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Advanced pancreatic cancer

Phase 1

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Advanced KRAS mt endometrioid cancer

Phase 1

Metastatic uveal melanoma

Phase 2

VS-6766 + Other Combinations

Trial Name/Tumor Type Preclinical Phase 1 Phase 2 Phase 3 Market

KRAS mt NSCLC

VS-6766 + everolimus (mTORi) Phase 2

These studies are investigating treatments or outcomes that have not received approval from a health authority. We are working diligently to demonstrate the safety and efficacy of these products, but there is no guarantee that the outcome of these studies will result in approval. We invite you to review our expanded access policy.

Investigator Sponsored Trials (IST)

We believe in the power of collaboration to help us push forward with new and promising cancer treatments. Our Verastem Oncology Investigator Sponsored Trial (IST) program strives to advance medical and scientific knowledge for our product candidates and disease states of interest. We welcome partnerships with researchers and sponsoring institutions that build on this mission.

Investigator Sponsored Trial Form

For additional details regarding our IST program or to submit a research request, please download, complete and submit the form below via email to verastem-IST@verastem.com.

 

Research Collaborations

Verastem Oncology also accepts proposals for preclinical research collaborations. For more information, please reach out to us at research@verastem.com.

RAS Pathway: Examining the Most Frequently Mutated Oncogene in Human Cancers

Almost a third of all cancers in patients are associated with mutations of the RAS family of genes, which includes KRAS, NRAS, and HRAS. There are other oncogenes, including EGFR and BRAF, that also activate the RAS pathway—meaning an even higher percentage of cancers depend on this pathway for growth and survival. Patients with a RAS-mutated cancer tend to experience worse outcomes and a higher disease burden than those without RAS pathway mutations. Watch the video to see how customized combinations of VS-6766, a unique dual RAF/MEK inhibitor, including a combination with defactinib, a selective FAK inhibitor, have the potential to greatly expand the number of effective treatments for cancer patients who have limited options today.

Blocking the RAS Pathway Presents Challenges Due to Multiple Resistance Mechanisms

Cancer has a strong affinity for the RAS pathway and reacts to the blocking of any single target by either reactivating the RAS pathway elsewhere or activating parallel pathways to survive. For example, MEK inhibitors paradoxically induce MEK phosphorylation (pMEK) and RAS signaling by relieving ERK-dependent feedback inhibition of RAF. MEK inhibitors also cause compensatory activation of phosphorylated FAK (pFAK), and BRAF inhibition also induces compensatory activation of pFAK. Single-target therapies (eg, MEK inhibitors) are associated with resistance and may not be the best avenue to slowing tumor growth—and finding tolerable combination regimens with MEK inhibitors has been challenging. There has been only modest progress and a limited number of approved therapies. Novel therapies and combinations are urgently needed to deliver on the promise of better outcomes for patients.

VS-6766 Is a Novel, Dual RAF/MEK Inhibitor That May Achieve Vertical Blockade of the RAS Pathway

VS-6766 is thought to be the only dual vertical blocker of the RAS pathway in clinical development. VS-6766 blocks both RAF and MEK in a single molecule, suggesting it may help overcome resistance and ultimately block against tumor growth and proliferation. By inhibiting RAF phosphorylation of MEK, VS-6766 has the advantage of not inducing pMEK, and by inhibiting ERK signaling more completely, preliminary research indicates VS-6766 may confer enhanced therapeutic activity. When used alone, preliminary data show that VS-6766 demonstrates activity in refractory KRAS-mutant NSCLC adenocarcinoma and across RAS pathway mutations in refractory gynecologic cancers.

 

VS-6766 offers a novel intermittent dosing schedule and convenient oral regimen with the possibility of better tolerability than currently available MEK-only inhibitors. These characteristics make VS-6766 an optimal partner for combination therapy with agents from multiple target classes that may deliver better patient outcomes where they are needed most.

VS-6766 dual RAF/MEK inhibitor offers more complete blockade of RAS pathway

As a Parallel Pathway Inhibitor, Defactinib Has Demonstrated Synergy With VS-6766

Defactinib selective focal adhesion kinase or FAK inhibitor curbs parallel pathway signaling - has shown synergy with VS-6766

Cancer’s strong affinity for the RAS pathway means that it maintains its growth and survival in response to vertical blocking, by either reactivating the RAS pathway elsewhere or activating parallel pathways (eg, PI3K/AKT/mTOR, FAK, RhoA, YAP). Because of this, novel combinations may be required to achieve the deepest and most durable response.

Defactinib (VS-6063) is a selective focal adhesion kinase (FAK) inhibitor that inhibits parallel pathway signaling and has demonstrated synergy with VS-6766. In clinical observations, VS-6766 induced elevated pFAK (Y397) as a potential resistance mechanism in the majority of patients, while the combination of VS-6766 and defactinib reduced this compensatory pFAK signal.

 

Exploring the Potential of Defactinib

Defactinib has been assessed as both a monotherapy and in combination with patients with solid tumors. As a monotherapy, defactinib demonstrated clinical activity in heavily pre-treated KRAS-mutant NSCLC and in other advanced non-hematologic malignancies. In both monotherapy and in combination with VS-6766 (RAF/MEK inhibitor), PD-1 inhibitors, and chemotherapy, defactinib showed a manageable safety profile. Because screens for synergy with defactinib identified MEK inhibitors and VS-6766 as potential combination partners, Verastem Oncology is moving forward with clinical development of defactinib in combination with VS-6766 and other medications.

The Clinical Development Strategy for VS-6766 Turns Potential into Possible New Treatments

Defactinib selective focal adhesion kinase or FAK inhibitor curbs parallel pathway signaling - has shown synergy with VS-6766

Blocking a single node in the RAS pathway may not provide the best response. For better outcomes, novel combination therapies that address both vertical blockade and parallel inhibition may be needed to achieve the deepest and most durable response. The combination of VS-6766 and defactinib provides RAF/MEK vertical blockade and FAK parallel inhibition to overcome key resistance mechanisms.

Combining VS-6766 with Other Agents Gives It the Potential to Become a Backbone of Therapy

Strong preclinical synergy data have been demonstrated with vertical blockers, such as inhibitors of KRAS G12C, EGFR, SHP2, SOS1, and ERK1/2, and parallel pathway inhibitors of FAK, CDK4/6, and PI3K/AKT/mTOR, suggesting a broad range of possible combination partners. VS-6766 also offers favorable tolerability with an established twice-weekly dosing regimen, which may help patients stay on therapy longer.

 

By better controlling the RAS signaling network, customized RAS-targeted treatment combinations with VS-6766 have the potential to greatly expand the number of effective treatment options for specific subsets of cancer patients who have limited options today. This can be life-changing.