Udai Banerji, MD @udai_banerji @IRC_London @royalmarsden @VerastemOncolog #KRASMutations #cancer #research VS-6766, a unique inhibitor of the RAF/MEK signaling pathway for patients with K...

Udai Banerji, MD @udai_banerji @IRC_London @royalmarsden @VerastemOncolog #KRASMutations #cancer #research VS-6766, a unique inhibitor of the RAF/MEK signaling pathway for patients with K...

User Photo
Cancer-News

3 months
202 Views
Share
Want to watch this again later?
Sign in to add this video to a playlist. Login
0 0
Category:
Description:

Udai Banerji, MD, MBBS, DNB, Ph.D., FRCP from The Institute of Cancer Research and The Royal Marsden and Jon Pachter, Chief Scientific Officer at Verastem Oncology speak on Lancet Oncology on Verastem’s VS-6766 (formerly CH5126766), a unique inhibitor of the RAF/MEK signaling pathway for patients with KRAS mutant tumors including non-small cell lung cancer (NSCLC) and separately, low-grade serous ovarian cancer (LGSOC)


BOSTON—(COMPANY WIRE)—Sep. 16, 2020--Verastem, Inc. (Nasdaq: VSTM) (also known as Verastem Oncology), a biopharmaceutical company committed to advancing new medicines for cancer-fighting patients, today announced updated results from the ongoing Phase 1/2 FRAME investigator-initiated study evaluating its RAF / MEK inhibitor VS-6766 in combination with its FAK inhibitor defactinib, which showed robust response rates, Dr. Udai Banerji from the Institute of Cancer Research and The Royal Marsden at the 2nd Annual RAS-Targeted Drug Development Summit will present these data in a virtual oral presentation today.

The Food and Drug Administration ( FDA) recently met with Verastem, and the FDA supports the Company's adaptive study design for the proposed Phase 2 registration-directed trials evaluating VS-6766 and defactinib in patients with recurrent LGSOC. For both recurrent LGSOC and KRAS mutant non-small cell lung cancer, Verastem plans to initiate registration-directed clinical trials by the end of 2020. Verastem plans to send New Drug Applications to the FDA seeking accelerated approval for the VS-6766 / defactinib combination in both LGSOC and KRAS mutant NSCLC, anticipating a positive outcome from these registration-directed trials.

Modified Step 1/2 FRAME analysis Findings for LGSOC patients

The overall response rate (ORR) was 41 percent (7 of 17 patients) among the patients with LGSOC (n=17), all partial responses (PRs). The ORR was 56 percent (5 of 9 patients) among patients with KRAS-G12 mutant LGSOC (n=9). Of the seven responding patients, five had received one or more previous MEK inhibitors. The ORR was 50 percent (3 of 6 patients) in patients with KRAS mutant LGSOC receiving the prescribed Phase 2 dosing (RP2D) regimen. The LGSOC cohort of the FRAME trial remains ongoing, with 53% (9 out of 17 patients) still under study as of the 17 August 2020 data cut-off date, with three patients receiving treatment for a period of two years or more.

Rash (4 percent) and elevated creatine kinase (4 percent) were the most common Grade 3 treatment-related adverse effects (TEAEs) reported in the prescribed Phase 2 dosing regimen. No patients were discontinued because of TEAEs from the FRAME study.

In patients with KRAS mutant LGSOC, the novel, sporadic, combination dosing schedule used in the FRAME study continues to show promising clinical activity, even in patients who had previously improved after treatment with the MEK inhibitor.

Preclinical findings from studies examining the combination of VS-6766 and Defactinib with G12C inhibitors

In order to improve their inhibition of the ERK signaling pathway, KRAS-G12C inhibitors can benefit from new combination approaches. VS-6766 demonstrated synergy with KRAS-G12C inhibitors in reducing cancer cell viability across a panel of KRAS-G12C mutant NSCLC and colorectal cancer (CRC) cell lines in the preclinical results that will be presented today at the conference. This combination improved cellular anti-cancer activity associated with deeper and more stable ERK signaling pathway inhibition compared to G12C inhibition alone. The RAF / MEK dual inhibitor VS-6766 was more successful than trametinib in KRAS-G12C mutant NSCLC models in mice when compared to equivalent dose levels, both alone and in combination with a G12C inhibitor. The combination of G12C inhibitor with VS-6766 and FAK inhibitor caused tumor regressions in all mice of ~30 percent in the KRAS-G12C NSCLC models studied.

About the analysis of Step 1/2 FRAME

The FRAME study is an open-label, investigator-initiated study in patients with KRAS mutant solid tumors including LGSOC, non-small cell lung cancer ( NSCLC), and colorectal cancer (CRC) to evaluate the safety, dose-response, and preliminary efficacy of the VS-6766 / defactinib combination. Dr. Banerji is leading the FRAME analysis and it is being performed in the United Kingdom. In this study, a twice-weekly dose-escalation schedule was used to administer VS-6766 and was administered three out of every four weeks. Defactinib was given on a twice-daily escalation schedule of doses, including three out of every four weeks. Three cohorts were tested for dose levels: cohort 1 (VS-6766 3.2 mg, defactinib 200 mg); cohort 2a (VS-6766 4 mg, defactinib 200 mg); and cohort 2b (VS-6766 3.2 mg, defactinib 400 mg). Phase 2 prescribed dose was calculated to be 3.2 mg VS-6766, 200 mg defactinib. New cohorts for pancreatic cancer, KRAS mutant endometrial cancer, and KRAS-G12V mutant NSCLC are now being extended in the FRAME research.
About VS-6766-666

A special inhibitor of the RAF / MEK signaling pathway is VS-6766 (formerly known as CH5126766, CKI27, and RO5126766). VS-6766 blocks both MEK kinase activity and the ability of RAF to phosphorylate MEK, in contrast to other MEK inhibitors in development. This unusual mechanism allows MEK signaling to be blocked by VS-6766 without the compensatory activation of MEK, which seems to limit the effectiveness of other inhibitors.

About Defactinib and 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 the Orphan Drug status for defactinib for ovarian cancer and mesothelioma. The effect of FAK inhibition on enhancing immune response by decreasing 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.1,2

About the Combination of VS-6766 / Defactinib

In ~30 percent of all human cancers, RAS mutant tumors are present, have traditionally posed a challenging treatment obstacle, and are frequently associated with a significantly worse prognosis. Resistance to single agents, the discovery of tolerable combination regimens with MEK inhibitors, and new developmental RAS inhibitors targeting only a subset of all RAS mutated cancers are the difficulties associated with finding new therapeutic options for these types of cancers.

The combination of VS-6766 and defactinib in patients with KRAS mt tumors has been shown to be clinically successful. The combination of VS-6766 and defactinib is being tested in patients with LGSOC, KRASmt NSCLC, and colorectal cancer (CRC) in an ongoing investigator-initiated Phase 1/2 FRAME trial. At the 2nd Annual RAS-Targeted Drug Development Summit in September 2020, revised data from this study demonstrated 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 role of VS-6766 and defactinib in KRAS-G12V NSCLC based on an observation of higher response rates seen in NSCLC patients with KRAS-G12V mutations in the study. The FRAME study was extended to include new cohorts in pancreatic cancer, KRASmt endometrial cancer, and KRAS-G12V NSCLC in August 2020.

Up Next Autoplay
>