Verastem, Inc. (NASDAQ:VSTM), focused on discovering and developing drugs to treat cancer by the targeted killing of cancer stem cells, announced positive results from the Phase 1 portion of its Phase 1/1b study of defactinib (VS-6063) in combination with paclitaxel in patients with ovarian cancer that were presented at the 2013 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in Boston. VS-6063, the Company's lead drug candidate, targets cancer stem cells through potent inhibition of focal adhesion kinase (FAK). In addition to these clinical data, several preclinical studies of both VS-6063 and VS-5584, the Company's potent and selective dual mTORC1/2 and PI3K inhibitor, in multiple in vivo and in vitro tumor models were presented.
"The combination of VS-6063 and paclitaxel was well tolerated in the Phase 1 dose escalation and we are actively enrolling patients in the expansion cohort," said Dr. Joanna Horobin, Verastem Chief Medical Officer. "The ability to combine these drugs opens up a broad range of potential therapeutic options for clinical testing, as paclitaxel is one of the most widely used chemotherapeutics available for clinicians treating cancer. In addition, we are encouraged by the early signs of clinical activity, including a complete response in one of the patients, from the dose escalation phase."
"The six VS-6063 and VS-5584 posters presented at this meeting expand our understanding of the activity and underlying biological mechanisms of these promising compounds," said Dr. Jonathan Pachter, Verastem Head of Research. "These include data illustrating VS-6063's activity with paclitaxel in both clinical and preclinical studies, which may have implications across paclitaxel-treated cancers, desirable effects on the closely related FAK and PYK2 kinases, and mechanistic insights into the relationship between loss of the merlin tumor suppressor and FAK inhibitor sensitivity. These results also highlight the activity of these compounds in multiple models of difficult-to-treat tumor types, including ovarian cancer, mesothelioma and breast cancer."
"These presentations build upon a growing body of scientific evidence that VS-6063 and VS-5584 are potent inhibitors of cancer stem cells and provide further support for a robust clinical development program for each," said Robert Forrester, Verastem President and Chief Executive Officer. "Given the tremendous unmet medical need in oncology, and the great potential for extending therapeutic response by targeting cancer stem cells, it remains our urgent mission to advance these novel therapies for patients in need."
A summary of the data presented by Verastem at the conference is below:
Title: Phase 1/1b Study of the FAK Inhibitor Defactinib (VS-6063) in Combination with Weekly Paclitaxel for Advanced Ovarian Cancer
Abstract #: 937
Date and Time: Sunday, Oct 20, 2013 12:30 PM - 7:30 PM
Session: Poster Session A; Clinical Trials 1
Location: Exhibit Hall C-D
Summary: Results from the Phase 1 dose escalation portion of the study were presented. Six patients with advanced or refractory ovarian cancer, all of whom had prior taxane exposure and were platinum resistant, were enrolled. VS-6063 was orally administered continuously at a dose of 200mg BID in the first cohort and was escalated to 400mg BID in the second cohort. The standard dose of paclitaxel 80mg/m2 was administered on days 1, 8 and 15, every 28 days. Combination therapy was well tolerated with no dose limiting toxicities observed. There was no apparent increase in the severity and incidence of paclitaxel related toxicities and VS-6063 did not alter paclitaxel exposure. Based on these results, the recommended Phase 2 dose of VS-6063 was determined to be 400mg BID in combination with weekly paclitaxel at 80mg/m2.
Two patients demonstrated significant decreases, or normalization, of CA-125, a marker that becomes elevated with disease progression in ovarian cancer. One patient in the VS-6063 200mg BID cohort experienced an ongoing complete response as confirmed by Response Evaluation Criteria in Solid Tumors (RECIST) with repeated radiologic scans and a second patient in the VS-6063 400mg BID cohort continues to experience prolonged stabilization of her disease. Patient recruitment remains ongoing in the expansion Phase 1b open-label, multicenter portion of the study, where Verastem expects to enroll a total of approximately 15 patients at three U.S. locations.
A copy of the poster presentation is available here.
Title: Merlin Loss as a Biomarker for Defactinib (VS-6063) Sensitivity: High Frequency in Malignant Mesothelioma Tumors
Abstract #: 848
Date and Time: Sunday, Oct 20, 2013 12:30 PM - 7:30 PM
Session ID: Poster Session A; Biomarkers
Location: Exhibit Hall C-D
Summary: The Neurofibromatosis 2 (NF2) tumor suppressor gene that encodes the protein merlin is disrupted in approximately 50% of MPM patients, and low merlin is correlated with increased sensitivity to the FAK inhibitor, VS-6063. Various methods for measuring the presence or absence of merlin and NF2 were evaluated using MPM patient-derived xenograft tumor models. This study utilized immunohistochemistry (IHC) and Fluorescence In situ Hybridization (FISH) to correlate the measurement of merlin and NF2, respectively, and demonstrated that merlin is a predictive biomarker for NF2. These data support the clinical development of a merlin IHC test for the evaluation of NF2-mutated MPM, and further support the premise that merlin is a predictive biomarker for responsiveness to VS-6063.
A copy of the poster presentation is available here.
Title: Defactinib (VS-6063) Targets Cancer Stem Cells Directly and Through Inhibition of Tumor-Associated Macrophages and Cytokine Production
Abstract #: 863
Date and Time: Monday, Oct 21, 2013 12:30 PM - 7:30 PM
Session: Poster Session B; Therapeutic Agents: Small Molecule Kinase Inhibitors 2
Location: Exhibit Hall C-D
Summary: In addition to being a potent FAK inhibitor, study findings have demonstrated that VS-6063 also inhibits the activity of PYK2, a closely related protein kinase and only other member of the FAK kinase family. Several lines of evidence suggest that dual targeting of FAK and PYK2 should confer greater antitumor efficacy than inhibition of either target alone. Based on the observation of reduced macrophage infiltration in PYK2 knockout mice, the effects of PYK2 inhibition on tumor-associated macrophages (TAMs), which have been correlated with poor prognosis in multiple cancer types, including mesothelioma and breast cancer, were investigated.
Study results demonstrated that VS-6063 inhibited production of specific cytokines that are responsible for increasing cancer stem cells in mesothelioma and breast cancer in a dose dependent manner, whereas a FAK-only reference inhibitor had no effect on these cytokines. Results also demonstrated that VS-6063 substantially reduced the number of TAMs in cancer xenograft models. The dual inhibition of FAK and PYK2 by VS-6063 effectively decreases both the presence of TAMs in tumors and the ability of TAMs to release cytokines that stimulate CSC proliferation and survival, and may therefore provide the opportunity for a more durable clinical response than inhibition of FAK alone.
A copy of the poster presentation is available here.
Title: Dual mTORC1/2 and PI3K Inhibitor VS-5584 Preferentially Targets Cancer Stem Cells
Abstract #: 889
Date and Time: Monday, Oct 21, 2013 12:30 PM - 7:30 PM
Session ID: Poster Session B; Cancer Stem Cells 2
Location: Exhibit Hall C-D
Summary: VS-5584 is a highly potent dual inhibitor of mTORC1/2 and PI3K that preferentially targets cancer stem cells in vitro and in vivo. VS-5584 has equipotency against all four human Class I PI3K isoforms and the mTOR kinase. Study data demonstrated that VS-5584 decreased cancer stem cells across multiple cell lines including triple negative breast cancer cells (SUM159), while paclitaxel increased the proportion of cancer stem cells. In small cell lung cancer models (H69), VS-5584 effectively eliminated the cancer stem cell population, with a corresponding substantial delay in tumor regrowth following cisplatin treatment. Similarly, ex vivo treatment with VS-5584 preferentially reduced cancer stem cells in primary tumor specimens from patients with breast cancer or ovarian cancer. Further, oral dosing with VS-5584 was found to substantially reduce cancer stem cells in vivo in the MDA-MB-231 triple negative and MCF-7 ER+ breast cancer xenograft models.
A copy of the poster presentation is available here.
Title: Malignant Mesothelioma Lacking Merlin Shows Enhanced Sensitivity to the FAK Inhibitor Defactinib (VS-6063): Elucidation of the Merlin-FAK Relationship
Abstract #: 765
Date and Time: Tuesday, Oct 22, 2013 12:30 PM - 7:30 PM
Session ID: Poster Session C; Therapeutic Agents: Small Molecule Kinase Inhibitors 3
Location: Exhibit Hall C-D
Summary: Approximately 50% of malignant pleural mesothelioma (MPM) patients exhibit a gene mutation that results in the lack of expression of functional merlin protein. Merlin loss is a critical driver of MPM tumorigenesis and is related, at least in part, to up-regulation of FAK activity. Data from this preclinical study demonstrated that merlin negative cells were especially vulnerable to FAK inhibition. Study data also demonstrated that MPM cell lines lacking expression of merlin were found to be more sensitive to VS-6063 than MPM cell lines with wild-type merlin expression. Oral dosing of VS-6063 induced significant tumor growth inhibition in a merlin-negative MPM model. When used in combination with pemetrexed or cisplatin, VS-6063 blocked the enrichment of cancer stem cells by these chemotherapeutic agents. Taken together, these data support the clinical development of VS-6063 in MPM patients (stratified by merlin status) with a confirmed response following first line platinum/pemetrexed therapy.
A copy of the poster presentation is available here.
Title: FAK Inhibitor Defactinib (VS-6063) Enhances the Efficacy of Paclitaxel and Preferentially Targets Ovarian Cancer Stem Cells
Abstract #: 899
Date and Time: Tuesday, Oct 22, 2013 12:30 PM - 7:30 PM
Session ID: Poster Session C; Therapeutic Agents: Small Molecule Kinase Inhibitors 3
Location: Exhibit Hall C-D
Summary: Amplification and overexpression of FAK has been observed in aggressive human cancers, including ovarian and breast cancers, and is required for the proliferation and survival of cancer stem cells. In this in vitro study, results demonstrated that VS-6063, a potent and orally active FAK inhibitor, synergistically enhanced the efficacy of paclitaxel in vitro in models of ovarian cancer. In addition, VS-6063 preferentially reduced cancer stem cells and attenuated the induction of cancer stem cells by either carboplatin or paclitaxel.
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