06 June 2022 | Monday | News
Image Source : Public Domain
Merck, a leading science and technology company, today provided an update on the progress of the company’s innovative oncology development pipeline focused on DNA damage biology. With clinical programs designed to further advance standards of care in core tumors and assess the potential of novel mechanisms of action, including an industry-leading portfolio of DNA Damage Response inhibitors (DDRi), the company continues to build its focused leadership in the oncology space.
“Within our clinical-stage pipeline and our discovery programs, we have the opportunity to unlock and address DNA biology and apply a diversity of mechanisms to the treatment of multiple cancers,” said Victoria Zazulina, M.D., Head of Development Unit Oncology for the Healthcare business of Merck. “We have advanced our DDRi portfolio in a number of settings, as well as agents like xevinapant that could enhance cancer cell death by synergizing with other treatments, such as chemotherapy or radiotherapy.”
Advancing Understanding of Novel Mechanisms
The company has advanced the development of its orally administered ataxia telangiectasia and Rad3-related (ATR) inhibitor M1774. Following completion of the monotherapy dose-escalation part of the DDRiver Solid Tumors 301 study, a monotherapy dose for M1774 has been confirmed for further evaluation in Phase Ib. Findings, which show a favorable exposure-safety relationship for M1774, will be shared at an upcoming congress. The ongoing study will assess M1774 as a single agent in patients with whose tumors have specific DDR mutations (defined loss-of-function mutation in ARIDIA, ATRX and/or DAXX, and ATM), and in combination with the poly-ADP ribose polymerase (PARP) inhibitor niraparib.
The ATR pathway is one of the most promising in the DDRi field as illustrated by recent data at the American Association for Cancer Research Annual Meeting. The development of M1774 will build on learnings from the exploration of the intravenous ATR inhibitor berzosertib, which has been studied in approximately 1,000 patients to date in multiple combinations, including with chemotherapy, radiotherapy, immunotherapy and PARP inhibitors across company- and investigator-sponsored studies.
Following an interim analysis of the ongoing global Phase II DDRiver SCLC 250 trial of berzosertib in combination with topotecan in patients with relapsed, platinum-resistant small cell lung cancer (SCLC), the decision has been made to discontinue the study due to low probability of meeting the pre-defined objective of this trial. The safety profile for berzosertib plus topotecan was consistent with that observed in other clinical trials to date. SCLC remains a difficult-to-treat disease, with minimal advances in the past 20 years. This is particularly true for patients whose disease is resistant to first-line platinum-based chemotherapy, underscoring the need for additional treatment options. The company will continue its open innovation approach, with ongoing external studies exploring berzosertib in additional combinations and clinical settings.
“While we did not see the outcomes we hoped for with this combination in this particularly challenging population of patients with platinum-resistant SCLC, we are confident in the potential of ATR inhibition, as combination with chemotherapy is only one avenue to take advantage of DNA Damage Response. We continue to progress our oral ATR inhibitor, M1774, and other investigational treatments in our DDRi portfolio as we evaluate the totality of data for berzosertib to assess our path forward,” said Zazulina.
Addressing Unmet Needs in Head and Neck Cancer
In addition to inhibiting specific pathways of the DNA Damage Response, the company is exploring other mechanisms that can synergize with DNA damaging agents by modulating cancer cell death caused by these treatment modalities. With the Phase III development program for the potentially first-in-class Inhibitor of Apoptosis Proteins (IAPs) inhibitor xevinapant, the company is building on its long-standing leadership in the treatment of squamous cell carcinoma of the head and neck (SCCHN).
Working to Progress Treatment Paradigms in Bladder Cancer
Based on the results of the Phase III JAVELIN Bladder 100 study and emerging real-world data, BAVENCIO® (avelumab) first-line maintenance therapy has advanced the standard of care in locally advanced or metastatic urothelial carcinoma. The recently opened Phase II JAVELIN Bladder Medley study will evaluate whether optimization of first-line maintenance treatment by adding a novel therapy to avelumab could improve outcomes for patients. This randomized umbrella study will evaluate avelumab monotherapy versus the combination of avelumab with the company’s investigational anti-TIGIT antibody M6223 in the first-line maintenance setting in patients with advanced urothelial carcinoma whose disease did not progress with first-line platinum-containing chemotherapy. The biomarker analysis of the JAVELIN Bladder 100 study suggests that the combination of avelumab and M6223 is rational, given the impact of TIGIT expression and Fc-gamma mutational status on avelumab efficacy. The study will also evaluate avelumab in combination with Nektar Therapeutics’ interleukin-15 (IL-15) receptor agonist, NKTR-255, and in combination with Gilead Sciences’ Trodelvy® (sacituzumab govitecan-hziy).
*Trodelvy is a registered trademark of Gilead Sciences.