Merck Advances ATR Inhibitor Berzosertib in Small Cell Lung Cancer With New Published Data and Initiation of Phase II Trial With Registrational Intent

Darmstadt, Germany:  

Merck, a leading science and technology company, today announced key clinical advancements for berzosertib (M6620), an investigational, potent and selective ataxia telangiectasia and Rad3-related (ATR) inhibitor. Berzosertib is the leading asset in the company’s DNA damage response (DDR) inhibitor program and one of the most advanced ATR inhibitors in oncology clinical development industry-wide.

Results from a Phase II proof-of-concept study conducted by the US National Cancer Institute (NCI) (NCT02487095)* and published in Cancer Cell showed that berzosertib in combination with the chemotherapy topotecan resulted in an objective response rate (ORR) of 36% among patients with relapsed small cell lung cancer (SCLC), including durable responses among a majority of responding patients with platinum-resistant disease.¹ The NCI is also conducting a separate Phase II trial of berzosertib in combination with topotecan versus topotecan monotherapy in SCLC that has relapsed (NCT03896503)* which is currently the only randomized controlled trial of the combination in this population.

Merck also initiated a global Phase II study to further assess berzosertib in combination with topotecan for the treatment of relapsed, platinum-resistant SCLC (DDRiver SCLC 250). The first patient has been enrolled in the open-label, single-arm trial, which plans to include approximately 80 participants at about 41 study sites across Asia, Europe, and North America.

“Small-cell neuroendocrine cancers, including small cell lung cancer, are associated with very poor prognoses, and are a major clinical challenge with no effective therapeutic options. In this study, the combination of berzosertib and topotecan showed higher than expected response rates and durable responses in patients with platinum-resistant SCLC, highlighting the therapeutic potential of this combination for patients with this recalcitrant cancer type,” said Anish Thomas, MBBS, M.D., investigator and NIH Lasker Clinical Research Scholar at the Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, and lead investigator of the study. Dr. Thomas is collaborating with Merck KGaA, Darmstadt, Germany through a Cooperative Research and Development Agreement (CRADA).

Topotecan is the chemotherapeutic standard-of-care for second-line treatment of SCLC and is associated with low response rates, particularly in platinum-resistant disease.¹ Findings from the NCI study highlight the vulnerability of SCLC tumors to ATR inhibition as a result of high levels of replication stress and the potential for the combination of berzosertib and topotecan to enhance the efficacy of topotecan among chemotherapy-resistant patients.¹ These data build on earlier published results from Phase I of this study which also suggested a potential benefit of this combination in participants with platinum-resistant SCLC.²

“We are encouraged by these promising results, and are eager to further investigate berzosertib in a potentially registrational trial in SCLC as part of our front-running leadership in the research of DNA damage response,” said Danny Bar-Zohar, M.D., Global Head of Development for the Healthcare business sector of Merck.

These results are in addition to results from an NCI-sponsored open-label, randomized, Phase II study (NCI protocol 9944) evaluating berzosertib in combination with gemcitabine versus gemcitabine alone for the treatment of recurrent, platinum-resistant high-grade serous ovarian cancer, which were published in The Lancet Oncology in 2020. The study, conducted through a separate CRADA between NCI and Merck KGaA, Darmstadt, Germany, showed a benefit of adding berzosertib to gemcitabine in this treatment setting including improvement in progression-free survival, and is the first randomized study of an ATR inhibitor in any tumor type.³

As part of its new DDRiver™ Clinical Trials program, the company is investigating DDR inhibitor targeting pathways across more than ten trials in various tumor types.

NCI Study Results

In the Phase II single-arm study of berzosertib plus topotecan in patients with SCLC whose disease had progressed on prior therapy, 25 patients were evaluable for the primary endpoint of ORR as measured by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), and the secondary endpoints of progression-free survival (PFS) and overall survival (OS) and duration of response (DOR). Berzosertib 210 mg/m² was administeredintravenously on days 2 and 5, and topotecan 1.25 mg/m² was given intravenously on days 1 through 5 in 21-day cycles; treatment continued until disease progression.¹

The confirmed ORR was 36% (95% CI, 18.0–57.5; all partial response).¹ Most patients (68.0%) experienced tumor regressions.¹ Responses were observed in patients with both platinum-sensitive (60.0% [95% CI, 14.7–94.7]) and platinum-resistant (30.0% [95% CI, 11.9–54.3]) disease.¹ Median DOR was 6.4 months (95% CI, 1.1–14.3), and four of the six (66.7%) responders with platinum-resistant SCLC had DOR of more than 6 months.¹ Median PFS was 4.8 months (95% CI, 2.8–7.4), with PFS rates at 4 months and 6 months of 60.0% (95% CI, 38.4-76.1) and 36.0% (95% CI, 18.2–54.2).¹ Median OS was 8.5 months (95% CI, 5.6-13.6);¹ OS rates at 6 months and 12 months were 68.0% (95% CI, 46.1–82.5) and 32.0% (95% CI, 15.2–50.2).¹

Among 26 patients evaluable for safety, the most common treatment-related adverse events (AE) were anemia (96.2%), lymphopenia (96.2%), thrombocytopenia (92.3%), and neutropenia (50.0%), nausea (50.0%) and vomiting (42.3%).¹ The most common grade 3 or 4 AEs were lymphopenia (69.2%), thrombocytopenia (57.7%), anemia (53.8%), and neutropenia (15.4%).¹ No treatment-related deaths occurred.¹ Most AEs were attributable to topotecan, which as monotherapy is associated with a high frequency of myelosuppression.^1,4

*Additional information on these clinical trials are available at clinicaltrials.gov, through identifier numbers NCT02487095 and NCT03896503. Patients interested in enrolling in these berzosertib and topotecan combination clinical trials can call the National Cancer Institute’s toll-free number 1-800-4-Cancer (1-800-422-6237) (TTY: 1-800-332-8615).

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