Merck Reports Promising Efficacy Data of ATR Inhibitor Berzosertib in Combination with Topotecan for Recurrent Small Cell Lung Cancer

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On April 12, Merck KGaA announced key clinical progress for berzosertib (M6620). Berzosertib is an investigational, potent and selective inhibitor of ataxia telangiectasia and Rad3-related protein (ATR).

Results from a Phase II proof-of-concept study (NCT02487095) conducted by the National Cancer Institute (NCI) demonstrated that berzosertib in combination with the chemotherapy agent topotecan achieved an objective response rate (ORR) of 36% (95% CI: 18.0–57.5; all partial responses) in patients with recurrent small cell lung cancer (SCLC), with tumor regression observed in the majority of patients (68.0%). Responses were observed in both platinum-sensitive (60.0%) and platinum-resistant (30.0%) patients. The median duration of response (DOR) was 6.4 months, and 4 out of 6 patients (66.7%) with platinum-resistant SCLC had a DOR exceeding 6 months. The median progression-free survival (PFS) was 4.8 months, with PFS rates at 4 and 6 months of 60.0% and 36.0%, respectively. The median overall survival (OS) was 8.5 months, with OS rates at 6 and 12 months of 68.0% and 32.0%, respectively.

The NCI is also conducting a separate Phase II trial to evaluate berzosertib in combination with topotecan versus topotecan monotherapy for the treatment of recurrent SCLC (NCT03896503).

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

Topotecan is the standard-of-care chemotherapy for second-line treatment of small cell lung cancer (SCLC) and is associated with low response rates, particularly in platinum-resistant disease. Results from the NCI study highlight that SCLC tumors are vulnerable to ATR inhibition due to high levels of replication stress, and that combining berzosertib with topotecan has the potential to enhance the efficacy of topotecan in patients with chemotherapy-resistant disease. These data build upon previously published early-phase I results from this study, which also indicated potential benefits of this combination therapy in patients with platinum-resistant SCLC.

These results supplement the findings of the NCI-sponsored, open-label, randomized, Phase II study (NCI protocol 9944), which evaluated the efficacy of berzosertib in combination with gemcitabine versus gemcitabine monotherapy for recurrent, platinum-resistant high-grade serous ovarian cancer. The study results were published in The Lancet Oncology in 2020. Conducted under a separate Cooperative Research and Development Agreement (CRADA) between the NCI and Merck, the study demonstrated that the addition of berzosertib to gemcitabine improved progression-free survival in this treatment setting. Notably, this was the first randomized study to evaluate an ATR inhibitor across any tumor type.

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