Addition of M6620 to gemcitabine prolongs PFS in platinum-resistant ovarian cancer

BARCELONA, Spain — The addition of the ATR kinase inhibitor M6620 to gemcitabine extended PFS without additional toxicity among patients with platinum-resistant, high-grade serous ovarian cancer, according to randomized phase 2 study results presented at European Society of Medical Oncology Congress.

“Platinum-resistant ovarian cancer is associated with poor prognosis and represents an important unmet medical need,” Panagiotis A. Konstantinopoulos, MD, PhD, director of translational research in gynecologic oncology at Dana-Farber Cancer Institute and associate professor of medicine at Harvard University, said during his presentation. “Weekly gemcitabine has shown similar activity as pegylated liposomal doxorubicin in two [previous] randomized phase 3 studies and is a standard regimen used in the management of [this disease].”

High-grade serous ovarian cancers exhibit genomic instability and high replication stress because of the loss of G1/S checkpoints due to TP53 mutations, the presence of homologous recombination alterations, and amplification of the MYC and CCNE1 oncogenes.

Konstantinopoulos and colleagues randomly assigned 70 women to gemcitabine plus M6620 (n = 34; mean age, 61 years) or gemcitabine alone (n =36; mean age, 64 years).

Study protocol placed no restriction on the number of prior lines of therapy; however, women could only have a maximum of one prior regimen in the platinum-resistant setting.

Gemcitabine was administered at 1,000 mg/m² on days 1 and 8 of each 21-day cycle. M6620 (Berzosertib, Merck) was administered at 210 mg/m² on days 2 and 9 of each cycle. Treatment continued until disease progression or unacceptable toxicity. Patients in the gemcitabine-alone group had the option to switch to the combination group upon disease progression.

PFS served as the primary endpoint. Safety, objective response rate and clinical benefit rate served as secondary endpoints.

Results showed a median PFS of 14.7 weeks among women who received gemcitabine alone and 22.9 weeks among women who received the combination (HR = 0.57; 90% CI, 0.33-0.99).

Patients with platinum-free interval of 3 months or less derived the greatest benefit from M6620 (HR = 0.31; 90% CI, 0.13-0.77). Among patients with platinum-free interval greater than 3 months, researchers reported no statistically significant PFS difference between treatment groups (HR = 0.95; 90% CI, 0.46-1.97).

When including patients who crossed over, median OS was 47 weeks among patients who started with the combination and 49.1 weeks among patients who started with gemcitabine alone (HR = 1.17; 90% CI, 0.67-2.05).

However, an analysis censored for patient crossover showed median OS of 47 weeks among patients who started with the combination regimen and 40.4 weeks among patients who started with gemcitabine alone (HR = 0.82; 90% CI, 0.46-1.44).

Twelve patients (33.3%) in the gemcitabine group and seven (21%) in the combination-therapy group experienced disease progression.

One patient in the gemcitabine arm died due to sepsis, and one patient in the combination arm died due to pneumonitis. Overall, researchers reported similar rates of grade 3 or higher toxicity in each group.

“Addition of the ATR inhibitor M6620 to gemcitabine in platinum-resistant high-grade serous ovarian cancer met the primary endpoint of this exploratory phase 2 trial,” Konstantinopoulos said. “The finding that the PFS benefit was seen solely among [patients with platinum-free interval of 3 months or less] may reflect that these tumors are more likely to be enriched for biomarkers of replicative stress that are likely to predispose to response to ATR inhibition. Further evaluation of M6620 in combination with gemcitabine [for patients with this disease] is warranted.” – by John DeRosier

Reference:

Konstantinopoulos P, et al. Abstract LBA60; Presented at: European Society for Medical Oncology Congress. Sept. 27-Oct. 1, 2019; Barcelona, Spain.

Disclosures: Konstantinopoulos reports consultant roles with AstraZeneca, Merck, Pfizer Tesaro, and Vertex. Please see the abstract for all other authors’ relevant financial disclosures.