Combining an ataxia telangiectasia and rad3-related (ATR) inhibitor with topoisomerase 1 (TOP1) yielded an objective response in more than a third of patients with small-cell lung cancer (SCLC) in a phase-2 proof-of-concept trial. SCLC is one of the small-cell neuroendocrine cancers (SCNCs) occurring in various primary sites that lack effective treatments. "SCLC is a recalcitrant cancer, with most patients dying within a year of their diagnosis," Dr. Anish Thomas of the National Cancer Institute in Bethesda told Reuters Health by email. "This work identified a combination of drugs targeting replication stress as an effective therapy for small-cell cancers. We observed durable cancer shrinkages in some patients with platinum-resistant small-cell tumors that are typically fatal within weeks of recurrence." "Replication stress" is a hallmark of out-of-control cell growth in many cancers that can damage DNA and force cancer cells to constantly repair themselves. As reported in Cancer Cell, Dr. Thomas and colleagues combined and administered the ATR inhibitor M6620 and the TOP1 inhibitor topotecan to 25 SCLC patients (median age, 63; 65% men; 92% white) who had relapsed after at least one prior chemotherapy. Specifically, IV M6620 (210 mg/m2 over 60 minutes on days 2 and 5) was given concurrently with IV topotecan (1.25 mg/m2 over 30 minutes every 23 hours on days 1 through 5), in 21-day cycles. The objective response rate was 36% as measured by Response Evaluation Criteria in Solid Tumors, achieving the primary efficacy endpoint. As Dr. Thomas noted, durable tumor regressions were observed in patients with platinum-resistant SCNCs, typically fatal within weeks of recurrence. Overall, SCNCs with high neuroendocrine differentiation, and with greater replication stress, were more likely to respond. "These findings highlight replication stress as a potentially transformative vulnerability of SCNCs, paving the way for rational patient selection in these cancers, now treated as a single disease," the authors state. Dr. Thomas said, "Together, this work highlights the vulnerability of small-cell tumors to ATR inhibition as a result of high levels of replication stress, and the potential for the combination of berzosertib and topotecan to yield durable tumor responses among chemotherapy-resistant patients." Two ongoing clinical trials are investigating the combination in a larger patient population, he added. Dr. Giuseppe Giaccone, associate director for Clinical Research at the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine in New York City, told Reuters Health by email, "The use or ATR inhibitors with chemotherapy is logical, especially in a tumor type like SCLC where proliferation is very high and chemotherapy has a very high success rate, at least initially." "The results in the small group of patients treated with this combination are of interest," he said, "especially because activity was observed in platinum-resistant patients, where chemotherapy usually has poor activity." "The ability to potentially select patients for this approach in the future is also promising," he said. "In this small study, the ATR compound increased the myelosuppression caused by chemotherapy, and most patients did not receive immunotherapy before (immunotherapy has now become standard first-line treatment). Therefore, a randomized study will be necessary to demonstrate whether this combination is better than chemotherapy alone, and this study is, in fact, already ongoing." "Although of great interest, the markers that predict activity of this combination will need to be confirmed in a prospective study before they can be used to select patients," concluded Dr. Giaccone, who was not involved in the study. Dr. Hirva Mamdani, an assistant professor and member of the Thoracic Oncology and Phase I Therapeutics Program at the Barbara Ann Karmanos Cancer Institute in Detroit, said, "Targeting the replication-stress response in SCNC is an exciting approach with potential to transform the therapeutic landscape of the disease. These early clinical data provide a promising rationale for a larger study to confirm the efficacy of the combination and potentially bring a novel treatment strategy for SCLC." "This approach is not without challenges," she told Reuters Health by email. "Overlapping toxicity of the ATR inhibitor with topotecan, especially myelosuppression, remains a challenge. The optimum timing of ATR inhibitor administration in the context of topotecan dosing will need to be confirmed." "Additionally, despite the impressive (objective response rate), median progression-free survival was 4.8 months, indicating that most of these initial responses were not durable," said Dr. Mamdani, who also was not involved in the research. Dr. Thomas and several co-authors report financial ties to various drug companies. —Marilynn Larkin Source
