A phase 1b study evaluating the safety and preliminary efficacy of berzosertib in combination with gemcitabine in patients with advanced non-small cell lung cancer

Abstract

Objectives: Berzosertib (formerly M6620, VX-970) is an intravenous, highly potent and selective, first-in-class ataxia telangiectasia and Rad3-related (ATR) protein kinase inhibitor. We assessed the safety, tolerability, preliminary efficacy, and pharmacokinetics (PK) of berzosertib plus gemcitabine in an expansion cohort of patients with advanced non-small cell lung cancer (NSCLC). The association of efficacy with TP53 status and other tumor markers was also explored. Materials and methods: Adult patients with advanced histologically confirmed NSCLC received berzosertib 210 mg/m 2 (days 2 and 9) and gemcitabine 1000 mg/m 2 (days 1 and 8) at the recommended phase 2 dose established in the dose escalation part of the study. Results: Thirty-eight patients received at least one dose of study treatment. The most common treatmentemergent adverse events were fatigue (55.3%), anemia (52.6%), and nausea (39.5%). Gemcitabine had no apparent effect on the PK of berzosertib. The objective response rate (ORR) was 10.5% (4/38, 90% confidence interval [CI]: 3.7-22.5%). In the exploratory analysis, the ORR was 30.0% (3/10, 90% CI: 9.0-61.0%) in patients with high loss of heterozygosity (LOH) and 11.0% (1/9, 90% CI: 1.0-43.0%) in patients with low LOH. The ORR was 33.0% (2/6, 90% CI: 6.0-73.0%) in patients with high tumor mutational burden (TMB), 12.5% (2/16, 90%

Targeting K-Ras-mediated DNA damage response in radiation oncology: Current status, challenges and future perspectives

“… ATR M6620 phase I GEM advanced NSCLC well tolerated. [129] +/- CB ST including CRC well tolerated. complete response in ATM loss CRC [130] TPT ST including NSCLC and PaCa MTD of combination was well tolerated enhanced DNA DSB in combination partially active in TPT-non-responding NSCLC [131] CHK1 AZD7762 phase I GEM ST including CRC and lung cancer MTD of 21 mg, stable disease [132] phase II GEM PaCa not superior to GEM [133] LY26063618 phase II GEM + CDDP advanced nonsquamous NSCLC improved PFS increased risk of thromboembolism [134] pemetrexed advanced or metastatic NSCLC partial response (9.1 %) stable disease (36.4 %) no association between p53 status and response [135] WEE1 AZD1775 phase II GEM + RT LAPaCa well tolerated improved OS [110] – RAS and TP53 mutations mCRC improved PFS [109] FTase tipifarnib ...…”

R-Loops and R-Loop-Binding Proteins in Cancer Progression and Drug Resistance

“…This makes ATR an attractive target for cancer therapies [ 72 ]. Indeed, ATR inhibitors are currently in clinical trials for the treatment of advanced solid tumors [ 73 , 74 , 75 , 76 ]. Interestingly, ATR acts partially through R-loops.…”

Everything Comes with a Price: The Toxicity Profile of DNA-Damage Response Targeting Agents

“…In phase I trials testing ATR inhibitors berzosertib and ceralasertib with chemotherapy, hematological AEs (neutropenia, anemia and thrombocytopenia), fatigue and emesis were the most common toxicities [ 22 , 96 , 97 , 98 ]. Two randomized phase II studies confirmed that the addition of berzosertib to gemcitabine in ovarian cancer patients and to cisplatin/gemcitabine in urothelial cancer patients increased the incidence and severity of hematological toxicities and the rate of nausea and vomiting [ 21 , 87 ].…”