The combination of the anti–PD-L1 antibody durvalumab and the ATR kinase inhibitor ceralasertib may help overcome inherent immune resistance and reinvigorate antitumor activity in patients with advanced non–small cell lung cancer (NSCLC), according to a recent study published by Besse et al in Nature Medicine.
Background
“Patients with advanced [NSCLC] face significant challenges when standard-of-care treatments fail,” stressed senior study author John Heymach, MD, PhD, Chair of Thoracic/Head & Neck Medical Oncology at The University of Texas MD Anderson Cancer Center. “For these [patients], options become limited, emphasizing the urgent need for innovative approaches,” he added.
Study Methods and Results
In the phase II umbrella HUDSON study, researchers assigned 268 patients with advanced NSCLC whose tumors progressed following standard therapy to receive one of four targeted therapies in combination with durvalumab: ceralasertib, the PARP inhibitor olaparib, the STAT3 antisense oligonucleotide danvatirsen, or the anti–CD73 monoclonal antibody oleclumab. They noted that the median age of the patients was 63 to 64 years, and 58% of them identified as male.
The researchers analyzed the patients’ tumor molecular characteristics prior to therapy. They then categorized them into biomarker-matched or biomarker-unmatched treatment cohorts based on ATM alterations, homologous recombination repair defects, STK11/LKB1 alterations, or high CD73 expression.
They discovered that durvalumab plus ceralasertib provided the greatest clinical benefit compared with the other treatment combinations—demonstrating an objective response rate of 13.9% vs 2.6%. Compared with those in the other treatment groups, the patients in the durvalumab-plus-ceralasertib group had a median progression-free survival of 5.8 months vs 2.7 months and a median overall survival of 17.4 months vs 9.4 months. In patients with ATM-altered NSCLC, which should sensitize the tumors to ATR inhibitors, the objective response rate increased to 26.1%. Further, the researchers reported that durvalumab plus ceralasertib had a manageable safety profile.
Conclusions
“Our study represents a promising advancement in addressing this unmet need and holds the potential to offer more effective therapeutic strategies to improve outcomes for this population,” concluded Dr. Heymach.
As a result of the positive findings, the efficacy of durvalumab plus ceralasertib is currently being examined in a randomized phase III trial (ClinicalTrials.gov identifier NCT05450692) involving patients with immunotherapy-refractory NSCLC.
Disclosure: The research in this study was supported by AstraZeneca. For full disclosures of the study authors, visit nature.com.
