Unlocking a New Era in Lung Cancer Treatment With Durvalumab and Ceralasertib

Lung Cancer Illustration

A study from The University of Texas MD Anderson Cancer Center reveals that combining targeted therapy and immunotherapy, specifically durvalumab and ceralasertib, significantly benefits patients with non-small cell lung cancer (NSCLC).

Phase II trial finds durvalumab plus ceralasertib boosted immune response and improved outcomes in patients with lung cancer.

A specific combination of targeted therapy and immunotherapy may better help patients with non-small cell lung cancer (NSCLC) overcome inherent immune resistance and reinvigorate anti-tumor activity, according to a new study led by a researcher from The University of Texas MD Anderson Cancer Center.

Results from the Phase II umbrella HUDSON study, published today (February 13) in Nature Medicine, demonstrated that the anti PD-L1 antibody, durvalumab, coupled with the ATR inhibitor, ceralasertib, provided the greatest clinical benefit of four combinations evaluated.

This pair had an objective response rate (ORR) of 13.9% compared to just 2.6% with the other tested combinations. Median progression-free survival (PFS) was 5.8 months versus 2.7 months for other combinations, while median overall survival (OS) was 17.4 months versus 9.4 months. In patients with ATM alterations, which should sensitize tumors to ATR inhibitors, the ORR increased to 26.1%. Durvalumab-ceralasertib had a manageable safety profile.

John Heymach

John Heymach, M.D., Ph.D. Credit: The University of Texas MD Anderson Cancer Center

Addressing an Unmet Need

“Patients with advanced non-small cell lung cancer face significant challenges when standard-of-care treatments fail,” said corresponding author John Heymach, M.D., Ph.D., chair of Thoracic/Head & Neck Medical Oncology. “For these individuals, options become limited, emphasizing the urgent need for innovative approaches. 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.”

This study enrolled 268 patients with advanced NSCLC who progressed following standard-of-care therapy. The median age of participants was 63-64 years; 58% were male.

Patients on the trial received one of four targeted therapies in combination with durvalumab: ceralasertib (ATR kinase inhibitor), olaparib (PARP inhibitor), danvatirsen (STAT3 antisense oligonucleotide) or oleclumab (anti-CD73 monoclonal antibody).

Tumor molecular characteristics were analyzed before treatment, and patients were categorized into biomarker-matched or -unmatched treatment cohorts based on ATM alterations, homologous recombination repair defects, STK11/LKB1 alterations, or high CD73 expression.

Future Directions

The promising results of durvalumab plus ceralasertib have led to further investigation in a randomized Phase III trial for patients with immunotherapy-refractory NSCLC. This ongoing research underscores the potential of combining targeted therapy with immunotherapy to enhance treatment efficacy for NSCLC patients.

Reference: “Biomarker-directed targeted therapy plus durvalumab in advanced non-small-cell lung cancer: a phase 2 umbrella trial” by Benjamin Besse, Elvire Pons-Tostivint, Keunchil Park, Sylvia Hartl, Patrick M. Forde, Maximilian J. Hochmair, Mark M. Awad, Michael Thomas, Glenwood Goss, Paul Wheatley-Price, Frances A. Shepherd, Marie Florescu, Parneet Cheema, Quincy S. C. Chu, Sang-We Kim, Daniel Morgensztern, Melissa L. Johnson, Sophie Cousin, Dong-Wan Kim, Mor T. Moskovitz, David Vicente, Boaz Aronson, Rosalind Hobson, Helen J. Ambrose, Sajan Khosla, Avinash Reddy, Deanna L. Russell, Mohamed Reda Keddar, James P. Conway, J. Carl Barrett, Emma Dean, Rakesh Kumar, Marlene Dressman, Philip J. Jewsbury, Sonia Iyer, Simon T. Barry, Jan Cosaert and John V. Heymach, 13 February 2024, Nature Medicine.
DOI: 10.1038/s41591-024-02808-y

This trial was supported by AstraZeneca.

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