Durvalumab and Ceralasertib Blaze a New Trail in NSCLC Therapy

Significance 

Non-small cell lung cancer (NSCLC) represents the most common type of lung cancer, accounting for about 85% of all lung cancer cases. NSCLC comprises several subtypes, including adenocarcinoma, squamous cell carcinoma, and large cell carcinoma, each differing in their cellular makeup and behavior. Treatment for NSCLC varies based on the stage of the disease, the patient’s overall health, and specific characteristics of the cancer, such as genetic mutations or biomarkers. In recent years, immunotherapy has emerged as a significant advancement in the treatment of various cancers, including NSCLC. Immunotherapy leverages the body’s immune system to recognize and fight cancer cells more effectively. Durvalumab is a monoclonal antibody that plays an important role in this therapeutic approach, particularly for NSCLC. Durvalumab targets Programmed Death-Ligand 1 (PD-L1), which is expressed on the surface of many cancer cells, including some NSCLC cells. PD-L1 binds to the PD-1 receptor on T-cells, effectively “turning off” these cells and preventing them from attacking the cancer. By binding to PD-L1, durvalumab blocks its interaction with PD-1, thereby reactivating the T-cells and enabling them to recognize and destroy cancer cells. The effectiveness of durvalumab in treating NSCLC has been demonstrated in several clinical trials. It has been particularly beneficial in patients with locally advanced, unresectable NSCLC that has not progressed after standard platinum-based chemotherapy and radiation therapy. In such cases, durvalumab has been shown to improve progression-free survival and, in some studies, overall survival rates compared to standard care. However, there is a significant fraction of patients either do not respond to such treatments or develop resistance over time. The resistance mechanisms are multifactorial, involving alterations in DNA damage response and repair pathways, mutations in key tumor suppressor genes like STK11/LKB1, dysregulation in antigen-presentation pathways, and the presence of immunosuppressive cellular subsets within the tumor microenvironment.

A recent study published in Nature Medicine under the leadership of Professor John Heymach from MD Anderson Cancer Center reported the HUDSON phase 2 umbrella study, which evaluated the efficacy of combining durvalumab  with various agents such as ceralasertib (ATR kinase inhibitor), olaparib (PARP inhibitor), danvatirsen (STAT3 antisense oligonucleotide), and oleclumab (anti-CD73 monoclonal antibody) in patients who have previously experienced failure in treatments involving anti-PD-(L)1-containing immunotherapy and platinum-doublet therapy.

The HUDSON study was carefully designed to address these challenges by exploring combination regimens that target potential resistance mechanisms. The choice of combination therapies—durvalumab with either ceralasertib, olaparib, danvatirsen, or oleclumab—is informed by a deep understanding of the underlying biology of NSCLC and resistance to immunotherapy. For instance, the combination of durvalumab and ceralasertib is particularly noteworthy. Ceralasertib, an ATR kinase inhibitor, is posited to synergize with durvalumab by targeting DNA damage response pathways, thereby enhancing the immunogenicity of cancer cells and improving the efficacy of immunotherapy.

The authors showed that the combination of durvalumab and ceralasertib demonstrated the most significant clinical benefit among the tested regimens. This combination yielded an objective response rate of 13.9%, a median progression-free survival of 5.8 months, and a median overall survival of 17.4 months. These outcomes are particularly remarkable considering the refractory nature of the patient population under study. The data also suggest that patients with ATM alterations, hypothesized to be more vulnerable to ATR inhibition, benefit significantly from the durvalumab-ceralasertib regimen.

A critical aspect of the HUDSON study is its emphasis on biomarker analyses to tailor treatments to individual patients’ molecular profiles. This approach aligns with the principles of personalized medicine, aiming to maximize therapeutic efficacy while minimizing unnecessary exposure to potentially ineffective treatments. The authors’ findings highlight the importance of comprehensive genomic profiling in guiding treatment decisions and highlight the potential of combining targeted therapies with immunotherapy to overcome resistance mechanisms. It is important to mention that the authors evaluated the safety and tolerability profile of the combination regimens, especially durvalumab and ceralasertib, which was manageable, paving the way for further investigation possibly phase 3 clinical trials. Indeed, the HUDSON study not only contributes valuable insights into the mechanisms of resistance to immunotherapy in NSCLC but also sets a precedent for the design of future clinical trials that seek to integrate targeted therapies with immunotherapy in a biomarker-driven manner.

In conclusion, the HUDSON study represents a significant milestone in the ongoing quest to improve outcomes for patients with NSCLC, particularly those with tumors lacking targetable alterations and who have exhausted standard-of-care options. The study’s innovative design, rigorous biomarker analyses, and promising clinical outcomes provide a robust foundation for future research aimed at refining and expanding therapeutic options for this challenging patient population. The combination of durvalumab and ceralasertib, in particular, emerges as a promising therapeutic strategy warranting further exploration in the quest to enhance the efficacy of immunotherapy in NSCLC.

Durvalumab and Ceralasertib Blaze a New Trail in NSCLC Therapy - Medicine Innovates

About the author

John V. Heymach, M.D., Ph.D.

Department of Thoracic-Head & Neck Med Onc, Division of Cancer Medicine
MD Anderson Cancer Center

Dr. Heymach is the Chair of Thoracic/Head and Neck Medical Oncology at MD Anderson Cancer Center. He holds the David Bruton Endowed Chair in Cancer Research. As a physician-scientist, Dr. Heymach’s research focuses on investigating mechanisms of therapeutic resistance to targeted agents, understanding the regulation of angiogenesis in lung cancer, and the development of biomarkers for targeted agents and immunotherapy. His research has led to new therapeutic approaches for KRAS mutant lung cancer, small cell lung cancer (SCLC), EGFR mutant non-small cell lung cancer (NSCLC), adenoid cystic carcinoma, and oligometastatic NSCLC, many of which are now considered standard of care regimens or undergoing clinical testing. He serves as PI on 4 R01 awards investigating molecular subsets of lung cancer, and on an U01 focused on SCLC. He serves as the MDACC PI for the SU2C-ACS Lung Cancer Dream Team targeting KRAS mutant lung cancers, as the leader of the Lung CCSG Program, and the co-leader of the Lung Cancer Moon Shot. He is also the co-PI and project leader of the Lung SPORE. As a clinical investigator, he leads a number of biomarker-directed clinical trials using targeted and immunotherapy agents in lung cancer. He has directly mentored numerous fellows, including physician-scientists, and serves as chair of the NCI Molecular Cancer Therapeutics-1 study section.

Reference 

Besse B, Pons-Tostivint E, Park K, Hartl S, Forde PM, Hochmair MJ, Awad MM, Thomas M, Goss G, Wheatley-Price P, Shepherd FA, Florescu M, Cheema P, Chu QSC, Kim SW, Morgensztern D, Johnson ML, Cousin S, Kim DW, Moskovitz MT, Vicente D, Aronson B, Hobson R, Ambrose HJ, Khosla S, Reddy A, Russell DL, Keddar MR, Conway JP, Barrett JC, Dean E, Kumar R, Dressman M, Jewsbury PJ, Iyer S, Barry ST, Cosaert J, Heymach JV. Biomarker-directed targeted therapy plus durvalumab in advanced non-small-cell lung cancer: a phase 2 umbrella trial. Nat Med. 2024 Feb 13. doi: 10.1038/s41591-024-02808-y.

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