Consolidation ALK Tyrosine Kinase Inhibitors Versus Durvalumab or Observation After Chemoradiation in Unresectable Stage III ALK-Positive NSCLC

Amin H Nassar; Ritujith Jayakrishnan; Jamie Feng; Frances Shepherd; Elio Adib; Justin M Cheung; Jessica J Lin; Yufei Liu; Steven H Lin; Kaushal Parikh; Arthi Sridhar; Purnima Shakya; Thomas J Dilling; David Kaldas; Jhanelle E Gray; Anastasiya Lobachov; Jair Bar; Heike Luders; Christian Grohe; Shruti Gupta; Ticiana Leal; Bailey Fitzgerald; Fionnuala Crowley; Yu Fujiwara; Thomas U Marron; Molly Wilgucki; Joshua Reuss; Luxi Chen; Kamya Sankar; Jacqueline V Aredo; Joel W Neal; Heather A Wakelee; Rohit Thummalapalli; Helena Yu; Ryan Whitaker; Ana Velazquez; Meera Ragavan; Alessio Cortellini; David J Kwiatkowski; Abdul Rafeh Naqash; Sarah B Goldberg; So Yeon Kim

doi:10.1016/j.jtho.2024.09.1379

Consolidation ALK Tyrosine Kinase Inhibitors Versus Durvalumab or Observation After Chemoradiation in Unresectable Stage III ALK-Positive NSCLC

J Thorac Oncol. 2024 Sep 10:S1556-0864(24)02265-2. doi: 10.1016/j.jtho.2024.09.1379. Online ahead of print.

Authors

Amin H Nassar¹, Ritujith Jayakrishnan², Jamie Feng³, Frances Shepherd³, Elio Adib⁴, Justin M Cheung⁵, Jessica J Lin⁵, Yufei Liu⁶, Steven H Lin⁶, Kaushal Parikh⁷, Arthi Sridhar⁷, Purnima Shakya⁷, Thomas J Dilling⁸, David Kaldas⁹, Jhanelle E Gray¹⁰, Anastasiya Lobachov¹¹, Jair Bar¹¹, Heike Luders¹², Christian Grohe¹², Shruti Gupta¹³, Ticiana Leal¹³, Bailey Fitzgerald¹⁴, Fionnuala Crowley¹⁵, Yu Fujiwara¹⁴, Thomas U Marron¹⁶, Molly Wilgucki¹⁷, Joshua Reuss¹⁷, Luxi Chen¹⁸, Kamya Sankar¹⁸, Jacqueline V Aredo¹⁹, Joel W Neal¹⁹, Heather A Wakelee¹⁹, Rohit Thummalapalli²⁰, Helena Yu²¹, Ryan Whitaker²², Ana Velazquez²³, Meera Ragavan²⁴, Alessio Cortellini²⁵, David J Kwiatkowski³, Abdul Rafeh Naqash²⁶, Sarah B Goldberg², So Yeon Kim²

Affiliations

¹ Yale University School of Medicine, New Haven, Connecticut. Electronic address: [email protected].
² Yale University School of Medicine, New Haven, Connecticut.
³ Department of Medical Oncology and Hematology, University Health Network, Princess Margaret Cancer Centre, Toronto, Canada.
⁴ Dana-Farber Cancer Institute, Boston, Massachusetts.
⁵ Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
⁶ Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
⁷ Mayo Clinic, Rochester, Minnesota.
⁸ Department of Radiation Oncology, Moffitt Cancer Center, Tampa, Florida.
⁹ Department of Radiation Oncology, Moffitt Cancer Center, Tampa, Florida; Department of Internal Medicine, University of South Florida, Tampa, Florida; Department of Clinical Oncology, Cairo University, Cairo, Egypt.
¹⁰ Department of Thoracic Oncology, Moffitt Cancer Center, Tampa, Florida.
¹¹ Institute of Oncology, Chaim Sheba Medical Center, Ramat Gan, Israel; School of Medicine, Tel Aviv University, Tel Aviv, Israel.
¹² Klinik für Pneumologie-Evangelische Lungenklinik Berlin Buch, Berlin, Germany.
¹³ Department of Hematology and Medical Oncology, Thoracic Medical Oncology Program, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia.
¹⁴ Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
¹⁵ Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Brookdale Department of Geriatrics and Palliative Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
¹⁶ Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
¹⁷ Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
¹⁸ Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
¹⁹ Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California.
²⁰ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
²¹ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York.
²² Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, Tennessee.
²³ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.
²⁴ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California; Division of Research, Kaiser Permanente Northern California, The Permanente Medical Group, Oakland, California.
²⁵ Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Roma, Italy; Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Roma, Italy; Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, United Kingdom.
²⁶ Oklahoma University, Stephenson Cancer Center, Oklahoma City, Oklahoma.

PMID: 39260522
DOI: 10.1016/j.jtho.2024.09.1379

Abstract

Introduction: Patients with advanced ALK-positive NSCLC typically have poor response to immunotherapy; the benefit of consolidation durvalumab in patients with unresectable stage III ALK-positive NSCLC remains unclear. Herein, we compare the efficacy and safety of consolidation ALK tyrosine kinase inhibitor (TKI) versus durvalumab or observation after concurrent chemoradiation.

Methods: We conducted a retrospective study using a multicenter study of 17 institutions globally. Patients with unresectable stage III ALK-positive NSCLC treated between 2015 and 2022 were included. Patients received ALK TKI, durvalumab, or observation after concurrent chemoradiation. Real-world progression-free survival (rwPFS) and overall survival (OS) were estimated using Kaplan-Meier method. Treatment-related adverse events (trAEs) were classified by Common Terminology Criteria for Adverse Events version 5.0. Outcomes were assessed by multivariable Cox regression analysis.

Results: A total of 67 patients were included, of whom 39 (58%) were female. Median age was 57 (interquartile range: 49-67) years. Furthermore, 15 received consolidation ALK TKI, 30 received durvalumab, and 22 underwent observation. Baseline characteristics were similar across the three groups other than differences in race. After adjusting for stage, age, and nodal status, median rwPFS was significantly longer for ALK TKI (rwPFS not reached, 95% confidence interval [CI]: 22.7- not reached) versus durvalumab (11.3 mo, 95% CI: 8.9-18.5, hazard ratio [HR] = 0.12, 95% CI: 0.026-0.5, p-adjusted [p-adj] = 0.006) or observation (7.2 mo, 95% CI: 3.4-10.6, HR = 0.04, 95% CI: 0.009-0.2, p-adj < 0.0001). Durvalumab significantly improved median rwPFS compared with observation (HR = 0.37, 95% CI: 0.19-0.71, p-adj = 0.002). Median OS in the ALK TKI and durvalumab cohorts was significantly improved compared with patients on observation (ALK TKI-observation: p = 0.04; durvalumab-observation: p = 0.03). TrAE of any grade occurred in eight (53%) and 11 (37%) patients treated with ALK TKI and durvalumab, respectively. Grade greater than or equal to three trAEs occurred in 27% (n = 4) of patients treated with ALK TKI and 6.7% of patients treated with durvalumab.

Conclusions: Patients with ALK-positive NSCLC experience significantly improved rwPFS when treated with consolidation ALK TKI therapy, surpassing outcomes found with either durvalumab or observation. Although both ALK TKI therapy and durvalumab offer an extension in OS compared with observation alone, it seems that ALK TKI therapy is the superior choice, underscoring its pivotal role in enhancing patient survival.

Keywords: ALK inhibitors; Chemoradiation; Immunotherapy; Non–small cell lung cancer.