Molecular Profiling and Targeted Therapy for Advanced Thoracic Malignancies: A Biomarker-Derived, Multiarm, Multihistology Phase II Basket Trial

Author:

Lopez-Chavez Ariel1,Thomas Anish1,Rajan Arun1,Raffeld Mark1,Morrow Betsy1,Kelly Ronan1,Carter Corey Allan1,Guha Udayan1,Killian Keith1,Lau Christopher C.1,Abdullaev Zied1,Xi Liqiang1,Pack Svetlana1,Meltzer Paul S.1,Corless Christopher L.1,Sandler Alan1,Beadling Carol1,Warrick Andrea1,Liewehr David J.1,Steinberg Seth M.1,Berman Arlene1,Doyle Austin1,Szabo Eva1,Wang Yisong1,Giaccone Giuseppe1

Affiliation:

1. Ariel Lopez-Chavez, Anish Thomas, Arun Rajan, Mark Raffeld, Betsy Morrow, Ronan Kelly, Corey Allan Carter, Udayan Guha, Keith Killian, Christopher C. Lau, Zied Abdullaev, Liqiang Xi, Svetlana Pack, Paul S. Meltzer, David J. Liewehr, Seth M. Steinberg, Arlene Berman, Eva Szabo, Yisong Wang, and Giuseppe Giaccone, National Cancer Institute; Austin Doyle, Cancer Therapy Evaluation Program, Bethesda, MD; Ariel Lopez-Chavez, Christopher L. Corless, Alan Sandler, Carol Beadling, and Andrea Warrick, Knight...

Abstract

Purpose We conducted a basket clinical trial to assess the feasibility of such a design strategy and to independently evaluate the effects of multiple targeted agents against specific molecular aberrations in multiple histologic subtypes concurrently. Patients and Methods We enrolled patients with advanced non–small-cell lung cancer (NSCLC), small-cell lung cancer, and thymic malignancies who underwent genomic characterization of oncogenic drivers. Patients were enrolled onto a not-otherwise-specified arm and treated with standard-of-care therapies or one of the following five biomarker-matched treatment groups: erlotinib for EGFR mutations; selumetinib for KRAS, NRAS, HRAS, or BRAF mutations; MK2206 for PIK3CA, AKT, or PTEN mutations; lapatinib for ERBB2 mutations or amplifications; and sunitinib for KIT or PDGFRA mutations or amplification. Results Six hundred forty-seven patients were enrolled, and 88% had their tumors tested for at least one gene. EGFR mutation frequency was 22.1% in NSCLC, and erlotinib achieved a response rate of 60% (95% CI, 32.3% to 83.7%). KRAS mutation frequency was 24.9% in NSCLC, and selumetinib failed to achieve its primary end point, with a response rate of 11% (95% CI, 0% to 48%). Completion of accrual to all other arms was not feasible. In NSCLC, patients with EGFR mutations had the longest median survival (3.51 years; 95% CI, 2.89 to 5.5 years), followed by those with ALK rearrangements (2.94 years; 95% CI, 1.66 to 4.61 years), those with KRAS mutations (2.3 years; 95% CI, 2.3 to 2.17 years), those with other genetic abnormalities (2.17 years; 95% CI, 1.3 to 2.74 years), and those without an actionable mutation (1.85 years; 95% CI, 1.61 to 2.13 years). Conclusion This basket trial design was not feasible for many of the arms with rare mutations, but it allowed the study of the genetics of less common malignancies.

Publisher

American Society of Clinical Oncology (ASCO)

Subject

Cancer Research,Oncology

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