Molecular profiling and targeted therapy for advanced thoracic malignancies a biomarker-derived, multiarm, multihistology phase ii basket trial

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, Christopher L. Corless, Alan Sandler, Carol Beadling, Andrea Warrick, David J. Liewehr, Seth M. SteinbergArlene Berman, Austin Doyle, Eva Szabo, Yisong Wang, Giuseppe Giaccone

Research output: Contribution to journalArticlepeer-review

155 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1000-1007
Number of pages8
JournalJournal of Clinical Oncology
Volume33
Issue number9
DOIs
StatePublished - Mar 20 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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