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

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.

Trial registration: ClinicalTrials.gov NCT01306045.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.

© 2015 by American Society of Clinical Oncology.

Figures

Fig 1.

Flow diagram of patient population and treatment assignments. EGFR, epidermal growth factor receptor; NOS, not otherwise specified; NSCLC, non–small-cell lung cancer; PDGFRA, platelet-derived growth factor receptor alpha; SCLC, small-cell lung cancer; TM, thymic malignancy. (*) Successful molecular profiling was defined as having at least one core molecular analysis successfully performed.

Fig 2.

Frequency of genetic abnormalities in (A) non–small-cell lung cancer and (B) small-cell lung cancer.

Fig 3.

Overall survival in patients with non–small-cell lung cancer stratified by mutation. A, patients harboring ALK rearrangements; E, patients harboring EGFR mutations; K, patients harboring KRAS mutations; O, patients harboring other genetic abnormalities including mutations in BRAF, ERBB2, NRAS, PIK3CA, HRAS, NRAS, PTEN, and ERBB2 amplifications; W/P/U, patients with no mutations found or unsuccessful molecular profiling.

Fig A1.

Custom clinical trial design. National Cancer Institute Cancer Therapy Evaluation Program Protocol No. 8639/NCT01306045. EGFR, epidermal growth factor receptor; N, non–small-cell lung cancer; NOS, not otherwise specified; PDGFRA, platelet-derived growth factor receptor alpha; S, small-cell lung cancer; T, thymic malignancies.