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.

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.