Biomarker-integrated study of single agent targeting molecular alterations of PI3KCA, MET, ALK, ROS1, KRAS, NRAS or BRAF in advanced NSCLC: Phase 2 umbrella trial in China (CTONG1505)

Abstract

Background: Several genetically altered signaling pathways have been profiled in NSCLC, enabling advanced management of NSCLC using targeted therapies. This study investigated the therapeutic spectrum of NSCLC with uncommon molecular alterations by allocating patients to treatment arms based on molecular aberrations, alpelisib for PIK3CA mutation/amplification, capmatinib for MET IHC overexpression/amplification, ceritinib for ALK or ROS1 rearrangement, and binimetinib for KRAS, NRAS or BRAF mutation. Methods: The study was based on the umbrella design. Key objectives: investigate the feasibility of one trial for different agents based on biomarker-integrated analysis, assess anti-tumor activity, characterize safety, tolerability and PK profiles of individual agents. Key eligibility criteria: age ≥18 years; ECOG PS ≤ 2; failed prior treatment/unsuitable for chemotherapy. Documentation of locally determined molecular alterations of PI3KCA, MET, ALK, KRAS, NRAS or BRAF before treatment allocation was required. Results: Sixty-six patients with advNSCLC were enrolled (median age 58 years; 65.2% male: alpelisib, n = 2; capmatinib, n = 16; ceritinib, n = 26; binimetinib, n = 22). As of Feb 28, 2018, 10 patients in ceritinib and 2 in binimetinib arm were ongoing. Twenty-four patients had confirmed partial responses (36.4%): alpelisib, 0%; capmatinib, 18.8%; ceritinib, 73.1%; binimetinib, 9.1% (Figure). Highest mPFS (14.4 months) was in ceritinib arm. Most common treatment-related AEs: alpelisib: malaise, hyperglycemia, dysgeusia; capmatinib: nausea, anemia, peripheral oedema, decreased appetite; ceritinib: diarrhea, vomiting, ALT/AST elevation; binimetinib: mouth ulceration, AST, blood CPK increased, rash. Majority of AEs were grade 1/2. Conclusions: Objective responses/tumor shrinkage were observed in the study; highest ORR and mPFS were observed with ceritinib despite different patient numbers in 4 arms. All treatments were well tolerated; no new safety signals were observed. This study demonstrated the feasibility of an umbrella trial and importance of precision medicine in the management of advNSCLC with uncommon molecular alterations.