No 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; targeted therapies alpelisib (PI3Kai), capmatinib (METi), ceritinib (ALKi), and binimetinib (MEKi) were evaluated. Method: The study was based on the umbrella design. Key objectives: investigate feasibility of using one trial for different agents based on biomarker-integrated analysis, assess antitumor 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 before treatment allocation was required (alpelisib, 350 mg QD: PIK3CA mutation/amplification; capmatinib, 400 mg BID (tablet): MET IHC overexpression/amplification; ceritinib, 750 mg QD: ALK or ROS1 rearrangement; binimetinib, 45 mg BID: KRAS, NRAS or BRAF mutation). Result: Sixty-six patients with advNSCLC were enrolled (median age 58 years; 65.2% male: alpelisib, n¼2; capmatinib, n¼16; ceritinib, n¼26; binimetinib, n¼22). As of Feb 28, 2018, 10 patients in ceritinib and 2 in binimetinib arms were ongoing. Twenty-four patients had confirmed partial responses (36.4%): alpelisib, 0%; capmatinib, 18.8%; ceritinib, 73.1%; binimetinib, 9.1% (Figure). Longest mPFS (14.4 months) was in ceritinib arm. Among the most common treatment-related AEs: alpelisib: malaise, hyperglycemia, dysgeusia; capmatinib: nausea, anemia, peripheral edema, decreased appetite; ceritinib: diarrhea, vomiting, ALT/AST elevation; binimetinib: mouth ulceration, AST, blood CPK increased, rash. Most AEs were grade 1/2. Conclusion: Objective responses/tumor shrinkage were observed in the study; highest ORR and mPFS were observed with ceritinib, although patient numbers differed between 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.

PD-L1 inhibitors treatment is associated with impaired outcome in pts with advanced NSCLC pts. This reduction is independent of standard prognostic factors. Biological correlative analyses suggest a tumor immunosuppressed state in ACE inhibitor group. These results should be validated in larger prospective cohorts.