Treated PI 3 K-Positive Patients with Stage IV Squamous Cell Lung Cancer ( Lung-MAP Sub-Study )

Background: S1400B is a biomarker-driven Lung-MAP sub-study evaluating the phosphatidylinositide 3kinase (PI3K) inhibitor taselisib (GDC-0032) in patients with PI3K pathway-activated squamous NSCLC (SqNSCLC). Methods: Eligible patients had tumoral PIK3CA alterations by next generation sequencing and disease progression after at least one line of platinum-based therapy. Patients received 4 mg taselisib orally daily. The primary analysis population (PAP) was a subset of patients having substitution mutations believed to be associated with clinical benefit of PI3K inhibitors. Primary endpoint was response by RECIST 1.1; secondary endpoints included progression-free survival (PFS), overall survival (OS) and duration of response (DoR). Results: Twenty-six patients treated with taselisib comprised the full eligible population (FEP); 21 patients comprised the PAP. Median age in FEP was 68 y (53-83), 19 were male (73%). The study was closed for futility at interim analysis with one responder in the PAP (5% RR, 95% CI 0%-24%). Two possibly treatment-related deaths (1 respiratory failure, 1 cardiac arrest) were observed; 1 patient had Grade 4 and 11 had Grade 3 adverse events. Median PFS and OS in the PAP were 2.9 months (95% CI, 1.8-4.0 mos) and 5.9 months (95% CI, 4.2-7.8 mos), respectively. These numbers were nearly the same in the FEP. Conclusions: Study S1400B evaluating taselisib in PIK3CA altered SqNSCLC failed to meet its primary endpoint and was closed after an interim futility analysis. The trial is unique in cataloguing the diversity of PIK3CA mutations in SqNSCLC. M AN US CR IP T AC CE PT ED ACCEPTED MANUSCRIPT JTO-D-1900294 Revised Manuscript | Page 4 Introduction The Lung Master Protocol (Lung-MAP, SWOG 1400) is an umbrella protocol with a screening component and multiple independently conducted and analyzed treatment sub-studies. [1] Herein we report on the results of SWOG S1400B, a phase II Lung-MAP sub-study evaluating taselisib, a phosphoinositide-3 kinase (PI3K) inhibitor in patients with chemo-refractory SqNSCLC tumors harboring alterations in PI3KCA. PI3Ks are a family of lipid kinases involved in tumor cell proliferation, survival, and migration upon activation by growth factor receptors and integrins. PI3Ks catalyze phosphorylation of phosphatidylinositol-4, 5 bisphosphate to generate phosphatidylinositol-3, 4, 5 trisphosphate, a second messenger involved in phosphorylation of AKT and associated proteins in the AKT/mTOR pathway. [2, 3] Activating and transforming mutations, as well as amplification, in the p110 alpha isoforms of PI3K are commonly found in solid and hematological tumors. [4] Additionally, the PI3K/AKT pathway is activated in numerous types of cancer by receptor tyrosine kinase signaling, loss of phosphatase and tensin homolog (PTEN), or RAS mutations. [2, 5-8] PI3K alterations, including PI3K mutations and PTEN loss or mutations, are observed in 30%-50% of squamous lung cancers. PI3K mutations are observed in 2-5% of non-squamous and in 8-10% of sqNSCLC. [7], and human tumors carrying mutated PIK3CA or deleted PTEN have responded favorably to PI3K inhibition. [6] Taselisib is a potent, selective small molecule inhibitor of Class 1 PI3Ks developed by Genentech as an anticancer therapeutic agent that is a potent growth inhibitor in nonclinical models of PI3K mutant