Background: S1400 is a master platform trial designed to assess targeted therapies in SCC. Study C evaluated the response rate (RR) to P, a CDK 4/6 inhibitor, in pts with cell cycle gene abnormalities. Methods: Pts with SCC, PS 0-2, normal organ function, who had progressed after at least one prior platinum-based chemotherapy for any NSCLC indication were eligible. Tumor specimens were required and evaluated for gene alterations (Foundation Medicine, Foundation One NGS assay). Pts with CDK 4 or CCND1/2/ 3 amplifications were eligible. The study was originally designed as a phase II/III trial comparing P to docetaxel (D), but was modified to a 2-stage phase II trial with primary endpoint of response rate. If > 3 responses (R) of the first 20 pts were seen the study would continue to 40 pts, with 10 R for the 40 pts considered a positive study. Results: 89 pts (14% of pts screened) were assigned to S1400C, 53 pts enrolled (including 17 to D). One pt assigned to D re-registered to P. Frequency of cell cycle gene alterations for the enrolled pts: CCND1 amplification (n = 44, 83%); CCND2 amplification (n = 7, 13%); CCND3 amplification (n = 5, 9%); and CDK4 amplification (n = 3, 6%). (Note: some pts with multiple alterations.) Of the 37pts enrolled to P: 5 were ineligible (4 inadequate baseline labs, 1 did not progress on prior therapy). 1 not determinable for response. For the 32 eligible pts the median age was 67 (53-81), 21M/11F. Response: 2 PR (6% RR, 95% CI: 2%, 20%), 12 SD (38%, 95% CI: 21%, 54%) for a disease control rate (DCR) of 44% (95% CI: 27%, 61%). Median PFS was 1.7 mo (95% CI 1.6-2.9 mo). Of the 2 PR, one has progressed (duration of response, DOR, 7.7 mo), one still responding (DOR, 4 mo). Both responders had CCND1 amplification. 32 pts have been assessed for adverse events (AE). 4 experienced Grade 4 AE including lymphopenia (3), and thrombocytopenia (1). 13 others experienced Grade 3 treatment-related AE. Conclusions: 1. P failed to demonstrate the pre-specified RR to justify advancement to phase III. 2. P was well tolerated in this population. 3. Further analysis of those who derived benefit (e.g. response or prolonged SD) is underway. Clinical trial information: NCT02785939