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ObjectiveLung-MAP (SWOG S1400) is a master platform trial assessing targeted therapies in squamous NSCLC. Theobjective of study C (S1400C) was to evaluate the response rate to palbociclib, a cyclin-dependent kinase 4and cyclin-dependent kinase 6 inhibitor, in patients with cell cycle gene abnormalities.MethodsPatients with squamous NSCLC, a performance status of 0 to 2, and normal organ function who had progressedafter at least one prior platinum-based chemotherapy with cyclin-dependent kinase 4 gene (CDK4) or cyclin D1 gene (CCND1), cyclin D2 gene (CCND2), or cyclin D3 gene (CCND3) amplifications on tumor specimens were eligible. The study was originally designed as a phase II/III trial comparing palbociclib with docetaxel, but it was modified to a single-arm phase II trial with the primary end point of response when immunotherapy was approved. If two or fewer responses were seen in the first 20 patients, then the study would cease enrollment.ResultsA total of 88 patients (9% of patients screened) were assigned to S1400C, and 53 patients enrolled (including 17 to receive docetaxel). One patient who had been registered to receive docetaxel was re-registered to receive palbociclib after progression while taking docetaxel. The frequencies of cell cycle gene alterations in the eligible patients taking palbociclib (n= 32) were as follows: CCND1, 81% (n= 26); CCND2, 9% (n= 3); CCND3, 6% (n= 2); and CDK4, 3% (n= 1). In all, 32 eligible patients received palbociclib. There were two partial responses (response rate 6% [95% confidence interval (CI): 0%-15%]), both with CCND1 amplification. Twelve patients had stable disease (38% [95% CI: 21%-54%]). The median progression-free survival was 1.7 months (95% CI: 1.6-2.9 months) andthe median overall survival was 7.1 months (95% CI: 4.2-12.5).ConclusionPalbociclib as monotherapy failed to demonstrate the prespecified criteria for advancement to phase III testing.

5008 Background: Androgen receptor (AR) signaling is an important growth mechanism in mCRPC, providing the rationale for treatment with AR axis inhibitors such as ENZ and AAP. Targeting AR with anti-androgens such as ENZ can result in compensatory autocrine and paracrine androgenic stimulation. Therefore, using ENZ with the androgen biosynthesis inhibitor AAP to dampen these resistance mechanisms could improve clinical outcomes relative to ENZ alone. Methods: Men with progressive mCRPC by Prostate Cancer Working Group 2 criteria were eligible. Prior treatment with taxanes for mCRPC and any prior treatment with ENZ or AAP was exclusionary. Patients (pts) were randomized 1:1 to ENZ or ENZ/AAP at standard FDA-approved doses. Randomization was stratified by prior chemotherapy and Halabi prognostic three risk groups. Castrating therapy was maintained. The primary endpoint was overall survival (OS) defined as the date of randomization from date of death or last follow-up. The log-rank test had 90% power to detect a hazard ratio for OS of 0.77 with a one-sided type I error rate of 0.025. Secondary endpoints included radiographic progression free survival (rPFS) and on-treatment PSA declines. Exploratory endpoints included imaging changes, and changes in serum biomarkers such as androgens, angiokines, and circulating microRNA and RNA. The primary analysis was based on the stratified log-rank test adjusting on the stratification factors. Results: Between January 2014 and August 2016, 1311 men were randomized: 657 to ENZ and 654 to ENZ/AAP. Groups were well balanced between arms, including stratification variables. 15.6% of pts were high risk, 35.3% intermediate, and 48.1% low. Median OS was 33.6 mo (95% CI 30.5-36.4) and 32.7 mo (29.9-35.4) respectively, two-sided p = 0.53. Fifty percent PSA decline rate was 80% vs. 76.5%. Grade 3-5 adverse events (AE) (all attributions) were 55.6% and 68.8% respectively. Treatment discontinuation due to AEs occurred in 5% and 12%, pt withdrawal in 5% and 13%, and progression or death in 57% and 48% of pts respectively. Conclusions: Addition of abiraterone acetate to enzalutamide did not prolong survival in men with mCRPC. The combination resulted in more AEs than enzalutamide alone. Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org . Clinical trial information: NCT01949337.

9056 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.

Purpose In recent years, the incidence of cutaneous melanoma has increased more than that of any other cancer. Dacarbazine is considered the gold standard for treatment, having a response rate of 15% to 20%, but most responses are not sustained. Previously, we have shown that short exposure of primary cutaneous melanoma cells to dacarbazine resulted in the upregulation of interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF). The purpose of the present study was to determine how long-term exposure of melanoma cells to dacarbazine would affect their tumorigenic and metastatic potential in vivo. Materials and Methods The primary cutaneous melanoma cell lines SB2 and MeWo were repeatedly exposed in vitro to increasing concentrations of dacarbazine, and dacarbazine-resistant cell lines SB2-D and MeWo-D were selected and examined for their ability to grow and metastasize in nude mice. Results The dacarbazine-resistant cell lines SB2-D and MeWo-D exhibited increased tumor growth and metastatic behavior in vivo. This increase could be explained by the activation of RAF, MEK, and ERK, which led to the upregulation of IL-8 and VEGF. More IL-8, VEGF, matrix metalloproteinase-2 (MMP-2), and microvessel density (CD-31) were found in tumors produced by SB2-D and MeWo-D in vivo than in those produced by their parental counterparts. No mutations were observed in BRAF. Conclusion Our results have significant clinical implications. Treatment of melanoma patients with dacarbazine could select for a more aggressive melanoma phenotype. We propose that combination treatment with anti-VEGF/IL-8 or MEK inhibitors may potentiate the therapeutic effects of dacarbazine.

Platelet-derived growth factor (PDGF) and its cognate receptor are widely expressed on melanomas. Coexpression of the growth factor and receptor suggests their role in autocrine or paracrine growth mechanisms. Imatinib mesylate was previously reported to have specific activity in inhibiting select tyrosine kinase receptors, including PDGF and c-Kit. Melanoma cells express abundant levels of the PDGF receptor (PDGFR). Nevertheless, c-Kit expression is progressively lost as the cells take on a more highly metastatic phenotype. To investigate the potential of imatinib mesylate as a therapy for melanoma, we studied its effect on the growth of melanoma cells using an in vivo mouse model. Melanoma cells with high malignant potential (PDGFR-positive, c-Kit-negative) or low malignant potential (PDGFR-positive, c-Kit-positive) were injected subcutaneously into athymic nude mice. Mice were treated with imatinib mesylate (100 mg/kg three times weekly) or with phosphate-buffered saline for 4 to 6 wk. PDGFR-alpha and -beta were expressed on all melanoma cell lines tested. The level of PDGFR expression correlated with the metastatic potential of the melanoma cells: higher levels of PDGFR-alpha were expressed on cells with higher metastatic potential, and higher levels of PDGFR-beta were expressed on cells with lower metastatic potential. There was no significant difference in tumor size between treated and control mice. Immunohistochemical studies demonstrated inhibition of PDGFR phosphorylation on the tumors from mice treated with imatinib mesylate but not from control mice, suggesting that the receptors were functional and that the concentration of drug used was appropriate. Our data demonstrated that imatinib mesylate blocked both PDGFR-alpha and PDGFR-beta in vivo. It did not, however, affect the growth of melanoma cells expressing PDGFR, regardless of whether the cells expressed c-Kit.