Tu, Shi‐Ming

Abstract Background Treatment options for penile squamous cell carcinoma are limited. We sought to investigate clinical outcomes and safety profiles of patients with penile squamous cell carcinoma receiving immune checkpoint inhibitors. Methods This retrospective study included patients with locally advanced or metastatic penile squamous cell carcinoma receiving immune checkpoint inhibitors between 2015 and 2022 across 24 centers in the United States, Europe, and Asia. Overall survival and progression-free survival were estimated using the Kaplan-Meier method. Objective response rates were determined per Response Evaluation Criteria in Solid Tumours 1.1 criteria. Treatment-related adverse events were graded per the Common Terminology Criteria for Adverse Events, version 5.0. Two-sided statistical tests were used for comparisons. Results Among 92 patients, 8 (8.7%) were Asian, 6 (6.5%) were Black, and 24 (29%) were Hispanic and/or Latinx. Median (interquartile range) age was 62 (53-70) years. In all, 83 (90%) had metastatic penile squamous cell carcinoma, and 74 (80%) had received at least second-line treatment. Most patients received pembrolizumab monotherapy (n = 26 [28%]), combination nivolumab-ipilimumab with or without multitargeted tyrosine kinase inhibitors (n = 23 [25%]), or nivolumab (n = 16 [17%]) or cemiplimab (n = 15 [16%]) monotherapies. Median overall and progression-free survival were 9.8 months (95% confidence interval = 7.7 to 12.8 months) and 3.2 months (95% confidence interval = 2.5 to 4.2 months), respectively. The objective response rate was 13% (n = 11/85) in the overall cohort and 35% (n = 7/20) in patients with lymph node–only metastases. Visceral metastases, Eastern Cooperative Oncology Group (ECOG) performance status of 1 or higher, and a higher neutrophil/lymphocyte ratio were associated with worse overall survival. Treatment-related adverse events occurred in 27 (29%) patients, and 9.8% (n = 9) of the events were grade 3 or higher. Conclusions Immune checkpoint inhibitors are active in a subset of patients with penile squamous cell carcinoma. Future translational studies are warranted to identify patients more likely to derive clinical benefit from immune checkpoint inhibitors.

Abstract Background: The methylthioadenosine phosphorylase (MTAP) gene encodes an essential enzyme for the salvage pathway of adenosine synthesis and is frequently lost in different types of cancer including urothelial bladder carcinoma. Therefore, MTAP-deficient tumors are theoretically very sensitive to anti-folate agents such as pemetrexed that can effectively block the de novo pathway of adenosine synthesis and as a result, create a state of synthetic lethality. We thus hypothesize that tumor MTAP gene deficiency is associated with response to pemetrexed therapy in bladder cancer. Methods: In this study, we investigated MTAP gene deficiency rates in the TCGA database and confirmed MTAP protein loss by immunohistochemistry using a tumor tissue microarray containing bladder tumor tissues from 151 patients. We then performed in vitro and in vivo studies using MTAP-proficient and MTAP-deficient human bladder cancer cell lines. Functional loss of MTAP was verified with mass spectrometry, which detects its substrate methylthioadenosine (MTA) levels. We also correlated these pre-clinical studies with clinical response data on patients with metastatic bladder cancer treated with pemetrexed. Results: We identified that 27.8% bladder cancer patients have MTAP protein deficiency, which is consistent with exome sequencing data from the TCGA database. In vitro data showed MTAP-deficient human bladder cancer cell lines were significantly more sensitive to pemetrexed, with IC50 at least 40 times lower than MTAP-proficient cell lines. Subsequent knockdown of the MTAP gene in MTAP-proficient cell lines increased sensitivities to pemetrexed treatment. Consistent with the in vitro data, pemetrexed significantly inhibited the growth of MTAP-deficient or knockdown xenograft tumors but not MTAP-proficient tumors. Furthermore, 4 of 4 (100%) patients with MTAP-deficient metastatic bladder cancer responded to pemetrexed treatment, whereas only 1 of 11 (9%) patients with MTAP-proficient metastatic bladder cancer responded to pemetrexed. Conclusion: Our data demonstrate that MTAP gene loss in urothelial bladder cancer leads to a metabolic state of synthetic lethality with pemetrexed therapy. Therefore, bladder tumor MTAP loss should be further investigated as a potential biomarker for selection of patients for anti-folate therapy. Citation Format: Jianfeng Chen, Omar Alhalabi, Guangchun Han, Wei-Lien Wang, Xin-Qiao Zhang, Jian H. Song, Lidia P. Lopez, Sumankalai Ramachandran, Anh G. Hoang, Tyrone Garnett, Matthew Campbell, Amishi Y. Shah, Jennifer Wang, Arlene O. Siefker-Radtke, Shi-Ming Tu, Mark Titus, Charles C. Guo, Gary E. Gallick, Eleni Efstathiou, William F. Benedict, Christopher J. Logothetis, Thai H. Ho, Linghua Wang, Jianjun Gao. MTAP gene deficiency creates vulnerability to anti-folate therapy in urothelial bladder carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 385.

5078 Background: Strategies integrating androgen targeted and locoregional therapies are being increasingly used in PCa with regional spread, but are rarely curative. Angiogenesis inhibitors delay progression in castration resistant PCa and may synergize with ADT through endothelial cell apoptosis in hormone naïve patients (pts). We hypothesized that the frontline combination of ADT with the potent VEGF inhibitor Axi would improve PCa control relative to ADT alone and allow for meaningful time off systemic therapy after surgical consolidation. Methods: Pts with either clinically detected LN+ (TxN1M0 or TxNxM1a) or very high risk for LN PCa were treated with ADT for 2 mos and then randomized 2:1 to respectively add open label Axi (5 mg PO bid) vs. continue ADT alone for 4 mos until surgery. Those responding with PSA ≤5 ng/mL were offered prostatectomy and extended pelvic lymphadenectomy (RP). ADT +/- Axi was withheld postoperatively and PSA measured q3 mos until 1 y. Primary objective: proportion of pts progression free (FFP) 12 mos after RP, defined as PSA ≤1.0 ng/mL and no radiation or ADT, aiming to detect a 35% difference favoring ADT+Axi. Results: 72 pts completed accrual. We report on the 54 pts with LN+ disease: median age 62 y (range 42-76), pretreatment PSA 22.9 ng/mL (range 3.6 - 404.4), 38 N1 / 16 M1a. Table shows presurgical therapy outcomes. Path responses in the prostate were similar between arms, but in 5 ADT+Axi vs. 0 ADT LN+ pts there was no residual nodal disease. Testosterone recovery: 24/26 ADT+Axi and 9/9 ADT RP pts by 6 mos. 21/36 ADT+Axi and 15/18 ADT pts have failed; 1 y FFP estimates 48.0% (SE 8.6%) and 16.7% (SE 8.3%), respectively (p = 0.02). 1 y undetectable PSA 9 pts (6 ADT+Axi). No grade 4 toxicities or unexpected side-effects were observed. Conclusions: 1 year after RP, ADT+Axi resulted in proportionally greater number of LN+ PCa pts off treatment and progression free than ADT alone. Tissue analysis is evaluating predictors of benefit to further develop angiogenesis inhibition as part of combination strategies for hormone naïve PCa. Clinical trial information: NCT01409200. [Table: see text]

4519 Background: Tandem HDC with carbo/etoposide (CE) is curative for a portion of relapsed GCT pts. However, outcomes of refractory or high-risk relapsed pts remain poor. We tested a new HDC regimen of GemDMC, based on DNA damage repair inhibition. We combined BEV with HDC given their potential synergy and the high vascularity of GCT metastases. Methods: Eligibility: Intermediate (int)/high-risk (Beyer Model), creatinine ≤1.8 mg/dL and adequate organ function. HDC included BEV (5 mg/kg) preceding GemDMC (HDC #1) and ifosfamide/CE (ICE) (HDC #2). Following accrual of 42 pts, we amended the trial omitting BEV. The trial was powered to distinguish a target 50% 2-yr RFS from an expected 25% in this population. Results: We enrolled 69 male pts in cohorts 1 (BEV, N=42) and 2 (no BEV, N=27) (Table). Pts were heavily pretreated and most had refractory tumors. Main AE: mucositis and renal (4 HDC-related deaths in cohort 1, 1 in cohort 2). Tumor markers normalized in 90% pts with active tumors at HDC. After HDC, 19 pts were in CR and 28 in PRm- (of these, 22 had residual lesions resected with no viable tumor found in 20/22, 2 xRT, 4 monitored). Median f/u = 39 (2-105) mo. The 2-yr RFS rates in cohorts 1 and 2 = 52% and 78%, respectively. Their respective 2-yr OS rates = 55% and 81%. Conclusions: Sequential HDC with GemDMC–ICE shows encouraging outcomes in heavily pretreated and refractory GCT, exceeding the anticipated results. Addition of BEV increases toxicity but not tumor control. Clinical trial information: NCT00936936. [Table: see text]

259 Introduction: RA-223 prolongs OS in BM-CRPC pts but predictive markers are lacking. We hypothesized that molecular profiling of plasma-derived extracellular vesicles (EVs) from BM-CRPC pts treated with RA-223 would predict efficacy and inform development of combinations. Methods: Paired baseline (BL) and end of treatment (EoT) blood samples were collected from 25 pts treated with RA-223. Pts were stratified by median OS into 3 groups: 1) 6.3 months (range 3.3-8.5, n=5 pts, UnFav OS), 2) 18.2 months (range 12.6-19.4, n=7 pts, Middle OS) and 3) 27.6 months (range 23.1-33.8, n=13 pts, Fav OS). EVs were isolated from plasma and analyzed for specific proteins and RNA transcripts. Marker profiles by domain and analytic method were determined in pts from the stratified OS groups. Results: At EoT, there is enrichment of RNA transcripts and proteins involved in regulating immune responses, DNA Damage Response (DDR) and bone metabolism (Table). By benchmarking molecular signatures in pts with UnFav Os and Fav OS, we could analyze the molecular profiles of pts in the Middle OS group and stratify them to UnFav OS or Fav OS groups. Conclusion: Plasma-based molecular markers are predictive for RA-223 efficacy. An association between OS and immune and DDR profiles in men with BM-CRPC may indicate mechanism of action and identify subsets most likely to benefit. These preliminary results provide rationale for combination therapy with RA-223 and immune-checkpoint blockade or PARP inhibition. Clinical trial information: NCT02135484. [Table: see text]

169 Background: Cabozantinib (Cabo), a tyrosine kinase inhibitor of c-Met and VEGFR2, modulates the tumor microenvironment in a therapeutically favorable manner. We combined Cabo with androgen deprivation therapy (ADT) in patients (pts) with androgen-dependent metastatic prostate cancer (PCa) (NCT01630590). Methods: Pts received Cabo (starting dose 60 mg PO daily) and ADT with a GnRH analogue. Pts could receive up to 3 months of ADT prior to initiating Cabo. Bone scan (BS) and CT scans were performed every 12 weeks (wks). Efficacy endpoints included response in markers, BS and RECIST, and time to castrate-resistant progression defined by radiographic progression, clinical progression, or receipt of additional anti-cancer therapy. Results: From 01/27/2014 to 01/12/2016, 62 pts were enrolled: 94% (58/62) with bone metastasis, 56% (35/62) with measurable disease, 15% (9/62) with visceral involvement and 26% (16/62) with prior treatment of their primary tumor. 79% (49/62) of pts have high volume disease defined by > 4 bone lesions and/or involvement of viscera. Median time from start of ADT to start of Cabo was 3.4 wks. Improvements in BS were observed in 81% (44/54) of evaluable pts including complete responses (CR) in 15% (8/54). In evaluable pts with measurable disease, best response was stable disease in 9% (3/33), PR in 61% (20/33) and CR in 30% (10/33). Reductions in PSA > 90%, bone specific alkaline phosphatase > 50% and urine N-telopeptides > 50% occurred in 83% (50/60), 87% (34/39), 86% (19/22) of evaluable pts, respectively. With a median follow up of 21.4 months (mo), median PFS is 15.6 mo. Median duration of Cabo treatment is 13 mo. Most common toxicities are Grade 3 hypertension (16%), pulmonary embolus (6%), diarrhea (4%), fatigue (3%), nausea (3%), and deep venous thrombosis (3%) with no Grade 4 events. Cabo dose reductions to 40 and 20 mg occurred in 68% and 18% of pts, respectively, with discontinuations due to toxicity in 10% of pts. Conclusions: Cabo plus ADT has potent clinical activity in pts with high volume androgen-dependent PCa including improvements BS and reduction in markers of bone stromal function. Studies are underway to identify biomarkers predictive of best response. Clinical trial information: NCT01630590.

250 Background: Testicular germ cell tumor survivors (TGCTSs) contend with treatment side effects for decades after cure, and many have metabolic syndrome (MTS), a modifiable cardiometabolic risk factor. Because reliably predicting MTS could prompt interventionreducing risk, we analyzed clinical data and body composition in computed tomography (CT) scans to identify associations. Methods: In a retrospective review of 196 TGCTSs treated at a single institution from 1970 to 2007, we collected patient (pt) demographics, clinical data, body fat composition measures, and evidence from CT scans from baseline through posttreatment. NIH Image J was used to analyze cross-sectional CT images and measured subcutaneous adipose tissue, visceral adipose tissue, and skeletal muscle. Visceral fat-to-muscle ratio (VMR), visceral-to-subcutaneous fat ratio (VSR), and change in VMR and VSR from baseline to 3 to 5 years posttreatment (ΔVMR and ΔVSR) were calculated. We also gathered posttreatment glucose, blood pressure, lipid data, and body weight and height measured at time of scans. The 2001 U.S. National Cholesterol Education Program Adult Treatment Panel III guideline defined MTS. Univariate and multivariate logistic regression analyses identified associations. Results: Of the 167 pts included in the final analysis, 37.7% had MTS, 76.6% were white, and 68.9% had chemotherapy. Pts with MTS had significantly higher VMRs (p = .007) and VSRs (p = .021) than those without. Pts receiving chemotherapy and radiotherapy were significantly more likely to have MTS (p = .044 and p = .037). A multinomial logistic regression model including year of diagnosis, age, race, tumor histology, treatment, VSR, and VMR identified the association of high VMR and VSR with MTS; ΔVMR and ΔVSR were not statistically significant predictors. Conclusions: Body composition analyses identified VMR and VSR as significant predictors of MTS.