Msaouel, Pavlos

Small cell bladder cancer (SCBC) is a rare and aggressive disease, often treated with platinum/etoposide-based chemotherapy. Key molecular drivers include the inactivation of onco-suppressor genes (TP53, RB1) and amplifications in proto-oncogenes (MYC). We report a patient with SCBC who achieved an objective and prolonged response to lurbinectedin, which has been approved for metastatic small cell lung cancer, after developing disease progression on cisplatin/etoposide and nivolumab/ipilimumab. A genomic analysis of a metastatic biopsy prior to lurbinectedin initiation revealed a TP53 mutation and amplification of the cell cycle regulators E2F3 and MYCL. A repeat biopsy following the development of lurbinectedin resistance showed a new actionable ERBB2 alteration without significant change in the tumor mutation burden (six mutations/Mb). The present report suggests that lurbinectedin may be active and should be further explored in SCBC harboring TP53 mutations and amplifications in E2F3 and MYC family complexes.

4597 Background: NCCRCC are a diverse group of rare diseases with limited data to guide treatment. CABO is highly effective in clear cell RCC, but it is unknown whether it is superior to SUN, the historic standard of care for metastatic NCCRCC. Methods: CABOSUN II (NCT03541902) was a randomized phase II study at 3 centers for patients (pts) with metastatic NCCRCC. Sixty pts were planned to detect CABO as better than SUN with a 1-sided test. Pts were randomized 1:1 to CABO 60mg daily or SUN 50mg daily (4 weeks on, 2 weeks off). SUN dose modification to 2 weeks on, 1 week off was allowed for toxicity. Stratification was by papillary RCC (PRCC) vs. non-PRCC (NPRCC), good/intermediate vs. poor risk disease by IMDC criteria, and prior TKI use. The primary outcome was progression-free survival (PFS) by RECIST v1.1 compared between the 2 arms using the log-rank test. Secondary outcomes were objective response rate (ORR), overall survival (OS), and adverse event (AE) rates (2-sided tests). Results: 32 pts were randomized to CABO (N=15) or SUN (N=17) between 9/2018 and 6/2021. The trial stopped early due to a change in standard therapy for PRCC not based on these pts’ outcomes. Age range was 22-88 years with medians 57 and 61 for CABO and SUN. Pts were primarily white (84%) and male (72%), with good/intermediate risk (88%), and these were balanced between arms. More pts on the CABO arm had bone metastases (62% vs. 24%). NPRCC were chromophobe (N=6; 5 randomized to SUN), unclassified (N=5), and MiT family translocation (N=3; all randomized to CABO). With median follow-up of 33.3 months and 20 PFS events, median PFS for CABO vs. SUN was 8.2 vs. 13.8 months (1-sided p=0.96). There were no statistically significant differences in ORR or OS between the arms. AEs were in line with previous studies. Conclusions: CABO was not superior to SUN for metastatic NCCRCC in this study. Both arms had high rates of stable disease or better. Despite stratification by PRCC or NPRCC, there were major differences in NPRCC subtypes between the arms that may have impacted the results. More pts with chromophobe histology, an often indolent subtype, received SUN while all pts with MiT family translocation, a relatively aggressive subtype, received CABO. Permitted SUN dose modifications may have also influenced outcomes. While the PAPMET study showed CABO to be superior to SUN for PRCC, optimal treatments for rare, NPRCC remain a pressing need. Clinical trial information: NCT03541902 . [Table: see text]

The role of adjuvant therapy in renal cell carcinoma and urothelial carcinoma is rapidly evolving. To date, the U.S. Food and Drug Administration has approved sunitinib and pembrolizumab in the adjuvant setting for renal cell carcinoma and nivolumab for urothelial carcinoma based on disease-free survival benefit. The U.S. Food and Drug Administration held a joint workshop with the National Cancer Institute and the Society of Urologic Oncology in 2017 to harmonize design elements, including eligibility and radiologic assessments across adjuvant trials in renal cell carcinoma and urothelial carcinoma. Considerations from the discussion at these workshops led the U.S. Food and Drug Administration to draft guidances to help inform subsequent adjuvant trial design for renal cell carcinoma and urothelial carcinoma. Patient-centered decision-making is crucial when determining therapeutic choices in the adjuvant setting; utility functions can be used to help quantify each patient’s goals, values, and risk/benefit trade-offs to ensure that the decision regarding adjuvant therapy is informed by their preferences and the evolving outcomes data.

4521 Background: The MTAP gene encodes an essential enzyme for the salvage pathway of nucleotide synthesis and is frequently deleted in UBC. Anti-folate agents such as pemetrexed can effectively inhibit the de novo pathway of nucleotide synthesis and as a result, create a synthetic lethality in MTAP deficient UBC. We hypothesize that MTAP gene loss correlates with enhanced response to pemetrexed in UBC. Methods: We investigated MTAP gene deletion rates in the TCGA database and determined MTAP protein loss rates by immunohistochemistry (IHC) using a UBC tissue microarray (TMA) from 151 patients (pts). We then performed in vitro and in vivo studies using MTAP proficient and MTAP deficient bladder cancer cell lines. At the clinical level, we performed a retrospective analysis based on MTAP status of pts treated with pemetrexed as 2nd line at our institution between 2014 and 2018. We are now enrolling pts in a single-arm, open-label, phase II clinical trial (NCT02693717) with pemetrexed in pts with MTAP deficient UBC. Results: Per our TCGA and TMA IHC analyses, MTAP deficiency rate was 25.9% and 27.8%, respectively. MTAP deficient UBC cell lines were at least 40 times more sensitive to pemetrexed than MTAP proficient lines. Knockdown of the MTAP gene increased apoptosis rate by pemetrexed from approximately 20% to 60%. Additionally, pemetrexed significantly inhibited the growth of MTAP deficient or knockdown xenograft tumors but not MTAP proficient tumors. Retrospective analysis of 12 pts using RECIST criteria indicated that all 4 MTAP deficient UBC pts responded to pemetrexed whereas only 1 of 8 (12.5%) MTAP proficient UBC pts responded. Of the 6 pts enrolled on the clinical trial, 3 (50%) had complete or partial response, 1 had stable disease, 1 was not evaluable and 1 had disease progression. Combined analysis of the entire experience demonstrates a higher response rate in MTAP deficient UBC (70%) as compared to MTAP proficient UBC (12.5%). Conclusions: Our preclinical and clinical data demonstrate that MTAP loss in UBC leads to a state of synthetic lethality when treated with pemetrexed and should be further investigated as a novel biomarker to predict response to anti-folate agents.

Attenuated Edmonston lineage measles virus (MV-Edm) vaccine strains can preferentially infect and lyse a wide variety of cancer cells. Oncolytic MV-Edm derivatives are genetically engineered to express the human carcinoembryonic antigen (MV-CEA virus) or the human sodium iodide symporter (MV-NIS virus) and are currently being tested in clinical trials against ovarian cancer, glioblastoma multiforme, multiple myeloma, mesothelioma, head and neck cancer, breast cancer and malignant peripheral nerve sheath tumors. This review describes the basic and preclinical data that facilitated the clinical translation of MV-Edm strains, and summarizes the clinical results of this oncolytic platform to date. Furthermore, we discuss the latest clinically relevant MV-Edm vector developments and creative strategies for future translational steps.