Prospective clinical sequencing of advanced endometrial cancer can help refine prognosis and aid treatment decision making by simultaneously detecting microsatellite status, germline predisposition syndromes, and potentially actionable mutations. A small overall proportion of all patients tested received investigational, genomically matched therapy as part of clinical trials.

BackgroundThere are limited treatment options for patients with metastatic or recurrent cervical cancer. Platinum-based chemotherapy plus the anti-vascular endothelial growth factor antibody bevacizumab remains the mainstay of advanced treatment. Pembrolizumab is Food and Drug Agency approved for programmed death ligand 1 (PD-L1) positive cervical cancer with a modest response rate. This is the first study to report the efficacy and safety of the PD-L1 antibody atezolizumab in combination with bevacizumab in advanced cervical cancer.MethodsWe report the results from a phase II, open-label, multicenter study (NCT02921269). Patients with advanced cervical cancer were treated with bevacizumab 15 mg/kg intravenous every 3 weeks and atezolizumab 1200 mg intravenous every 3 weeks. The primary objective was to measure the objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety.ResultsIn the total evaluable population (n=10), zero patients achieved an objective response as assessed by Response Evaluation Criteria In Solid Tumors (RECIST) V.1.1, resulting in a confirmed ORR of 0%. Of note, there were two patients who achieved an unconfirmed PR. The DCR by RECIST V.1.1 was 60% (0% complete response, 0% partial response, 60% stable disease). Median PFS was 2.9 months (95% CI, 1.8 to 6) and median OS was 8.9 months (95% CI, 3.4 to 21.9). Safety results were generally consistent with the known safety profile of both drugs, notably with two high-grade neurologic events.ConclusionsThe combination of bevacizumab and atezolizumab did not meet the predefined efficacy endpoint, as addition of bevacizumab to PD-L1 blockade did not appear to enhance the ORR in cervical cancer.

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Background: Patients with highly mutated tumors, such as melanoma or smoking-related lung cancer, have higher rates of response to immune checkpoint blockade therapy, perhaps due to increased neoantigen expression. Many chemotherapies including platinum compounds are known to be mutagenic, but the impact of standard treatment protocols on mutational burden and resulting neoantigen expression in most human cancers is unknown. Methods: We sought to quantify the effect of chemotherapy treatment on computationally predicted neoantigen expression for high grade serous ovarian carcinoma patients enrolled in the Australian Ovarian Cancer Study. In this series, 35 of 114 samples were collected after exposure to chemotherapy; 14 are matched with an untreated sample from the same patient. Our approach integrates whole genome and RNA sequencing of bulk tumor samples with class I MHC binding prediction and mutational signatures extracted from studies of chemotherapy-exposed Caenorhabditis elegans and Gallus gallus cells. We additionally investigated the relationship between neoantigens, tumor infiltrating immune cells estimated from RNA-seq with CIBERSORT, and patient survival. Results: Greater neoantigen burden and CD8+ T cell infiltration in primary, pre-treatment samples were independently associated with improved survival. Relapse samples collected after chemotherapy harbored a median of 78% more expressed neoantigens than untreated primary samples, a figure that combines the effects of chemotherapy and other processes operative during relapse. The contribution from chemotherapy-associated signatures was small, accounting for a mean of 5% (range 0-16) of the expressed neoantigen burden in relapse samples. In both treated and untreated samples, most neoantigens were attributed to COSMIC Signature (3), associated with BRCA disruption, Signature (1), associated with a slow mutagenic process active in healthy tissue, and Signature (8), of unknown etiology. Conclusion: Relapsed ovarian cancers harbor more predicted neoantigens than primary tumors, but the increase is due to pre-existing mutational processes, not mutagenesis from chemotherapy.

4509 Background: Somatic DDR alts are associated with increased mutation load (ML) and improved clinical outcomes for platinum-treated mUC (Teo et al, CCR 2017). We examined the relationship between DDR alts and response to PD1/PDL1 blockade. Methods: mUC pts enrolled to phase 2 trials of atezolizumab or nivolumab who had targeted exon sequencing of 410 genes (MSK-IMPACT) were identified. Pts were dichotomized based on presence of alts in a panel of 34 DDR genes. Analyses were performed based on: (1) any DDR alts and (2) deleterious DDR alts (frameshift, splice site, nonsense or Hotspot point mutations). Study endpoint was overall response (OR) per RECIST. ML was defined as total number of nonsynonymous mutations by MSK-IMPACT. Fisher exact, Wilcoxon rank sum, and stratified logistic regression were used. Results: Fifty two pts were identified (atezo: n=18, nivo: n=34). Median age was 67 years (range: 32 – 84) and majority (44) was male. Median platinum-free interval was 10.2 months (range: 0.3 – 150.4). DDR and deleterious DDR were seen in 25 (48.1%) and 14 (26.9%) pts (including 2 MSI and 1 POLE). OR rate was 46.2%. Responses were associated with DDR alts but not with age, gender, treatment, platinum-free interval or ML (table). In univariate logistic regression model, DDR status was associated with OR (p<.001) while a trend was observed with ML as a continuous variable (p=.051). While DDR alts were associated with higher ML (all: p=.001, deleterious: p=.004), the effect of DDR alts on OR remained significant regardless of ML (>median: p=.027; ≤median: p=.023), indicating that the effect of DDR was independent of ML. Conclusions: DDR alts appeared to be associated with OR to PD1/PDL1 blockade and should be integrated into future validation efforts along with other potential predictors of response. [Table: see text]

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514 Background: Durable benefit with CTLA4 or PD1 blockade associates with high somatic mutation burden in melanoma and lung cancer (Snyder, NEJM 2014; Rizvi, Science 2015). The same studies suggest that tumor neoantigens arising from somatic mutations may be mediating this association. For RCC, a disease with a comparatively low mutation burden but good response to PD1 directed therapy, such associations are unknown. To examine these concepts, we used whole exome (WES) and transcriptome (RNAseq) sequencing of RCC samples from pts treated with nivolumab (Nivo). Methods: WES and RNASeq were performed on frozen pre-treatment tumor/normal tissue for 7 pts treated with Nivo and 1 pt treated with ipilimumab/Nivo (Ipi/Nivo) x 4 followed by Nivo. Efficacy was assessed by RECIST. Neoantigen prediction and HLA typing were performed in silico using NetMHC3.2 and ATHLATES, respectively. Expression of predicted neoantigens and putative pathways of resistance/response were investigated using DESeq-normalized reads. Results: Two of 7 Nivo-monotherapy pts achieved durable clinical benefit (DCB, PR > 12 months); 1 pt had a non-durable PR (5 months). For 2 Nivo/DCB pts, the burden of non-synonymous somatic mutations was 113 and 224 compared to a median of 95 in those with no DCB (range 53-124). The ratio of predicted neoantigens/total mutations was higher for pts with DCB/Objective response (all ≥ 0.5) compared to those with progressive disease (all < 0.5). The Ipi/Nivo pt experienced > 95% tumor regression ongoing 2+ years, but harbored the lowest mutation count (29) and lowest neoantigen/mutation ratio ( < 0.2) in the cohort. Across all pts, 80% of predicted neoantigens were expressed. Further, RNASeq findings differed distinctly for DCB vs. non-DCB pts in various genes of interest, including mediators of antigen presentation to T-cells (HLA-A, -B, -C; B2M) and composition of other immune regulators (CSF1R, LGALS1), but not for PDL1. Conclusions: In RCC, somatic mutations, particularly those causing tumor neoantigens, and the counterbalance between molecular immune compartments may be determinants of treatment benefit from Nivo and warrant future study. Their impact might be distinctly different in pts treated with combination immunotherapy.