Chung, Jon

PURPOSE To report the results of OPAL (ClinicalTrials.gov identifier: NCT03574779 ) cohort A, a single-arm substudy of niraparib plus dostarlimab and bevacizumab for the treatment of advanced, platinum-resistant ovarian cancer (PROC). METHODS Participants with PROC who received 1-2 previous lines of therapy were treated with niraparib (200 or 300 mg once daily), dostarlimab (500 mg once every 3 weeks for four 21-day cycles, followed by 1,000 mg once every 6 weeks), and bevacizumab (15 mg/kg once every 3 weeks). The primary end point was investigator-assessed objective response rate (ORR) per RECIST v1.1. Safety was also assessed. Exploratory biomarker end points included evaluation of changes in the tumor molecular profile and microenvironment using baseline and on-treatment tumor samples. RESULTS Of 41 enrolled participants (median age, 66.0 years [range, 37-83 years]), 9.8% had tumors that were BRCA-mutated, 19.5% were homologous recombination (HR)–deficient, and 17.1% were HR repair (HRR)–mutated. As of the cutoff date, all participants discontinued treatment. The ORR was 17.1% (80% CI, 9.8 to 27.0), including one complete response (2.4%); the disease control rate was 73.2% (80% CI, 62.3 to 82.2). Two participants withdrew before first postbaseline scan because of adverse events (AEs). Grade ≥3 treatment-emergent AEs were reported in 92.7% of participants, with the most common being hypertension (26.8%). Response was not correlated with BRCA, HRR, HR deficiency (HRD), or PD-L1 status. Changes suggesting immune activation were observed in on-treatment samples after triplet therapy. CONCLUSION Results demonstrated modest activity of niraparib, dostarlimab, and bevacizumab in participants with PROC, many of whom had prognostic factors for poor treatment response. Most participants with response were bevacizumab-naïve. No association was found with HRD, BRCA, or PD-L1 status. AEs were consistent with previous monotherapy reports, except that hypertension was reported more frequently.

Abstract Background: Immune checkpoint inhibitors (ICPIs) have led to dramatic improvement in outcome of several cancers. Program death ligand1 (PD-L1) staining and tumor mutational burden (TMB) have emerged as independent predictive biomarkers of ICPIs in lung cancer. Here we examine the landscape of TMB and PD-L1 expression in breast cancer and present a case of patient with high TMB and PD-L1 negative breast cancer with exceptional response to ICPIs. Methods: Hybrid-capture based comprehensive genomic profiling of 395 cancer related genes using the FoundationOne assay was performed on 14,867 breast carcinomas sequenced in the course of routine clinical care. Ventana (SP-263) PD-L1 status (n=1425) and hormone receptor status was available for a subset of patients. Subgroup analyses were performed based on histological type [invasive lobular carcinoma (ILC, n=740)], molecular subtypes [ER-positive (ER+; n= 1371), HER2-amplified (HER2+; n=1522), and TNBC (n=917)], patient age (≤45, 46-60, ≥61), and local vs. metastatic disease (n=5241 and 6710). Results: Consistent with previous reports, the rates of positive PD-L1 staining are highest in TNBC (14%) and lowest in HER2+, ILC, and ER+ disease (6.0%, 5.1%, 2.3%). Interestingly, the rate of PD-L1 positivity, defined as ≥1% tumor staining, was significantly lower in metastatic disease vs. local disease (6.3% vs. 11.1%; p = 0.005). The frequency of high TMB, defined as >10 mutations/mb, was greatest in ILC and HER2+ disease (13.6% and 9.9%) and lowest in TNBC and ER+ disease (7.0% and 6.9%). Rates of high TMB were associated with increased patient age (3.7%, 9.3%, and 12.8% frequency in patients ≤45, 46-60, and ≥61) and were significantly higher in metastatic vs. local disease (11.1% vs 5.3%; p<2E-23). PD-L1 positive and TMB high populations were not significantly co-occurrent (OR = 1.02, p = 0.87). Similar percentages of PD-L1 positivity were observed in both TMB low (9.3%) and TMB high (9.5%). However, among patients with very high TMB (>20 mut/mb), there was a significant association between TMB and PD-L1 positivity (OR = 2.6, p = 0.023). Nevertheless, even with high cutoff, 79% of the TMB high samples were PD-L1 negative. We also report on a stage IIIb (T4, N2, M0) ER+ HER2- breast cancer patient with high TMB (40muts/mb) and negative PD-L1 IHC who previously progressed on aromatase inhibitor with CDK4/6 inhibitor and chemotherapy but achieved durable complete response of > 1 year with nivolumab in combination with capecitabine. Conclusions: Predictive biomarkers for ICPIs are critical to identify a subset of breast cancer patients who may respond to immunotherapy. TMB high and PD-L1 positivity do not significantly co-occur and the majority of TMB high cases were PD-L1 negative. Nevertheless, this group of patients may still benefit with ICPIs. Further studies are needed to evaluate this subset of patients. Citation Format: Ethan Sokol, Lee Albacker, Aixa Soyano, Ricardo Parrondo, Brenda Ernst, Emmanuel Gabriel, Garrett Frampton, Jeffrey Ross, Siraj Ali, Jon Chung, Saranya Chumsri. Incidence of high tumor mutation burden (TMB) and PD-L1 positivity in breast cancers and potential response to immune checkpoint inhibitors (ICPIs) [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 4894.

4087 Background: The management of CCA has evolved as targeted and immune checkpoint inhibitor (ICPI) therapies have emerged. We used comprehensive genomic profiling (CGP) to characterize the genomic alterations (GA) that have potential to personalize therapy for CCA. Methods: 3634 CCA underwent hybrid capture based CGP on 0.8-1.1 Mb of the coding genome to identify GAs in exons and select introns in up to 404 genes, TMB, microsatellite status (MSI) and % monoallelic genome (gLOH). PD-L1 expression was determined by IHC (Dako 22C3). Results: 52% of CCA were female with a median age of 62 years (range 16 - > 89). The most common biopsy sites were liver (74%), lymph node (4%), bile duct (3.3%), and lung (2%). MSI-high was rare (1%), 118 and 47 cases had TMB > 10 and > 20 mut/mb respectively. Of the latter, 51% (24/47) were MSI-H. PD-L1 amplification (AMP) was present in 0.27%. Of 490 CCA tested, 43 (9%) were positive for PD-L1 expression. 11% of cases had gLOH > 16%, only 2 cases had both TMB > 20 and gLOH > 16%. GA were most common in TP53 (31%), CDKN2A (29%), KRAS (20%) and ARID1A (17%). Potentially targetable GAs included FGFR2 (11%, 85% fusions), BRAF (5%, 50% V600E), ERBB2 (5%, 72% AMP), MET (2%, 90% AMP), EGFR (0.52%) and rarer ( < 0.5%) FGFR3, RET, FGFR1, ALK, and ROS1 fusions. The FGFR2 fusions had 128 unique 3’ partner genes including BICC1 (26%), CCDC6 (3.2%), AHCYL1 (2.6%) and KIAA1217 (2.6%). FGFR2 fusions occurred in a mutually exclusive fashion from high gLOH (p < 0.002), but not high TMB. GA in IDH1 (15%) were mutually exclusive of FGFR2 fusions (p < 1e-13), but co-occurred with PBRM1 GA (23%, p < 1e-21), ARID1A (26% p < 1e-10). IDH1 GA had gLOH similar to the overall CCA population but were enriched for low TMB (p < 1e-3). Conclusions: Nearly 20% of CCA cases harbor targetable kinase GA, half of which were FGFR2 fusions. Independently, an additional 10% (gLOH) and 1% (high TMB, MSI and/or PD-L1 AMP) may benefit from PARP inhibitors and ICPI respectively. Independently, co-mutation of IDH1 and PBRM1/ARID1A defines a class of CCA that warrants further investigation for sensitivity to PARP inhibitors and may serve as a paradigm for other tumors (ie. gliomas) with a similar co-occurrence landscape.

4076 Background: Gallbladder carcinoma (GBC) is commonly diagnosed at an advanced, unresectable disease stage and has a poor prognosis. Comprehensive genomic profiling (CGP) has a developing role in guiding systemic, precision anti-cancer therapy. Methods: We performed hybrid capture-based CGP on FFPE samples for 491 consecutive advanced GBCs. Mean coverage depth was >550X for up to 315 cancer-related genes plus 37 introns from 28 genes frequently rearranged in cancer. All 4 classes of genomic alterations (GA) were detected. Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA. Results: Median age was 64 (range 25-88) and 69% (337/491) of patients were female. 96% (470), 2.9% (14), and 1.4% (7) of GBC patients had the diagnosis of adenocarcinoma, adenosquamous, or carcinoma not specified (NOS), respectively. Commonly altered genes were TP53 (62%), CDNK2A (31%), ARID1A (18%), and SMAD4 (15%), and most of the genetic aberrations (GA) were short variants. Potentially targetable SCNAs (including ERBB genes, MET, FGFRs, and the CCND1-FGF3/4/19 11q13 amplicon) were identified in 21% of cases (Table). Oncogenic BRAF, ALK, or FGFR2/3 rearrangements were found in 7 cases (1.4%). Moreover, 7.8% of cases had BRCA2 or ATM GA, and 0.8% had INI1loss suggesting benefit from PARP or EZH2 inhibitors, respectively. TMB was low; the 25th, 50th, and 75th percentiles were 2.5, 3.8 and 6.3 mutations/Mb, respectively. Less than 1% of cases had microsatellite instability. Radiological response to TKIs and immunotherapy was noted. Conclusions: In addition to the significant opportunity for anti-HER targeted therapies, other subsets of GBC cases harbored kinase GA (particularly SCNA), the 11q13 amplicon, or BRCA2/ ATM/ INI1mutations that are linked to therapeutic benefit. How the frequency of both driver SCNA and DNA repair alterations in GBC can be linked with inflammation awaits additional investigation. [Table: see text]