Liu, Joyce F.

5515 Background: Clear cell ovarian carcinoma (CCOC) is a chemoresistant subtype of ovarian cancer. Immune checkpoint inhibitors have been reported to have clinical activity in CCOC. Additionally, CCOC harbors molecular alterations suggesting a role for anti-angiogenic agents. We therefore conducted a single-arm two-stage phase 2 trial to investigate the clinical activity of the combination of the PD-1 inhibitor pembrolizumab with the anti-angiogenic tyrosine kinase inhibitor lenvatinib in patients (pts) with CCOC. Methods: Pts with CCOC and measurable disease received pembrolizumab 200 mg IV every 3 weeks and lenvatinib 20 mg daily. Pts could have received an unlimited number of prior therapies; prior bevacizumab and immune checkpoint inhibitors were allowed, but prior lenvatinib was exclusionary. Malignant bowel involvement was not allowed. Co-primary endpoints were objective response rate (H 0 5%; H a 25%) and rate of PFS at 6 months (mo) per RECIST v1.1 (H 0 10%; H a 30%), restricting the probabilities of type I and type II errors to 10% and 10%, respectively. Two pts with objective responses or 3 pts progression-free and alive at 6 mos were needed to proceed from stage 1 (n=18) to stage 2 (n=13); 5 pts with objective responses or 6 pts progression-free and alive at 6 mos were needed to declare the combination worthy of further study. Results: Data cut-off occurred 22-Oct-2024. Of 30 enrolled pts, 83.3% were white; the mean age among all pts was 54.1 years. 30% of pts (9/30) experienced a confirmed response (2 CR, 7 PR); an additional 3 pts (10%) experienced unconfirmed PRs and 4 pts (13.3%) had SD ≥6 mo. As of data cut-off, 3 pts (10%) had not yet reached their first radiographic assessments, and 17 pts were still receiving study therapy. With a median of 9.72 mo of follow up, 16 pts were alive and progression-free at 6 months. The estimated 6-month PFS was 75.96% (95% CI 53.82-88.51%). Median PFS was 10.9 mo. The estimated 12-month PFS was 48.86% (95% CI 23.67-70.04%). The most common any-grade TRAEs were hypertension (71%), hypothyroidism (66%), and fatigue (60%). There were no unanticipated TRAEs. Conclusions: The combination of pembrolizumab/lenvatinib demonstrates encouraging evidence of clinical activity in CCOC, with 9 pts experiencing a confirmed response and 16 pts alive and progression-free at 6 months. As both co-primary endpoints of the study were met, enrollment closed with 30 pts. Updated data for all pts will be reported. There were no new safety signals. Clinical trial information: NCT05296512 .

The NCCN Guidelines for Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer provide multidisciplinary diagnostic workup, staging, and treatment recommendations for this disease. These NCCN Guidelines Insights detail how the evolution of the use of PARP inhibitors as maintenance and single-agent regimens for the treatment of ovarian cancer informed panel recommendations in the guidelines.

TPS5642 Background: The landscape in the management of recurrent or persistent endometrial cancer (EC) continues to evolve. Anti-PD-1/PD-L1 immune checkpoint inhibitors (ICI) as monotherapy or when combined with the VEGF-targeted tyrosine kinase inhibitor, lenvatinib, have demonstrated promising response rates in patients (pts) with microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) and MS-stable (MSS)/MMR-proficient (MMRp) EC, respectively. Recent studies have also shown a benefit with adding ICI to standard of care chemotherapy in the frontline setting. Pts with MSI-H/dMMR tumors seem to derive the greatest benefit. Approximately, 30% of recurrent EC pts fall into this category. Pairing ICI with targeted therapies carries the potential to elicit prolonged anti-tumor effects. Atezolizumab (Atezo) is a humanized monoclonal PD-L1 inhibitor that has demonstrated monotherapy antitumor activity in relapsed recurrent EC, and other solid tumors (e.g. NSCLC, HCC) as monotherapy and as part of combinatorial therapy. The AFT-50/EndoMAP study is a phase IB/II non-randomized, multicenter, 2-arm, multi-cohort platform trial designed to evaluate the efficacy and safety of biomarker-driven combination regimens, both with Atezo (AFT-50A) and without Atezo (AFT-50B) with biomarker-defined targeted agents in pts with recurrent or persistent EC. Methods: Eligible pts have recurrent or persistent EC with no more than 2 prior lines of therapy. FoundationOne CDx (F1CDx) NGS assay will be used for genomic tumor profiling. In AFT-50A, pts may be eligible for one of the following doublets: Atezo+talazoparib (tumors with genomic loss of heterozygosity (gLOH ≥16%), Atezo+Trastuzumab emtansine (ERBB2/HER2 mutated or amplified tumors), and Atezo+Tiragolumab (MSI-H and/or TMB-H). The Atezo+bevacizumab (biomarker unmatched) and Atezo+ipatasertib (PIK3CA/PTEN/AKT1-altered tumors) cohorts have completed accrual. Each cohort will enroll ~20 pts with potential adjustment to account for statistical and clinical considerations. AFT-50A pts will receive Atezo in addition to a targeted agent (per study-approved dosing schedule) until progression, unacceptable toxicity, pt withdrawal, death, or study termination. AFT-50B pts will be eligible for inavolisib (PIK3CAm/PTEN and AKT1wt-altered tumors) + letrozole or giredestrant + abemaciclib (RB1wt, estrogen receptor positive tumors). The primary endpoint for AFT-50A is confirmed overall response rate (ORR) for each arm, and for AFT-50B is 6-month progression free survival. Secondary endpoints include disease control rate, duration of response, OS, safety and tolerability. As a platform study, additional arms may be added, as supported by evolving understanding of EC and molecular targets. EndoMAP is actively enrolling at 20 sites in the US with a target of 25 sites nationwide. Clinical trial information: NCT04486352 .

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.

PURPOSE The multicenter, open-label, randomized phase 2 NCI-9944 study ( NCT02595892 ) demonstrated that addition of ATR inhibitor (ATRi) berzosertib to gemcitabine increased progression-free survival (PFS) compared to gemcitabine alone (hazard ratio [HR]=0.57, one-sided log-rank P = .044, which met the one-sided significance level of 0.1 used for sample size calculation). METHODS We report here the final overall survival (OS) analysis and biomarker correlations (ATM expression by immunohistochemistry, mutational signature 3 and a genomic biomarker of replication stress) along with post-hoc exploratory analyses to adjust for crossover from gemcitabine to gemcitabine/berzosertib. RESULTS At the data cutoff of January 27, 2023 (>30 months of additional follow-up from the primary analysis), median OS was 59.4 weeks with gemcitabine/berzosertib versus 43.0 weeks with gemcitabine alone (HR 0.79, 90% CI 0.52 to 1.2, one-sided log-rank P = .18). An OS benefit with addition of berzosertib to gemcitabine was suggested in patients stratified into the platinum-free interval ≤3 months (N = 26) subgroup (HR, 0.48, 90% CI 0.22 to 1.01, one-sided log-rank P =.04) and in patients with ATM-negative/low (N = 24) tumors (HR, 0.50, 90% CI 0.23 to 1.08, one-sided log-rank P = .06). CONCLUSION The results of this follow-up analysis continue to support the promise of combined gemcitabine/ATRi therapy in platinum resistant ovarian cancer, an active area of investigation with several ongoing clinical trials.

TPS5634 Background: The prognosis for women with recurrent or persistent EC after progressing on first-line chemotherapy is poor, with a median overall survival (OS) of 12 months, highlighting the need for more efficacious therapies for this population. Immune checkpoint inhibitors either as monotherapy or when combined with kinase inhibitors have recently demonstrated encouraging response rates in pts with microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) and MS-stable (MSS)/MMR-proficient (MMRp) EC, respectively. Atezo is a humanized monoclonal anti-programmed cell death ligand 1 (PD-L1) inhibitor that has demonstrated monotherapy antitumor activity with an acceptable safety profile in relapsed recurrent EC. Atezo has shown compelling clinical efficacy for pts with certain solid tumors (e.g., urothelial, NSCLC, triple negative breast cancer) as monotherapy and as part of combinatorial therapy. The AFT-50 EndoMAP trial is a platform trial designed to evaluate the efficacy and safety of Atezo in combination with biomarker-defined targeted agents in pts with recurrent or persistent EC. Recognizing pts may have either progressed through or received a checkpoint inhibitor in a prior line of therapy, a non atezo cohort will also be open to enrollment. Methods: This is a phase IB/II non-randomized, multicenter, multicohort, biomarker-driven platform study consisting of two cohorts: A (atezo containing) and B (non atezo). Eligible pts have recurrent or persistent EC and have received no more than 2 prior lines of therapy. FoundationOne CDx (F1CDx) NGS assay will be used for genomic tumor profiling. In cohort A, pts may be eligible for one of the following doublets: Atezo+ipatasertib (PIK3CA/PTEN/AKT1-altered cancers), Atezo+talazoparib (tumors with genomic loss of heterozygosity (LOH) ≥16%), Atezo+Trastuzumab emtansine (ERBB2/HER2 mutated and/or amplified tumors), Atezo+Tiragolumab (MSI-H and/or TMB>10 mut/MB), and Atezo+bevacizumab (biomarker unmatched). Pts will receive Atezo in addition to the targeted agent (at the study approved dosing schedule) until progression, unacceptable toxicity, pt or physician decision to withdraw from the study, death, or study termination. Pts in cohort B, will be eligible for inavolisib (PIK3CA/PTEN/AKT1-altered cancers) + letrozole. Each cohort will enroll ~20 pts; however, the exact size of the cohort may be adjusted. The primary endpoint for Cohort A is confirmed overall response rate (ORR) for each cohort, and for Cohort B is progression free survival at 6 months. Secondary endpoints include disease control rate, duration of response, OS, safety and tolerability, 6-month PFS (cohort A). As a platform study, additional arms may be added, as supported by evolving understanding of EC and molecular targets. EndoMAP is actively enrolling at 17 sites in the US with a target of 25 sites nationwide. Clinical trial information: NCT04486352 .

5512 Background: The multicenter, open-label, randomized phase 2 NCI-9944 study (NCT02595892) demonstrated that addition of ATR inhibitor (ATRi) berzosertib to gemcitabine increased progression-free survival (PFS) compared to gemcitabine alone (HR = 0.57, one-sided log-rank p = 0.044, which met the one-sided significance level of 0.1 used for sample size calculation). Final overall survival (OS) and corresponding biomarker analyses are reported here. Methods: Patients (pts) with platinum-resistant high-grade serous ovarian cancer and unlimited previous lines of cytotoxic therapy in the platinum-sensitive setting but no more than one line of cytotoxic therapy in the platinum-resistant setting, were randomized 1:1 to gemcitabine/berzosertib versus gemcitabine alone. Randomization was stratified based on platinum free interval (PFI), PFI≤3 months versus > 3 months. Crossover from gemcitabine to gemcitabine/berzosertib was allowed upon disease progression by RECIST 1.1. OS was a secondary endpoint while preplanned exploratory correlative studies included assessment of DNA repair pathways and replication stress (RS) alterations by targeted gene sequencing and/or immunohistochemistry (IHC). Results: Seventy pts were randomly assigned to treatment with gemcitabine/berzosertib (34 pts) or gemcitabine alone (36 pts); 15 pts crossed over from gemcitabine to gemcitabine/berzosertib. At the final OS analysis (92.9% maturity), median follow-up was 53.2 weeks in the gemcitabine/berzosertib and 43 weeks in the gemcitabine alone groups. Median OS in the intent-to-treat (ITT) population was 59.4 weeks in the gemcitabine/berzosertib group versus 43.0 weeks in the gemcitabine alone group (HR 0.79, 90% CI 0.52-1.2, one-sided p = 0.18). However, when patients who crossed over to gemcitabine/berzosertib were excluded from analysis, a significant OS benefit was observed with gemcitabine/berzosertib (HR 0.60, 90%CI 0.37−0.97); HR was 0.26 (90% CI 0.1−0.7) in pts with PFI≤3 months and 0.89 (90%CI 0.50−1.59) in pts with PFI > 3 months. Furthermore, significant OS benefit was observed in pts with RS-low tumors (HR 0.39, 90%CI 0.17−0.91, defined as tumors harboring no genomic RS alterations related to loss of RB pathway regulation and/or oncogene-induced RS) but not in pts with RS-high tumors (HR 0.74, 90%CI 0.35−1.56). Additional targeted gene sequencing and IHC analyses as well as analyses adjusting for patient crossover will be reported at the meeting. Conclusions: In the ITT population, gemcitabine/berzosertib did not significantly improve OS versus gemcitabine alone. Pts with PFI≤3 months and pts with RS-low tumors may derive a survival advantage from addition of berzosertib to gemcitabine in the platinum-resistant setting. Clinical trial information: NCT02595892 .

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States, with less than half of patients living >5 years following diagnosis. The NCCN Guidelines for Ovarian Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with ovarian, fallopian tube, and primary peritoneal cancers. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines, including revised guidance on alternative chemotherapy regimens for patients with advanced age and/or comorbidities, a new algorithm for recurrent low-grade serous carcinoma based on developing research and novel therapeutic agents, and updated language regarding tumor molecular analysis applications in ovarian cancer.

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States and is the country’s fifth most common cause of cancer mortality in women. A major challenge in treating ovarian cancer is that most patients have advanced disease at initial diagnosis. These NCCN Guidelines discuss cancers originating in the ovary, fallopian tube, or peritoneum, as these are all managed in a similar manner. Most of the recommendations are based on data from patients with the most common subtypes─high-grade serous and grade 2/3 endometrioid. The NCCN Guidelines also include recommendations specifically for patients with less common ovarian cancers, which in the guidelines include the following: carcinosarcoma, clear cell carcinoma, mucinous carcinoma, low-grade serous, grade 1 endometrioid, borderline epithelial, malignant sex cord-stromal, and malignant germ cell tumors. This manuscript focuses on certain aspects of primary treatment, including primary surgery, adjuvant therapy, and maintenance therapy options (including PARP inhibitors) after completion of first-line chemotherapy.

Abstract Background: The combination of cediranib (ced) and olaparib (olap) improves progression-free survival and overall response rates (ORR) in women with recurrent plat sensitive high-grade serous (HGS) ovarian cancer compared to olap alone. In this Phase 2 study of ced/olap in women with relapsed ovarian cancer (NCT02345265), we observed an ORR of 74% with ced/olap in plat sensitive relapsed patients (pts) and an ORR of 20% in plat resistant pts. BROCA-HR was performed to characterize tumor HRD status and to correlate this with the activity of ced/olap in the plat sensitive and resistant settings. Methods: Pts with relapsed ovarian cancer across 11 centers were enrolled to 2 cohorts, either plat sensitive or resistant. All pts received ced 30mg daily and olap tablets 200mg BID. Archival, pre-treatment, and on-treatment biopsies were collected on all pts where safely feasible; pts also had the option of undergoing a post-progression biopsy. A baseline blood sample was collected for germline testing and matched control. Available samples were sequenced with BROCA-HR, and HRD status was determined by (1) presence of an HR-related mutation or (2) an increase in loss of heterozygosity (LOH) score. Results: 72 pts were enrolled, with 70 pts receiving study treatment (35 plat sensitive and 35 plat resistant). BROCA-HR analysis is complete on 60 samples, with 10 samples in final analysis. The concordance of HRD status by presence of an HR-related mutation or by LOH score was relatively low (agreement=36/60=60%, Cohen's Kappa=0.28). In 19 pts with a germline BRCA mutation, 16 were HRD+ by LOH (LOH high), 2 were HRD- by LOH (LOH low), and 1 not quantifiable. 3 pts had a somatic BRCA mutation; 1 was LOH high, 1 LOH low, and 1 not quantifiable. 4 pts had non-BRCA somatic HR-related mutations (3 CDK12; 1 ATR); 3 were LOH high and 1 LOH low. Of the 34 pts without HR-related mutations, 15 were LOH high, 16 were LOH low, and 3 not quantifiable. In 29 plat sensitive pts with BROCA-HR results, 18 were HRD+ by mutation (12 germline BRCA, 3 somatic BRCA, 3 somatic other), and 16 were HRD+ by LOH (LOH high). The ORR in plat sensitive pts by HRD status with available HRD results was: 22/29=75.9% (13/18=72% HRDmut+; 9/11=82% HRDmut-); (12/16=75% LOH high; 6/9= 67% LOH low). In 31 plat resistant pts with BROCA-HR results, 8 were HRD+ by mutation (7 germline BRCA, 0 somatic BRCA, 1 somatic other), and 19 were HRD+ by LOH. The ORR in plat resistant pts by HRD status with available HRD results was: 7/31=22.6% (4/8=50% HRDmut+; 3/23=13% HRDmut-, P=0.05); (7/19=37% LOH high; 0/11= 0% LOH low, P=0.03). Updated results with the full data set are pending. Conclusion: Ced/olap has clinical activity in women with relapsed ovarian cancer, both in the plat sensitive and plat resistant settings. In women with plat sensitive disease, where response rates are high, HRD status by presence of an HR-related mutation or LOH status does not appear to provide significant additional information regarding likelihood of response. In women with plat resistant disease, the presence of HRD by an HR-related mutation or LOH status is correlated with a higher likelihood of response. Citation Format: Joyce F Liu, Su-Chun Cheng, Robert M Wenham, Andrea E Wahner Hendrickson, Deborah K Armstrong, Nancy Chan, David E Cohn, Jung-Min Lee, Richard T Penson, Mihaela Cristea, James Abbruzzese, Koji Matsuo, Alexander B Olawaiye, Jennifer Curtis, Geoffrey Shapiro, Ursula A Matulonis, Elise Kohn, Percy Ivy, Elizabeth M Swisher. Correlation of homologous recombination deficiency (HRD) status by BROCA-HR sequencing with response to combination cediranib and olaparib in relapsed ovarian cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A074. doi:10.1158/1535-7163.TARG-19-A074