Faculty Bibliography

OBJECTIVES/OBJECTIVE:Patients with germline mutations in mismatch repair genes (MLH1, MSH2, MSH6, PMS2) associated with Lynch syndrome (LS) have an increased lifetime risk of endometrial cancer (EC). Multi-gene panel testing (MGPT) is a recent hereditary cancer risk tool enabling next-generation sequencing of numerous genes in parallel. We determined the prevalence of actionable cancer predisposition gene mutations identified through MGPT in an EC patient cohort. METHODS:A single center retrospective cohort study was conducted of patients with EC who had a clinical indication for genetic testing and who underwent MGPT as part of standard of care treatment between 2012 and 2021. Pathogenic mutations were identified and actionable mutations were defined as those with clinical management implications. Additionally, the number of individuals identified with LS was compared between MGPT and tumor-based screening. RESULTS:The study included a total of 224 patients. Thirty-three patients [14.7%, 95% confidence interval (CI) = 10.4-20.1] had actionable mutations. Twenty-one patients (9.4%, 95% CI = 5.9-14.0) had mutations in LS genes (4 MLH1, 5 MSH2, 7 MSH6, 4 PMS2, 1 Epcam-MSH2). MGPT revealed two patients with LS (9.5% of LS cases) not identified through routine tumor-based screening. Thirteen patients (5.8%, 95% CI = 3.1-9.7) had at least one actionable mutation in a non-Lynch syndrome gene (6 CHEK2, 2 BRCA2, 2 ATM, 2 APC, 1 RAD51C, 1 BRCA1). CONCLUSIONS:Germline MGPT is both feasible and informative as it identifies LS cases not found on tumor testing as well as additional actionable mutations in patients with EC.

OPINION STATEMENT/UNASSIGNED:Poly-ADP-ribose polymerase inhibitors (PARPi) are a class of anti-cancer drugs that target DNA repair pathways and have shown promising efficacy in patients with ovarian cancer in recent clinical trials. To date, there have been 9 FDA PARPi approvals/indications in ovarian cancer since 2014, highlighting the importance of this class of agents in the treatment of ovarian cancer. BRCA1/2-mutated tumors or other forms of homologous recombination deficient (HRD) tumors are particularly susceptible to PARP inhibition and have seen the greatest benefits of improvement in response rate and progression-free survival (PFS) in clinical trials. Patients with homologous recombination-proficient tumors also receive benefit, especially when a nice response to paltinum is noted, but to a lesser extent. PARP inhibitors now have FDA approval and indications in first-line and recurrent maintenance, and treatment. PARP inhibitor use as maintenance therapy in the front-line setting is now considered the standard of care in patients with BRCA1/2 mutations based on the SOLO-1/GOG-3004/ENGOT study. PARP inhibitors are also recommended per ASCO guidelines in all patients with ovarian cancer as front-line maintenance therapy based on the PRIMA/ENGOT-OV26/GOG-3012 trial. The combination of PARP inhibitor, olaparib, and the anti-angiogenesis inhibitor bevacizumab is also approved as maintenance therapy after front-line chemotherapy treatment in patients with HRD tumors and is an option for patients who have initiated bevacizumab with their chemotherapy treatment. PARPi are also FDA approved and can be utilized as a treatment in third-line and beyond in recurrent ovarian cancer patients with BRCA1/2 mutations and HRD tumors. In this review, we will cover in detail when PARP inhibitor use is appropriate in ovarian cancer, as well as the various clinical factors to take into consideration when selecting a PARP inhibitor regimen.

BACKGROUND:Dostarlimab is a humanized monoclonal antibody that binds with high affinity to PD-1, resulting in inhibition of binding to PD-L1 and PD-L2. We report interim data from patients with endometrial cancer (EC) participating in a phase I trial of single-agent dostarlimab. METHODS:GARNET, an ongoing, single-arm, open-label, phase I trial of intravenous dostarlimab in advanced solid tumors, is being undertaken at 123 sites. Two cohorts of patients with EC were recruited: those with dMMR/MSI-H disease (cohort A1) and those with proficient/stable (MMRp/MSS) disease (cohort A2). Patients received dostarlimab 500 mg every 3 weeks for 4 cycles, then dostarlimab 1000 mg every 6 weeks until disease progression. The primary endpoints were objective response rate (ORR) and duration of response (DOR) per RECIST V.1.1, as assessed by blinded independent central review. RESULTS:Screening began on April 10, 2017, and 129 and 161 patients with advanced EC were enrolled in cohorts A1 and A2, respectively. The median follow-up duration was 16.3 months (IQR 9.5-22.1) for cohort A1 and 11.5 months (IQR 11.0-25.1) for cohort A2. In cohort A1, ORR was 43.5% (95% CI 34.0% to 53.4%) with 11 complete responses and 36 partial responses. In cohort A2, ORR was 14.1% (95% CI 9.1% to 20.6%) with three complete responses and 19 partial responses. Median DOR was not reached in either cohort. In the combined cohorts, the majority of treatment-related adverse events (TRAEs) were grade 1-2 (75.5%), most commonly fatigue (17.6%), diarrhea (13.8%), and nausea (13.8%). Grade≥3 TRAEs occurred in 16.6% of patients, and 5.5% discontinued dostarlimab because of TRAEs. No deaths were attributable to dostarlimab. CONCLUSION:Dostarlimab demonstrated durable antitumor activity in both dMMR/MSI-H (ORR 43.5%) and MMRp/MSS EC (ORR 14.1%) with a manageable safety profile. TRIAL REGISTRATION NUMBER:NCT02715284.

BACKGROUND:Despite significant increase in COVID-19 publications, characterization of COVID-19 infection in patients with gynecologic cancer remains limited. Here we present an update of COVID-19 outcomes among people with gynecologic cancer in New York City (NYC) during the initial surge of severe acute respiratory syndrome coronavirus 2 (coronavirus disease 2019 [COVID-19]). METHODS:Data were abstracted from gynecologic oncology patients with COVID-19 infection among 8 NYC area hospital systems between March and June 2020. Multivariable logistic regression was utilized to estimate associations between factors and COVID-19 related hospitalization and mortality. RESULTS:Of 193 patients with gynecologic cancer and COVID-19, the median age at diagnosis was 65.0 years (interquartile range (IQR), 53.0-73.0 years). One hundred six of the 193 patients (54.9%) required hospitalization; among the hospitalized patients, 13 (12.3%) required invasive mechanical ventilation, 39 (36.8%) required ICU admission. Half of the cohort (49.2%) had not received anti-cancer treatment prior to COVID-19 diagnosis. No patients requiring mechanical ventilation survived. Thirty-four of 193 (17.6%) patients died of COVID-19 complications. In multivariable analysis, hospitalization was associated with an age ≥ 65 years (odds ratio [OR] 2.12, 95% confidence interval [CI] 1.11, 4.07), Black race (OR 2.53, CI 1.24, 5.32), performance status ≥2 (OR 3.67, CI 1.25, 13.55) and ≥ 3 comorbidities (OR 2.00, CI 1.05, 3.84). Only former or current history of smoking (OR 2.75, CI 1.21, 6.22) was associated with death due to COVID-19 in multivariable analysis. Administration of cytotoxic chemotherapy within 90 days of COVID-19 diagnosis was not predictive of COVID-19 hospitalization (OR 0.83, CI 0.41, 1.68) or mortality (OR 1.56, CI 0.67, 3.53). CONCLUSIONS:The case fatality rate among patients with gynecologic malignancy with COVID-19 infection was 17.6%. Cancer-directed therapy was not associated with an increased risk of mortality related to COVID-19 infection.

Background Dostarlimab is a humanized programmed death 1 (PD-1) receptor monoclonal antibody that blocks interaction with the ligands PD-L1 and PD-L2. Dostarlimab is approved as a monotherapy in adult patients (pts) with mismatch repair deficient (dMMR; US) or dMMR/microsatellite-instability high (EU) recurrent or advanced endometrial cancer that has progressed progressing on or following prior treatment with a platinum-containing regimen. GARNET is a phase 1 study assessing antitumor activity and safety of dostarlimab monotherapy in pts with solid tumors. Methods Pts with dMMR solid tumors, mismatch repair proficient endometrial cancer, and non-small cell lung cancer that progressed on or after prior therapy received 500 mg of dostarlimab IV every 3 weeks (Q3W) for 4 cycles, then 1000 mg IV every 6 weeks (Q6W) for up to 2 years or until disease progression or discontinuation. Here, we report TRAEs by cycle. Results A total of 515 pts were included. Of these pts, 60 (11.7%) experienced TRAEs leading to treatment interruption, and 25 (4.9%) experienced TRAEs leading to discontinuation. TRAEs of any grade with overall incidence of >=10% of pts are shown (table 1). The majority of TRAEs occurred during cycles 1-3, with highest incidence during cycle 1. Grade 3 or 4 TRAEs were rare; those seen in >=1% of pts are shown. Immune-related (ir) TRAEs of any grade with overall incidence of >=2% of pts are shown. Most cases (96.9%) of irTRAEs occurred during cycles 1-8. The peak incidence of hypothyroidism occurred during cycle 4; in addition, frequency was increased during cycles 5-8, compared with cycles 1-4. No deaths were attributed to dostarlimab. Abstract 370 Table 1 Time course of adverse events in the GARNET trial Conclusions No new safety signals were detected with dostarlimab compared to other anti-PD-1 inhibitors. Most TRAEs were low grade. The majority of TRAEs and grade >=3 TRAEs occurred in the first 3 cycles (first 12 weeks), but some cases occurred later, suggesting a need for ongoing monitoring. Few increases in the incidence of TRAEs were seen during cycle 5 following the transition to the 1000-mg Q6W dosing schedule; the TRAEs with increased incidence after the transition were fatigue and lipase increased. An increase in the frequency of the irTRAE hypothyroidism was seen after transitioning to the 1000-mg Q6W schedule

ABSTRACT/UNASSIGNED:The emergence of clinical trial data for poly(ADP-ribose) polymerase inhibitors (PARPi), in BRCA-associated ovarian cancer (epithelial ovarian cancer [EOC]) in 2009 (Lancet 2010;376:245-251) unleashed a rapid series of additional asset development and clinical trial activation across all lines of EOC treatment, ultimately leading to 8 new approvals of 3 different PARPi in EOC since 2014. Monotherapy iPARPi were approved as frontline maintenance treatment for all patients with EOC who respond to platinum-based chemotherapy irrespective of biomarker (niraparib) and for BRCA-associated cancers (olaparib) (https://www.azpicentral.com/lynparza_tb/lynparza_tb.pdf#page=1; https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208447s015s017lbledt.pdf). Combination of olaparib and bevacizumab was approved as maintenance for patients in response to platinum-based and bevacizumab containing frontline therapy whose tumor is characterized as homologous recombination deficient and as approved test by the Food and Drug Administration, inclusive of BRCA-associated cancers (N Engl J Med 2019;381:2416-2428). Niraparib, olaparib, and rucaparib were also approved as maintenance treatment following response to platinum-based therapy in the recurrent setting irrespective of biomarker (https://www.azpicentral.com/lynparza_tb/lynparza_tb.pdf#page=1; https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208447s015s017lbledt.pdf; https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209115s003lbl.pdf). All 3 PARPi were also approved as treatment in lieu of chemotherapy for patients with BRCA-associated cancers in third line and beyond (https://www.azpicentral.com/lynparza_tb/lynparza_tb.pdf#page=1;https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209115s003lbl.pdf) and platinum-sensitive homologous recombination deficient in the fourth line and beyond (https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208447s015s017lbledt.pdf), as well as the National Comprehensive Cancer Network listed in combination with bevacizumab for treatment of patients with platinum-sensitive recurrent disease (https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf). Ongoing clinical trials in all lines of treatment are evaluating combinations of therapies to improve efficacy among biomarker negative tumors as well as overcome acquired PARPi resistance due to prior use.

Objectives Dostarlimab is a humanized programmed death 1 (PD-1) receptor monoclonal antibody that blocks interactions with PD-1 ligands. GARNET is a phase 1 study assessing antitumor activity and safety of dostarlimab monotherapy in patients with advanced solid tumors. Methods This multicenter, open-label, single-arm study is conducted in 2 parts: dose escalation and expansion. Patients with advanced or recurrent mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) endometrial cancer (EC) or mismatch repair-proficient (MMRp) EC that progressed on or after a platinum regimen received dostarlimab 500 mg intravenously Q3W for 4 cycles, then 1000 mg Q6W until disease progression or discontinuation. Primary endpoints were objective response rate (ORR) and duration of response by BICR using RECIST v1.1. Here we report ORR in dMMR/ MSI-H and MMRp EC by prior lines of therapy (LOTs). Results Efficacy analyses included 108 dMMR/MSI-H and 142 MMRp patients. ORR was 43.5% in dMMR/MSI-H and 13.4% in MMRp. ORR was slightly higher (47.8%) in patients with dMMR/MSI-H with 1 prior LOT but lower (35.9%) in those who received >=2 prior LOTs. In the MMRp population, ORR was similar, regardless of prior LOTs. Safety has been previously reported.1 Conclusions Dostarlimab demonstrated antitumor activity in recurrent or advanced dMMR/MSI-H and MMRp EC regardless of number of prior LOTs. Patients with dMMR/MSI-H EC who received 1 prior LOT had slightly higher ORR than those who received >=2 prior LOTs. 1. Oaknin A, et al. Ann Oncol 2020;31(suppl 4):S1142-S1215