Faculty Bibliography

Objectives Progression-free survival (PFS) is a rational surrogate primary endpoint in ovarian cancer (OC) trials. However, PFS is subject to biases, with validity dependent upon proper methodologic assessment. Therefore, blinded independent centralized radiologic review (BICR) is often recommended. We evaluated BICR and investigator-assessed evaluation of progressive disease (PD) in the PRIMA/ ENGOT-ov26/GOG-3012 trial examining niraparib monotherapy in intent-to-treat (ITT) and homologous recombination deficient (HRd) populations. Methods In the randomized, double-blind, placebo-controlled phase 3 PRIMA/ENGOT-ov26/GOG-3012 trial, patients with newly diagnosed stage III/IV OC were assigned to receive either niraparib or placebo. The primary endpoint was PFS (per RECIST v.1.1) by BICR. Discordance between BICR and investigator assessments of PD ([#BICR reviews with unconfirmed PD assessment]/[total# investigator-triggered reviews]) was monitored throughout the study. A training intervention was developed for BICR reviewers based on PD determination in OC. Results In an initial patient subset (n=80), a 39% discordance rate was identified between BICR and investigator-assessed PD by the sponsor, most commonly due to peritoneal carcinomatosis or fluid collections arising from new non-target lesions. After reviewer intervention, final discordance rate between BICR and investigator improved to 12% and 13% for ITT (N=733) and HRd (n=373) populations, respectively (figure 1). Across the entire study population, median PFS and hazard ratios for the ITT and HRd populations were comparable between BICR and investigator (table 1). Conclusions PRIMA/ENGOT-ov26/GOG-3012 highlights the need to optimize BICR and investigator concordance using early, specialized OC-specific training to maximize trial validity. (Figure Presented)

Objectives Mismatch repair (MMR) deficiency is caused by loss of expression of MMR proteins, MLH1, PMS2, MSH2, and/or MSH6, that function as heterodimers (MLH1/PMS2 and MSH2/ MSH6) to mediate DNA repair. Loss of function caused by mutation or epigenetic methylation leads to defective MMR and genomic instability. MMR deficient (dMMR) tumors can respond to anti-programmed death 1 (PD-1) therapy. We report on a post-hoc analysis of ORR with loss of MMR dimers and mutation status of MMR genes in patients with dMMR endometrial cancer (EC) treated with dostarlimab. Methods GARNET is a multicenter, open-label, single-arm phase 1 study. Cohort A1 enrolled patients with dMMR advanced/recurrent EC. Patients received 500 mg dostarlimab intravenously Q3W for 4 cycles, then 1000 mg Q6W until disease progression, discontinuation, or withdrawal. MMR protein status (presence or loss) was determined by local IHC. MMR gene mutation was determined by Foundation One. MLH1 loss without MMR gene mutation was a surrogate indicator for epigenetic methylation. Results Cohort A1 included 143 patients; MMR gene mutation data was available for 101 (table 1). Cohort A1 ORR was 45.5%. 66% of patients had loss of MLH1/PMS2; ORR was 48.9%. 11.2% of patients had loss of MSH2/MSH6; ORR was 56.2%. ORR was 41.7% for MLH1 loss with MMR gene mutation and 39.4% for MLH1 loss without MMR gene mutation. Conclusions Patients with dMMR advanced/recurrent EC benefitted from dostarlimab, with no noticeable difference by dimer-pair loss or MMR gene methylation/mutation status. These data suggest route to MMR deficiency does not influence response to dostarlimab

Objectives Universal mismatch repair (MMR) immunohistochemistry (IHC) in endometrial cancer began at our institution in July 2015. In April 2017, genetic counselors (GC) obtained IHC data and contacted physicians to approve genetic counseling for Lynch Syndrome (LS) in eligible patients. We assessed if this protocol increased frequency of genetic counseling referrals (GCRs) and genetic testing (GT) in patients with abnormal MMR IHC. Methods We retrospectively (7/2015-6/2021) identified patients with abnormal MMR IHC at a large urban hospital. GCR and GT rates were compared between cases from 7/2015-4/ 2017 (pre-protocol) and 5/2017-6/2021 (post-protocol) with Fisher's exact test. Results Of 717 patients with IHC testing, 156 (21.8%) had abnormal MMR results: MLH1/PMS2, 123; MSH2/MSH6, 10; MSH2/PMS2, 1; MSH6, 13; MLH1, 2; PMS2, 7. MLH1 hypermethylation was identified in 114 (73.1%) patients; 42 (26.9%) patients met criteria for LS screening with GT based on IHC results. Of 42 patients, 16 (38.1%) were identified before and 26 (61.9%) after protocol initiation. GCRs significantly increased from 11/16 (68.8%) to 25/26 (96.2%) in the pre-protocol versus post-protocol groups, p=0.02. There was no statistically significant difference in GT frequency between groups (10/16, 62.5% vs 23/26, 88.5%, p=0.06). Of 33 patients undergoing GT, 16 (48.5%) had LS: MSH6, 9; MSH2, 4; PMS2, 2; MLH1, 1. Conclusions Increased frequency of GCRs was observed following the protocol change, which is important as LS screening has clinical implications for patients and their families. Reflex protocols can maximize identification of patients for germline GT; alternatively universal GT can be considered in endometrial cancer (Levine et al. 2021)

Objectives We evaluated the feasibility of a facilitated referral pathway for cascade genetic testing (GT) for patients with mutations associated with gynecologic cancers. Methods This is a prospective cohort study of patients with BRCA1, BRCA2, BRIP1, MSH2, MLH1, MSH6, PMS2, EPCAM, RAD51C, and RAD51D mutations from March 2019-March 2022. Eligible patients were offered a facilitated referral pathway for GT for first and second-degree relatives (figure 1). Decision Regret Scale and Impact of Events Scale assessed psychological impact at 3-months. The primary outcome was the proportion of patients with a relative who successfully completed GT. Results Of 583 eligible patients, 73 (13%) enrolled in our study. Reasons for declining participation were: no eligible relatives or previously tested (235, 40%), lost to follow-up (105, 18%), does not want to discuss GT with family (55, 9%), relatives not interested (50, 9%), language (38, 7%), and other (27, 5%). Of 73 enrolled patients, 45 (62%) contacted at least one relative to discuss GT within two months of enrollment. Twelve patients had at least one relative who participated in our facilitated referral pathway, but only 2 (3%) relatives completed GT through our pathway. Two additional relatives underwent GT separately. Of 20 patients who completed 3-month psychological impact questionnaires, 13 (65%) had no regret, and 19 (95%) had none to subclinical range stress. Conclusions Although over 50% of patients contacted family members regarding GT, only 3% had a relative undergo GT via our facilitated referral pathway. Comprehensive novel efforts to simplify access to GT for relatives are desperately needed. (Figure Presented)

Purpose: Locally advanced cervical cancer was defined by an international consensus panel as a high priority malignancy during the COVID-19 pandemic, recommending prompt initiation of definitive treatment and completion of treatment (PMID 32563593). The objective of this study was to study the clinical outcomes of patients (pts) with cervical cancer treated with definitive chemoradiation (CRT) and brachytherapy (BT) at our institution in 2019 (pre-COVID) and in 2020 (peri-COVID).
Material(s) and Method(s): This was a retrospective cohort study of pts with FIGO Stage IB2-IVA cervical cancer at our institutions from 1/1/2019 to 12/31/2020. Pts received CRT followed by intracavitary brachytherapy (IC) with two operative insertions one week apart, or interstitial (IS) BT with one operative insertion. BT treatment was planned using image-guided CT or MR delineation. Pre-COVID was defined by initiation of CRT in 1/2019-12/2019, and peri-COVID was defined by initiation in 1/2020-10/2020. Process changes peri-COVID included limited on-site staff (e.g., minimal OR staff, no trainees, remote physics team), universal implementation of COVID-19 testing prior to surgery, and CT instead of MR-delineation based treatment. Outcomes of interest were time to treatment initiation and completion and differences in treatment planning modality or dosimetry. Fisher's exact and Mann Whitney U tests were used with significance p<0.05.
Result(s): Thirty-one pts were included, with 18 patients undergoing treatment pre-COVID and 13 peri-COVID. The median age at diagnosis pre-COVID was 57.7 (range 23-77) and for peri-COVID, 45.5 (range 28-62, p=0.06). There were no differences in non-English speaking pts (44% vs 59%, p=0.71) or uninsured pts (11% vs 33%, p=0.184) between the two cohorts. Median time to initiation of treatment from biopsy diagnosis was 52 days (range 13-209) in 2019 and for peri-COVID, 55.5 (range 20-173, p=0.71). During COVID, four pts had delayed initiation to treatment >100 days: two related to fertility, and one due to fear of COVID-19. For this pt, tumor size progressed from 2.3 cm to 4.2 cm maximal dimension. One pt treated in 2020 tested positive following treatment and did not require hospital admission. All pts except one completed CRT with RT: 25 pts pelvic RT (45 Gy), 3 pelvic and para-aortic RT (45 Gy with 57.5 Gy concomitant boost to nodes), 8 pts pelvic RT (45Gy) with sequential parametrial boost (50.4-59.4 Gy) using IMRT with no dose differences between pre and peri-COVID (Table 1). No pts required treatment breaks and the median overall treatment time was 50 days (range 31-85) in 2019 vs 50 days (range 43-63) in 2020 (p=0.710).
Conclusion(s): Despite the significant burden of the COVID-19 pandemic on our health care system, all cervical cancer pts receiving CRT met standard of care including CRT and BT within the recommended time frame with no significant differences in dosimetric treatment parameters pre- and peri-COVID. Delays in treatment initiation of treatment initiation were seen in 30% of pts in the peri-COVID period, suggesting that patients may have had increased barriers to access care. More follow-up is needed to determine how the Covid pandemic impacted cervical cancer outcome measures.
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Background: Median age of EC diagnosis is 62 y, yet most EC deaths occur in pts >65 y (median 70 y). Unmet need in older pts is not addressed by current standard of care. Dostarlimab is an anti-programmed death receptor 1 (PD-1) antibody. We report a post-hoc analysis of dostarlimab antitumor activity and safety by age in pts with dMMR/microsatellite instability high (MSI-H) EC and MMR proficient (MMRp)/MS stable (MSS) EC.
Method(s): GARNET (NCT02715284) is a Phase I, single-arm study of dostarlimab in pts with advanced/recurrent (A/R) solid tumors. Pts with dMMR/MSI-H EC were enrolled in Cohort A1 and pts with MMRp/MSS EC in Cohort A2. Pts were stratified: <65 y, >=65 to <75 y, or >=75 y at baseline. Antitumor activity and safety were assessed. Data cut was March 1, 2020.
Result(s): In Cohort A1 (n=129), 51.2% of pts were <65 y, 39.5% were >=65 to <75 y, and 9.3% were >=75 y. In Cohort A2 (n=161), 43.5% were <65 y, 44.7% were >=65 to <75 y, and 11.8% were >=75 y. In the efficacy-evaluable population (measurable disease at baseline; >=24 w follow up), objective response rates (ORRs) (95% confidence interval [CI]) per RECIST v1.1 assessed by BICR were similar across age groups for pts with dMMR/ MSI-H EC (<65 y: 45.3% [31.6-59.6] vs >=65 to <75 y: 43.9% [28.5-60.3] vs >=75 y: 45.5% [16.7-76.6]) and for pts with MMRp/MSS EC (<65 y: 9.1% [3.4-18.7] vs >=65 to <75 y: 16.9% [9.0-27.7] vs >=75 y: 21.1% [6.1-45.6]). There were few Grade >=3 treatment-related adverse events (TRAEs) (for pts with dMMR/MSI-H EC [n=129]: 13.6% vs 13.7% vs 8.3%, respectively) and for MMRp/MSS EC [n=161]: 22.9% vs 19.4% vs 5.3%, respectively); observed TRAEs were similar between groups.
Conclusion(s): Dostarlimab antitumor activity and safety for pts with dMMR/MSI-H EC and MMRp/MSS EC were comparable across age groups, with low Grade >=3 TRAE incidence. Older pts with A/R dMMR/ MSI-H EC experienced broadly similar treatment benefits as younger pts

Introduction/Background LIO-1 (NCT04042116) assesses the combination of lucitanib, an oral anti-angiogenic, multikinase inhibitor administered using safety-based dose titration, and nivolumab, an inhibitor of programmed cell death receptor 1 (PD-1). Here, we present phase 2 study results of this combination in 4 advanced gynaecological malignancies. Methodology LIO-1 enrolled patients with advanced, recurrent or metastatic endometrial cancer (EC), cervical cancer (CC), high-grade ovarian cancer (OC) or EC/OC with clear-cell histology (EOCC). Patients with EC, CC or EOCC received >=1 prior platinum-based chemotherapies (CC, +/- bevacizumab; EOCC, + taxane); patients with OC received >=2 prior chemotherapies (including >=1 platinum doublet). Patients received lucitanib at a starting dose of 6 mg QD plus intravenous nivolumab 480 mg every 28 days. Lucitanib dose could be escalated to 8 mg then 10 mg QD. The data cutoff was 14 April 2022. Results Total treated was 124 patients; 31 (25.0%) patients are ongoing. At data cutoff, 32 (25.8%) patients escalated to lucitanib 8 mg and 20 (16.1%) to 10 mg. The confirmed best overall response rates at data cutoff were: EC cohort, 5/22 (22.7%); CC cohort, 12/46 (26.1%); OC cohort, 4/33 (12.1%); EOCC cohort, 6/23 (26.1%). Among EC-cohort patients, confirmed responses were reported for 2/5 patients who received prior PD-1 inhibitor (both were non-responders to prior PD-1 inhibitor). Among EC-cohort patients with known microsatellite status, confirmed responses were observed in 3/14 with microsatellite stability and 2/3 with high instability. Grade >=3 treatment-emergent adverse events (TEAEs) considered study-treatment related were reported in 55 (44.4%) patients, with the most frequent being hypertension (n=30 [24.2%]). TEAEs leading to lucitanib dose reduction or discontinuation occurred in 21 (16.9%) and 20 (16.1%) patients, respectively. Conclusion Lucitanib + nivolumab displays anti-tumour activity in patients with advanced gynaecological malignancies, including clear-cell cancer. Effective dose titration resulted in manageable safety, similar to previous reports

Introduction/Background Mismatch repair (MMR) deficiency is caused by loss of expression of MMR proteins, MLH1, PMS2, MSH2, and/or MSH6, that function as heterodimers (MLH1/PMS2 and MSH2/MSH6) to mediate DNA repair. Loss of function caused by mutation or epigenetic methylation leads to defective MMR and genomic instability. MMR deficient (dMMR) tumours can respond to anti-programmed death 1 (anti-PD-1) therapy. We report a post hoc analysis of objective response rate (ORR) with loss of MMR dimers and mutation status of MMR genes in patients with dMMR endometrial cancer (EC) treated with dostarlimab. Methodology GARNET is a multicentre, open-label, single-arm phase 1 study. Cohort A1 enrolled patients with dMMR advanced/recurrent EC. Patients received 500 mg of dostarlimab intravenously Q3W for 4 cycles, then 1000 mg Q6W until disease progression, discontinuation, or withdrawal. MMR protein status (presence or loss) was determined by local immunohistochemistry. MMR gene mutation was determined by FoundationOne. MLH1 loss without MMR gene mutation was a surrogate indicator for epigenetic methylation. Results Cohort A1 included 143 patients; MMR gene mutation data were available for 101 patients (table 1). Cohort A1 ORR was 45.5%. 66% of patients had loss of MLH1/PMS2; ORR was 48.9%. 11.2% of patients had loss of MSH2/ MSH6; ORR was 56.2%. ORR was 41.7% for MLH1 loss with MMR gene mutation and 39.4% for MLH1 loss without MMR gene mutation. Conclusion Patients with dMMR advanced/recurrent EC benefitted from dostarlimab, with no noticeable difference by dimer-pair loss or MMR gene methylation/mutation status. These data suggest the route to MMR deficiency does not influence response to dostarlimab

Introduction/Background Biomarkers are used to classify endometrial cancer (EC) into molecular subtypes such as TCGA and/or a surrogate classification (POL mutated [mut], mismatch repair/microsatellite instability [MMR/MSI], TP53mut, and no specific mutation profile [NSMP]) or by estrogen receptor (ER) status. Here, we report on a post hoc analysis of objective response rate (ORR) by a surrogate classification for EC in patients receiving dostarlimab monotherapy. Methodology GARNET is a multicentre, open-label, single-arm phase 1 study. Patients were assigned to cohort A1 (MMR deficient/MSI-high [dMMR/MSI-H EC]) or A2 (MMR proficient/microsatellite stable [MMRp/MSS] EC) based on local assessment. Patients received 500 mg of dostarlimab IV Q3W for 4 cycles, then 1000 mg Q6W until disease progression, discontinuation, or withdrawal. The primary endpoints were ORR and duration of response by blinded independent central review. Molecular subtype was determined by POL and TP53 mutation status by Foundation Medicine, and MMR/MSI status was determined by local immunohistochemistry or next-generation sequencing; all others were assigned as NSMP. The hierarchy for classification was POLmut MMR/MSI TP53 status NSMP. ER status was determined by local immunohistochemistry testing. Only patients with samples available for additional biomarker testing were included in the biomarker assessment. Results 143 patients with dMMR/MSI-H EC and 156 patients with MMRp/MSS were included in the efficacy-evaluable population. ORRs were determined for molecular subtypes and ER expression (table 1). Safety has been previously reported. Conclusion The observed ORRs in each molecular subgroup were consistent with the overall ORR in each cohort. Differences by ER expression status were not observed. These findings support the importance of testing patients with EC for MMR/MSI biomarker status as a predictor of response. Additionally, data suggest that TP53 mutation or ER expression should not modify treatment approach. The data are of interest for hypothesis generation

Introduction/Background Dostarlimab is a programmed death 1 (PD-1) inhibitor approved in the US as monotherapy in patients with mismatch repair deficient (dMMR) advanced/ recurrent endometrial cancer (EC) that has progressed on or after platinum-based chemotherapy or dMMR solid tumours that have progressed on or after prior treatment, with no satisfactory alternative treatment options; and in the EU as monotherapy in patients with dMMR/microsatellite instability-high (MSI-H) advanced/recurrent EC that has progressed on or after platinum-based chemotherapy. We report efficacy endpoints by immune-related RECIST (irRECIST) per investigator assessment (IA) for the EC cohorts of the GARNET trial. Methodology GARNET is a multicentre, open-label, singlearm phase 1 study. Assignment to cohort A1 (dMMR/MSIH EC) or A2 (mismatch repair proficient [MMRp]/microsatellite stable [MSS] EC) was based on local assessment. Patients received 500 mg of dostarlimab intravenously Q3W for 4 cycles, then 1000 mg Q6W until disease progression, discontinuation, or withdrawal. Immune-related endpoints (irORR, irDOR, and irPFS) were prespecified secondary endpoints. Results The irRECIST efficacy-evaluable population included 152 patients with dMMR/MSI-H EC and 160 patients with MMRp/MSS EC with measurable disease at baseline and >=6 months' follow-up per IA. irORR and irDOR were similar to the primary endpoints of ORR and DOR by BICR per RECIST v1.1 (table 1). For dMMR/MSI-H, median irPFS was 11.2 mo versus median PFS of 6.0 mo, although the probability of remaining progression free at 6, 12, or 18 mo was similar. Safety was previously reported. Conclusion In line with the study primary endpoints, secondary efficacy endpoints by irRECIST demonstrate the benefit of dostarlimab in patients with EC