Madeline Polak

A Phase II, Two-Stage Study of Letrozole and Abemaciclib in Estrogen Receptor–Positive Recurrent Endometrial Cancer

PURPOSE Estrogen receptor (ER)–positive endometrial cancers (ECs) are characterized by phosphatidylinositol 3-kinase (PI3K) and receptor tyrosine kinase (RTK)/RAS/β-catenin (CTNNB1) pathway alterations in approximately 90% and 80% of cases, respectively. Extensive cross-talk between ER, PI3K, and RTK/RAS/CTNNB1 pathways leads to both ligand-dependent and ligand-independent ER transcriptional activity as well as upregulation of cyclin D1 which, in complex with cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), is a critical regulator of cell cycle progression and a key mediator of resistance to hormonal therapy. We hypothesized that the combination of the aromatase inhibitor letrozole and CDK4/6 inhibitor abemaciclib would demonstrate promising activity in this setting. METHODS We conducted a phase II, two-stage study of letrozole/abemaciclib in recurrent ER-positive EC. Eligibility criteria included measurable disease, no limit on prior therapies, and all EC histologies; prior hormonal therapy was allowed. Primary end points were objective response rate by RECIST 1.1 and progression-free survival (PFS) rate at 6 months. RESULTS At the data cutoff date (December 03, 2021), 30 patients (28 with endometrioid EC) initiated protocol therapy; 15 (50%) patients had prior hormonal therapy. There were nine total responses (eight confirmed), for an objective response rate of 30% (95% CI, 14.7 to 49.4), all in endometrioid adenocarcinomas. Median PFS was 9.1 months, PFS at 6 months was 55.6% (95% CI, 35.1 to 72), and median duration of response was 7.4 months. Most common ≥ grade 3 treatment-related adverse events were neutropenia (20%) and anemia (17%). Responses were observed regardless of grade, prior hormonal therapy, mismatch repair, and progesterone receptor status. Exploratory tumor profiling revealed several mechanistically relevant candidate predictors of response ( CTNNB1, KRAS, and CDKN2A mutations) or absence of response ( TP53 mutations), which require independent validation. CONCLUSION Letrozole/abemaciclib demonstrated encouraging and durable evidence of activity in recurrent ER positive endometrioid EC.

Letrozole, abemaciclib and metformin in endometrial cancer: a non-randomized phase 2 trial

Based on preclinical studies showing synergism with simultaneous inhibition of the estrogen receptor (ER), CDK4/6 and PI3K pathways and based on window of opportunity studies showing that metformin suppresses PI3K/mTOR signaling in endometrial cancer (EC), we conduct a non-randomized phase 2 study of letrozole/abemaciclib/metformin in ER positive endometrioid EC (NCT03675893). Primary objectives include objective response rate (ORR) and rate of progression-free survival (PFS) at 6 months (PFS6) while secondary objectives include PFS, overall survival, duration of response and toxicity. Twenty-five patients initiate protocol therapy [letrozole 2.5 mg orally (PO) once a day (qd), abemaciclib 150 mg PO twice a day (bid) and metformin 500 mg PO qd]. ORR is 32% (3 complete and 5 partial responses, 95% CI 14.9%-53.5%), Kaplan Meier estimate of PFS6 is 69.8% (95% CI 46.9%-84.3%) and median PFS is 19.4 months (95% CI 5.7 months-not estimable). No patients discontinue therapy because of toxicity. There are no objective responses among TP53 mutated ECs and among NSMP (no specific molecular profile) tumors with RB1 or CCNE1 alterations; CTNNB1 mutations correlate with clinical benefit. Pharmacokinetic analyses demonstrate that administration of letrozole and abemaciclib with metformin result in a more than 3-fold increase in metformin exposure.

Mutational Signature 3 Detected from Clinical Panel Sequencing is Associated with Responses to Olaparib in Breast and Ovarian Cancers

Abstract Purpose: The identification of patients with homologous recombination deficiency (HRD) beyond BRCA1/2 mutations is an urgent task, as they may benefit from PARP inhibitors. We have previously developed a method to detect mutational signature 3 (Sig3), termed SigMA, associated with HRD from clinical panel sequencing data, that is able to reliably detect HRD from the limited sequencing data derived from gene-focused panel sequencing. Experimental Design: We apply this method to patients from two independent datasets: (i) high-grade serous ovarian cancer and triple-negative breast cancer (TNBC) from a phase Ib trial of the PARP inhibitor olaparib in combination with the PI3K inhibitor buparlisib (BKM120; NCT01623349), and (ii) TNBC patients who received neoadjuvant olaparib in the phase II PETREMAC trial (NCT02624973). Results: We find that Sig3 as detected by SigMA is positively associated with improved progression-free survival and objective responses. In addition, comparison of Sig3 detection in panel and exome-sequencing data from the same patient samples demonstrated highly concordant results and superior performance in comparison with the genomic instability score. Conclusions: Our analyses demonstrate that HRD can be detected reliably from panel-sequencing data that are obtained as part of routine clinical care, and that this approach can identify patients beyond those with germline BRCA1/2mut who might benefit from PARP inhibitors. Prospective clinical utility testing is warranted.

Randomized Phase II Study of Gemcitabine With or Without ATR Inhibitor Berzosertib in Platinum-Resistant Ovarian Cancer: Final Overall Survival and Biomarker Analyses

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.

Serial Circulating Tumor DNA Sequencing to Monitor Response and Define Acquired Resistance to Letrozole/Abemaciclib in Endometrial Cancer

PURPOSE In a phase II study, letrozole/abemaciclib demonstrated an objective response rate of 30% and a median progression-free survival (PFS) of 9.1 months in recurrent estrogen receptor–positive endometrial cancer (EC). While tissue-based tumor profiling revealed several mechanistically relevant candidate baseline genomic predictors of response, circulating tumor DNA (ctDNA) is a less invasive alternative to monitor therapeutic efficacy and define acquired resistance. METHODS Serial plasma specimens were obtained at baseline, C2D1, C3D1, C8D1, the time of objective response, and the time of progression. Samples were analyzed using the Guardant Reveal assay to assess methylation-based tumor fraction (TF), with the Guardant360 assay providing genotyping of >700 genes in samples with detectable ctDNA. Treatment response was assessed using a measure of the relative change in TF pre- versus on-treatment. RESULTS A total of 99 of 102 (97%) samples from 28 patients were successfully analyzed. Patients with above median baseline TF exhibited worse median PFS (2.0 months v 16.5 months, P < .005, hazard ratio [HR], 24.1) and worse overall survival (OS) (10.7 months v not yet reached, P < .005, HR, 14.8). Patients with molecular response (MR) after the first or second cycle of letrozole/abemaciclib therapy had significantly better median PFS and OS regardless of the cutoff used for definition of MR. ctDNA analysis of postprogression specimens identified several acquired genomic alterations associated with resistance to letrozole/abemaciclib therapy in more than half of the patients, including PI3K pathway, receptor tyrosine kinase ( FGFR1 , 2 and ERBB2 alterations), cell cycle pathway ( RB1 and CCNE1 alterations), and ESR1 and MAPK pathway alterations. Two of the three patients with mismatch repair–deficient ECs acquired ESR1 mutations at the time of progression. CONCLUSION Baseline and on-treatment ctDNA dynamics may provide an early indication of benefit from letrozole/abemaciclib in EC. ctDNA at the time of progression may identify resistance alterations that may inform subsequent therapy.

RESOLVE: Abemaciclib + Letrozole +/- Metformin, Zotatifin, or Gedatolisib in Endometrial or Low-Grade Serous Ovarian Cancer

This research study is studying a combination of targeted therapies as a possible treatment for estrogen-receptor positive (ER+) endometrial cancer and low-grade serous ovarian cancer. The drugs involved in this study are: * Abemaciclib (also known as Verzenio™) * Letrozole (also known as Femara®) * Metformin (also known as Glucophage®) * Zotatifin (also known as eFT226) * Gedatolisib (also known as PF-05212384)