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ASCO 2022 Breast/Gyn

CME

Key Studies in Breast and Gynecologic Cancers: Independent Conference Coverage of the 2022 ASCO Annual Meeting

Physicians: Maximum of 1.50 AMA PRA Category 1 Credits™

Released: August 17, 2022

Expiration: August 16, 2023

Joyce O'Shaughnessy
Joyce O'Shaughnessy, MD
Angeles Alvarez Secord
Angeles Alvarez Secord, MD, MHSc
CME/CE Information

Activity

Progress
1
Course Completed

GARNET Cohorts A1 and A2: Update From Phase I Trial of Dostarlimab in Patients With Advanced or Recurrent dMMR/MSI-H or pMMR/MSS Endometrial Cancer—Background

Angeles Alvarez Secord, MD, MHSc:
Moving to endometrial cancer, I will review updated results from endometrial expansion cohorts in the phase I GARNET trial of the anti–PD-1 antibody dostarlimab. 

Dostarlimab is approved by the FDA and European Medicines Agency specifically for patients with recurrent or advanced, mismatch repair–deficient (dMMR) endometrial cancers with progression on or after a platinum‑containing regimen, as well as by the FDA for tumor‑agnostic consideration for patients with dMMR recurrent or advanced solid tumors following progression on prior treatment when no satisfactory alternatives are available.35,36  This is important in the context of a rising incidence of endometrial cancer, increasing by 132% in the past 30 years, along with increased deaths.37 During the course of my years as a provider, I have seen an influx of patients with advanced or recurrent endometrial cancer.

The standard of care for first‑line treatment of advanced endometrial cancer is paclitaxel and carboplatin, which yields a 13‑month PFS.37 Previous ancillary analyses of the GARNET trial have demonstrated a benefit of dostarlimab treatment in patients with advanced or recurrent, dMMR/microsatellite instability (MSI)–high endometrial cancer.38 The current update presents a third prespecified interim analysis of efficacy and safety of dostarlimab in patients with advanced or recurrent endometrial cancer, including in a cohort of patients with MMR-proficient (pMMR) or microsatellite stable (MSS) disease.39

GARNET Cohorts A1 and A2: Study Design

Angeles Alvarez Secord, MD, MHSc:
The multicenter, open‑label, multicohort, single‑arm phase I GARNET study included cohorts with various solid tumors. The 2 endometrial cancer expansion cohorts included 153 patients in cohort A1 with dMMR/MSI‑high disease and 161 patients in cohort A2 with pMMR/MSS. Tumor MMR status was determined by immunohistochemistry. Patients in both cohorts received 500 mg IV of dostarlimab every 3 weeks for 4 cycles, which was then increased and extended to 1000 mg IV every 6 weeks until disease progression or withdrawal.

The coprimary endpoints were ORR, DoR by central review, and safety.

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GARNET Cohorts A1 and A2: Baseline Characteristics

Angeles Alvarez Secord, MD, MHSc:
The 2 cohorts had similar median age, 65 and 66 years, and most patients had stage III/IV disease.

The histologic biomarkers in this study are interesting. In cohort A1, the patients with dMMR/MSI-H, 64.3% had grade 1/2 endometrioid cancer,14.7% had grade 3 endometrioid cancer, and 5% had serous cancers, which are usually relatively uncommon. Another 2.8% had undifferentiated cancers and 4.9% had mixed carcinomas. By contrast, only 23.1% of patients in cohort A2 had grade 1 or 2 endometrioid cancers and there was a large preponderance of patients with serous cancers, at 40.4%; 9% of patients had grade 3 endometrioid cancers and 7.1% had each of clear cell and mixed cancers.

All patients had been previously treated. In Cohort A1, approximately one quarter of patients had received at least 2 previous regimens. In cohort A2, 42.9% had received 2 prior regimens and approximately 11% had received 3 or more. Approximately 25% to 30% of the patients had received adjuvant therapy, and 61% to 71% received prior radiation.

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GARNET Cohorts A1 and A2: Primary Endpoint Analysis

Angeles Alvarez Secord, MD, MHSc:
With a median follow-up of 27.6 months, cohort A1 showed an ORR of 45.4% with a CR rate of 16.1%. With median follow-up of 33.0 months, cohort A2 had an ORR of 15.4%, with 2.6% having a CR, and 12.8% having a partial response. Disease control rate was very high in both cohorts at 60.1% in cohort A1 and 34.0% in cohort A2.

The median time from cycle 1 to best response was approximately 2.7-2.8 months in each cohort, which is relatively fast. Knowing whether a patient is responding quickly is helpful, and it is a common question patients may ask.

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GARNET Cohorts A1 and A2: PFS

Angeles Alvarez Secord, MD, MHSc:
The estimated probability of PFS was 46.4% at 12 months and 40.1% at 24 months in Cohort A1 and a bit lower in cohort A2, just 13.3% at 12 months and 9.4% at 24 months. That is not unexpected; the pMMR/MSS cohort is a group that, for the most part, is expected not to do as well. From the Kaplan-Meier curve we can see there is a small number of patients, approximately 8, in the pMMR group in whom therapy appears to prevent disease progression.

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GARNET Cohorts A1 and A2: OS

Angeles Alvarez Secord, MD, MHSc:
Looking at OS at 24 months, 60.5% of patients in cohort A1 were alive and the median OS had not yet been reached after 4 years, which is outstanding. Outcomes were less exciting in the poorer prognosis cohort A2, although 38.4% of patients were still alive at 24 months and the median OS was 16.9 months.

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GARNET Cohorts A1 and A2: Safety

Angeles Alvarez Secord, MD, MHSc:
The safety analysis did not reveal any new concerning AEs regarding immunotherapy. Grade ≥3 immune-related AEs occurred in 8% of patients overall. Treatment was discontinued due to AEs in 9% of patients in each cohort.

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GARNET Cohorts A1 and A2: TRAEs

Angeles Alvarez Secord, MD, MHSc:
The most common AEs in either cohort were fatigue (13.7% to 21.7%), diarrhea (13.0% to 16.3%), nausea (12.4% to 14.9%), and asthenia (8.1% to 15.7%), none of which are surprising. Hypothyroidism is a very common immune‑related treatment AEs, but grade >2 events occurred only in approximately 8% of patients in each cohort, and the remainder of the incidence of other immune‑related AEs, including arthralgia and elevated liver enzymes, was relatively low.

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GARNET Cohorts A1 and A2: Conclusions

Angeles Alvarez Secord, MD, MHSc:
These long‑term survival data show a significant benefit of dostarlimab immunotherapy in the dMMR cohort, with an ORR of 45.4% and a median DoR not yet reached.

There appears to be some activity with dostarlimab in patients who are pMMR/MSS, but I think we need to better understand the biomarker analysis used here. For example, did some of these patients have tumor mutational burden–high tumors although they are pMMR/MSS? Is there another biomarker that may identify patients most likely to benefit from immunotherapy?

GARNET Cohorts A1 and A2: Implications

Angeles Alvarez Secord, MD, MHSc:
In this update from the GARNET study, the ORR for patients identified as pMMR/MSS was 15.4% and the median DoR for those who responded was 19.4 months. These outcomes are clinically meaningful, but more work needs to be done to identify who is likely to respond to dostarlimab in this group of patients.

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