Dostarlimab/Chemo Reveals OS Profit No matter MMR Standing in Endometrial Most cancers


Robert L. Coleman, MD, FACOG, FACS

The addition of dostarlimab-gxly (Jemperli) to chemotherapy, adopted by dostarlimab monotherapy, demonstrated a statistically important and clinically significant enchancment in total survival (OS) vs placebo plus chemotherapy in sufferers with main superior or recurrent endometrial most cancers, with advantages noticed throughout molecular subgroups and no matter mismatch restore (MMR) standing, in line with up to date findings from half 1 of the section 3 RUBY trial (NCT03981796) offered on the 2024 ESMO Gynecologic Cancers Congress.1

At a median follow-up of 37.2 months for the general inhabitants, sufferers handled with dostarlimab plus chemotherapy adopted by dostarlimab (n = 245) achieved a median OS of 44.6 months (95% CI, 32.6–not evaluable [NE]) in contrast with 28.2 months (95% CI, 22.1-35.6) in these handled with placebo plus chemotherapy (n = 249; HR, 0.69; 95% CI, 0.54-0.89; P = .002). Notably, 38.2% of sufferers within the placebo arm acquired subsequent immunotherapy.

Within the mismatch restore–poor (dMMR)/microsatellite instability–excessive (MSI-H) inhabitants, the median OS was NE (95% CI, NE-NE) within the dostarlimab arm (n = 53) vs 31.4 months (95% CI, 20.3-NE) within the placebo arm (n = 65; HR, 0.32; 95% CI, 0.17-0.63; nominal P = .0002) at a median follow-up of 36.6 months. Within the placebo arm, 41.5% of sufferers within the dMMR/MSI-H inhabitants acquired subsequent immunotherapy.

There was additionally a clinically significant OS distinction within the mismatch restore–proficient (pMMR)/microsatellite steady (MSS) inhabitants at a median follow-up of 37.5 months. The median OS was 34.0 months (95% CI, 28.6-NE) within the dostarlimab group (n = 192) vs 27.0 months (95% CI, 21.5-35.6) within the placebo group (n = 184; HR, 0.79; 95% CI, 0.60-1.04; nominal P = .0493). Notably, 37.0% of sufferers within the placebo arm on this subgroup acquired subsequent immunotherapy.

“These knowledge affirm dostarlimab plus chemotherapy as a brand new commonplace of look after sufferers with main superior or recurrent endometrial most cancers, no matter MMR standing,” presenting creator Robert L. Coleman, MD, FACOG, FACS, of Sarah Cannon Analysis Institute in Nashville, Tennessee, mentioned in a presentation of the information.

In July 2023, prior knowledge from RUBY supported the FDA approval of dostarlimab together with carboplatin and paclitaxel, adopted by dostarlimab monotherapy, for grownup sufferers with main superior or recurrent endometrial most cancers that’s dMMR or MSI-H.2

The up to date evaluation included knowledge for OS, time to second development (PFS2), and security. Coleman and colleagues additionally performed an exploratory evaluation on OS outcomes by molecular classification.1

Throughout RUBY, 494 sufferers with main superior or recurrent endometrial most cancers had been randomly assigned to both dostarlimab plus carboplatin and paclitaxel, adopted by dostarlimab monotherapy; or placebo plus carboplatin and paclitaxel, adopted by placebo monotherapy.

On the September 22, 2023, knowledge cutoff, 130 sufferers within the dostarlimab arm discontinued therapy as a consequence of loss of life from any trigger (n = 96), consent withdrawal (n = 26), lack of follow-up (n = 5), or different causes (n = 3). Eighty-eight sufferers remained in follow-up, and 27 sufferers had been nonetheless receiving dostarlimab. Within the placebo arm, 160 sufferers discontinued examine therapy as a consequence of loss of life from any trigger (n = 133), consent withdrawal (n = 20), lack of follow-up (n = 5), or different causes (n = 2). Sixty-seven sufferers had been in follow-up, and 22 remained on placebo.

Enrolled sufferers offered with both dMMR/MSI-H (dostarlimab arm, 21.6%; placebo arm, 26.1%) or pMMR/MSS illness (78.4%; 73.9%), and had been White (77.1%; 76.7%), Black (11.4%; 12.4%), or Asian (2.9%; 3.2%). Sufferers within the dostarlimab had a median age of 64 years (vary, 41-81) vs 65 years (vary, 28-85) within the placebo arm. Notably, 48.2% and 54.2% of sufferers, respectively, had been at the least 65 years of age.

Furthermore, some sufferers acquired prior exterior pelvic radiation (dostarlimab arm, 16.7%; placebo arm, 18.1%). Illness standing included main stage II (18.4%; 18.9%), main stage IV (33.9%; 33.3%), or recurrent (47.8%; 47.8%). Nearly all of sufferers had an ECOG efficiency standing of 0 (60.2%; 65.0%).

Moreover, sufferers had a median BMI of 30.8 (vary, 17.6-60.6) and 32.8 (vary, 17.7-68.0) within the dostarlimab and placebo arms, respectively, and 86.5% and 88.0% of sufferers had measurable illness at baseline in these respective teams. A minority of sufferers acquired prior anticancer therapy (dostarlimab arm, 19.6%; placebo arm, 20.9%), together with carboplatin-paclitaxel (14.7%; 15.7%). Histology sorts included carcinoma (10.2%; 7.6%), endometrioid (54.7%; 54.6%), serous adenocarcinoma (20.4%; 20.9%), or different (14.7%; 16.9%).

Molecular classification was carried out for all sufferers with whole-exome DNA sequencing (WES) outcomes (n = 400/494), and an exploratory evaluation examined OS distinction in sufferers with dMMR/MSI-H illness who underwent WES (HR for dostarlimab vs placebo, 0.40; 95% CI, 0.19-0.83), these harboring TP53 mutations (HR, 0.59; 95% CI, 0.33-1.03), and sufferers with no particular molecular profile (HR, 0.89; 95% CI, 0.61-1.29). Notably, HR for sufferers with POLE mutations was not relevant, since all sufferers within the dostarlimab arm (n = 2) and placebo arm (n = 3) had been alive at knowledge cutoff. Coleman famous that the findings from molecular subgroup evaluation had been in keeping with findings from the primary interim evaluation.

Extra knowledge from the general inhabitants confirmed that 49.0% of sufferers on the dostarlimab arm acquired any follow-up anticancer remedy vs 69.5% of sufferers within the placebo arm. Subsequent therapies included immunotherapy (dostarlimab arm, 35.0%; placebo arm, 54.9%) with both pembrolizumab (Keytruda; 10.8%; 23.7%), pembrolizumab plus lenvatinib (Lenvima; 20.8%; 26.0%), dostarlimab (0%; 1.7%), or different (4.2%; 6.9%).

Moreover, a clinically significant PFS2 profit was noticed for the dostarlimab routine within the total inhabitants (HR, 0.66, 95% CI, 0.52-0.84). The median PFS2 was 32.3 months (95% CI, 24.6-NE) within the dostarlimab group vs 18.4 months (95% CI, 14.9-22.0) within the placebo group.

Within the dMMR/MSI-H inhabitants, the median PFS2 was NE (95% CI, NE-NE) for the dostarlimab arm and 21.6 months (95% CI, 13.4-39.1) for the placebo arm (HR, 0.33; 95% CI, 0.18-0.63). Within the pMMR/MSS inhabitants, the median PFS2 was 24.6 months (95% CI, 20.1-32.6) for the dostarlimab arm vs 15.9 months (95% CI, 13.6-22.0) for the placebo arm (HR, 0.74; 95% CI, 0.57-0.97).

Concerning security, all sufferers within the dostarlimab arm (n = 241) and placebo arm (n = 246) skilled any treatment-emergent adversarial impact (TEAE); 72.2% and 60.2% skilled grade 3 or increased TEAEs; 39.8% and 28.0% skilled critical TEAEs; and 40.7% and 60.3% had any treatment-related immune-related AE.

TEAEs that led to discontinuation of dostarlimab or placebo in 19.1% and eight.1% of sufferers, respectively. Moreover, 8.3% and 6.1% of sufferers had any TEAE that led to discontinuation of carboplatin within the dostarlimab and placebo arms, respectively; 10.8% and 10.2% had any TEAE resulting in discontinuation of paclitaxel; 2.1% and 0% had any TEAE resulting in loss of life. Notably, 0.8% of sufferers within the experimental arm skilled any TEAE associated to dostarlimab that led to loss of life. Notably, the median length of total therapy was 43.0 weeks (vary, 3.0-192.6) for the dostarlimab arm vs 36.0 weeks (vary, 2.1-193.1) for the placebo arm.

Disclosures: Dr Coleman reported receiving grants or contracts from AstraZeneca, Clovis, Genelux, Genmab, Immunogen, Merck, and Roche/Genentech; consulting charges from AbbVie, Agenus, Alkermes, AstraZeneca, Clovis, Deciphera, Genelux, Genmab, GSK, Immunogen, Novocure, Merck, OncoQuest, Onxerna, Regeneron, and Roche/Genentech; honoraria from AstraZeneca, Clovis, Merck, and Roche/Genentech; and participation on an information security monitoring board or advisory board with Eisai/BMS and VBL Therapeutics.

References

  1. Powell MA, Auranen A, Willmott L, et al. Dostarlimab plus chemotherapy in main superior or recurrent endometrial most cancers within the RUBY trial: total survival by MMR standing and molecular subgroups. Introduced at: 2024 ESMO Gynecological Cancers Congress; June 20-22, 2024; Florence, Italy. Summary 37MO.
  2. Jemperli (dostarlimab) plus chemotherapy accepted within the US as the primary new frontline therapy choice in a long time for dMMR/MSI-H main superior or recurrent endometrial most cancers. Information launch. GlaxoSmithKline. July 31, 2023. Accessed July 2, 2024. https://www.gsk.com/en-gb/media/press-releases/jemperli-plus-chemotherapy-approved-in-us-for-new-indication/

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