Dostarlimab-chemo a new SoC for endometrial cancer?

In the second interim analysis of part 1 of the phase III ENGOT-EN6-NSGO/GOG-3031/RUBY trial, dostarlimab plus carboplatin/paclitaxel (CP) chemotherapy delivered a significant survival benefit in women with primary advanced or recurrent endometrial cancer.

“Dostarlimab plus CP demonstrated a statistically significant and clinically meaningful overall survival (OS) improvement in the overall population,” said Dr Matthew Powell from Washington University School of Medicine, St Louis, Missouri, US, at SGO 2024.

At a median follow-up of 37.2 months, there was a 31-percent median OS improvement in the dostarlimab vs placebo arm (44.6 vs 28.2 months; hazard ratio [HR], 0.69; p=0.002). “This represents a 16.4-month improvement … despite the fact that over 38 percent of [placebo recipients] went on to receive immunotherapy,” said Powell.

In the dMMR/MSI-H* cohort, median OS with dostarlimab-CP vs placebo-CP was not estimable [NE] vs 31.4 months (HR, 0.32; p=0.0002). “This was a substantial, unprecedented OS benefit,” he added.

Among those with MMRp/MSS** disease, median OS was 34 months in the dostarlimab arm and 27 months in the placebo arm (HR. 0.79; p=0.0493). According to Powell, the 7-month difference is clinically meaningful.

A consistent OS benefit was seen across most exploratory subgroups. [Powell, et al, SGO 2024]

There were consistent signals in terms of median progression-free survival 2 (PFS2). The difference between the dostarlimab and placebo arms was substantial in the dMMR/MSI-H cohort (NE vs 21.6 months; HR, 0.33) and clinically meaningful in the overall (32.3 vs 18.4 months; HR, 0.66) and MMRp/MSS populations (24.6 vs 15.9 months; HR, 0.74).

Compared with placebo-CP, dostarlimab-CP was tied to higher rates of grade ≥3 treatment-emergent adverse events (TEAEs; 72 percent vs 60 percent), serious TEAEs (40 percent vs 28 percent), any treatment-related immune-related AE (41 percent vs 16 percent), and TEAEs that led to dostarlimab or placebo discontinuation (19 percent vs 8 percent).

Nonetheless, Powell noted that most TEAEs were grade 1/2, except anaemia (which is typically grade 3 but manageable). There were no new safety signals with the additional follow-up.

Dismal outcomes

CP has been the standard of care (SoC) for first-line treatment of primary advanced recurrent endometrial cancer for nearly 2 decades, noted Powell. “Unfortunately, outcomes are dismal, with a median OS of <3 years.” [Discov Med 2011;12:205-212; J Clin Oncol 2004;22:2159-2166]

The team randomized 494 patients (median age 64.5 years) 1:1 to IV dostarlimab 500 mg plus CP or placebo-CP Q3W for six cycles, followed by dostarlimab 1,000 mg or placebo Q6W for up to 3 years or until disease progression. Over 85 percent of patients had measurable disease at baseline and about 20 percent had prior anticancer treatment. The most common histology was endometrioid (55 percent), followed by serous adenocarcinoma (20 percent).

The PFS benefit and early OS trend seen with dostarlimab-CP in the first interim analysis of RUBY has led to its approval for the treatment of primary advanced or recurrent dMMR/MSI-H endometrial cancer. [https://ca.gsk.com/en-ca/media/press-releases/jemperli-dostarlimab-for-injection-plus-carboplatin-and-paclitaxel-approved-in-canada-as-a-treatment-option-for-primary-advanced-or-recurrent-dmmrmsi-h-endometrial-cancer; https://www.gsk.com/en-gb/media/press-releases/jemperli-plus-chemotherapy-approved-as-the-first-and-only-frontline-immuno-oncology-treatment-in-the-european-union, accessed 2 May 2024]

“[The current] data confirm dostarlimab plus CP as a new SoC for patients with primary advanced or recurrent endometrial cancer, regardless of MMR status,” Powell concluded.