Potential Game Changer for Endometrial Cancer

HONOLULU -- An investigational PD-1 inhibitor achieved objective responses in 30% of patients with recurrent or advanced endometrial cancer, according to a study reported here.

The overall response rate included almost half of patients with microsatellite instability-high (MSI-H) tumors. Dostarlimab produced responses in patients with MSI-H, microsatellite stable (MSS), and microsatellite status unknown tumors. An additional 53% of patients had stable disease.

The results have major implications for management of recurrent/advanced endometrial cancer, a condition that has limited treatment options, Ana Oaknin, MD, of Vall d'Hebron Hospital in Barcelona, said at the Society of Gynecologic Oncology meeting.

"I think it will be a practice-changing study in all comers because we saw a great response rate in MSS, and most importantly durable response in this group of patients as well," Oaknin told MedPage Today. "I think both patients [MSI-H and MSS] will benefit from dostarlimab, although the clinical benefit is greater in the patients with MSI-high. But nevertheless, I think that MSS patients will benefit as well."


Ana Oaknin, MD, presenting the findings at SGO

Prior studies of checkpoint inhibitors in recurrent/advanced endometrial cancer demonstrated modest activity, with response rates generally less than 10%, said Kunle Odunsi, MD, PhD, of Roswell Park Comprehensive Cancer Institute in Buffalo, New York. The results reported by Oaknin were impressive, but raised questions that need to be addressed to optimize the use of checkpoint inhibitors in endometrial cancer; namely, why did half of the patients with MSI-H tumors not respond and why did patients with MSS tumors respond?

"[This study] has the potential to be practice changing because it provided clinically meaningful results, but it needs translational studies to help understand the results," said Odunsi.

Additionally, trial results have to be considered in the context of a recent study that showed at least comparable results with the combination of pembrolizumab and lenvatinib for advanced endometrial cancer, he added.

Few treatment options exist for endometrial cancer that has progressed after first-line therapy. Most patients receive single-agent chemotherapy, which is associated with objective response rates of 7-13%, Oaknin noted. Pembrolizumab (Keytruda) has the only approved indication for recurrent endometrial cancer, limited to patients with MSI-H tumors. Approval of the indication was based primarily on a study showing a 36% response rate in 14 patients.

Dostarlimab competitively inhibits the PD-1 receptor by simultaneously blocking the binding of PD-L1 and PD-L2 ligands. The monoclonal antibody demonstrated significant clinical activity in various tumor types, including second-line therapy for non-small cell lung cancer not previously treated with a PD-1 inhibitor.

Three-fourths of endometrial cancers are MSS and the remaining tumors are MSI-H. Oaknin reported findings from the GARNET trial, a phase I/II study to assess the safety and clinical activity of dostarlimab in patients with advanced solid tumors. Phase I was a dose escalation study, and the ongoing phase II component included multiple expansion cohorts, with accrual goals of 65 patients with MSI-H endometrial cancer and 125 with MSS endometrial cancer. Data analysis included 125 evaluable patients (41 MSI-H, 79 MSS, and four with unknown MSI status).

Eligible patients had disease progression during or after treatment with platinum-based chemotherapy. All patients had received no more than two prior regimens for recurrent/advanced disease. Prior treatment could not include agents targeting PD-1, PD-L1, or PD-L2.

The results showed that 20 (48.8%) patients with MSI-H tumors achieved objective responses with dostarlimab, as well as 16 (20.3%) of the MSS subgroup, and one (20%) patient with MSI status unknown. Overall, 37 of 125 (29.6%) evaluable patients attained objective responses, including six (4.8%) complete responses, two in patients with MSI-H tumors, and four in the MSS subgroup.

Dostarlimab led to a disease control rate (response plus stable disease) of 52.8% in all 125 patients -- 63.4% of the MSI-H subgroup and 46.8% of the MSS subgroup. Oaknin reported that 83.8% of responses were ongoing at last follow-up (median follow-up, 10 months). Median duration of response had yet to be reached, but 89% of patients remained on treatment for more than 6 months and 49% for more than a year. Among the responding patients, 85% had >50% reduction in tumor burden.

A total of 88 (70.4%) patients had treatment-emergent adverse events (TEAEs), the most common being fatigue (14.4%), diarrhea (12.8%), and nausea (12.0%). Oaknin said that seven (5.6%) patients had grade ≥3 immune-related TEAEs.

The study was supported by Tesaro.

One or more investigators disclosed relationships with Roche, AstraZeneca, Pharma Mar, Clovis Oncology, Tesaro, Immunogen, Genmab, AbbVie Deutschland, Ability Pharmaceuticals, Advaxis, Aeterna Zentaris, Amgen, Aprea Therapeutics, EISAI, F. Hoffmann-La Roche, Regeneron, Merck Sharp & Dohme de Espana, and Millennium Pharmaceuticals.

Source: https://www.medpagetoday.com/meetingcoverage/sgo/78704

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