Dostarlimab exhibits promising antitumor exercise in mismatch repair-deficient, competent endometrial most cancers

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Treatment with dostarlimab induced sustained anti-tumor activity in patients with advanced or recurrent DNA mismatch repair deficiency (dMMR) and competent (MMRp) endometrial cancer. This emerges from updated results of the Phase 1 GARNET study (NCT02715284), which was presented during the ESMO virtual congress 2020

In addition, the compound showed a remarkable disease control rate (DCR) and a promising safety profile.

The results indicated that the PD-1 antibody produced an objective response rate (ORR) of 44.7% in patients with dMMR disease and 13.4% in patients with MMRp disease. In the dMMR cohort (n = 103), 11 complete responses (CRs) and 35 partial responses (PRs) were observed. Thirteen patients achieved stable disease (SD) while 39 patients experienced disease progression. In the MMRp cohort (n = 142), 3 patients had CRs, 16 PRs, 31 had stable disease, and 77 patients had progressive disease.

The median duration of response (DOR) was not reached in either the dMMR cohort (range 2.63-28.09 +) or the MMRp cohort (range 1.54+ to 30.36+). In addition, the DCRs with dostarlimab in the dMMR cohort and the MMRp cohort were 57.3% (95% CI, 47.2-67.0) and 35.2% (95% CI, 27.4-43, 7).

“Dostarlimab has shown sustained anti-tumor activity in both dMMR and MMRp-advanced and recurrent endometrial cancer,” said Dr. Ana Oaknin, lead study author and head of the gynecological cancer program at the Vall d’Hebron Institute of Oncology in Barcelona, ​​Spain in a presentation during the congress. “The dMMR status determined by immunohistochemistry (IHC) was associated with a higher response rate. Dostarlimab also demonstrated remarkable DCR in patients with MMRp endometrial cancer, a cohort made up of a higher percentage of patients with type II disease, which has historically been associated with a poorer prognosis. “

In the single-arm phase 1 study, researchers investigated monotherapy with dostarlimab in patients with advanced solid tumors. Part 2B of the study included 5 expansion cohorts: dMMR / microsatellite instability high (MSI-H) endometrial cancer (cohort A1), MMRp (cohort A2), non-small cell lung cancer (cohort E), dMMR / MSI -H non-endometrial cancer (Cohort F) and platinum-resistant ovarian cancer without BRCA mutations (Cohort G)

At the 2020 ESMO virtual congress, Oaknin shared data from the two endometrial cancer cohorts: dMMR and MMRp. The repair status of the mismatch was determined by IHC. In Part 2B of the study, the PD-1 inhibitor was administered at the recommended dose determined from Parts 1 and 2A of the study: 500 mg intravenously (IV) every 3 weeks for 4 cycles, followed by 1000 mg IV every 6 Weeks to disease progression.

To be eligible, patients must have completed treatment with or after treatment with platinum doublet therapy, received 2 or fewer prior lines of therapy for recurrent or advanced disease, and had a measurable disease at baseline. In addition, patients could not have received previous PD-1 / PD-L1 inhibitor therapy and were required to undergo screening based on local MMR / MSI tests performed in a certified local laboratory and have MMR-IHC – Results confirmed.

The primary endpoints of the study were ORR and DOR.

Previous results of the GARNET study were presented during the 2020 Society of Gynecological Oncology Virtual Congress. In a cohort of 71 patients with endometrial cancer, dostarlimab induced an ORR of 42% (95% CI, 31-55); This included a CR rate of 13% and a PR rate of 30% .3 The DCR with the drug was 58%, and with a mean follow-up time of 11.2 months, the mean DOR had not yet been reached.

As of March 1, 2020, a total of 126 patients in the dMMR cohort and 145 patients in the MMRp cohort were enrolled in the study and treated with dostarlimab. These patients form the study safety population. To be eligible for inclusion in the efficacy population, participants were required to have at least 6 months of follow-up time for the study with at least 1 measurable lesion at baseline. According to Oaknin, a total of 103 patients in the dMMR cohort and 142 in the MMRp cohort met these criteria.

The demographic and fundamental characteristics between the two cohorts were found to be similar, with the largest difference being in relation to histology. In the dMMR cohort, the most common histology was endometroid carcinoma type I with 68.0% (n = 70) and 23.2% (n = 33) in the MMRp cohort. The majority of participants in the latter cohort, or 76.8% (n = 109), had type II endometrial cancer compared to 31.1% (n = 32) in the dMMR cohort. Of the 109 MMRp patients, 54 had serous histology.

In addition, 63.1% (n = 65) received 1 previous line of therapy in the dMMR cohort and 45.8% (n = 6%) in the MMRp cohort; 26.2% (n = 27) and 43.7% (n = 62) received 2 previous lines; and 10.7% (n = 11) and 10.6% (n = 15) received 3 or more previous lines of treatment, respectively.

Additional results from the study showed that Kaplain Meier’s estimated likelihood of patients responding at 6 months in the dMMR and MMRp cohort was 97.8% and 83.0%, respectively. At 12 months these estimated rates were 90.6% and 61.3% and at 18 months 79.2% and 61.3%, respectively.

The median follow-up time in the dMMR cohort was 16.3 months, while the follow-up time in the MMRp cohort was 11.5 months. In the dMMR cohort, 89% of patients (n = 41/46) continued to respond to treatment at the time of the data interruption; This also applied to 63.2% (n = 12/19) of the members of the MMRp cohort. “The response time among respondents to Dostarlimab was quite long, and the majority of those who did respond remained responding at the time of the data interruption,” noted Oaknin.

In terms of safety, 95.2% (n = 120) of patients in the dMMR cohort (n = 126) and 100% of patients in the MMRp cohort (n = 145) experienced treatment-related adverse reactions of any kind. Grade 3 or higher TEAEs were observed in 48.4% (n = 61) and 55.9% (n = 81) of those in the dMMR and MMRp cohorts, respectively.

In 63.5% (n = 80) of the dMMR cohort and 71.7% (n = 104) of the MMRp cohort, any degree of toxicities associated with study treatment was reported. Grade 3 or higher treatment-related adverse reactions occurred in 13.5% (n = 17) and 19.3% (n = 28) of patients in the dMMR and MMRp cohorts, respectively. Serious treatment-related toxicities were reported in 9.5% (n = 12) and 9.0% (n = 13) of patients, respectively.

The three most common TRAEs of all degrees of severity were fatigue (13.5% for dMMR and 20.7% for MMRp), diarrhea (15.9% and 13.1%), and nausea (12.7% and 14 , 5%). Grade 3 TRAEs or higher included anemia (4.0% and 1.4%), alanine aminotransferase (ALT; 1.6% and 1.4%), and diarrhea (1.6% and 1.4%).

The three main immune-related TRAEs of all types included hypothyroidism (5.6% and 7.6%), diarrhea (4.8% and 3.4%), and elevated aspartate aminotransferase (AST; 1.6% and 2.8%) . Grade 3 or higher immune-related TRAEs included increased ALT (1.6% and 1.4%), diarrhea (1.6% and 1.4%), and increased amylase (0.8% and 1.4%) .

Four percent of patients (n = 5) in the dMMR cohort developed TRAEs that led to discontinuation of treatment, and 6.9 percent (n = 10) of patients in the MMRp cohort. These toxicities included increased ALT (0.8% in dMMR and 1.4% in MMRp), increased AST (0.8% and 0.7%, respectively), and increased transaminases (1.6% and 0%). In particular, no deaths related to study treatment were reported.

“No new safety signals were seen and only 5% of patients stopped dostarlimab because of TRAEs,” concluded Oaknin. “Finally, I have to emphasize that these cohorts represent the largest prospective evaluation of PD-L1 / PD-1 therapy for endometrial cancer to date and that follow-up is still ongoing.”

References

  1. Oaknin A., Gilbert L., Tinker AV, et al. Safety and antitumor activity of dostarlimab in patients with advanced or recurrent DNA mismatch repair deficiency (dMMR) or competent (MMRp) endometrial cancer: results from GARNET. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Summary LBA36.
  2. GSK presents new data from the GARNET study demonstrating the potential of dostarlimab in the treatment of a subgroup of women with relapsed or advanced endometrial cancer. Press release. GlaxoSmithKline plc. April 23, 2020. Accessed September 19, 2020. https://bit.ly/33N1C7n.

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