Dostarlimab Produces Durable Responses With Acceptable Safety in dMMR Solid Tumors

Thierry André, MD

Dostarlimab-gxly (Jemperli) was found to have durable antitumor activity with manageable toxicity in patients with mismatch repair–deficient (dMMR) and/or microsatellite instability–high (MSI-H) solid tumors, according to Thierry André, MD, who added that these data underscore the need to test for these markers to identify those who might derive benefit from the immunotherapy.

Data from the phase 1 GARNET study (NCT02715284) presented during the 2022 ASCO Annual Meeting showed that among 327 patients with dMMR solid tumors, dostarlimab produced an objective response rate (ORR) of 44.0% (95% CI, 38.6%-49.6%), with a median duration of response (DOR) that had not yet been reached. Notably, 72.2% of patients continued to respond to treatment for 12 months or longer.

At a median follow-up of 27.7 months, the median progression-free survival (PFS) with the immunotherapy was 6.9 months (95% CI, 4.2-13.6), and the median overall survival (OS) had not yet been reached (95% CI, 31.6–not reached).

“It is now clear that there is a predictive factor of efficacy for a PD-1 inhibitor: if a tumor is dMMR or MSI-H,” André said. “For this reason, it is important [that we] screen all [patients with] solid tumors [so that we] have the opportunity to find [these mutations] and open the door to therapy with an anti–PD-1 compound.

In an interview with OncLive^®, André, a professor of medical oncology at the Sorbonne Université in Paris, France, as well as the head of the Medical Oncology Department at the Saint Antoine Hospital, Assistance Publique Hôpitaux de Paris, further discussed the results of the phase 1 GARNET study with dostarlimab and the significance of these findings for those with dMMR/MSI-H solid tumors.

OncLive^®: Could you discuss the key objectives and design of the GARNET study?

André: [GARNET] was a phase 1 study, with 327 patients included. The primary objective [of the study] was to evaluate the response rate and the duration of response with dostarlimab for adult patients with dMMR advanced tumors.

There are 2 cohorts on the trial: 1 cohort [included those with] dMMR endometrial cancer who had progressed on or after a platinum-based chemotherapy regimen, [and the other] evaluated patients with [dMMR solid tumors that were not endometrial cancer who progressed after systemic therapy and had no satisfactory alterative options.]

The first part of the study was [the] phase 1 [portion], and dostarlimab was administered at a dose of 500 mg given every 3 weeks for 4 cycles, followed by 1000 mg every 6 weeks.

What were the key findings presented during the 2022 ASCO Annual Meeting?

[At the meeting,] we presented results [regarding] the ORR, as well as the PFS and OS [with dostarlimab] in this heavily pretreated population. [Notably,] all patients had received [at least 1] previous line of therapy [and had] progressive disease.

The response rates were consistent across [the cohorts and ranged from 43%] to 45%, [and the median] duration of response [had] not [been] reached at this time. With this research, [the estimated probability of] PFS at 24 [months was about] 40%, and [the estimated probability of] OS [at this time point was] about 58% in this population.

It is interesting that dostarlimab, an anti–PD-1 compound, can change things for these patients. [In all 327 patients, the disease] control [rate was 85.4%]; these patients had long-term [disease] control which provides them with the opportunity to go back to daily life. [Also, patients] continued [to respond to treatment] with time. Overall, it seems to be amazing results for this population.

What should be known about the safety profile of this agent?

The safety data were [as expected with] this type of compound. There was a relatively low rate of grade 3/4 treatment-related AEs. Moreover, if we only take into consideration grade 3 or higher AEs, [the rate was] approximately 16%. [With dostarlimab, we saw the same kinds of] treatment-related AEs [that we typically see with] immunotherapies. We saw some colitis, skin toxicities, and pneumonitis, [among others]. Overall, this [agent has an acceptable toxicity [profile].

Other data with dostarlimab in those with rectal cancer read out during the meeting. Could you speak to those findings and their clinical significance?

At the 2022 ASCO Annual Meeting, we saw an incredible presentation on results [from a phase 2 trial (NCT04165772) examining dostarlimab] in [14 patients with] locally advanced rectal cancer]. On the study, all patients [achieved] a clinical complete response.

It has really been a dream; it is clear that neoadjuvant therapy with an anti–PD-1 agent such as dostarlimab in gastrointestinal cancer can open a [door to the] watch-and-wait strategy to avoid surgery to remove the primary tumor. The rate of CR is very high [with this agent] in [these patients] and it is a huge hope for patients to [be able to] avoid surgery and [to] have the opportunity to cure the disease without the necessity to resect the primary tumor.

Reference

André T, Berton D, Curigliano G, et al. Efficacy and safety of dostarlimab in patients (pts) with mismatch repair deficient (dMMR) solid tumors: analysis of 2 cohorts in the GARNET study. J Clin Oncol. 2022;40(suppl 16):2587. doi:10.1200/JCO.2022.40.16/suppl.2587