Promising data are reported for tumours with dMMR, MSI-H and rare POLE alterations, reinforcing the role of molecular testing for tissue-agnostic treatment
Preliminary data from the GARNET trial show durable antitumour activity of monotherapy with the anti-PD-1 monoclonal antibody dostarlimab in patients with advanced or recurrent mismatch repair-deficient (dMMR) and microsatellite instability–high (MSI-H) or polymerase epsilon (POLE)–altered solid tumours, for whom treatment opportunities are currently limited (JAMA Netw Open. 2023;6(11):e2341165).
In the phase I, open-label, single-group, multicenter study, a total of 363 patients with dMMR and MSI-H and/or POLE-altered tumours and at least one prior line of therapy, received the immuno-monotherapy at a recommended therapeutic dose of 500 mg intravenously every 3 weeks for 4 cycles, then 1000 mg intravenously every 6 weeks until discontinuation.
Efficacy and safety of the immune-checkpoint inhibitor were assessed across multiple tumour types, including endometrial cancers (43.1%) and colorectal cancer (24.8%).
In the interim analysis, overall response rate (ORR) was of 44.0% in the dMMR population, while the median duration of response (mDOR) was not reached (range, 1.18 to 47.21 months). Median follow-up was of 27.7 months. Similar results were reported for the full efficacy population, including patients with dMMR and MSI-H or POLE-altered tumours, at a median follow-up of 29.1 months Durable responses to treatment, lasting 12 months or longer, were reported in 72.2% of responders with dMMR. Median progression-free survival (mPFS) was 6.9 months (95% CI, 4.2-13.6 months) and 7.0 months (95% CI, 4.2-13.8 months) in dMMR and in the full efficacy population respectively, and median overall survival (mOS) was not reached in all populations.
The safety profile of dostarlimab in dMMR and MSI-H or POLE-altered solid tumours was consistent with other immune checkpoint inhibitors, and no new safety concerns were identified.
“This study demonstrated similar ORR, mDOR, and mPFS in all tumour types, regardless of histology or cell of origin, further supporting the significance of dMMR as an agnostic tumour biomarker and emphasising the importance of testing for dMMR status through companion tests, such as immunohistochemistry, for immunotherapy”, says Dr Carmen Criscitiello, European Institute of Oncology, Milan, Italy.
Dostarlimab is approved in the European Union as a monotherapy in dMMR/MSI-H recurrent or advanced endometrial cancer that has progressed on or after platinum-based chemotherapy. In the United States, the Food and Drug Administration has approved the anti-PD-1 agent for patients with dMMR recurrent or advanced solid tumours that have progressed on or following prior treatment and who have no satisfactory alternative treatment options, adding dostarlimab to the list of approved tumour-agnostic agents. “Given the consistent and high levels of antitumour activity across various tumour types reported in the GARNET trial, it appears appropriate to have the MMR status assessed to select patients who are more likely to respond to dostarlimab, with tumour mutational burden (TMB) and PD-L1 as complementary biomarkers,” continues Criscitiello.
Patients with pathogenic POLE alterations have demonstrated benefits from immune checkpoint inhibitor therapy, however knowledge is currently lacking on the efficacy of PD-L1 inhibition in this biomarker-selected population (JCO Precis Oncol. 2022 Feb:6:e2100267). “In this trial, dostarlimab showed to deliver a promising antitumour efficacy also in this poorly investigated tumour-altered population, with an impressive ORR of 54.5%, an undetermined DOR after 3 years or more of median follow-up, and a PFS of one year or longer, aligning with findings from other immune checkpoint inhibitors,” concludes Criscitiello. “Future studies exploring the role of POLE alterations, as well as TMB and PD-L1 expression, are needed to improve patient selection for the monotherapy, in addition to dMMR and MSI-H.”