For patients with newly diagnosed high-risk endometrial cancer, postsurgical Keytruda (pembrolizumab) and chemotherapy with or without radiation did not result in an improvement to disease-free survival (DFS; the time after diagnosis a patient shows no signs of their disease returning) when compared with treatment via chemotherapy with or without radiation, although a clinically meaningful benefit was experienced by patients whose tumors were mismatch repair deficient (dMMR), study results have shown.
Interim results of the phase 3 ENGOT-en11/GOG-3053/KEYNOTE-B21 trial were presented during the ESMO Congress 2024.
Keytruda plus chemotherapy is approved as a frontline treatment for patients with advanced or recurrent endometrial cancer, irrespective of mismatch repair (MMR) status. The decision was based on data showing that the combination reduced the risk of disease progression or death in patients with endometrial cancer regardless of MMR status.
At a median follow-up of 23.9 months in the intent-to-treat (ITT) population, findings of the protocol-specified third interim analysis showed that the median DFS was not reached in either arm, meaning more than half of the patients in each arm had still not experienced signs of their disease returning. The two-year DFS rates were 75% and 76% in the Keytruda and placebo arms, respectively.
However, the median DFS was also not reached with Keytruda or placebo in patients with dMMR tumors (281 patients), but the two-year DFS rates were 92% and 80%, respectively. In those whose tumors were mismatch repair proficient (pMMR), the median DFS was not reached in either arm. These two-year DFS rates were 69% and 75%, respectively.
“The subgroup analysis by MMR status suggests a clinically meaningful benefit in DFS for the dMMR subgroup — which is about 25% of the population — a biomarker population well established to have a high [tumor mutational burden] and an inflamed phenotype with elevated PD-L1 expression,” lead study author Dr. Toon Van Gorp, a gynecologist oncologist in the Department of Gynecology and Obstetrics at UZ Leuven, in Leuven, Belgium, said in an oral presentation during the meeting.
Currently in the curative intent, adjuvant setting, systemic chemotherapy with or without radiation is the standard treatment for patients with high-risk endometrial cancer, with five-year DFS rates between 58% and 65% with chemotherapy or chemoradiation.
The coprimary end points (main results measured at the end of the study) were investigator-assessed DFS and overall survival (OS; the time a patient lives, regardless of disease status) in the intention-to-treat population.
At the data cutoff date of March 4, 2024, there were 111 (27%) and 96 (23%) DFS events in the Keytruda and placebo arms in the pMMR subgroup compared with eight (6%) and 25 (18%) in the dMMR subgroup, respectively. OS data were immature at the time of the interim analysis, meaning the average number of deaths did not occur in time for data collection.
Regarding safety, any-grade side effects occurred in all patients in both arms; grade 3 or higher side effects occurred in 71% of patients on the Keytruda arm compared with 63% of those on the placebo arm. There were no treatment-related deaths.
Treatment discontinuation rates occurred in 24% and 16% of patients on the Keytruda and placebo arms; treatment discontinuations led to death in 3% and 1% of patients, respectively. There were similar rates between arms of the different chemotherapy and radiation discontinuations, Van Gorp noted.
Immune-related side effects and infusion reactions occurred in 42% of Keytruda-treated patients; these were grade 3 to 5 (severe to deadly) in 10% of patients, led to treatment discontinuation in 6%, and led to death in one patient. In the placebo arm, these rates were 24%, 4%, and 4%, respectively; no patients died because of immune-related side effects or infusion reactions.
In the safety population, side effects occurring in at least 25% of patients in the Keytruda and placebo arms comprised alopecia (hair loss, 63%; 65%), anemia (low red blood cell count, 52%; 52%), nausea (44%; 48%), diarrhea (40%; 38%), decreased neutrophil count (a type of white blood cell; 35%; 32%), constipation (33%; 30%), peripheral neuropathy (numbness or tingling in the hands and feet; 29%; 34%); decreased white blood cell count (34%; 28%), arthralgia (joint pain or soreness; 29%; 30%) and fatigue (28%; 30%).
Immune-mediated AEs and infusion reactions occurring in at least 1% of patients in either treatment arm were consistent with the known safety profiles of checkpoint inhibitors, Van Gorp explained. These included hypothyroidism, hyperthyroidism, infusion reactions, severe skin reactions, pneumonitis (inflammation of the lung tissue), thyroiditis (inflammation of the thyroid gland), colitis (inflammation of the colon), adrenal insufficiency and gastritis (inflammation of the stomach lining).
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