LBA43 - Updated response data and analysis of progression free survival by mechanism of mismatch repair loss in endometrial cancer (EC) patients (pts) treated with pembrolizumab plus carboplatin/paclitaxel (CP) as compared to CP plus placebo (PBO) in the NRG GY018 trial

Background

NRG GY018 identified a 70% and 46% reduction in the risk of disease progression or death in advanced stage or recurrent dMMR and pMMR EC patients treated with pembrolizumab plus CP. The relationship between mechanism of MMR deficiency and clinical outcomes in dMMR EC patients is not well understood.

Methods

819 pts were randomized 1:1 to pembrolizumab + CP or PBO + CP Q3W for 6 cycles followed by maintenance pembrolizumab or PBO Q6W for up to 2 years. MMR status was assessed by local and central immunohistochemistry (IHC). For patients with measurable disease at enrollment, updated best response (RECIST 1.1) was examined in both patient cohorts. Mechanism of MMR loss was determined by review of local MMR IHC results and presence/absence of MLH1 promoter hypermethylation. The effect of mechanism of MMR loss on PFS was examined in dMMR patients treated with pembrolizumab.

Results

Local and central MMR IHC had strong agreement, kappa 0.88 (95% CI 0.84-0.91). The ORR was improved in the pembrolizumab arm of both patient cohorts (dMMR: 81.5% vs. 70.7%, OR 1.83 (95% CI 0.92-3.66) and pMMR: 70.7% vs. 58.1%, OR 1.74 (95% CI 1.18-2.58)). The CR rate in the dMMR and pMMR EC cohorts was higher when pembrolizumab was added to CP (15% vs 32% dMMR; 8% vs 15% pMMR). Median DOR was significantly improved with addition of pembrolizumab, dMMR 28.7 mo vs 6.2 mo (HR 0.22; 95% CI 0.13-0.37, p<.0001) and pMMR 9.2 mo vs 6.2 mo (HR 0.47; 95% CI 0.34-0.64, p<.0001). In 223 central-dMMR pts, 72% had MLH1 promoter hypermethylation, 13% had MMR protein loss secondary to gene mutation, and 15% were not evaluable. Mechanism of MMR loss was not a significant predictor of PFS (85% versus 75% progression free at 12 months in mutated vs methylated pts). Median PFS and OS were not reached irrespective of mechanism of MMR loss.

Conclusions

In NRG GY018, no difference in PFS was identified in dMMR EC patients based on mechanism of MMR loss. With more mature clinical follow up, the magnitude of benefit in both patient cohorts treated with pembrolizumab was maintained, with significant improved in ORR, and DOR.

Clinical trial identification

NCT04214067.

Editorial acknowledgement

Legal entity responsible for the study

NCI/CTEP.

Funding

Merck.

Disclosure

R.N. Eskander: Financial Interests, Personal and Institutional, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Myriad, Seagen, Immunogen, Nuvectis Pharma, Gilead, Regeneron, Acrivon; Non-Financial Interests, Institutional, Local PI: Merck, Novocure, Xencor, CanaryBio. All other authors have declared no conflicts of interest.