Real world impact of pembrolizumab availability for deficient mismatch repair metastatic colorectal cancer.

Abstract

Background: Keynote 177 was a practice changing study, with pembrolizumab versus dealers’ choice chemotherapy +/- biologic significantly improving progression free survival in patients (pts) with previously untreated deficient mismatch repair (dMMR) metastatic colorectal cancer (mCRC). A high rate (29.4%) of pembrolizumab treated pts had stopped treatment at or before first response evaluation due to progressive disease as best response. Pembrolizumab availability in routine care is anticipated to benefit individual pts otherwise treated with chemotherapy. Additional pts not fit for chemotherapy, but fit for first line (1L) pembrolizumab, may be able to receive active treatment, which could increase the dMMR mCRC population benefit. Pembrolizumab availability may also drive increased MMR testing, which may impact the proportion of pts with dMMR mCRC. Methods: We analysed data from the TRACC registry of pts with mCRC in Australia comparing patient treatment across two cohorts. The first cohort was pts diagnosed from 1/1/2015 to 31/7/2021 when immunotherapy was only available via trial, self-funding or through a limited access program and the second cohort was pts diagnosed from 1/8/2021 to 23/1/2024, following the government’s Pharmaceutical Benefits Scheme reimbursement (PBSr) of pembrolizumab as 1L treatment for dMMR mCRC. We also examined early treatment discontinuation rates for pembrolizumab treated pts after PBSr. Results: Of 2819 mCRC pts overall, 2344 (83%) had known MMR status. Of pts tested 163 (7%) were dMMR. Pts with dMMR mCRC were older (mean age 66.6 vs 62.2, p < 0.01) and had more co-morbidities (59% vs 47% for modified Charlson Comorbidity Index ≥ 3, p < 0.01). They were also more likely to have a right side primary (67% vs 31%, p < 0.01), BRAF V600E mutation (49% vs 11%, p < 0.01) and peritoneal or brain metastases (34% vs 22%, p < 0.01). Before PBSr of pembrolizumab, 85 of 117 (73%) dMMR mCRC pts received 1L treatment; 62/85 (73%) chemotherapy, 19/85 (22%) immunotherapy and 4/85 (5%) combination BRAF inhibitor and EGFR inhibitor. Following PBSr, an increased proportion (40 of 46) of dMMR mCRC pts received any 1L treatment (87% vs 73%, p = 0.05), with 1/40 (2.5%) receiving chemotherapy and 39/40 (97.5%) pembrolizumab. In a landmark analysis of these 39 pts, 12 of 19 (63%) that had started treatment ≥ 6 months ago remained on pembrolizumab. Conclusions: A high proportion of Australian pts with mCRC are undergoing dMMR testing. Increasing testing, including of more elderly pts, may increase the proportion of mCRC pts that are dMMR compared to that reported for trial populations. dMMR mCRC pts have multiple adverse prognostic features. The broad availability of pembrolizumab, such as through the Australian PBSr, looks likely to lead to an increased proportion of pts receiving any 1L therapy. Early data suggests the expected clinical benefit, with a low rate of early treatment discontinuation.