In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 8_suppl ( 2019-03-10), p. 43-43
Abstract:
43 Background: PD-1 targeting with pembrolizumab or nivolumab leads to durable clinical benefits in patients (pts) with microsatellite instability-high (MSI-H) tumors. However, 30-35% of mCRC pts with MSI-H tumors will experience progressive disease (PD) as a best response when treated with anti-PD1 agents, highlighting the need of additional predictive biomarkers. Methods: We performed a retrospective multi-center clinical investigation to evaluate the impact of TMB, age, gender, stage at initial presentation, pattern of metastatic disease, tumor grade, and RAS/RAF status on response to anti-PD1/PD-L1 in MSI-H mCRC. TMB and MSI status were determined by hybrid capture-based next-generation sequencing (Foundation Medicine [FM]). The TMB distribution in MSI-H CRC was estimated from a large data set from FM. Results: 22 eligible MSI-H mCRC pts were identified across 5 cancer centers: 19 pts received pembrolizumab, 1 pt received nivolumab, 1 pt received nivolumab + ipilimumab, and 1 pt received durvalumab + tremelimumab. Among tested variables, TMB (as a continuous variable) showed the strongest association with an objective response (OR; p 〈 0.001). Also, both univariate and multivariate analyses supported that TMB serves as an independent prognostic variable in predicting progression-free survival (PFS; p 〈 0.001 and p 〈 0.01, respectively). Using log-rank statistics, the optimal predictive cut-point for TMB was estimated between 37-41 mutations/Mb to dichotomize pts into TMB high and TMB low groups. All 13 pts (100%) with TMB high had an OR, while only 2/9 (22%) pts with TMB low had an OR and 6/9 had PD. The median PFS for TMB high pts has not been reached (no progressors, median follow-up 〉 18 mos), while the median PFS for TMB low pts was 2 mos. Amongst 821 MSI-H CRC cases tested at FM, the 25 th , 35 th , 50 th and 75 th percentile TMB cutoffs were 33.1, 37.4, 46.1, and 61.8 mutations/Mb, respectively. Our optimal TMB cut-point range suggests that MSI-H mCRC with the lowest 35 th percentile of TMB have a low likelihood of benefit from anti-PD1. Conclusions: These TMB findings require validation in prospective trials and may guide the sequencing of PD-1 inhibitor monotherapy in MSI-H mCRC.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/JCO.2019.37.8_suppl.43
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2019
detail.hit.zdb_id:
2005181-5
Permalink