Association of multiplex-immunofluorescence (m-IF) and gene expression signature with prognosis and bevacizumab (bev) treatment outcomes in NRG oncology/NSABP C-08: Implications for combining immune checkpoint blockade (ICB) and bev.
Authors: Pogue-Geile Katherine L. , Joy Marion E , Wang Ying , Kim Rim S , Gavin Patrick G , Fumagalli Debora , Yothers Greg , Allegra Carmen Joseph , Srinivasan Ashok , Finnigan Melanie , Jacobs Samuel A. , George Thomas J. , Suga Jennifer Marie , Hopkins Judith O. , Saito Naoyuki G. , Wolmark Norman , Paik Soonmyung , Lucas Peter C. 
Published: January 2022

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Background: NRG Oncology/NSABP C-08 tested the efficacy of adding bev to mFOLFOX in patients (pts) with stage II or III colon cancer. In an unplanned analysis we showed that MMR status was predictive of bev benefit with dMMR pts receiving statistically significant bev benefit. More recently, we showed that immune cells and immune checkpoint proteins have differential effects on prognosis and bev benefit in C-08 (ASC0 2021). As part of a preplanned secondary objective of an NCTN-CCSC approved protocol, we tested the association of VEGFR, VEGFA, and CD31, with clinical outcomes and treatment benefit in dMMR and pMMR pts enrolled in C-08. To determine what subset of pts within C-08 received bev benefit, we tested the 10-gene IFNɣ signature (Ayers et al 2017), which has been shown to associate with response to ICB in other studies. Methods: VEGFR, VEGFA, and CD31 were quantitated in tumors from C-08 pts (N=1,485) using m-IF and the Vectra Pathology System and inForm software. Gene expression data of C-08 (n=387) via DASLR microarrays was used to test the IFNɣ signature for association with bev benefit in dMMR and pMMR pts. All markers were tested for associations with prognosis and bev benefit in dMMR and pMMR pts using recurrence-free interval, median cut points, and Cox models. Results: VEGFR, VEGFA, and CD31 were not prognostic in the total C-08 cohort nor in dMMR or pMMR subsets. However, high VEGFR was associated with bev benefit in dMMR pts p=0.0012, HR=0.08 [95% CI; 0.025-0.224], n=117) but not in pts with pMMR (n=555) (int p=0.03). Pts whose tumors showed higher expression of the IFNɣ signature had a better prognosis than did pts with a low signature. Importantly, in the entire C-08 cohort with available DASL data, pts with low IFNɣ signatures received bev benefit (p=0.034, HR=0.59 [95% CI: 0.36-0.97], n=211). When low IFNɣ tumors were further split by MMR status both dMMR and pMMR pts showed a trend to receive bev benefit, however, numbers of pts were too small to make firm conclusions (dMMR no bev vs. bev p=0.02, n=11; pMMR no bev vs. bev, p=0.051, n=167). Conclusions: High VEGFR is associated with bev benefit in dMMR pts. In agreement with other studies, we observe that the IFNɣ signature is associated with a good prognosis in C-08, however, unique to this study is the observation that IFNɣ low is associated with bev benefit in the entire C-08 cohort. The association of high IFNɣ signature with ICB response seen in several other studies, plus our observation that low IFNɣ is associated with bev benefit in C-08, suggests that bev and ICB are most efficacious on different subsets of pts. Current clinical trial, GI-004, is testing the efficacy of the bev + atezolizumab combination. Examination of these markers may be informative. Support: PA DOH, U10CA-180868, -180822, -196067, Genentech, Sanofi; NSABP Clinical trial information: 00096278.