Voltage: Investigator-initiated clinical trial of nivolumab monotherapy and subsequent radical surgery following preoperative chemoradiotherapy in patients with microsatellite stable locally advanced rectal cancer.

Abstract

3606 Background: Chemoradiotherapy (CRT) with surgery (S) is standard for patients (pts) with locally-advanced rectal cancer (LARC), and nivolumab (nivo) is active in microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). We studied nivo and radical S following CRT (50.4 Gy with capecitabine 1,650 mg/m2) in T3–4 NanyM0 LARC. Methods: Phase I included testing of a recommended phase II dosing schedule (RP2S). Efficacy and safety were studied in phase II pts and those given RP2S in phase I. In Cohort A-1, for microsatellite stable (MSS) LARC pts, the primary endpoint was centrally confirmed pathologic complete response (pCR) rate using AJCC tumor regression grading. The estimated required sample size assuming null and alternative hypotheses pCR = 10% and 30% was 37 pts, with a 1-sided alpha of 5% and power of 90%. Cohort A-2 was exploratory and included a maximum of 5 MSI-H pts. Results: Nivo 240 mg q2 weeks x 5 cycles, following CRT but pre-S, was the RP2S. From 1/17 to 6/18, 37 pts were enrolled in Cohort A-1. Eleven pts (30%; 90% CI 18-44%) showed pCR (AJCC grade (gr) 0). Including the 3 pts (8%) graded AJCC 1, 14 (38%) had major pathologic responses. In addition, clinical CR was observed in 1 pt (3%) refusing S after nivo. Both MSI-H LARC Cohort A-2 pts showed pCRs. Immune-related severe adverse events were observed in 2 pts (gr 3 myasthenia and gr 2 interstitial nephritis); both fully recovered and had S. No treatment-related deaths were observed. pCR rates of 60% (6/10) and 19% (5/27) (p = 0.038, Fisher exact test) were seen in pts with tumor cells with PD-L1 ≥1% and < 1% IHC staining, respectively, performed on biopsy samples taken pre-CRT. Rates of 62% (8/13) and 10% (1/10) (p = 0.029) were seen in 23 pts with samples analyzable by flow cytometry, according to CD8+ lymphocyte /regulatory T cell (CD8/Treg) ratios ≥2 and < 2, respectively. Conclusions: A promising pCR rate of 30%, with mild toxicity, was shown in MSS LARC pts treated with nivo plus radical S. PD-L1 expression and elevated CD8/Treg ratio may be better predictors of nivo benefit, warranting further study in a larger cohort. Clinical trial information: NCT02948348.

Immunotherapy in Colorectal Cancer: Current and Future Strategies

“…Patients diagnosed with rectal cancer could be candidates for a combined treatment with RT and ICIs because preoperative chemoradiation (CRT) is one of the standard treatments in rectal cancer and upregulates PD-L1 expression [53,54]. In the phase I/II investigator-initiated VOLT-AGE trial (NCT02948348) of nivolumab monotherapy and subsequent radical surgery following preoperative CRT in patients with MSS locally-advanced rectal cancer, 11 (30%) and 14 (38%) of 37 patients with MSS were CR and major responses by pathological examination, respectively, suggesting their potential for future use in non-operative management [55].…”

Immunotherapy for the treatment of colorectal cancer

“…While the majority of patients with pMMR/MSS locally advanced rectal cancer will benefit from neoadjuvant FOLFOX, most will not achieve a CR and two ongoing studies are investigating the role of neoadjuvant ICI in improving CR rate in pMMR/MSS locally advanced rectal cancer. In the multicenter phase Ib/II VOLTAGE trial, patients with locally advanced rectal cancer receive concurrent chemoRT followed by nivolumab and subsequent radical surgery (NCT02948348) 61,62 . NRG‐GI002 is an ongoing randomized phase II trial investigating FOLFOX followed by chemoRT with concurrent capecitabine ± either pembrolizumab or veliparib (NCT02921256) (Table 3).…”

“…achieved a pathologic complete response (pCR) ( locally advanced rectal cancer receive concurrent chemoRT followed by nivolumab and subsequent radical surgery (NCT02948348). 61,62 NRG-GI002 is an ongoing randomized phase II trial investigating FOLFOX followed by chemoRT with concurrent capecitabine ± either pembrolizumab or veliparib (NCT02921256) ( Table 3).…”

Emerging Trends for Radio-Immunotherapy in Rectal Cancer

“…Many clinical trials exploring the synergistic effect of combining RT with checkpoint blockade in solid cancers are ongoing [ 186 , 187 , 188 ]. In this line, a few trials are evaluating the combination of RT and immune checkpoint inhibition in RC (e.g., NCT02298946 [ 196 ], NCT02948348 [ 197 ], NCT04124601, NCT04262687, NCT04558684), but always in combination with chemotherapy. A brief summary of the relevant radio-immunotherapy clinical trials in RC is presented in Table 1 .…”

“…Encouraging safety and toxicity profiles from these studies indicate that radio-immunotherapy combinations could represent a valid opportunity for RC patients. For instance, in the VOLTAGE trial (NCT02948348) where patients received CRT followed by nivolumab, only mild toxicity was reported, with 7.7% of patients experiencing immune-related grade 3/4 side effects [ 197 ]. Moreover, 30% of patients with locally advanced pMMR/MSS RC reached pCR compared to 60% of dMMR/MSI-H RCs [ 197 ].…”