Short-term results of VOLTAGE-A: Nivolumab monotherapy and subsequent radical surgery following preoperative chemoradiotherapy in patients with microsatellite stable and microsatellite instability-high locally advanced rectal cancer.

Abstract

4100 Background: Chemoradiotherapy (CRT) followed by radical surgery (S) is standard therapy for patients (pts) with locally advanced rectal cancer (LARC). Sequential use of an anti-PD-1 antibody after radiation demonstrates synergistic effects in in vivo models, and an anti-PD-1 antibody is effective in pts with microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). We studied nivolumab (nivo) and radical S following CRT (50.4 Gy with capecitabine 1,650 mg/m2) in T3–4 NanyM0 LARC. Methods: After the quality-assured CRT, 240 mg q2 weeks x 5 cycles of nivo and radical S were investigated. In cohort A-1, for pts with microsatellite stable (MSS) LARC, the primary endpoint was a centrally confirmed pathological 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%. In Cohort A-2, 5 pts with MSI-H LARC were included in an exploratory manner. Results: From Jan/2017 to Oct/2019, a targeted number of pts was included and assessed. In cohort A-1, 30% (11/37; 90% CI 18-44%) of pCR (AJCC grade (gr) 0) rate and 38% (14/37) of major pathological response (MPR) (AJCC gr 0+1) rate were observed. Clinical CR was observed in one additional pt (3%) refusing S after nivo. In cohort A-2, 60% (3/5) of pCR rate and 60% (3/5) of MPR rate were observed. As of Jan/2020, only 2 pts (1 local and 1 metastatic) in cohort A-1 and none in cohort A-2 recurred. Immune-related severe adverse events were observed in 3 pts (gr 3 myasthenia, gr 3 interstitial nephritis, and gr 2 peripheral motor neuropathy); all fully recovered and received radical S. During the follow-up period, one additional pt with gr 2 colitis was observed. No treatment-related deaths were observed. Conclusions: Promising pCR rates of 30% and 60%, with mild toxicities, were shown in MSS and MSI-H LARC pts treated with nivo plus radical S after CRT, suggesting the candidate therapy for the future non-surgical approach. Clinical trial information: NCT02948348 .

Immunotherapy for Early Stage Colorectal Cancer: A Glance into the Future

“…To note, similar histological results have been reported for patients with the resection of residual lesions after ICI treatment for metastatic MSI/dMMR CRC [67,68]. In the phase II VOLTAGE-A study evaluating nivolumab followed by radical surgery after chemoradiotherapy for patients with rectal cancer, 60% of complete pathological responses were observed among MSI/dMMR cases (three out of five) [69].…”

Total Neoadjuvant Therapy vs Standard Therapy in Locally Advanced Rectal Cancer

“…In addition, immune checkpoint inhibitors such as durvalumab, avelumab, and nivolumab and other novel agents such as peposertib, a DNA protein kinase inhibitor, and aflibercept, an angiogenesis inhibitor, are being investigated in a TNT setting. 32 , 33 , 34 , 35 , 36 A list of recent and ongoing TNT trials that are yet to be published is included in eTable 2 in the Supplement . 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 …”

Immune Checkpoint Inhibition as a Strategy in the Neoadjuvant Treatment of Locally Advanced Rectal Cancer

“…For example, clinical trial evidence from lung cancer has shown that survival is increased when immune checkpoint inhibition is delivered after radiation in the stage III setting. [110] Preliminary findings from the VOLTAGE-A trial in LARC [115] also showed encouraging results with sequential treatment. In contrast, preclinical evidence from Dovedi et al [101] implies that earlier use of immunotherapy and specifically its combination with radiation may lead to improved responses.…”

“…Given the potential overlapping adverse reactions with combination treatment, the safety data from these trials are eagerly awaited. To date, there have been encouraging results from the VOLTAGE trial (NCT02948348; see Table 2) [115] in which of 39 patients, no grade 4 nivolumab-related adverse events were recorded and all severe immune-related adverse events had fully resolved before surgery. Accounting for the one patient who refused surgical resection following a complete clinical response to treatment, 38 (97%) of 39 patients proceeded to radical surgery.…”