ADVERTISEMENT
O-010
VOLTAGE: Investigator-initiated clinical trial of nivolumab monotherapy and subsequent radical surgery following preoperative chemoradiotherapy in patients with microsatellite stable locally advanced rectal cancer
Introduction
Chemoradiotherapy (CRT) with surgery 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 surgery following CRT (50.4 Gy with capecitabine 1,650 mg/m2) in T 3–4 N any M 0 LARC.
Chemoradiotherapy (CRT) with surgery 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 surgery following CRT (50.4 Gy with capecitabine 1,650 mg/m2) in T 3–4 N any M 0 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.
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-surgery, was the RP2S. From January 2017 to June 2018, 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 patient (3%) refusing surgery 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 surgery. No treatment-related deaths were observed. pCR rates of 60% (6/10) and 19% (5/27) (P = .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 = .029) were seen in 23 pts with samples analyzable by flow cytometry, according to CD8+ lymphocyte/regulatory T cell (CD8/T reg) ratios ≧2 and <2, respectively.
Nivo 240 mg q2 weeks x 5 cycles, following CRT but pre-surgery, was the RP2S. From January 2017 to June 2018, 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 patient (3%) refusing surgery 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 surgery. No treatment-related deaths were observed. pCR rates of 60% (6/10) and 19% (5/27) (P = .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 = .029) were seen in 23 pts with samples analyzable by flow cytometry, according to CD8+ lymphocyte/regulatory T cell (CD8/T reg) ratios ≧2 and <2, respectively.
Conclusion
A promising pCR rate of 30%, with mild toxicity, was shown in MSS LARC pts treated with nivo plus radical surgery. PD-L1 expression and elevated CD8/T reg ratio may be better predictors of nivo benefit, warranting further study in a larger cohort.
A promising pCR rate of 30%, with mild toxicity, was shown in MSS LARC pts treated with nivo plus radical surgery. PD-L1 expression and elevated CD8/T reg ratio may be better predictors of nivo benefit, warranting further study in a larger cohort.
Publisher
Oxford University Press
Source Journal
Annals of Oncology
