Neoadjuvant chemotherapy and serplulimab in MSS/pMMR locally advanced rectal cancer (FIRM): A phase II trial.

Abstract

119 Background: PD-1 inhibitor shows poor efficacy in MSS locally advanced rectal cancer (LARC). Radiotherapy activates tumor immunogenicity, and current evidence have shown that combination of neoadjuvant chemoradiotherapy (nCRT) with PD-1 inhibitor enhances tumor regression and improves pathological complete response (pCR) rate in MSS LARC. However, nCRT induces radiation toxicities including radiation proctitis, anastomotic fistula and anal dysfunction. Moreover, radiotherapy is not feasible for high position LARC. Radiotherapy-free neoadjuvant strategy warrants further exploration. Neoadjuvant mFOLFOX6 circumvents radiation toxicity but achieves only 6.6% pCR rate (FOWARC trial, JCO 2016). Preclinical studies suggested oxaliplatin and 5FU have immune-sensitizing effects. Thus, we conducted the first proof of concept trial exploring a radiotherapy-free neoadjuvant immuno-chemotherapy (nICT) regimen, which employed a multicenter, single arm, phase 2 design to evaluate the efficacy and safety of mFOLFOX6 plus serplulimab in MSS/pMMR LARC. Methods: Patients (pts) with cT3/4 or cN+, MSS and pMMR LARC located ≤15 cm from anal verge were eligible. Pts received 6 cycles of neoadjuvant mFOLFOX6 and serplulimab, followed by surgery and adjuvant mFOLFOX6. The primary endpoints were pCR rate and major pathological response (MPR) rate. Enrollment of 30 pts was planned, with hypothesis of an increased pCR of 24% compared with reported data of 6.6% after conventional mFOLFOX6. The per-protocol set (PPS) was defined as pts who completed ≥4 cycles of nICT for primary endpoint assessment. Results: Among 30 enrolled patients, 28 completed ≥4 cycles of nICT and were included in PPS. 2 discontinued due to adverse events. The pCR was achieved in 42.9% (12/28) of pts, and MPR in 67.9% (19/28). For high LARC (>10 cm from anal verge, ineligible for nCRT), the pCR and MPR rates were 71.4% and 85.7%. Radiologic response of tumor regression showed complete response in 57.1% (16/28) and partial response in 39.3% (11/28) of pts. One pt had stable disease and received nCRT. 27 pts proceeded to TME and were included in surgical set. TRG 0, 1, 2, and 3 were observed in 44.4%, 11.1%, 40.7%, and 3.7% of pts. Downstaging was achieved in 22 pts (81.5%). The Grade 3 TRAEs were lymphocyte decrease (4 pts), neutropenia (3 pts) and bilirubin elevation (1 pts). No Grade 4-5 TRAEs or anastomotic fistula were observed. Conclusions: mFOLFOX6 plus serplulimab showed promising efficacy and manageable safety in MSS LARC. pCR rate unexpectedly reached 42.9%, showing an improvement compared with the reported 6.6% pCR rate of chemotherapy, and were comparable to nCRT plus anti-PD-1 regimens. This is the first proof of concept trial to explore a nICT strategy for MSS LARC, which spares pts from radiation toxicities and shows particularly applicability for high LARC. We are launching a randomized controlled trial (FIRM02) for further validation. Clinical trial information: NCT06688786 .