PURPOSE In patients with resectable gastric/gastroesophageal junction (GEJ) adenocarcinoma, surgery plus perioperative platinum-based chemotherapy is the standard of care. Perioperative chemotherapy remains debatable for gastric/GEJ adenocarcinoma with deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H). PATIENTS AND METHODS NEONIPIGA (ClinicalTrials.gov identifier: NCT04006262 ) phase II study evaluated neoadjuvant nivolumab 240 mg once every two weeks ×6 and ipilimumab 1 mg/kg once every six weeks ×2, followed by surgery and adjuvant nivolumab 480 mg once every four weeks (nine injections) in patients with locally advanced resectable dMMR/MSI-H, clinical (c) tumor (T)2-T4 node (N)x metastasis (M)0 gastric/GEJ adenocarcinoma. The primary end point was a pathological complete response (pCR) rate. RESULTS Between October 2019 and June 2021, 32 patients with dMMR/MSI-H gastric/GEJ adenocarcinoma were enrolled. The median age was 65.5 years (range, 40-80). Clinical stages were cT2-T3N0 (n = 9), cT2-T3N1 (n = 22), and cT3N1M1 (n = 1, wrongly included). With a median follow-up of 14.9 months (95% CI, 10.6 to 17.6), 32 patients received neoadjuvant immunotherapy (27 patients completed all cycles). Neoadjuvant therapy-related grade 3/4 adverse events occurred in six patients (19%). Twenty-nine patients underwent surgery; three did not have surgery and had complete endoscopic response with tumor-free biopsies and a normal computed tomography scan (two refused surgery and one had metastasis at inclusion). The rate of surgical morbidity (Clavien-Dindo classification) was 55% (one postoperative death occurred). All 29 patients had an R0 resection, and 17 (58.6%; 90% CI, 41.8 to 74.1) had pCR (pathological T0N0). Becker tumor regression grades 1a, 1b, 2, and 3 were observed in 17 patients, three (including two pathological T0N1), two, and seven patients, respectively. Of the 29 patients with surgery, 23 received adjuvant nivolumab. At database lock, no patient had relapse and one died without relapse. CONCLUSION Nivolumab and ipilimumab-based neoadjuvant therapy is feasible and associated with no unexpected toxicity and a high pCR rate in patients with dMMR/MSI-H resectable gastric/GEJ adenocarcinoma.

244 Background: In pts with resectable gastric adenocarcinoma or OGA, radical surgery is the only curative option and perioperative chemotherapy seems worthless for those with MSI/dMMR tumors. Methods: We conducted phase II study evaluating the efficacy of neo-adjuvant nivolumab and ipilimumab followed by adjuvant nivolumab in pts with resectable MSI/dMMR, T2-T4 NxM0 tumors. Treatment consisted of nivolumab 240 mg every 2 weeks (6 infusions) and ipilimumab 1 mg/kg every 6 weeks (2 infusions), followed by radical surgery 5 weeks (±1 week) after last injection of nivolumab. Pts with Becker tumor regression grade (TRG) < 3 were treated with adjuvant nivolumab 480 mg every 4 weeks (9 infusions). The primary objective was pathological complete response (pCR) rate. Results: From 10/2019 to 06/2021, a total of 32 pts were enrolled (all had dMMR±MSI-H status; 16 with gastric cancer and 16 with OGA). The median age was 65.5 years (range, 40-80). Initial stage was: usT3Nx = 22, usT2Nx = 4, and usTxNx = 6 (not evaluable by ultrasound endoscopy). At data lock, 32 pts had terminated neo-adjuvant period and 27 (84%) completed all 6 neo-adjuvant cycles. 8 pts (32%) experienced G3/4 adverse events (AEs) during neo-adjuvant treatment. 29 pts underwent surgery; 2 refused surgery and had complete endoscopic response with tumor-free biopsies, 1 had surgery not performed in relation with a metastatic progression. The median delay between last injection and surgery was 35 days (extreme, 25-170). Overall surgical morbidity (54%, n = 14) was related to: anastomotic leakage = 4, pancreatitis = 2, pneumonia = 2, and other = 6. The incidence of post-operative mortality was 3.8% (n = 1) due to cardiovascular AE at post-operative day 3. All the 29 pts who underwent surgery had R0 resection: 17 (59%) had pCR (i.e., TRG 1a as per Becker grade, ypT0N0) and 4 (14%) had TRG 1b as per Beker grade (< 10% residual tumor per tumor bed). 1 pt had TRG 2 (10-50% of residual tumor) and 7 pts had TRG 3 (˃50% of residual tumor) as per Becker grade, per local pathological assessment (central pathological review is awaited). With a median follow-up of 10.9 months, 1 pt had metastatic relapse, 1 pt died without relapse and 30 pts were recurrence/progression-free. Conclusions: Neo-adjuvant therapy with nivolumab and ipilimumab is feasible and is associated with a high pCR rate in pts with MSI/dMMR resectable OGA. Data will be updated for the congress. Clinical trial information: NCT04006262.

Microsatellite instability (MSI) is a tumor phenotype related to a deficient DNA mismatch repair system (dMMR). This phenotype, observed in 5% of metastatic mCRC but 10–18% of localized CRC, is associated with high tumor mutational burden with highly immunogenic neoantigens. It has emerged as a major predictive biomarker for the efficacy of ICIs. In this review, we will present a comprehensive overview of the literature concerning the efficacy of ICIs in MSI/dMMR mCRC, with a focus on new developments in first-line metastatic setting. Then, we will present current and future challenges of immuno-oncology for patients with MSI/dMMR metastatic CRC.

Over the past years, colorectal cancer (CRC) was subtyped according to its molecular and genetic characteristics, allowing the development of therapeutic strategies, based on predictive biomarkers. Biomarkers such as microsatellite instability (MSI), RAS and BRAF mutations, HER2 amplification or NTRK fusions represent major tools for personalized therapeutic strategies. Moreover, the routine implementation of molecular predictive tests provides new perspectives and challenges for the therapeutic management of CRC patients, such as liquid biopsies and the reintroduction of anti-EGFR monoclonal antibodies. In this review, we summarize the current landscape of targeted therapies for metastatic CRC patients, with a focus on new developments for EGFR blockade and emerging biomarkers (MSI, HER2, NTRK).

Background: Several studies reported improved outcomes with conventional treatments (CT, i.e., chemotherapy ± targeted therapy) administered after immune checkpoints inhibitors (ICI) in certain tumor types. No data are available concerning patients (pts) with metastatic colorectal cancer (mCRC) harboring mismatch repair deficiency/microsatellite instability (dMMR/MSI). We aimed to assess the outcomes of dMMR/MSI mCRC pts receiving CT after ICI failure. Methods: We conducted a retrospective multicenter study investigating the outcomes of all dMMR/MSI mCRC pts who received post-ICI CT between 2015 and 2020. Results: 31 pts (male 61%, median age 56 years) were included. ICI was an anti-PD(L)1 monotherapy in 71% of pts, and 61% received >2 lines before post-ICI CT. The overall response rate and disease control rate were 13% and 45%, with a median progression-free survival (PFS) and overall survival of 2.9 and 7.4 months, respectively. No association of the outcomes with either ICI efficacy or anti-angiogenic agents was observed. Prolonged PFS (range 16.1–21.3 months) was observed in 4 pts (13%). Conclusions: Although conducted on a limited number of patients, our results do not support an association of previous ICI treatment with an enhanced efficacy of CT in dMMR/MSI mCRC. However, prolonged disease control was observed in several cases, suggesting that some pts might derive an unexpected benefit from post-ICI treatments.

13 Background: Optimal treatment duration with immune checkpoint inhibitors (ICI) for MSI/dMMR mCRC pts remains to be determined. Different durations are used, usually a fixed duration of 2 years or treatment until progression or toxicity. The GERCOR NIPICOL phase II study evaluated 1 year of therapy with nivolumab plus ipilimumab for MSI/dMMR mCRC pts. Here, we present the efficacy data with 16 months of additional follow-up since the primary analysis. Methods: MSI/dMMR mCRC pts previously treated with fluoropyrimidine, oxaliplatin, and irinotecan ± targeted therapies received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg Q3W for 4 cycles, then nivolumab 3 mg/kg Q2W until progression or a maximum of 20 cycles. Second course of nivolumab was permitted for pts who completed the predefined year of treatment and had later progressive disease (PD). Objectives were to evaluate response rates, progression-free survival (PFS) per iRECIST, and overall survival (OS). A landmark analysis was performed for PFS in pts who remained alive and progression-free at 1 year (theoretical end of treatment). Results: Of 57 pts included between Dec 2017 and Nov 2018, 36 (63%) completed the predefined 1-year duration of treatment. Reasons of premature treatment discontinuation were PD or death (n = 13), adverse event (n = 7), and the pt wish (n = 1). Overall median follow-up was 34.5 months. One, 2, and 3-year PFS rates were respectively 75.4% (95% CI 62.0-84.6), 70.0% (95% CI 56.2-80.1), and 70.0% (95% CI 56.2-80.1). One, 2, and 3-year OS rates were 84.1 (95% CI 71.7-91.4), 78.4% (95% CI 65.1-87.1), and 73.1% (95% CI 58.4-83.4), respectively. 42/57 pts were progression-free and alive at 1 year. Among them, median follow-up was 35.0 months and the 24-month PFS rate was 92.9% (95% CI 79.5-97.6%). PD was observed in three pts whose 12-month status was stable disease (SD). These three pts received a second course of nivolumab: two achieved PR and one had PD. Conclusions: Nivolumab plus ipilimumab with a fixed duration of 1 year continued to show durable activity in pts with chemoresistant MSI/dMMR mCRC after 3 years of follow-up. Reexposure to nivolumab seems to provide additional antitumor activity for pts experiencing late resistance after discontinuation of immunotherapy. Clinical trial information: NCT033501260.

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