Background: Perioperative therapy for locally advanced (LA) GC/GEJ adenocarcinoma is standard of care. Although immune checkpoint blockade (ICB) following chemoradiotherapy and resection significantly improves disease free survival (DFS) for esophageal cancer, the effectiveness of ICB together with chemotherapy in LA GC/GEJ cancer is unknown. Methods: This is a multicenter, single-arm, phase II clinical trial of pembrolizumab 200 mg every 3 weeks with capecitabine 625 mg/m2 twice daily and oxaliplatin 130 mg/m2 every 3 weeks (CAPOX) in patients with resectable GC/GEJ adenocarcinoma. Subjects with ECOG PS of 0-1 received CAPOX with pembrolizumab for 3 cycles prior to and 3 cycles following surgery with an additional cycle of pembrolizumab just prior to surgery and 12 months of maintenance pembrolizumab following adjuvant chemoimmunotherapy. The primary endpoint was pathologic complete response (pCR) rate. The study had 80% power to detect an increase in pCR rate from 3% to 15% with a one-sided alpha of 0.05. Secondary endpoints included overall response rate, DFS, and overall survival (OS). This study was registered with ClinicalTrials.gov (NCT02918162). Results: Between 02/10/2017 and 06/17/2021, 36 patients were enrolled with 34 (21 gastric and 13 GEJ) evaluable for efficacy. The median age was 65 years and 17 (50%) patients had an ECOG PS of 1. In total, 29 (85%) patients underwent resection. Seven patients achieved a pCR (20.6% of evaluable patients and 24.1% of those who underwent resection). An additional 6 (17.6%) patients achieved a near CR and 8 (23.5%) demonstrated a significant treatment effect on pathologic review. One patient was deemed unfit for surgery, 2 expired prior to surgery, and 2 were found to have metastatic disease during surgery. At the time of data cut-off, the median follow-up was 19 mo. Of those who underwent resection, 4 (13.7%) experienced disease recurrence and 5 (17.2%) expired. The probability of survival at 1 and 2 years was 0.91 (0.82-1.0) and 0.80 (0.64-0.99), respectively. The median DFS and OS have not been reached. Of the 35 patients who received treatment, treatment related adverse events (AEs) of grade greater than or equal to 3 were reported in 18 (51%) patients. Grade greater than or equal to 3 immune-related AEs were reported in 10 (29%) patients. Three grade 5 AEs occurred, two possibly treatment-related (gastric hemorrhage and gastric perforation) and one unrelated to treatment (cardiac arrest). Conclusion: In LA GC/GEJ adenocarcinoma, the combination CAPOX and pembrolizumab resulted in a pCR rate of 20.6%. The combination was well tolerated and 85.3% of patients underwent surgical resection. This trial met its primary endpoint supporting further investigation of this regimen as an alternative for patients who are unlikely to tolerate triple combination chemotherapy. Correlative studies are in progress. Citation Format: Alexander Grenander Raufi, Shing Lee, Michael May, Armando Del Portillo, Naomi Sender, Sarah Sta Ana, Katarzyna Gautier, Emily Alouani, Haeseong Park, Paul Oberstein, Manish Shah, Gulam A. Manji. Phase II trial of perioperative pembrolizumab plus capecitabine and oxaliplatin followed by adjuvant pembrolizumab for resectable gastric and gastroesophageal junction (GC/GEJ) adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT009.
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.
About 5% of the patients with metastatic colorectal cancers (mCRC) present microsatellite instability (MSI)/deficient mismatch repair system (dMMR). While metastasectomy is known to improve overall and progression‐free survival in mCRC, specific results in selected patients with dMMR/MSI mCRC are lacking. Our study aimed to describe metastasectomy results, characterize histological response and evaluate pathological complete response (pCR) rate in patients with dMMR/MSI mCRC. We retrospectively reviewed data from all consecutive patients with dMMR/MSI mCRC who underwent surgical metastasectomy between January 2010 and June 2021 in 17 French centers. Primary outcome was to assess the pCR rate defined by tumor regression grade (TRG) 0. Secondary endpoints included relapse‐free survival (RFS) and overall survival (OS), and explored TRG as predictive factor for RFS and OS. Among the 88 patients operated, 109 metastasectomies were performed in 81 patients after neoadjuvant treatment [chemotherapy ± targeted therapy (CTT): 69, 85.2%; immunotherapy (ICI): 12, 14.8%], and pCR was achieved in 13 (16.1%) patients. Among the latter, pCR rate were 10.2% in the patients having received CTT (N = 7) and 50.0% in the patients treated with ICI (N = 6). Radiological response did not predict TRG. With a median follow‐up of 57.9 (IQR 34.2‐81.6) months, median RFS was 20.2 (15.4‐not reached) months, median OS was not reached. Major pathological responses (TRG0 + TRG1) were significantly associated with longer RFS (HR 0.12, 95% CI 0.03‐0.55; P = .006). The pCR rate of 16.1% achieved with neoadjuvant treatment in patients with dMMR/MSI mCRC is consistent with previously reported rates in pMMR/MSS mCRC. Immunotherapy showed better pCR rate than chemotherapy ± targeted therapy. Further prospective trials are needed to validate immunotherapy as neoadjuvant treatment in resectable/potentially resectable dMMR/MSI mCRC and identify predictive factors for pCR.
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