Single-cycle neoadjuvant pembrolizumab in patients with stage I-III MMR-deficient colon cancer: Final analysis of the RESET-C study.
Camilla Qvortrup|Copenhagen University Hospital - Rigshospitalet
Abstract：19
Background:
Neoadjuvant treatment with immune checkpoint inhibitors has shown remarkable responses in patients with deficient mismatch repair (dMMR) colorectal cancer. However, the optimal choice and duration of treatment have yet to be established.
Methods:
RESET-C (NCT05662527) was an investigator-initiated, phase II, single-arm, multicenter study investigating the efficacy and safety of single-cycle neoadjuvant pembrolizumab in 85 patients with resectable stage I-III dMMR colon cancer. Additional inclusion criteria were ≥ 18 years of age, no indication for neoadjuvant therapy, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. After inclusion, patients received one cycle of pembrolizumab 4mg/kg (maximum 400mg) and underwent surgery within three to five weeks. A tumor-response evaluation was done before surgery, including blood samples, a computed tomography scan of the chest and abdomen, and a colonoscopy. The primary endpoint was the pathological complete response (pCR) rate according to Mandard tumor regression grading (Clopper-Pearson method). Secondary endpoints included surgical complications, safety of pembrolizumab, major pathological response (Mandard tumor regression grade 1 or 2), and disease-free survival.
Results:
Between February 2023 and March 2024, 85 patients were included. The median age was 74 years (IQR, 68-79), 72% were women, and 60% had clinical stage III disease. All patients received pembrolizumab, and 84 patients proceeded to surgery. One patient with stage I disease decided not to undergo surgery. A pCR rate of 44% (37/84; 95% CI, 33-55) and a major pathological response rate of 57% (48/84; 95% CI, 46~68) were found. A significantly higher pCR rate was seen in patients with stage I-II (20/33) versus stage III (17/51) disease (61% vs 33%; p=0.02). A total of 41 surgical complications were seen in 31 patients (37%; 95% CI, 27-48). Of these, eight complications were Clavien-Dindo grade 3a or above, including three patients with anastomotic leakages and two deaths within 30 days. The patients who died were aged 80 and 81, had ECOG performance status 1, and clinical stage IIIB and IIIC disease, respectively. Seven out of 85 patients (8%; 95% CI, 3-16) experienced grade 3 adverse events, three of which were treatment-related. No grade 4 or 5 adverse events were registered. Finally, data on the association between endoscopically evaluated clinical complete response and pCR, along with the 1-year disease-free survival rate expected in January 2025, will be reported.
Conclusions:
A single cycle of neoadjuvant pembrolizumab was efficacious and safe in patients with localized dMMR colon cancer. For most patients with clinical stage I-II disease, a single cycle sufficed to achieve pCR.
Preliminary results from a randomized, open-label, phase 2 study of botensilimab (BOT) with or without balstilimab (BAL) in refractory microsatellite stable metastatic colorectal cancer with no liver metastases (MSS mCRC NLM).
Marwan Fakih|Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center
Abstract：23
Background: BOT is an Fc-enhanced, multifunctional anti-CTLA 4 antibody designed to improve Fc gamma receptor-mediated effector functions and extend the reach of I-O to tumor types such as MSS mCRC. Here we present preliminary data from a randomized, open-label, phase 2 study in patients (pts) with MSS mCRC NLM treated with BOT ± BAL (anti-PD 1; NCT05608044). The study aimed to inform dose and contribution of components based on the primary endpoint of objective response rate (ORR) by RECIST 1.1 per investigator, and safety, and was not powered for statistical comparisons between arms.
Methods: A total of 234 pts (intent-to-treat [ITT]) were randomized to BOT (up to 4 doses) 75 or 150 mg every 6 wks (Q6W), BOT 75 or 150 mg Q6W plus BAL 240 mg Q2W (up to 2 years), or standard of care (SOC; regorafenib or trifluridine/tipiracil).
Results: Median age was 58 yrs (range 23—90), 50% male, 39% rectal, 44% 3L+, 43% ECOG 1, 58% KRAS mutant, 4% NRAS mutant, 83% prior bev, all MSS and/or pMMR by local testing. Key characteristics were well balanced with some exceptions including median time from diagnosis of metastatic disease to study entry (30 mos across arms; 45 mos SOC) and presence of peritoneal metastases (34% across arms; 42% 75 mg BOT / 240 mg BAL; 27% SOC). As of July 29, 2024, median follow-up was 9.8 mos. Key efficacy and safety data are shown (Table). Image based endpoints by blinded independent review, as well as overall survival will be reported in the future. Grade ≥3 treatment-related adverse events (TRAEs) were highest with SOC followed by BOT + BAL combination, and then BOT monotherapy, with dose dependency. Treatment-related immune-mediated diarrhea/colitis (imDC) was manageable and highest with 150 mg BOT / 240 mg BAL. No new safety signals and no treatment-related deaths occurred.
Conclusions: The study met the objectives of informing dose and contribution of components. Overall ORR was higher with BOT + BAL vs BOT monotherapy. ORR was highest with 75 mg BOT / 240 mg BAL with less toxicity as compared to 150 mg BOT / 240 mg BAL. Consistent with published data, there were no objective responses in SOC whereas most responses seen with BOT + BAL were ongoing, similar to the durable responses observed in the ph1 study. These responses are differentiated from previous I-O-only combinations and SOC, supporting further investigation of 75 mg BOT / 240 mg BAL vs SOC in a planned global ph3 trial.
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