PD-1 blockade alone for mismatch repair deficient (dMMR) locally advanced rectal cancer.

Abstract

16 Background: Total neoadjuvant therapy with induction chemotherapy and chemoradiation (chemoRT) is the standard treatment for locally advanced rectal adenocarcinomas. Mismatch repair deficient (dMMR) rectal tumors respond poorly to neoadjuvant chemotherapy. PD-1 blockade is effective in patients with metastatic dMMR colorectal cancers, but its efficacy has not been established in the neoadjuvant setting. The purpose of this study is to evaluate the clinical benefit of neoadjuvant PD-1 blockade in dMMR locally advanced rectal cancer. Methods: We designed a prospective, single-arm, phase II study in which patients with stage II and III dMMR rectal cancer receive neoadjuvant dostarlimab (anti-PD-1) for a total of 6 months. The co-primary objectives are to determine the overall response rate (ORR) and pathologic complete response (pCR) or clinical complete response rate (cCR) with or without chemoRT. Tumor assessment with endoscopic evaluation is performed at baseline, 6 weeks, 3 months and 6 months; imaging is performed at pretreatment baseline, 3 months and 6 months. Patients with cCR by previously established criteria are eligible for non-operative management without chemoRT. Those with residual disease after neoadjuvant dostarlimab receive standard chemoRT. Following chemoRT, any patient failing to achieve a cCR is then managed surgically. Results: A total of 13 patients have been enrolled, with median age 52 years (range 26-78), 77% female, and 92% with node-positive disease by rectal MRI. The ORR is 100% in the 12 patients who have undergone at least a 3-month evaluation. Seven patients have completed induction therapy and all 7 (100%) have achieved a cCR and are undergoing observation without chemoRT or surgery. The rate of progressive disease thus far is 0%. No patients have required chemoRT or surgery. There have been no serious adverse events. Conclusions: Single agent neoadjuvant PD-1 blockade with dostarlimab is effective and well-tolerated in locally advanced dMMR rectal adenocarcinoma and allows patients to avoid chemoradiation and surgery. This suggests a potential new paradigm for treatment of dMMR locally advanced rectal cancer. Follow up and further patient accrual is ongoing. Clinical trial information: NCT04165772.

Recent advances in the management of gastric adenocarcinoma patients

“…Patients with MSI-H/dMMR GAC have had dramatic results with immune checkpoint therapy, as evident with MSI-H/dMMR metastatic colorectal cancer 9 – 12 . Programmed death-1 blockade is under investigation in localized MSI-H/dMMR solid tumors 13 , 14 . Lumish et al recently reported the results of 12 localized stage II or III MSI-H/dMMR rectal cancer patients who achieved 100% objective response rate (ORR) with dostarlimab, an anti-PD-1 agent 13 .…”

“…Programmed death-1 blockade is under investigation in localized MSI-H/dMMR solid tumors 13 , 14 . Lumish et al recently reported the results of 12 localized stage II or III MSI-H/dMMR rectal cancer patients who achieved 100% objective response rate (ORR) with dostarlimab, an anti-PD-1 agent 13 . This phase 2 trial reported on seven patients who completed induction therapy.…”

Total neoadjuvant therapy (TNT) using 5FU and oxaliplatin followed by higher dose concurrent 5FU in locally advanced high-risk rectal adenocarcinoma including signet ring and mucinous cancers resulting in good complete response rates

“…Future studies might take into consideration biomarkers such as circulating tumor DNA (ctDNA) following NAT that might inform adjuvant strategies in patients with persistent ctDNA after NAT and surgical resection. Alternatively, identifying LARC patients with MSI might warrant an alternative sequence of NAT, CRT followed CT and potentially incorporation of ICIs either alone or in combination with CRT (40). Importantly, the current study highlights the real-world feasibility, e cacy, and safety of this protocol in an LMIC setting with pCR and 2-year DFS rates which are comparable to contemporary studies done in No surgery done represents the patients who were initiated on or completed TNT but did not undergo surgery.…”

The Multimodal Management of Locally Advanced Rectal Cancer: Making Sense of the New Data

“…A recent abstract presented at the 2022 ASCO Gastrointestinal Cancers Symposium suggests that most patients with hypermutated tumors achieve a cCR to PD-1 blockade. 96 Although the follow-up is short, the results of this trial are provocative and suggest that most tumors positive for microsatellite instability/hypermutation are candidates for organ preservation.…”