EP379 - Not always perfect: Incomplete response after immunotherapy for MMR deficient rectal cancer

Purpose/Background: Immune checkpoint inhibitor therapy has emerged as the standard of care for dMMR/MSI-H rectal cancer.
Here we present two patients who did not achieve a complete response to ICI.

Methods/Interventions: Patient 1 is a 42 year old male initially diagnosed with clinical T3 N1 M0, in May 2023. The tumor was noted to have MSH2 and MSH6 loss on immunohistochemistry (IHC). Molecular profiling with next generation sequencing (NGS) demonstrated MSI-high status with a high tumor mutation burden (TMB) of 40 mutations per megabase (mut/Mb). Subsequent Myriad Genetics testing confirmed a Lynch syndrome diagnosis with heterozygous germline MSH2 mutation (c.2634+1G>A). He was initially treated at an outside institution with 54 Gy of chemoradiation followed by 4 cycles of consolidation chemotherapy. He then presented to our institution, and then underwent 12 cycles of immunotherapy. Post-treatment scans revealed incomplete response, and endoscopy revealed a severe stricture at the location of the disease, so he underwent a low anterior resection. His final pathology revealed residual adenocarcinoma, < 0.1 cm, in the tumor bed, and 19 lymph nodes negative for tumor (yp T1 N0).

Patient 2 is a 71 year old female diagnosed with clinical T3 N2a M0 rectal adenocarcinoma after being worked up for constipation. The tumor was noted to be MMR deficiency by IHC (MSH2 absent, MSH6 indeterminate). Subsequent polymerase chain reaction (PCR) testing had low DNA yield but resulted as MSI-L. Given the discrepancy in findings, she also had blood-based NGS testing (Guardant 360) which confirmed MSI-H status and high TMB (30.72 mut/Mb). With these findings, she met eligibility criteria and was consented for the AZUR-1 trial (NCT05723562). She underwent 8 cycles of immunotherapy, but interval scans showed essentially unchanged appearance of the tumor over the next few months. With this in mind, tumor board consensus was to transition the patient from immunotherapy to chemoradiation followed by definitive management.

Results/Outcomes: Patient 1 demonstrated Lynch syndrome, and had an incomplete response and ultimately underwent LAR with TME and loop ileostomy with final pathology demonstrating small residual disease.

Patient 2 had a more equivocal picture with disconcordance between her MMR PCR testing and NGS testing. Even though she met the criteria for immunotherapy, she did not show any response even after 8 cycles. She is being transitioned to chemoradiation from immunotherapy, with plan for definitive treatment to follow.

Conclusion/Discussion: Several studies have demonstrated the efficacy of ICIs in MSI-H tumors. The CheckMate 142 trial demonstrated significant response rates with nivolumab in metastatic colorectal cancers, leading to its FDA approval for dMMR/MSI-H tumors. The phase II trial by Cercek et al showed even more impressive results with a 100% clinical response rate in patients with MSI-H LARC receiving dostarlimab. These findings have shifted treatment paradigms towards immunotherapy with NCCN guidelines now recommending ICIs as a preferred treatment regimen for MSI-H rectal cancer.
However, despite these promising data, our two case reports emphasize the limits of ICIs in some patients.
This underscores the heterogeneity within MSI-H tumors that may be influenced by factors such as tumor microenvironment, tumor mutation burden, and potential intratumoral heterogeneity and the need for predictive biomarkers to help risk stratify patients and more individually tailor therapeutic strategies.

Patient #1
Magnetic resonance imaging-T2 scans of patient in case #1 before immunotherapy initiation and after 12 cycles of pembrolizumab. Interval imaging demonstrated partial but incomplete response of the tumor.

Patient #2
Magnetic resonance imaging-T2 scans of patient in case #2 before treatment initiation and after 8 cycles of dostarlimab. Interval imaging demonstrated essentially unchanged appearance of the primary rectal tumor.