SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 154,270 new cases of CRC will be diagnosed in the United States in 2025 and about 52,900 patients will die of the disease. The lifetime risk of developing CRC is about 1 in 23.
The majority of CRC cases (about 75 %) are sporadic whereas the remaining 25 % of the patients have a family history of the disease. Only 5-6 % of patients with CRC with a family history background are due to inherited mutations in major CRC genes, while the rest are the result of accumulation of both genetic mutations and epigenetic modifications of several genes. Colorectal Cancer is a heterogeneous disease classified by its genetics, and even though the diagnosis of Colorectal Cancer in the US is dropping among people 65 years and older, the incidence has been rising in the younger age groups, with 12% of Colorectal Cancer cases diagnosed in people under age 50.
The DNA MisMatchRepair (MMR) system is responsible for molecular surveillance and works as an editing tool that identifies errors within the microsatellite regions of DNA and removes them. Defective MMR system leads to MSI (Micro Satellite Instability) and hypermutation, with the expression of tumor-specific neoantigens at the surface of cancer cells, triggering an enhanced antitumor immune response. MSI is therefore a hallmark of defective/deficient DNA MisMatchRepair (dMMR) system and occurs in 15% of all colorectal cancers. Defective MMR can be a sporadic or heritable event. Approximately 65% of the MSI high colon tumors are sporadic and when sporadic, the DNA MMR gene is MLH1. Defective MMR can manifest as a germline mutation occurring in MMR genes including MLH1, MSH2, MSH6 and PMS2. This produces Lynch Syndrome often called Hereditary Nonpolyposis Colorectal Carcinoma – HNPCC, an Autosomal Dominant disorder that is often associated with a high risk for Colorectal and Endometrial carcinoma, as well as several other malignancies including Ovary, Stomach, Small bowel, Hepatobiliary tract, Brain and Skin. MSI is a hallmark of Lynch Syndrome-associated cancers. MSI high tumors tend to have better outcomes and this has been attributed to the abundance of tumor infiltrating lymphocytes in these tumors from increase immunogenicity. These tumors therefore are susceptible to blockade with immune checkpoint inhibitors.
MSI testing is performed using a PCR or NGS based assay and MSI-High refers to instability at 2 or more of the 5 mononucleotide repeat markers and MSI-Low refers to instability at 1 of the 5 markers. Patients are considered Micro Satellite Stable (MSS) if no instability occurs. MSI-L and MSS are grouped together because MSI-L tumors are uncommon and behave similar to MSS tumors. Tumors considered MSI-H have deficiency of one or more of the DNA MMR genes. MMR gene deficiency can be detected by ImmunoHistoChemistry (IHC). NCCN Guidelines recommend MMR or MSI testing for all patients with a history of Colon or Rectal cancer. Unlike Colorectal and Endometrial cancer, where MSI-H/dMMR testing is routinely undertaken, the characterization of Lynch Syndrome across heterogeneous MSI-H/dMMR tumors is unknown.
Nivolumab (OPDIVO®) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, whereas Ipilimumab (YERVOY®) is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152). Blocking the Immune checkpoint proteins unleashes the T cells, resulting in T cell proliferation, activation and a therapeutic response. The FDA in 2018, granted accelerated approval to Ipilimumab for use in combination with Nivolumab, based on CheckMate-142, for the treatment of patients with MSI-H or dMMR metastatic CRC, that has progressed following treatment with a Fluoropyrimidine, Oxaliplatin, and Irinotecan. The FDA in July, 2017, granted accelerated approval to single agent Nivolumab for treatment of this same group of patients.
The CheckMate 8HW is an ongoing Phase III, multinational, open-label, randomized trial evaluating Nivolumab plus Ipilimumab as compared with Nivolumab alone or chemotherapy, in patients with MSI-H or dMMR metastatic CRC. In this study, patients with unresectable or mCRC and MSI-H/dMMR status by local testing who had received 0-1 prior line of therapy were randomly assigned in a 2:2:1 ratio to receive either Nivolumab monotherapy (N=353), Nivolumab plus Ipilimumab combination therapy (N=354), or the investigator’s choice of chemotherapy (mFOLFOX6 or FOLFIRI with or without Bevacizumab or Cetuximab (N=132). Patients who had previously received two or more prior lines of therapy for unresectable or metastatic disease were randomly assigned, in a 1:1 ratio, to receive Nivolumab plus Ipilimumab or Nivolumab alone. In the Nivolumab monotherapy arm, patients received Nivolumab 240 mg IV once every two weeks for six doses, followed by 480 mg IV every four weeks. In the Nivolumab plus Ipilimumab arm, patients were given Nivolumab 240 mg IV plus Ipilimumab 1mg/kg IV every three weeks for four doses, followed by Nivolumab 480 mg IV every four weeks. The median patient age was 64 years and tumor location was in the right colon in two thirds of the patients. Treatments continued until disease progression or unacceptable toxicity in all treatment groups or a maximum of 2 years. The dual Primary end points were Progression-Free Survival (PFS) as determined by Blinded Independent Central Review (BICR) comparing Nivolumab plus Ipilimumab to chemotherapy in the first-line therapy setting, and PFS comparing Nivolumab monotherapy to Nivolumab plus Ipilimumab across all lines of therapy, in patients with centrally confirmed MSI-H/dMMR metastatic CRC. At a median follow-up of 31.5 months the results from the prespecified interim analysis (the primary analysis) showed that the PFS outcomes were significantly better with Nivolumab plus Ipilimumab than with chemotherapy (HR=0.21; P<0.001).
The researchers herein reported the first results from the other dual Primary endpoint of PFS for Nivolumab plus Ipilimumab versus Nivolumab monotherapy across all lines of therapy in patients with centrally confirmed MSI-H/dMMR metastatic CRC. Of all the randomized patients 296 in the Nivolumab plus Ipilimumab group and 286 in the Nivolumab monotherapy group had centrally confirmed MSI-H/dMMR status. With a median follow-up of 47.0 months, Nivolumab plus Ipilimumab demonstrated clinically meaningful and statistically significant improvement in PFS by BICR versus Nivolumab monotherapy, with a median PFS Not Reached (NR) in the Nivolumab plus Ipilimumab group, compared to 39.3 months for those on Nivolumab monotherapy (HR=0.62; P= 0.0003). The PFS rates at 12, 24, and 36 months were higher in the Nivolumab plus Ipilimumab group at 76%, 71%, 68% versus 63%, 56%, 51% for Nivolumab monotherapy.
The Objective Response Rate (ORR) was significantly higher with Nivolumab plus Ipilimumab at 71%, compared to 58% with Nivolumab alone (P=0.0011). No new safety concerns were identified
It was concluded that the CheckMate 8HW study met its dual Primary endpoints, with Nivolumab plus Ipilimumab demonstrating a statistically significant and clinically meaningful improvement in PFS compared to Nivolumab monotherapy across all lines of therapy in MSI-H/dMMR metastatic CRC. Moreover, Nivolumab plus Ipilimumab was associated with higher ORR, confirming its potential as a new standard of care for patients with MSI-H/dMMR metastatic CRC. The CheckMate 8HW study is a pivotal contribution to the treatment landscape of MSI-H/dMMR metastatic Colorectal cancer, providing compelling evidence for the use of Nivolumab plus Ipilimumab in the first-line and beyond.
First results of nivolumab (NIVO) plus ipilimumab (IPI) vs NIVO monotherapy for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) from CheckMate 8HW. Andre T, Elez E, Lenz H-J, et al. J Clin Oncol 43, 2025 (suppl 4; abstr LBA143)
