Durable clinical benefit with nivolumab and low-dose ipilimumab in the first-line treatment of microsatellite instability (MSI)-high metastatic colorectal cancer

Last year, data from the phase II CheckMate-142 trial showed that immunotherapy with nivolumab in combination with low-dose ipilimumab provides durable clinical benefit in previously treated patients with microsatellite instability high (MSI-H)/mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC). During ESMO 2018, results of the same study show that this immunotherapeutic combination is also effective and tolerable in the first-line treatment of MSI-high/dMMR patients. In this setting, nivolumab plus low-dose ipilimumab induced tumour shrinkage in 84% of patients, and a complete response in 7%. After a median follow-up of 13.8 months, the medians for duration of response (DoR), progression-free survival (PFS) and overall survival (OS) were not yet reached. The treatment combination also proved to be well tolerated with only 16% of high-grade treatment related adverse events (TRAEs).

Approximately 4% of all mCRC patients harbour mutations in genes that are involved in DNA repair and are classified as being MSI-high/dMMR. When treated with chemotherapy in the first-line setting, patients with MSI-high tumours have a shorter survival (~14-19 months) than those with non-MSI-high tumours (~17-25 months). The phase II CheckMate-142 trial previously showed that chemotherapy-resistant patients with MSI-high mCRC derive durable benefit from combination immunotherapy with nivolumab and low-dose ipilimumab. In this setting, nivolumab plus low-dose ipilimumab was associated with an overall response rate (ORR) of 55% and a 12-month OS rate of 85%. In addition to the study arms evaluating nivolumab or nivolumab plus low-dose ipilimumab in previously treated MSI-high/dMMR patients, CheckMate 142 also includes a study arm assessing dual immune checkpoint inhibition as first-line treatment in this disease setting. The results of this study arm were presented during ESMO 2018.

The first-line arm of the study included 45 patients with MSI-high/dMMR mCRC. The median age in this cohort was 66 years and 51% of patients was male. Patients were treated with nivolumab at a dose of  3 mg/kg every 2 weeks in combination with low-dose ipilimumab every 6 weeks until disease progression. Of note, this ipilimumab schedule differs from the schedule used in the relapsed study arm, where ipilimumab was given every 3 weeks. The primary endpoint of the trial was objective ORR, with disease control rate (DCR), DoR, OS, PFS and safety as secondary objectives.

The median number of nivolumab and ipilimumab doses was 24 and 8, respectively, both corresponding to 48 weeks of therapy. Study-drug related AEs were a reason to discontinue therapy in 7% of patients. The ORR was reported at 60%, with 7% of patients demonstrating a complete response. These responses were observed regardless of tumour PD-L1 expression, BRAF or KRAS mutation status, or the diagnosis of Lynch syndrome. In total, 84% of patients experienced a reduction in tumour burden from baseline. It took a median of 2.6 months to respond to treatment (remarkably, in two patients it took more than a year before a first response was seen). The median duration of response was not yet reached and in 82% of the responding patients the response was ongoing at the time of data cut-off. Three quarters of responders already had a response that lasted for 6 months or more. All but one of the responders were still alive at the time of the analysis. The median PFS was not yet reached but at 12 months, 77% of patients were alive and free of progression. The median for OS was also not reached with 83% of patients being alive at 12 months.

Any grade TRAEs occurred in 78% of patients, reaching grade 3/4 severity in 16%. Serious TRAEs with grade 3/4 severity were observed in 7% of patients. Any grade select TRAEs with potential immune-mediated aetiology occurred in the skin (33%), in the endocrine system (24%), in the liver (13%), in the gastrointestinal system (11%), in the lungs (2%), and in the kidneys (2%). Hepatic, gastrointestinal, pulmonary and renal TRAEs resolved in 100% of patients, while skin and endocrine TRAEs resolved in 45% and 60% of patients, respectively.

In summary, the combination of low-dose ipilimumab and nivolumab demonstrated robust and durable clinical benefit in the first-line treatment of MSI-high/dMMR mCRC. The combination was well tolerated with only 16% of grade 3/4 TRAEs and a low rate of TREA-induced treatment discontinuation. As such, these data suggest that nivolumab and ipilimumab may be a first-line treatment option for these patients. The ongoing phase III KEYNOTE-177 study is also addressing MSI-high mCRC and is comparing first-line treatment with pembrolizumab versus chemotherapy with or without targeted therapy. The first results of this trial are expected in 2019.

Reference

Lenz H-J, Van Cutsem E, Limon M, et al. Durable clinical benefit with nivolumab (NIVO) plus low-dose ipilimumab (IPI) as first-line therapy in microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). Presented at ESMO 2018; Abstract LBA18_PR.