Nivolumab/Ipilimumab Approaches EU Approval for Post-Chemo dMMR or MSI-H Metastatic CRC

Ian M. Waxman, MD

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion for the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) as an option for patients with mismatch repair deficient (dMMR) or microsatellite instability–high (MSI-H) metastatic colorectal cancer (mCRC) following fluoropyrimidine-based combination therapy.

The recommendation is supported by data from the phase 2 CheckMate-142 trial (NCT02060188), which demonstrated that the combination had robust activity when used as frontline treatment in this patient population.

Earlier data from the trial showed that the doublet led to an overall response rate (ORR) of 46% (95% CI, 35%-58%) in a cohort of 119 patients with dMMR or MSI-H mCRC who had previously received fluoropyrimidine, oxaliplatin, and irinotecan.² These findings resulted in the July 2018 FDA approval of nivolumab/ipilimumab for this subset of patients with mCRC.

Updated data showed that after a longer follow-up of a median of 19.9 months, the ORR achieved with the doublet was 64% (95% CI, 49%-78%) per investigator assessment, and this benefit proved to be consistent across all subsets examined.³ Moreover, 84% (95% CI, 71%-94%) of patients experienced disease control for 12 weeks or longer and 84% of evaluable patients experienced a reduction in tumor burden from baseline.

“Metastatic CRCs with dMMR or MSI-H biomarkers can be difficult to treat, and patients who progress on or after first-line chemotherapy still face a great unmet need despite overall progress in the field,” Ian M. Waxman, MD, development lead of gastrointestinal cancers at Bristol Myers Squibb, stated in a press release. “The CHMP’s positive opinion further supports our goal to advance rational combinations that target distinct but complementary immune pathways. We look forward to the EC’s decision later this year and are excited by the potential positive impact this novel combination could have for patients in need throughout the European Union.”

In the multicohort, nonrandomized phase 2 CheckMate-142 trial, investigators set out to examine the safety and efficacy of nivolumab-based therapies in patients with mCRC. The trial enrolled patients with histologically confirmed metastatic or recurrent CRC who had MSI-H/dMMR status per local laboratory and had not previously received treatment for metastatic disease.

A total of 45 study participants received nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg every 3 weeks for 4 doses, followed by nivolumab at 3 mg/kg as a monotherapy every 2 weeks until progressive disease, death, or intolerable toxicity.

The primary end point of the trial was ORR per investigator assessment and RECIST v1.1 criteria, while secondary end points included ORR per blinded independent central review (BICR), DCR, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.

The median age of patients was 66 years (range, 21-85), 56% had an ECOG performance status of 0, 62% had stage I to III disease at the time of diagnosis, and 18% had Lynch syndrome. Moreover, 58% of patients had a PD-L1 expression of less than 1% at baseline, 27% had an expression of at least 1%, and 16% had unknown PD-L1 status. Thirty-eight percent of patients had BRAF-mutated disease, 29% had BRAF or KRAS wild-type disease, 22% had KRAS-mutated disease, and 11% had unknown mutational status.

At the January 2019 data cutoff, 47% of participants were still receiving treatment and the most frequently cited reason for discontinuation was progressive disease. Additional data indicated that the median time to response was 1.6 months per BICR assessment and 2.6 months per investigator assessment. The median DOR had not yet been reached.

Moreover, the median PFS and OS had not yet been reached, either. The estimated 12-month PFS rate was 77%, while the 15-month PFS rate was 75%. The estimated 12- and 15-month OS rates were both 84%.

Seventy-eight percent of patients experienced any grade of treatment-related adverse effects (TRAEs); 20% of these patients reported a TRAE that was grade 3 or 4 in severity. Sixteen percent of patients had a serious TRAEs; 11% of these were noted to be grades 3 or 4. TRAEs experienced by more than 15% of participants included pruritus (33%), hypothyroidism (18%; 2% grade 3 or 4), arthralgia (18%), and asthenia (16%; 2% grade 3 or 4).

In September 2020, the Pharmaceuticals and Medical Devices Agency granted approval to the combination of nivolumab and ipilimumab for use in Japan in patients with MSI-H, unresectable, advanced, or recurrent CRC that has progressed following chemotherapy.

References

1. Bristol Myers Squibb receives positive CHMP opinion recommending Opdivo (nivolumab) plus Yervoy (ipilimumab) for treatment of mismatch repair deficient or microsatellite instability–high metastatic colorectal cancer after prior chemotherapy. News release. Bristol Myers Squibb. May 21, 2021. Accessed May 24, 2021. https://bit.ly/3wsujTG
2. Overman MJ, Lonardi S, Wong KYM, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol. 2018;36(8):773-779. doi: 10.1200/JCO.2017.76.9901.
3. Lenz H-J, Lonardi S, Zagonel V, et al. Nivolumab plus low-dose ipilimumab as first-line therapy in microsatellite instability-high/DNA mismatch repair deficient metastatic colorectal cancer: clinical update. J Clin Oncol. 2020;38(suppl 4):11. doi:10.1200/JCO.2020.38.4_suppl.11