Nivolumab/Ipilimumab Approved in Europe for dMMR or MSI-H Metastatic Colorectal Cancer

Ian M. Waxman, MD

The European Commission has approved the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) for use in adult patients with mismatch repair deficient (dMMR) or microsatellite instability–high (MSI-H) metastatic colorectal cancer (mCRC) following previous fluoropyrimidine-based combination chemotherapy.¹

The approval is based on data from the phase 2 CheckMate-142 trial (NCT02060188), which showed that the doublet elicited an objective response rate (ORR) of 64.7% (95% CI, 55.4%-73.2%) in patients with MSI-H/dMMR mCRC who previously received fluoropyrimidine, oxaliplatin, and irinotecan. Notably, 12.6% of patients experienced a complete response to treatment.²

“Metastatic CRC is an aggressive disease with a poor prognosis, leaving patients with a critical need for additional treatment options beyond standard chemotherapy,” Ian M. Waxman, MD, development lead, gastrointestinal cancers, at Bristol Myers Squibb, stated in a press release. “With this approval, patients in the European Union with dMMR or MSI-H mCRC will now have the first dual immunotherapy treatment available to them, and we look forward to working with stakeholders to advance this rational combination.”

In the ongoing, multi-cohort, nonrandomized phase 2 trial, investigators are examining the safety and efficacy of nivolumab-based therapies in patients with mCRC. To participate, patients needed to have histologically confirmed metastatic or recurrent CRC and dMMR/MSI-H status per local laboratory. Notably, patients could not have previously received treatment for metastatic disease.

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 is ORR per investigator assessment and RECIST v1.1 criteria, and other key end points comprised ORR per blinded independent central review (BICR), disease control rate (DCR), duration of response, progression-free survival, overall survival, and safety.

The median age of patients on the trial was 66 years (range, 21-85). Fifty-six percent of patients had an ECOG performance status of 0, 62% had stage I to III disease at the time of diagnosis, 58% had a tumor PD-L1 expression of less than 1%, and 18% had Lynch syndrome. Regarding mutational status, 29% had tumors that harbored BRAF/KRAS wild-type mutations, 38% harbored BRAF mutations, 22% had KRAS mutations, and 11% had unknown status.

At a median follow-up of 19.9 months (range, 15.1-24.6), the DCR was 78% (95% CI, 63%-89%) with nivolumab plus ipilimumab per BICR and 84% (95% CI, 71%-94%) per investigator assessment. The median time to response per BICR or investigator was 1.6 months (range, 1.2-16.3) and 2.6 months (range, 1.2-13.8), respectively. The median DOR with the dual immunotherapy had not yet been reached.

Notably, 84% of evaluable patients experienced a reduction in tumor burden from baseline. The median PFS has not yet been reached with the combination (n = 45). The 12-month PFS rate was 77% (95% CI, 62%-87%) with the doublet, and the 15-month rate was 75% (95% CI, 59%-85%). The median OS had not been reached either, but the 12- and 15-month rates were both 84% (95% CI, 70%-92%).

When broken down by subgroup, the ORR was higher in those under 65 years (68%; n = 15/22) vs those 65 years of age or older (61%; n = 14/23); those who were male (74%; n = 17/23) vs female (55%; n = 12/22); those with an ECOG performance status of 1 (70%; n = 14/20) vs 0 (60%; n = 15/25); those with right-sided tumors (69%; n = 18/26) vs left-sided tumors (60%; n = 9/15); those with BRAF-mutated disease (76%; n = 13/17) vs those with BRAF/KRAS wild-type disease (62%; n = 8/13) or those with KRAS-mutated disease (60%; n = 6/10); and those who had not received prior adjuvant or neoadjuvant therapy (65%; n = 17/26) vs those who have (63%; n = 12/19).

Regarding safety, 78% of patients (n = 45) experienced any-grade treatment-related toxicities, and 20% were grade 3 or 4 in severity. Sixteen percent of patients experienced a serious treatment-related adverse effect (TRAE) and in 11% of patients this was grade 3 or 4. A total of 5 patients discontinued treatment because of a TRAE with the dual immunotherapy regimen.

The most common AEs reported with nivolumab plus ipilimumab included fatigue (58%), diarrhea (41%), musculoskeletal pain (39%), rash (38%), pruritus (35%), nausea (30%), cough (29%), pyrexia (29%), abdominal pain (22%), arthralgia (22%), decreased appetite (22%), upper respiratory tract infection (21%), vomiting (21%), headache (19%), dyspnea (19%), hypothyroidism (18%), constipation (18%), oedema (16%), dizziness (14%), hyperthyroidism (12%), dry skin (11%), and hypertension (10%). Most of the toxicities were determined to be grade 1 or 2 in severity.

In July 2018, the FDA granted an accelerated approval to nivolumab plus ipilimumab for the treatment of adult and pediatric patients aged 12 years and older with MSI-H or dMMR mCRC after progression on a fluoropyrimidine, oxaliplatin, and irinotecan based on data from CheckMate-142.³ In September 2020, the combination was approved in Japan to expand its use to patients with MSI-H, unresectable advanced or recurrent CRC that had progressed after chemotherapy.⁴

References

1. Bristol Myers Squibb receives European Commission approval for Opdivo (nivolumab) plus Yervoy (ipilimumab) for the treatment of mismatch repair deficient or microsatellite instability–high metastatic colorectal cancer after prior chemotherapy. News release. Bristol Myers Squibb. June 29, 2021. Accessed June 29, 2021. https://bit.ly/2U5IwIh
2. 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
3. Bristol-Myers Squibb’s Opdivo (nivolumab) + low-dose Yervoy (ipilimumab) is the first immuno-oncology combination approved for MSI-H/dMMR mCRC patients who progressed following treatment with a fluoropyrimidine, oxaliplatin and irinotecan. News release. Bristol Myers Squibb. July 11, 2018. Accessed June 29, 2021. https://bit.ly/2uaofBD
4. Opdivo and Yervoy combination therapy approved in Japan to expand use for the treatment of microsatellite instability high (MSI-high) colorectal cancer, and Opdivo for additional dosage and administration in monotherapy dosing regimen. News release. Ono Pharmaceutical Co., Ltd. and Bristol Myers Squibb. September 25, 2020. Accessed June 29, 2021. https://bit.ly/2UHt19E