Nivolumab Plus Low-Dose Ipilimumab Provides Robust, Durable Clinical Benefit in Frontline MSI-H/dMMR mCRC

Heinz-Josef Lenz, MD

The combination of nivolumab (Opdivo) and low-dose ipilimumab (Yervoy) resulted in a deep and durable clinical benefit when used in the first-line treatment of patients with microsatellite instability–high (MSI-H)/mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC), according to findings from the phase 2 CheckMate-142 trial (NCT02060188).¹

Results published in the Journal of Clinical Oncology showed that at a median follow-up of 29.0 months (range, 24.2-33.7), the doublet elicited an objective response rate (ORR) of 69.0% (n = 31/45; 95% CI, 53.0%-82.0%) per investigator assessment, and 62.0% (n = 28; 95% CI, 46.5%-76.2%) per blinded independent central review (BICR), in this patient population.

“The data show that nivolumab plus low-dose ipilimumab demonstrated robust and durable clinical benefit and was well tolerated as a first-line treatment for patients with MSI-H/dMMR mCRC,” Heinz-Josef Lenz, MD, FACP, of USC Norris Comprehensive Cancer Center, and colleagues, wrote. “Based on these promising data, randomized studies are warranted.”

For the first-line cohort of the multicenter, open-label, multicohort, phase 2 CheckMate-142 trial, investigators enrolled patients who had histologically confirmed mCRC, measurable disease per RECIST v1.1 criteria, MSI-H/dMMR status, and who were at least 18 years of age, had an ECOG performance status of 0 or 1.

Patients could not have previously received therapy for metastatic disease. Moreover, those with any serious uncontrolled medical disorder, autoimmune disease, active brain or leptomeningeal metastases, or malignancy apart from select cancers, were excluded.

Study participants were given nivolumab at a dose of 3 mg/kg once every 2 weeks plus low-dose ipilimumab at a dose of 1 mg/kg once every 6 weeks. Treatment was administered until progressive disease or study discontinuation due to adverse effects (AEs), death, withdrawn consent, or study end.

Dose interruptions of less than 6 weeks were allowed to manage treatment-related toxicities. Additionally, upon disease progression, additional treatment was permitted if the patient tolerated the study drug and was determined to have derived benefit per investigator assessment.

The primary end point of the trial was investigator-assessed ORR per RECIST v1.1 criteria. Secondary end points included duration of response (DOR), ORR per blinded independent central review (BICR), and disease control rate (DCR). Other important end points included investigator- and BICR-assessed progression-free survival (PFS), overall survival (OS), safety and tolerability, and patient-reported outcomes (PROs).

The study enrolled patients between December 2016 and October 2017. The median age of study participants was 66 years (range, 21-85) and 51% were male. Moreover, 38% of patients had tumors that harbored BRAF mutations, and 22% harbored KRAS mutations.

Earlier data from the trial showed that at a median follow-up of 12.0 months and 13.4 months, respectively, single-agent nivolumab and nivolumab plus low-dose ipilimumab followed by nivolumab monotherapy resulted in high and durable responses in patients with MSI-H/dMMR mCRC who had previously received 1 or 1 treatments.

At a data cutoff of October 2019, 33% of patients were still receiving treatment, and 67% had discontinued therapy. The most common reason for discontinuation was progressive disease (18%), followed by maximum clinical benefit (13%), AEs not associated with study drug (11%), patient request to stop treatment (9%), or loss to follow-up (2%).

Of the patients who discontinued treatment, 11 went on to receive subsequent therapy, which included surgery (n = 6); systemic therapy (n = 6) in the form of chemotherapy with or without biologics, regorafenib (Stivarga), or nivolumab monotherapy; and radiotherapy (2%).

Participants received a median of 34 doses of nivolumab and 12 doses of ipilimumab. Seventy-one percent of patients had a relative dose intensity of at least 90% for nivolumab and 84% had this intensity for ipilimumab. The median duration of therapy was 11.0 months (range, 0.0-29.0).

Additional data indicated that the doublet resulted in an ORR of 62.0% (95% CI, 46.5%-76.2%) per BICR. Notably, responses were observed in all subgroups evaluated on the trial, including those with BRAF or KRAS positivity. The investigator-assessed ORR in the BRAF-positive subgroup was 76%, and this rate was 80% in the KRAS-mutant subgroup.

The investigator-assessed DCR was 84% with nivolumab plus low-dose ipilimumab, and the DCR per BICR was 78%. The median time to response with the doublet was 2.7 months (range, 1.2-27.7), and the median DOR had not yet been reached (range, 1.4+ to 29.0+).

Moreover, 74% of patients who responded to the regimen were still in response at the time of data cutoff, and 71% of responders had responses that persisted for at least 1 year. Of 43 response-evaluable patients, 84% experienced reduced tumor burden from baseline, and most patients had their response deepen with longer follow-up. Further tumor shrinkage was observed in some patients while off treatment.

The median PFS had not yet been reached in the overall population, nor in the subgroups of patients who harbored BRAF or KRAS mutations. The 12-month PFS rate in the overall population was 76.4% (95% CI, 60.5%-86.6%); at 18 and 24 months, these rates were 76.4% (95% CI, 60.5%-86.6%) and 73.6% (95% CI, 57.2%-84.5%), respectively.

Among those harboring a KRAS mutation, the PFS rate at 24 months was 87.5% (95% CI, 38.7%-98.1%); this rate was 76.5% (95% CI, 48.8%-90.4%) in those harboring a BRAF mutation. The median OS had also not been reached in the overall population. The 12-, 18-, and 24-month OS rates were 84.1% (95% CI, 69.5%-92.1%), 81.7% (95% CI, 66.8%-90.4%), and 79.4% (95% CI, 64.1%-88.7%), respectively.

Ninety-eight percent of patients completed the PRO questionnaire at baseline, and at least 80% of patients did so through week 115, with the exception of weeks 55, 73, 103, and 109; during those weeks, completion rates ranged from 70% to 75%. Health-related quality of life appeared to be stable for over the treatment period according to EORTC QLQ-C30 and EQ-5D.

Changes in EORTC QLQ-C30 from baseline indicated a trend toward reduced symptoms, but statistically significant and clinically meaningful improvements were only observed for insomnia (-12.6% [95% CI, -18.7 to -6.6]; P < .001) at the majority of time points from week 7 to week 115. The overall scores for improved dyspnea (-4.1 [95% CI, -8.2 to -0.1; P = .047) were noted to be statistically significant but not clinically meaningful.

Scores for diarrhea, nausea or vomiting, constipation, and cognitive functioning were mostly unchanged from baseline.

Regarding safety, 80% of patients reported any-grade treatment-related AEs (TRAEs) with the doublet, which included pruritus (36%), arthralgia (20%), and hypothyroidism (18%). Grade 3 TRAEs comprised colitis (4%), adrenal insufficiency (2%), asthenia (2%), congestive cardiomyopathy (2%), gastroenteritis (2%), hypophosphatemia (2%), hypothyroidism (2%), increased alanine aminotransferase (2%), increased aspartate aminotransferase (2%), increased blood creatinine (2%), increased transaminases (2%), and pneumonitis (2%).

One patient experienced respiratory failure and hyponatremia that was grade 4 in severity. No grade TRAEs were reported. Sixteen percent of patients experienced serious toxicities, 11% of which were grade 3 in severity.

Thirteen percent of patients experienced any-grade TRAEs that resulted in treatment discontinuation; this included grade 2 arthritis, congestive cardiomyopathy, and encephalitis (n = 1); grade 3 gastroenteritis and increased blood creatinine (n = 1); and grade 4 respiratory failure (n = 1). Ten patients died; 8 of these cases were due to disease and 2 were because of toxicities not determined to be associated with study treatment.

“The limitations of this study include its nonrandomized design, the absence of a standard-of-care or anti–PD-1 monoclonal antibody monotherapy comparator arm, and its small sample size,” the study authors concluded.

A confirmatory phase 3 trial, CheckMate-8HW (NCT04008030), is currently underway.

Reference

1. Lenz H-J, Cutsem EV, Limon ML, et al. First-line nivolumab plus low-dose ipilimumab for microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: the phase II CheckMate 142 study. J Clin Oncol. Published online October 12, 2021. doi:10.1200/JCO.21.01015