Nivolumab/Ipilimumab Combo More Effective than Monotherapy in mCRC

Michael J. Overman, MD

Nivolumab (Opdivo) treatment provided antitumor responses in patients with microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC), whether given as a single agent or in combination with ipilimumab (Yervoy). Interim data from the phase II CheckMate-142 trial was presented at the 2016 ASCO Annual Meeting.

At a follow-up of ≥12 weeks, the investigator-assessed objective response rate (ORR) was 25.5% (95% CI, 15.4-38.1) with single-agent nivolumab and 33.3% (95% CI, 18.6-50.9) for the combination. The progression-free survival (PFS) rates at 6 months were 45.9% (95% CI, 29.8-60.7) and 66.6% (95% CI, 45.5-81.1), respectively.

“The results are encouraging and support continued evaluation of nivolumab monotherapy and nivolumab plus ipilimumab in patients with MSI-H mCRC and potentially other tumors with mismatch repair defects,” lead study author Michael J. Overman, MD, University of Texas MD Anderson Cancer Center, said when presenting the data at ASCO.

The incidence of MSI-H is approximately 15% in early-stage CRC and 4% in stage IV CRC. “MSI-H is known to have an exceptionally high tumor burden,” said Overman.

The open-label, international, non-comparative phase II CheckMate-142 study enrolled patients with recurrent or metastatic colorectal cancer, including MSI-H patients and microsatellite stable (MSS) patients. The majority of patients were less than 65 years old and had an ECOG performance status of 1.

Seventy MSI-H patients received 3 mg/kg of nivolumab every 2 weeks and 30 patients received 4 doses of nivolumab (3 mg/kg) combined with ipilimumab (1 mg/kg) followed by nivolumab (3 mg/kg) every 2 weeks until progression or unacceptable toxicity. Among MSS patients, 1 cohort of 10 patients received nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg and the other cohort of 10 patients received nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg.

Among MSI-H patients who received single-agent nivolumab, the rates of stage I/II, III, and IV disease were 21.4%, 34.3%, and 42.9%, respectively. The rates ofKRAS/BRAFwild-type, BRAF-positive, andKRAS-positive patients were 37.1%, 15.7%, and 32.9%, respectively. Mutation status was unknown for 14.3% of patients. All patients had prior treatment, with 12.9% receiving 1 previous regimen and 30% and 55.7% receiving 2 and ≥3 previous regimens, respectively. Prior radiotherapy had been received by 37.1% of patients.

The rates of stage I/II, III, and IV disease in MSI-H patients who received the nivolumab/ipilimumab regimen were 6.7%, 53.3%, and 40%, respectively. The rates ofKRAS/BRAFwild-type, BRAF-positive, andKRAS-positive patients in this combo group were 20%, 20%, and 46.7%, respectively. Mutation status was unknown for 13.3% of patients. All patients had prior treatment, with 6.7% receiving 1 previous regimen and 50% and 43.3% receiving 2 and ≥3 previous regimens, respectively. Prior radiotherapy had been received by 23.3% of patients.

In the MSI-H group, 67.1% (n = 47) of patients in the monotherapy arm and 60% of patients in the combination arm remained on treatment at the data cutoff.

Among MSI-H patients receiving nivolumab monotherapy who were followed for ≥12 weeks (n = 47), there were 12 responses (25.5%) that were all partial responses. Fourteen patients (29.8%) had stable disease and 17 patients (36.2%) had progressive disease. A reduction in target lesion size occurred in 56% of patients. The median time to response was 2.12 months (95% CI, 1.3-13.6) and the median duration of response was not estimable.

The median PFS in MSI-H patients receiving monotherapy was 5.3 months. The 6-month overall survival (OS) rate was 75% and the 9- and 12-month OS rates were both 65.6%. The median OS was 17.1 months (95% CI, 8.6 to not estimable).

In MSI-H patients who received the nivolumab/ipilimumab regimen who were followed for ≥12 weeks (n = 27), there were 9 responses (33.3%) that were all partial responses. Fourteen patients (51.9%) had stable disease and 3 patients (11.1%) had progressive disease. A reduction in target lesion size occurred in 81% of patients. The median time to response was 2.73 months (95% CI, 1.2-6.9) and the median duration of response was not estimable.

The median PFS in MSI-H patients receiving the combination has not yet been reached. The 6- and 9-months OS rates were both 85.1%. The median OS was not yet reached.

Among MSS patients who received 1 mg/kg of nivolumab and 3 mg/kg of ipilimumab, there was 1 patient response, the median PFS was 2.28 months (95% CI, 0.62-4.40) and the median OS was 11.53 months (0.62 to not estimable).

There were no responses among MSS patients who received 3 mg/kg of nivolumab and 1 mg/kg of ipilimumab. The median PFS in this group was 1.31 months (95% CI, 0.89-1.71) and the median OS was 3.73 (95% CI, 1.22-5.62).

Among MSI-H patients who received monotherapy, 58.6% (n = 41) had an adverse event (AE). The most common all-grade AEs were fatigue (18.6%), diarrhea (14.3%), pruritus (11.4%), nausea (7.1%), and pyrexia (4.3%). Grade 3/4 AEs, including fatigue and diarrhea, occurred in 14.3% of patients. AEs led to treatment discontinuation for 4 (5.7%) patients.

In the MSI-H group that received the combination regimen, AEs of any grade occurred in 83.3% (n = 25) of patients. The most common all-grade AEs were fatigue (20%), diarrhea (43.3%), pruritus (16.7%), nausea (20%), and pyrexia (23.3%). Grade 3/4 AEs, including pruritus, occurred in 26.7% of patients. AEs led to treatment discontinuation for 4 (13.3%) patients.

Among MSS patients who received 1 mg/kg of nivolumab and 3 mg/kg of ipilimumab, 80% (n = 8) had an AE. The most common all-grade AEs were diarrhea (4 patients), asthenia (3), nausea (3), pyrexia (3), vomiting (3), fatigue (2), and dry skin (2). Grade 3/4 AEs—including diarrhea (1 patient), asthenia (2), nausea (1), and vomiting (1)—occurred in 70% (n = 7) of patients. AEs led to treatment discontinuation for 5 (50%) patients.

Among MSS patients who received 3 mg/kg of nivolumab and 1 mg/kg of ipilimumab, 80% (n = 8) had an AE. The most common all-grade AEs were diarrhea (2 patients), asthenia (1), nausea (2), pyrexia (2), vomiting (1), fatigue (2), and cough (2). Grade 3/4 AEs, including fatigue, occurred in 30% (n = 3) of patients. AEs led to treatment discontinuation for 2 (20%) patients.

In a press release, David Feltquate, MD, PhD, development lead, Oncology Life Cycle Management, at Bristol-Myers Squibb, the manufacturer of nivolumab and ipilimumab, commented on the initial findings from CheckMate-142.

“We believe the data presented at ASCO support our hypothesis that the combination of Opdivo with Yervoy has the potential to lead to greater clinical activity than Opdivo monotherapy in patients with MSI-H metastatic colorectal cancer. We are encouraged by the preliminary results from our ongoing efforts to evaluate the full potential of this combination regimen across a range of malignancies.”

Overman MJ, Kopetz S, McDermott RS, et al. Nivolumab ± ipilimumab in treatment (tx) of patients (pts) with metastatic colorectal cancer (mCRC) with and without high microsatellite instability (MSI-H): CheckMate-142 interim results.J Clin Oncol34, 2016 (suppl; abstr 3501).