Immunotherapy Combination Active in Subset of Patients With Colorectal Cancer

Opdivo (nivolumab) showed promise both as a monotherapy and in combination with Yervoy (ipilimumab) for patients with high microsatellite instability (MSI-H) metastatic colorectal cancer (mCRC), according to interim data from the phase 2 CheckMate-142 trial presented at the 2016 Annual American Society of Clinical Oncology (ASCO) meeting.

At a follow-up of at least 12 weeks, the investigator-assessed objective response rate (ORR) was 25.5 percent with single-agent Opdivo and and 33.3 percent for the combination. The progression-free survival (PFS) rates at six months were 45.9 percent and 66.6 percent, respectively.

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

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

The open-label, international, non-comparative phase 2 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 one.

Seventy MSI-H patients received three mg/kg of Opdivo every two weeks and 30 patients received four doses of Opdivo (three mg/kg) combined with Yervoy (one mg/kg) followed by Opdivo (three mg/kg) every two weeks until progression or unacceptable toxicity. Among MSS patients, one cohort of 10 patients received Opdivo at one mg/kg plus Yervoy at three mg/kg and the other cohort of 10 patients received Opdivo at three mg/kg plus Yervoy at one mg/kg.

Among MSI-H patients who received single-agent Opdivo, the rates of stage 1/2, 3 and 4 disease were 21.4 percent, 34.3 percent and 42.9 percent, respectively. The rates of KRAS/BRAF wild-type, BRAF-positive, and KRAS-positive patients were 37.1 percent, 15.7 percent, and 32.9 percent, respectively. Mutation status was unknown for 14.3 percent of patients. All patients had prior treatment, with 12.9 percent receiving one previous regimen and 30 percent and 55.7 percent receiving two and three or more previous regimens, respectively. Prior radiotherapy had been received by 37.1 percent of patients.

The rates of stage 1/2, 3 and 4 disease in MSI-H patients who received the Opdivo/Yervoy regimen were 6.7 percent, 53.3 percent, and 40 percent, respectively. The rates of KRAS/BRAF wild-type, BRAF-positive, and KRAS-positive patients in this combo group were 20 percent, 20 percent and 46.7 percent, respectively. Mutation status was unknown for 13.3 percent of patients. All patients had prior treatment, with 6.7 percent receiving one previous regimen and 50 percent and 43.3 percent receiving two and at least three previous regimens, respectively. Prior radiotherapy had been received by 23.3 percent of patients.

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

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

The median PFS in MSI-H patients receiving monotherapy was 5.3 months. The six-month overall survival (OS) rate was 75 percent and the nine- and 12-month OS rates were both 65.6 percent. The median OS was 17.1 months.

In MSI-H patients who received the Opdivo/Yervoy regimen who were followed for at least 12 weeks (27 patients), there were nine responses (33.3 percent) that were all partial responses. Fourteen patients (51.9 percent) had stable disease and three patients (11.1 percent) had progressive disease. A reduction in target lesion size occurred in 81 percent of patients. The median time to response was 2.73 months 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 six- and nine-months OS rates were both 85.1 percent. The median OS was not yet reached.

Among MSS patients who received one mg/kg of Opdivo and three mg/kg of Yervoy, there was one patient response, the median PFS was 2.28 months and the median OS was 11.53 months (0.62 to not estimable).

There were no responses among MSS patients who received three mg/kg of Opdivo and one mg/kg of Yervoy. The median PFS in this group was 1.31 months and the median OS was 3.73.

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

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

Among MSS patients who received one mg/kg of Opdivo and three mg/kg of Yervoy, 80 percent (eight patients) had an AE. The most common all-grade AEs were diarrhea (four patients), asthenia (three), nausea (three), pyrexia (three), vomiting (three), fatigue (two) and dry skin (two). Grade 3/4 AEs—including diarrhea (one patient), asthenia (two), nausea (one) and vomiting (one)—occurred in 70 percent (seven patients) of patients. AEs led to treatment discontinuation for five (50 percent) patients.

Among MSS patients who received three mg/kg of Opdivo and one mg/kg of Yervoy, 80 percent (tseight patien) had an AE. The most common all-grade AEs were diarrhea (two patients), asthenia (one), nausea (two), pyrexia (two), vomiting (one), fatigue (two) and cough (two). Grade 3/4 AEs, including fatigue, occurred in 30 percent (three patients) of patients. AEs led to treatment discontinuation for two (20 percent) patients.

In a press release, David Feltquate, development lead, Oncology Life Cycle Management, at Bristol-Myers Squibb, the manufacturer of Opdivo and Yervoy, 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.”