Two recent clinical trials have demonstrated intriguing findings for new combination regimens for patients with microsatellite stable or instable metastatic colorectal cancer.
Chief among the combinations that have shown the most potential are the PD-L1 inhibitor atezolizumab (Tecentriq) and the MEK inhibitor cobimetinib (Cotellic), which was explored as a combination therapy for patients with microsatellite stable mCRC. Additionally, a second study, known as CheckMate-142, explored the PD-1 inhibitor nivolumab (Opdivo) with the CTLA-4 inhibitor ipilimumab (Yervoy) for microsatellite instable mCRC.
In the phase Ib study of the PD-L1/MEK inhibitor, the combination showed an investigator-assessed objective response rate (ORR) of 17% in 23 patients. An ORR of 20% was observed in 22 patients withKRAS-mutant tumors. In the ongoing phase II CheckMate-142 study, the investigator-assessed ORR was 25.5% in patients who received single-agent nivolumab (95% CI, 15.4-38.1) and 33.3% in those who received the combination (95% CI, 18.6-50.9).
"I think it's really exciting. I think we robustly confirm the activity of PD-1 targeting [in CRC]. We're seeing some of the highest response and stable-disease rates that we've seen in many different types of solid tumors with immune checkpoint therapy," CheckMate-142 lead investigator Michael J. Overman, MD, from The University of Texas MD Anderson Cancer Center, toldTargetedOnc. "Going forward, I think we're going to see these immune checkpoints being moved into earlier lines of therapy. There are already studies that are investigating that."
In the open-label, international, non-comparative trial, 70 patients with microsatellite instability (MSI)-high tumors received nivolumab every 2 weeks. Additionally, 30 patients received nivolumab combined with ipilimumab followed by nivolumab every 2 weeks until progression or unacceptable toxicity. Among microsatellite stable patients, 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-high 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.
Additionally, 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 progression-free survival (PFS) rates at 6 months were 45.9% with single-agent nivolumab (95% CI, 29.8-60.7) and 66.6% with the combination (95% CI, 45.5-81.1). The median PFS in the MSI-high group with 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).
“The results are encouraging and support continued evaluation of nivolumab monotherapy and nivolumab plus ipilimumab in patients with MSI-high mCRC and potentially other tumors with mismatch repair defects,” said Overman. “MSI-high is known to have an exceptionally high tumor burden.”
Among the MSI-high group receiving nivolumab monotherapy who were followed for ≥12 weeks (n = 47), there were 12 partial responses (25.5%). Fourteen patients (29.8%) had stable 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 question that's really open now and is of great interest is, 'Do they really just replace chemotherapy in the MSI-high population?' I think there are some early data in the refractory base that shows that that could really be the case, but how that works out or if there is a combination approach that's best is what will play out in the future," said Overman.
Among patients with microsatellite stable tumors 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 microsatellite stable tumors with the 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).
"This study is still ongoing. It was a two-stage design with monotherapy and combination therapy, and so the second stage of the combination therapy is still open and still enrolling," said Overman. "Clearly, we need more follow-up from the combination arms, because those were started later based on the design, so the follow-up is much shorter. The first future step would be to do further follow-up on this data."
The combination of atezolizumab and cobimetinib was explored more exclusively in those with microsatellite stable tumors. The use of the MEK inhibitor was based upon an observed upregulation of major histocompatibility complex class I (MHC I) expression on tumor cells and increased intratumoral T-cell infiltration. It was theorized that cobimetinib could enhance the anti-PD-L1 activity of atezolizumab in patients with microsatellite stable mCRC.
“Microsatellite instabilityhigh colorectal cancers are associated with a deficiency in DNA mismatch repair and a high mutation burden which demonstrates response to single-agent therapy targeting the PD-L1/PD-1 axis; however, the majority of mCRC patients are microsatellite stable and have lower response rates to PD-L1/PD-1 blockade,” said lead investigator Johanna C. Bendell, MD, from the Sarah Cannon Research Institute. “So what do we do with the remaining 96% of patients?”
In the study, 23 patients received cobimetinib at 20, 40, or 60 mg orally daily for 21 days of a 28-day cycle plus fixed-dose atezolizumab 800 mg IV every 2 weeks. Patients had received a median of 3 prior therapies (range, 1-5). Twenty-two patients had tumors withKRASmutations and one patient had aKRASwild-type tumor.
The 6-month OS rate was 72%. Partial response confirmed per RECIST v1.1 was achieved by 4 patients, with an additional 5 patients having stable disease. Among responding patients, the duration of response ranged from 4.0 to 7.7 months. No patients with MSIhigh disease were identified among the responders. There were 3 patients with a partial response with microsatellite stable tumors or MSI-low by local testing, and the status of 1 patient with partial response was unknown.
"Responses are ongoing in 3 of 4 responding patients," Bendell said. "Tumor volume reduction was not associated with PD-L1 status."
In theKRAScohort, median PFS was 2.3 months (95% CI, 1.8-9.5) but the median OS was not evaluable (95% CI, 6.5-NE). The 6-month PFS was 39% (95% CI, 0.16-0.61) and the 6-month OS was 77% (95% CI, 0.57-0.97).
“These results suggest that cobimetinib can sensitize tumors to atezolizumab by increasing MHC I expression on tumor cells and promoting intratumoral CD8 T-cell accumulation,” Bendell said.
Both trials continue to enroll patients with mCRC. The CheckMate-142 study hopes to enroll 96 total patients (NCT02060188), and an expansion cohort has been opened to further explore atezolizumab plus cobimetinib. The estimated enrollment for the full study is 151 patients (NCT01988896).