Drug Pair Is Promising in Metastatic Colorectal Cancer

A new drug combination — Tecentriq (atezolizumab) plus Cotellic (cobimetinib) – is showing promise for the treatment of certain patients with colorectal cancer.

In fact, the combination induced a 31 percent disease control rate (DCR) in patients with heavily-pretreated metastatic colorectal cancer (mCRC).

In results from a two-stage phase 1b study presented at the 2018 Gastrointestinal Cancers Symposium, the overall response rate (ORR) was 8 percent (seven patients). All responses were partial responses (PRs).

Nineteen patients (23 percent) had stable disease (SD) as best response. DCR, defined as PR + SD at least six weeks, was 31 percent. Fifty-one patients (61 percent) had progressive disease.

The Tecentriq and Cotellic combination of an anti—PD-L1 inhibitor with a MEK 1/2 inhibitor represents the first potential immune-modifying combination for patients with microsatellite stable (MSS) mCRC, according to the investigators.

“We all know that patients with refractory colorectal cancer certainly need more treatment options and, to this point, for the 95 percent of patients with microsatellite stable disease, we’ve not seen very much activity with single-agent checkpoint inhibitors,” said Johanna C. Bendell, M.D.

“We saw preclinical evidence that suggests that adding atezolizumab, which is a PD-L1 inhibitor, and cobimetinib, a MEK1/2 inhibitor, potentially would have a synergistic effect,” added Bendell, chief development officer, Sarah Cannon Research Institute.

Eighty-four patients had enrolled in the study as of May 17, 2017; 57 were KRAS mutant-type, 25 were KRAS wild-type, and the status of two patients was unknown. Sixty-six (79 percent) had received five or more previous systemic therapies.

At baseline, 42 patients (50 percent) were MSS, 9 (11 percent) were microsatellite instability (MSI)-low and 1 (1 percent) was MSI-high. MSI status was unknown for 32 patients (38 percent).

The median patient age was 56.5 years (range, 23-81) and 44 percent of patients were female. For PD-L1 expression, 57 percent were immune cell (IC) 0/1 and 8 percent were IC2/3. PD-L1 expression was unknown for 29 patients (35 percent).

Stage 1 established 60 mg of Cotellic as the treatment dose for patients with chemotherapy-refractory or locally advanced mCRC in stage 2. In stage 2, patients were assigned to a Cotellic regimen of 21 days on/7 days off (59 patients) or 14 days on/14 days off (21 patients). Patients in both groups received 800 mg of Tecentriq every two weeks.

At the Sept. 4, 2017, data cutoff, ORR was 8 percent in KRAS wild-type patients, with a DCR of 32 percent. In KRAS-positive patients, ORR was 9 percent with a DCR of 30 percent.

The median duration of response was 14.3 months. Among the seven patients who responded to treatment, four had MSS and one had MSI-low disease. MSI status was unknown in the remaining two patients.

The median overall progression-free survival (PFS) was 1.9 months. The median PFS was 2.5 months in MSS patients, two months in KRAS-mutant patients, and 1.8 months in KRAS wild-type patients. The six-month PFS rate was 18 percent overall, 27 percent in MSS patients, 22 percent in KRAS-mutant patients, and 9 percent in KRAS wild-type patients.

The median overall survival (OS) was 9.8 months, with a six-month OS rate of 65 percent and a 12-month OS rate of 43 percent. For MSS patients, the median OS was 13 months, with a six-month OS rate of 71 percent and a 12-month OS rate of 51 percent.

The median OS was 9.5 months in KRAS mutant patients, with a six-month OS rate of 67 percent. The median OS was 10.0 months in KRAS wild-type patients, with a six-month OS rate of 65 percent and a 12-month OS rate of 43 percent.

“Importantly, the 12-month overall survival was 43 percent, which compares very favorably to historical data for regorafenib [Stivarga] of a 12-month overall survival of 24 percent,” Bendell said.

Investigators concluded that the combination was generally well tolerated and the majority of adverse events (AEs) were manageable.

Overall, 98 percent of the cohort experienced any-grade, any-cause AEs, and 96 percent experienced treatment-related(TR) AEs. There were no grade 5 AEs recorded, but 32 patients (38 percent) experienced grade 3/4 AEs.

Rash, diarrhea, fatigue and increased blood creatine phosphokinase were the most common grade 3/4 TRAEs (5 percent each).

Thirty-eight patients (45 percent) experienced serious AEs, and 10 (12 percent) had serious TRAEs. Twenty patients (24 percent) withdrew due to AEs. Eleven (13 percent) withdrew due to AEs associated with Tecentriq and 20 (24 percent) due to AEs associated with Cotellic.

Bendell added that this combination is currently under evaluation in the randomized, phase 3 IMblaze370 (NCT02788279) trial. The three-arm trial is comparing the Cotellic /Tecentriq combination with Tecentriq monotherapy or single-agent Stivarga in patients with previously treated, unresectable locally advanced or metastatic colorectal adenocarcinoma. Investigators completed accrual about a year ago and data are scheduled to be released later this year.