Atezolizumab Combo Not Superior to Regorafenib for mCRC

Johanna C. Bendell, MD

Atezolizumab (Tecentriq) alone or in combination with cobimetinib (Cotellic) failed to show superior overall survival (OS) compared with regorafenib (Stivarga) for patients with chemorefractory metastatic colorectal cancer (CRC), according to findings from the IMblaze370 study presented at the 2018 World Congress on Gastrointestinal Cancer.

In the phase III study, the median OS with the combination of the PD-L1 inhibitor atezolizumab with the MEK inhibitor cobimetinib was 8.9 months (95% CI, 7.00-10.61) compared with 8.5 months with the multikinase inhibitor regorafenib (HR, 1.00; 95% CI, 0.73-1.38; P = .9871). For atezolizumab monotherapy, the median OS was 7.1 months (95% CI, 6.05-10.05), with a hazard ratio of 1.19 compared with regorafenib (95% CI, 0.83-1.71; P = .3360).

“Dual inhibition of the PD-L1 immune checkpoint and the MAP kinase-mediated immune suppression may not be sufficient to generate the immune response that we need for antitumor activity," said lead investigator Johanna C. Bendell, MD, chief development officer, Sarah Cannon Research Institute at Tennessee Oncology. "A hazard ratio of 1.00 shows that this combination may be active but not more active than regorafenib alone."

The IMblaze370 study randomized 363 patients mCRC in a 2:1:1 ratio to atezolizumab plus cobimetinib (n = 183), atezolizumab alone (n = 90), or single-agent regorafenib (n = 90). Most patients were microsatellite stable (MSS; 89% to 93%). Enrollment of patients with microsatellite instability (MSI)-high status, which typically predicts response to immunotherapy, was limited to 5% of the study population, although the actual enrollment numbers were lower.

In the combination arm, atezolizumab was administered at 840 mg intravenously every 2 weeks and cobimetinib was given at 60 mg orally for 21 days followed by 7 days off treatment. Single-agent atezolizumab was administered at 1200 mg every 3 weeks. Regorafenib was given at a starting dose of 160 mg orally for 21 days with 7 days off.

Baseline characteristics were similar across arms. Patients had a median age of 56 to 59 years. ECOG performance status was 1 for approximately half of patients while the remainder had a status of 0. A third of patients were less than 18 months since diagnosis of their first metastasis and a quarter had received more than 3 prior lines of therapy. Thirty-four percent to 40% of patients were RAS wild-type and 34% to 43% had PD-L1 expression on ≥1% of immune cells.

There were no differences in progression-free survival (PFS) between the arms, Bendell noted. For the combination compared with regorafenib, the hazard ratio for PFS was 1.25 (95% CI, 0.94-1.65). For atezolizumab versus regorafenib, the hazard ratio was 1.39 (95% CI, 1.00-1.94).

The best objective response rate (ORR) was 2.7% with the combination compared with 2.2% in both monotherapy groups. There were no complete responses. The median duration of response was 11.4, 4.8, and 9.2 months for the combination, atezolizumab monotherapy, and regorafenib, respectively.

More patients in the regorafenib arm had stable disease for ≥6 weeks (32.2%) compared with the combination (23.5%) and atezolizumab monotherapy (18.9%). The disease control rate with the combination was 26.2% compared with 21.1% and 34.4% for single-agent atezolizumab and regorafenib, respectively.

The 12-month OS rate was 38.5% with atezolizumab/cobimetinib compared with 27.2% with the immunotherapy alone and 36.6% with regorafenib. In an exploratory analysis, the combination was superior to atezolizumab monotherapy; however, this finding was not deemed statistically significant (HR, 0.81; 95% CI, 0.60-1.10).

Consistent OS findings were seen in subgroup analyses, with no statistically significant differences. For the combination compared with regorafenib, the hazard ratio was 0.80 for those with PD-L1—positive disease and was 1.26 in the PD-L1–negative group. For RAS-mutant tumors, the HR was 0.81 and for RAS wild-type tumors the HR was 1.39.

A small number of patients with MSI high status were included in the study (N = 6). Intriguingly, 2 of 3 patients enrolled with MSI-high status had a response to atezolizumab and cobimetinib. In the atezolizumab monotherapy group, 1 of 3 patients with MSI-high status responded. No patients with MSI-high status were enrolled in the regorafenib arm.

"There were no statistically significant differences in OS by clinical or biomarker subgroups, including patients with MSS or extended RAS mutation disease," said Bendell. "We did see some activity in MSI high disease but the patient numbers were limited."

The median dose intensity was 80% for regorafenib compared with 93% for cobimetinib and 98% for atezolizumab in the combination and 100% as a single agent. The median number of cycles was 2 for cobimetinib and regorafenib compared with 4 for atezolizumab in combination and 3 as a monotherapy.

Grade 3/4 treatment-related adverse events (TRAEs) were experienced by 45% of patients in the combination group compared with 10% for single-agent atezolizumab and 49% with regorafenib. Two patients in the combination group and 1 in the regorafenib arm experienced grade 5 TRAEs.

There were more serious TRAEs in the combination group (26%) compared with regorafenib (11%) and single-agent atezolizumab (8%). AEs led discontinuation of any treatment for 21% of patients in the combination group and for 4% and 9% for the single-agent immunotherapy and regorafenib, respectively.

"Looking at the dose intensity of cobimetinib and regorafenib, it looks like people are dose reducing regorafenib for tolerability,” said Bendell. "When patients had AEs in the cobimetinib arm it was discontinued versus dose reductions with regorafenib; however, the chance of this affecting the overall outcomes of the study is negligible."

The most common any cause all-grade AEs in the combination group, atezolizumab monotherapy, and the regorafenib arm, respectively, were diarrhea (65%, 19%, 38%), rash (46%, 9%, 24%), nausea (37%, 21%, 14%), fatigue (36%, 26%, 46%), pyrexia (33%, 16%, 25%), vomiting (28%, 14%, 10%), decreased appetite (27%, 24%, 41%), dermatitis acneiform (26%, 2%, 3%), and asthenia (21%, 13%, 21%). Hypertension (5%, 4%, 31%), weight decrease (4%, 8%, 21%), palmar-plantar erythrodysesthesia (2%, 1%, 53%), and dysphonia (0%, 1%, 24%) were significantly higher in the regorafenib group.

Extensive biomarker evaluations from the study are currently being conducted, including gene expression analyses. These will be presented at a future meeting, Bendell noted.

"We can't give up on potentially turning cold tumors into hot tumors to get microsatellite stable patients to respond to different immunotherapies," she concluded. "There are various combinations that are still in clinical trials, newer immunotherapy agents and different targeted agents in combination with the immunotherapies that hopefully will show more promising results and better outcomes for these patients."

Bendell J, Ciardiello F, Tabernero J, et al. Efficacy and safety results from IMblaze370, a randomised Phase III study comparing atezolizumab plus cobimetinib and atezolizumab monotherapy vs. regorafenib in chemotherapy-refractory metastatic colorectal cancer. Ann Oncol. 2018;29 (suppl 5; abstr LBA-004).