Immunotherapy plus Targeted Therapy Combination Active in Metastatic CRC
The combination of an immunotherapy and a targeted therapy demonstrated modest clinical activity but achieved durable responses in patients with metastatic colorectal cancer (mCRC) and had longer survival compared with historical standards, initial data from an ongoing trial presented at the 2018 Gastrointestinal Cancers Symposium showed.
Among the 84 patients, 7 had partial responses with the combination of atezolizumab (Tecentriq) and cobimetinib (Cotellic). The median duration of response was 14.3 months.
The median progression-free survival (PFS) was 1.9 months, and median overall survival (OS) was 9.8 months. And 66% of patients were alive at 6 months, with almost 50% at 12 months, reported Johanna C. Bendell, MD, Director, GI Cancer Research Program, Sarah Cannon Research Institute/Tennessee Oncology, Nashville.
“The combination of atezolizumab and cobimetinib was well-tolerated in heavily pretreated patients with locally advanced or metastatic colorectal cancer,” she said. “The 12-month overall survival compared favorably with the 12-month overall survival of 24% observed with regorafenib. Durable responses were observed regardless of KRAS status and in patients with microsatellite stable tumors, patient populations with a high unmet medical need.”
Patients with chemotherapy-refractory, locally advanced or mCRC typically have poor survival of 6 to 7 months. Single-agent PD-1/PD-L1 inhibitors have demonstrated minimal activity in microsatellite stable (MSS) mCRC.
“Microsatellite stable metastatic colorectal cancer is characterized by lower tumor mutational burden that results in fewer neoantigens compared with microsatellite instability [MSI]-high tumors,” Dr Bendell noted.
Preclinical studies suggested potential therapeutic synergy with the combination of atezolizumab and cobimetinib. To evaluate the combination, investigators conducted a 2-stage, phase 1b dose-escalation/cohort-expansion trial involving patients with several types of advanced solid tumors, including chemotherapy-refractory locally advanced or mCRC.
During the first stage, patients received atezolizumab 800 mg with cobimetinib at doses of 20 mg to 60 mg. During the expansion stage, all patients received atezolizumab 800 mg and cobimetinib 60 mg. The primary end points were safety and tolerability of the combination. Secondary end points included investigator-assessed objective response, PFS, and OS.
Patients were unselected for PD-L1 expression status, and MSI status was locally reported and centrally confirmed by next-generation sequencing–based scoring.
The study population included 84 patients with mCRC. They had a median age of 56.5 years, 79% had received ≥5 previous systemic therapies, 68% had KRAS mutations, 57% had low PD-L1 expression, and 50% had MSS tumors.
The majority of patients had treatment-related adverse events. The incidence of grade 3/4 adverse events was 38%, and serious adverse events occurred in 45% of patients (12% of events were judged to be treatment-related). Adverse events leading to withdrawal of treatment was 24%, which was more common with cobimetinib (24%) than with atezolizumab (13%).
The combination therapy resulted in an objective response rate of 8% and an additional 23% of patients had stable disease for ≥6 weeks, with a disease control rate of 31%. The overall median PFS was 2.5 months in patients with MSS tumors, 2.0 months in patients with KRAS mutations, and 1.8 months in those with KRAS wild type.
The median OS ranged from 9.5 months for patients with KRAS mutations to 10.0 months for those with KRAS wild type, to 13.0 months for patients with MSS tumors. The 6- and 12-month OS was 65% and 43%, respectively. The highest survival rate was in the subgroup of patients with MSS tumors (71% at 6 months vs 51% at 12 months).
“The combination of atezolizumab and cobimetinib represents the first potential immune-modifying combination for patients with microsatellite stable metastatic colorectal cancer,” Dr Bendell said. “Data from the confirmatory phase 3 study, known as IMblaze370, are anticipated later this year.”