The combination of the PD-L1 inhibitor atezolizumab and the VEGF inhibitor bevacizumab showed promising and durable antitumor activity in a phase Ib study of patients with advanced hepatocellular carcinoma.
Michael J. Pishvaian, MD, PhD
The combination of the PD-L1 inhibitor atezolizumab (Tecentriq) and the VEGF inhibitor bevacizumab (Avastin) showed promising and durable antitumor activity in a phase Ib study of patients with advanced hepatocellular carcinoma (HCC).
In the trial, the confirmed investigator-assessed objective response rate (ORR) was 32% per RECIST v1.1 criteria, with more than half of responders maintaining their response for at least 6 months and about one-fourth for at least 12 months, said lead investigator Michael J. Pishvaian, MD, PhD, at the 2018 ESMO Congress.
The investigator-assessed median progression-free survival (PFS) in 73 patients evaluable for efficacy was 14.9 months with a 6-month PFS of 65%. The median overall survival has not been reached (range, 0.8- ≥24.0 months).
In July the FDA granted breakthrough therapy designation to the combination as first-line treatment for patients with unresectable or advanced HCC.
Treatment options are limited for advanced HCC, representing an unmet need. Due to late appearance of symptoms, more than 80% of patients present with unresectable or advanced HCC. “We know that first-line therapy with tyrosine kinase inhibitors has certainly improved survival over placebo and these agents are active and should be used. But at the same time, responses and durable responses and complete responses are rare,” said Pishvaian, a gastrointestinal oncologist and head of the Phase I Program at the Georgetown Lombardi Comprehensive Cancer Center.
Immune checkpoint inhibitors have shown activity in the first-line treatment of HCC: an ORR of 23% has been reported for first-line nivolumab (Opdivo) in a phase I/II study.
The combination of bevacizumab and atezolizumab may be synergistic, based on preclinical data, he said. Bevacizumab may enhance the activity of atezolizumab by reversing VEGF-mediated immunosuppression to promote T-cell infiltration into the tumor, in theory increasing the anticancer immune response, which provided the rationale for studying this combination in the first-line setting of advanced HCC.
Pishvaian reported on the advanced HCC arm of a multi-arm study of atezolizumab plus bevacizumab that also included patients with gastric, pancreatic, and esophageal cancer, as well as first-line treatment of HCC in which the combination is being compared with atezolizumab alone. Eligible patients had measurable disease per RECIST v1.1, an ECOG performance status of 0 or 1, adequate hematologic and organ function, and no prior systemic therapy.
The median age of patients was 62 years. Fifty-seven percent were from Asian countries (excluding Japan) and 41% were from either Japan or the United States. The cause of HCC was hepatitis B virus infection in 50% of patients and hepatitis C virus infection in 29%; HCC was nonviral in 21%. “This was a patient population who had more advanced disease as demonstrated by 71% of patients who had extrahepatic spread as well as 53% of patients who had macrovascular invasive,” he said. Prior local therapy was permitted, 54% had prior transarterial chemoembolization, and 36% had prior radiotherapy.
At the clinical data cutoff of July 26, 2018, a total of 103 patients with unresectable or metastatic HCC who were treated with atezolizumab (1200 mg) plus bevacizumab (15 mg/kg), both given every 3 weeks, were evaluable for safety, and 73 were evaluable for efficacy with a minimum of 16 weeks of follow-up.
Of the 23 investigator-assessed responses, best response was a complete response (CR) in 1 (1%) patient and partial responses (PRs) in 22 (30%). Thirty-three (45%) patients had stable disease, for a disease control rate of 77%. The response rates did not differ by region or baseline characteristics. The median duration of response was ≥6 months in 52% of responders and ≥12 months in 26%. Nineteen of the 23 responders (83%) have ongoing responses with a median follow-up of 7.2 months.
The ORR, per RECIST v1.1, as assessed by independent review facility (IRF), was 27%. “But there were 4 CRs per IRF compared with 1 for investigator assessment,” said Pishvaian. The IRF-assessed disease control rate, at 75%, was similar to the investigator assessment. Median duration of response by IRF assessment was not reached, and the median PFS was 7.5 months.
The ORR per HCC mRECIST, which takes into account tumor necrosis and includes contrast enhancement in arterial phase imaging, was 34%, with 8 CRs (11%) and 17 PRs (23%).
No new safety signals were identified beyond the established safety profile of the individual agents. There were 28 treatment-related grade 3/4 adverse events, 10 of which were hypertension.
“If you remember where we were 20 years ago, we were unable to imagine that we could see at any time a disease control rate of 77% for HCC,” said invited discussant Michel Ducreux, MD, head of the Gastrointestinal Unit at the Gustave Roussy Institute, Villejuif, France and Professor of Oncology at University of Paris Sud. “This is something that is completely changing the landscape of the treatment of HCC.”
He said that the immunotherapy competition in the HCC setting is getting crowded, but that the bevacizumab and atezolizumab combination appears to be better in terms of ORR and PFS than other immunotherapies used as monotherapy or in combination. An ongoing phase III trial of the bevacizumab/atezolizumab combination should clarify its place in the HCC treatment armamentarium.
Pishvaian MJ, Less MS, Ryoo B-Y, et al. Updated safety and clinical activity results from a Phase Ib study of atezolizumab + bevacizumab in hepatocellular carcinoma (HCC). Presented at: ESMO 2018; October 19-12; Munich, Germany. LBA26.