Atezolizumab Combo Promising as Frontline HCC Therapy

Aiwu Ruth He, MD, PhD

The combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) demonstrated strong signals of efficacy with a tolerable safety profile as first-line therapy for patients with unresectable or metastatic hepatocellular carcinoma (HCC), according to preliminary findings from an early-stage study presented at the 2018 International Liver Cancer Association Annual Conference.

The objective response rate (ORR) was 61% by investigator assessment and 65% by independent review among 23 evaluable patients treated with the combination during the phase Ib GO30140 study, lead investigator Aiwu Ruth He, MD, PhD, reported at the conference. All of the investigator-assessed responses were partial, while there was 1 complete response by independent review.

Responses, which were assessed per RECIST v1.1 criteria, were durable, added He, who is an assistant professor at Georgetown University Medical School in Washington, DC. She said 10 responses were ongoing for ≥6 months, including 3 that have continued for ≥1 year, after a median follow-up of 10.3 months.

“A lot of the responses are deep, with significant tumor shrinkage, and the response is quite durable,” said He, adding that activity was seen across all subgroups, including at all levels of baseline alpha-fetoprotein. “The onset of response is quite early; the majority were observed at the first or second scan.”

The promising results prompted the FDA to grant a breakthrough therapy designation for the combination in this patient population in July. Next steps include an expansion phase of the study in which patients will be randomized to the combination or atezolizumab monotherapy and the phase III IMbrave150 study (NCT03434379) comparing atezolizumab/bevacizumab with sorafenib (Nexavar) in the frontline setting.

As single agents, atezolizumab has shown promising activity while bevacizumab has had modest effects, and “there is a strong scientific rationale to support the combination of bevacizumab and atezolizumab in the treatment of HCC,” He said.

The 2 drugs have complementary mechanisms of action, the investigator explained. Atezolizumab is a PD-L1 inhibitor that promotes T-cell activation and restores anticancer immunity, while bevacizumab increases T-cell infiltration by normalizing the tumor vascular and decreasing the activity of myeloid derived suppressor cells and regulatory T cells that dampen the immune response.

In the ongoing GO30140 study (NCT02715531), patients with HCC were treated every 3 weeks with atezolizumab at 1200 mg and bevacizumab at 15 mg/kg. The study is a basket trial that includes separate cohorts for different atezolizumab combinations with HER2-positive gastric, pancreatic, and esophageal cancers. The primary endpoints are safety and tolerability, while secondary endpoints include ORR, duration of response, and progression-free survival.

The trial is recruiting patients with HCC with a Child-Pugh score up to B7 who have not received prior systemic therapy. Among the 43 patients enrolled in the study, the median age was 62 years (range, 35-82) and 42% had an ECOG performance score of 0. In terms of Child-Pugh class status, 72% were A5, 23% were A6, and 5% were B7.

Additionally, 77% had either extrahepatic spread or macrovascular invasion. Prior treatment consisted of transarterial chemoembolization (56%) or radiotherapy (44%). As of the January 11, 2018, cutoff date, 43 patients were evaluable for safety and 23 for efficacy, with a minimum follow-up of 16 weeks during which there were 2 tumor assessments.

“There were no unexpected adverse effects based on the single-agent profiles,” said He.

Frequently observed all-cause adverse events (AEs) of any grade included decreased appetite (33%), fatigue (30%), rash (28%), diarrhea (23%), and hypertension (21%). Overall, 35% of participants experienced grade 3/4 AEs, including 28% with treatment-related AEs.

Serious AEs affected 26% of patients, including 7% related to treatment. There were 2 grade 5 AEs: 1 was cardiac arrest and 1 bacterial peritonitis; however, investigators do not believe they were treatment related.

“Bleeding is of special interest in patients treated with bevacizumab and with liver dysfunction. There was 1 reported grade 3 bleeding [event] from the tumor that was managed,” He said.

He AR, Baek-Yeol Ryoo BY, Lee KH, et al. Preliminary safety and clinical activity results from a phase Ib study of atezolizumab plus bevacizumab in hepatocellular carcinoma. Presented at: 2018 International Liver Cancer Association Annual Meeting; September 14-16; London, England. Abstract O-011.

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