First-line Immunotherapy Still Elusive in Advanced Liver Cancer

Alexander M. Castellino, PhD

September 28, 2019

BARCELONA, Spain — The promise of first-line immunonotherapy remains unrealized for patients with advanced hepatocellular carcinoma (HCC), but early promising results look good for a combination.

Nivolumab (Opdivo, Bristol-Myers Squibb) used as first-line treatment in patients with advanced HCC did not show significant difference in overall survival (OS) compared with the current standard of care, sorafenib (Nexavar, Bayer/Onyx Pharmaceuticals).

However, overall response rate (ORR) was nearly double on nivolumab (15% vs 7% for sorafenib). Complete and partial response rates were also higher for patients receiving nivolumab.

These results come from the CheckMate 459 trial, presented here at the European Society of Medical Oncology annual meeting.

"These results are unlikely to change the current standard of care. However, it is becoming more apparent that immunotherapy could have a role for the first-line treatment of advanced HCC, and the differences in response rates are clinically meaningful," Angela Lamarca, MD, of the Christie NHS Foundation Trust, Manchester, UK, commented in an ESMO statement.

She was disappointed that the higher response rate with nivolumab did not translate to improved survival. However, she noted that nivolumab has a favorable safety profile, which "becomes apparent in the form of less toxicity-related treatment discontinuation with nivolumab."

CheckMate 459 Results

CheckMate 459 enrolled 743 patients with advanced HCC to receive either nivolumab every 2 weeks (n = 371) or twice daily sorafenib (n = 372) until disease progression or unacceptable toxicity.

About half of the patients (45%) had HCC with nonviral etiology. Most patients had severe disease: approximately 80% had BCLC (Barcelona clinic liver cancer) stage C; more than 70% had vascular invasion or extrahepatic spread.

The majority of patients discontinued nivolumab (90%) or sorafenib (98%) due to disease progression. Median follow-up was 15.2 months for patients on nivolumab and 13.4 months for patients on sorafenib.

Median overall survival (OS) was 16.4 months for patients receiving nivolumab. The results were not significantly different from those who received sorafenib (median OS, 14.7 months; P = .0752).

Presenting the results, Thomas Yau, MD, of the University of Hong Kong, China, noted that the median OS of 14.7 months seen with sorafenib was higher than what has been seen historically in previous studies (eg, 10 months in the SHARP study and 12.3 months in the REFLECT study.)

Most patients in the study who progressed received subsequent therapy: 49% for nivolumab vs 53% for sorafenib. Systemic second-line treatment included other  tyrosine kinase inhibitors, chemotherapy, investigational agents, or immune-oncology agents. With 20% of patients on sorafenib receiving subsequent immune-oncology therapy, Yau suggested that second-line therapy may account for the higher than historical OS seen with sorafenib.

Discussant Arndt Vogel, MD, from Hannover Medical School, Germany, concurred. "The quantity and quality of post-study medication has changed," he said. He noted that regorafenib, lenvatinib, cabozantinib, and ramucirumab are other tyrosine kinase inhibitors in the second-line setting of advanced HCC that may account for some of the results.

The safety profile of nivolumab was better than that of sorafenib, with fewer treatment-related adverse events (TRAEs) leading to discontinuation. Grade 3/4 TRAEs occurred in 22% of patients on nivolumab and 49% of patients on sorafenib.

Yau also reported that health-related quality of life was better for patients on nivolumab.

When a member of the audience pointed out that CheckMate 459 should be considered a failed study, Yau said: "I am not a statistician, but a clinician who treats patients."

He pointed out that nivolumab demonstrated improvements in ORR and CR in first-line advanced HCC that should be considered clinically meaningful.  

"The package of efficacy, safety, and quality of life favors nivolumab," Vogel commented in his discussion, agreeing with Yau that these were clinically meaningful data.

Immunotherapy With Bevacizumab

Another presentation (abstract LBA 39) at the same session featured results from a phase 1b study (GO30140) showing that adding bevacizumab (Avastin, Roche/Genentech and biosimilars) to immunotherapy with atezolizumab (Tecentriq, Roche/Genentech) significantly improved progression-free survival (PFS) compared with atezolizumab alone.

Michael S. Lee, MD, of the Lineberger Comprehensive Cancer Center at the University of North Carolina in Chapel Hill, reported on data from two cohorts of the study.

In one cohort of 104 patients with unresectable, advanced HCC with a median follow-up of 12.4 months, the combination of atezolizumab and bevacizumab provided a median OS of 17.1 months, a median PFS of 7.4 months, and an ORR of 36%.

While the combination was being evaluated, patients were enrolled in a separate group of the study that compared the combination (n = 60) with atezolizumab alone (n = 59).

In this comparison, median PFS was significantly higher for patients receiving the combination (5.6 months vs 3.4 months for atezolizumab alone; hazard ratio, 0.55; P = .0108). ORR was also higher for patients on the combination (20% vs 17% for atezolizumab alone).

Lee reported that the adverse events seen with the combination were similar to those  previously seen with each of the two drugs, adding that the AEs were manageable and most were low grade.    

The results from this study were considered promising enough that the combination will now be evaluated in the phase 3 IMbrave150 study. Results are expected in 2022.

CheckMate 459 is funded by Bristol-Myers Squibb, manufacturer of nivolumab. IMbrave150 is supported by Roche, manufacturer of atezolizumab.

Yau reported receiving honoraria (institution) and having an advisory/consultancy role with Bristol-Myers Squibb. Lee receives research funding from Amgen, Bristol-Myers Squibb, Pfizer, EMD Serono, and Genentech/Roche. Vogel reports speaker, consultancy, and advisory roles with Roche, Bayer, Sanofi, Bristol-Myers Squibb, Lilly, Novartis, Eisai, AstraZeneca, Merck, Incyte, Medac, Ipsen, Servier, PierreFabre, MSD, BTG, and Janssen. He also receives research funding from Servier and serves as a commercial medical education provider for OncLive.

European Society for Medical Oncology (ESMO) 2019 Annual Meeting: Abstract LBA 38_PR (CheckMate 459) and LBA 39 (GO30140). Presented September 27, 2019.

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