Meeting NewsPerspective

HCC trial misses OS endpoint, but researchers report ‘clinically meaningful’ benefit with nivolumab

BARCELONA, Spain — Nivolumab did not significantly extend OS compared with sorafenib as first-line therapy for patients with advanced hepatocellular carcinoma, according to results of the randomized phase 3 CheckMate 459 trial presented at European Society for Medical Oncology Congress.

However, researchers concluded nivolumab (Opdivo, Bristol-Myers Squibb) demonstrated clinical benefit.

Median OS in this group was the longest achieved in any phase 3 trial to assess first-line therapy for patients with HCC, Thomas Yau, MBBS, MD, MRCP, FHKCP, FRCP, of University of Hong Kong, said during his presentation.

“Nivolumab also demonstrated clinically meaningful improvements in overall response rate and complete response rate, and patients had better quality of life,” Yau said.

Patients with advanced HCC whose tumors are not amenable to local therapy or surgical resection have few effective treatment options.

Sorafenib (Nexavar, Bayer), a multikinase inhibitor, is approved for first-line treatment of advanced HCC. However, efforts continue to identify therapeutic approaches that can extend survival and improve tolerability, according to study background.

Results of the CheckMate 040 trial showed the PD-1 inhibitor nivolumab induced durable responses, conferred a promising long-term survival benefit and exhibited a manageable safety profile for patients with advanced HCC regardless of tumor etiology or prior sorafenib treatment.

Yau and colleagues conducted the multicenter CheckMate 459 trial to compare the efficacy and safety of nivolumab with sorafenib for 743 adults with histologically confirmed advanced HCC who were not eligible for surgery or local therapy. All patients had Child-Pugh class A disease, as well as ECOG performance status of 0 or 1. No patients had received prior systemic therapy.

Researchers randomly assigned 371 patients to nivolumab dosed at 240 mg IV every 2 weeks. The other 372 patients received sorafenib (Nexavar, Bayer) dosed at 400 mg twice daily. Treatment continued until disease progression or unacceptable toxicity.

Baseline characteristics were well-balanced between treatment groups.

OS served as the primary endpoint. Objective response rate and PFS by blinded independent central review, efficacy by PD-L1 expression, and safety served as additional endpoints.

Minimum follow-up was 22.8 months.

Patients assigned nivolumab achieved longer median OS (16.4 months vs. 14.7 months; HR = 0.85; 95% CI, 0.72-1.02), but the difference did not reach the predefined threshold of statistical significance (P = .0419).

A numerically higher percentage of nivolumab-treated patients survived 12 months (59.7% vs. 55.1%) and 24 months (36.8% vs. 33.1%).

OS analysis by predefined subsets showed greater benefit among patients from Asia (HR = 0.74; 95% CI, 0.56-0.98), those with Barcelona Clinic Liver Cancer stage C disease (HR = 0.78; 95% CI, 0.65-0.95), and those with vascular invasion and/or extrahepatic spread (HR = 0.74; 95% CI, 0.61-0.9).

Researchers observed consistent treatment effect with nivolumab regardless of PD-L1 status, although they reported a trend toward improved OS among patients with PD-L1 expression of 1% or greater (median, 16.7 months vs. 15.2 months; HR = 0.84; 95% CI, 0.69-1.02).

Median PFS did not differ significantly between the nivolumab and sorafenib groups (3.7 months vs. 3.8 months; HR = 0.93; 95% CI, 0.79-1.1).

Researchers reported benefit with nivolumab with regard to ORR (OR = 2.41; 95% CI, 1.48-3.92), as well as rates of complete response (14% vs. 1%) and partial response (12% vs. 6%).

Nearly half of patients in both groups received subsequent therapy (49% for nivolumab and 53% for sorafenib), with 38% of those assigned nivolumab and 46% of those assigned sorafenib undergoing subsequent systemic therapy. Also, 20% of patients in the sorafenib group received subsequent immunotherapy.

The percentage of patients assigned sorafenib who received subsequent therapy may have contributed to the statistically negative trial results, Yau said.

Patients assigned sorafenib were more likely to experience grade 3/grade 4 treatment-related adverse events (49% vs. 22%) and discontinue therapy due to grade 3/grade 4 treatment-related adverse events (8% vs. 4%).

Sorafenib-treated patients also were more likely to experience skin events (any grade, 64% vs. 28%; grade 3/grade 4, 18% vs. 2%) and gastrointestinal events (any grade, 47% vs. 9%; grade 3/grade 4, 5% vs. 2%).

Researchers used FACT-Hep — a disease-specific questionnaire — to measure the effects of HCC and treatment on health care-related quality of life. Yau also reported “clinically meaningful differences” in favor of nivolumab through 113 weeks.

In addition, through 89 weeks, the rates of patients who reported experiencing worsening of treatment side effects was lower with nivolumab (range, 7% to 29%) than sorafenib (range, 32% to 53%).

“CheckMate 459 did not meet the predefined threshold of statistical significance for OS. However, nivolumab demonstrated clinically meaningful improvements in OS, ORR and complete response rate in first-line advanced HCC,” Yau said.

“Nivolumab demonstrated a favorable and manageable safety profile consistent with previous reports,” he added. “Improved quality of life and reduced treatment burden were observed for patients treated with nivolumab.” – by Mark Leiser

 

Reference: Yau T, et al. Abstract LBA38_PR. Presented at: European Society for Medical Oncology Congress; Sept. 27-Oct. 1, 2019; Barcelona, Spain.

 

Disclosures: Bristol-Myers Squibb funded this study. Yau reports a consultant/advisory role with and honoraria from Bristol-Myers Squibb. Please see the abstract for all other authors’ relevant financial disclosures.

BARCELONA, Spain — Nivolumab did not significantly extend OS compared with sorafenib as first-line therapy for patients with advanced hepatocellular carcinoma, according to results of the randomized phase 3 CheckMate 459 trial presented at European Society for Medical Oncology Congress.

However, researchers concluded nivolumab (Opdivo, Bristol-Myers Squibb) demonstrated clinical benefit.

Median OS in this group was the longest achieved in any phase 3 trial to assess first-line therapy for patients with HCC, Thomas Yau, MBBS, MD, MRCP, FHKCP, FRCP, of University of Hong Kong, said during his presentation.

“Nivolumab also demonstrated clinically meaningful improvements in overall response rate and complete response rate, and patients had better quality of life,” Yau said.

Patients with advanced HCC whose tumors are not amenable to local therapy or surgical resection have few effective treatment options.

Sorafenib (Nexavar, Bayer), a multikinase inhibitor, is approved for first-line treatment of advanced HCC. However, efforts continue to identify therapeutic approaches that can extend survival and improve tolerability, according to study background.

Results of the CheckMate 040 trial showed the PD-1 inhibitor nivolumab induced durable responses, conferred a promising long-term survival benefit and exhibited a manageable safety profile for patients with advanced HCC regardless of tumor etiology or prior sorafenib treatment.

Yau and colleagues conducted the multicenter CheckMate 459 trial to compare the efficacy and safety of nivolumab with sorafenib for 743 adults with histologically confirmed advanced HCC who were not eligible for surgery or local therapy. All patients had Child-Pugh class A disease, as well as ECOG performance status of 0 or 1. No patients had received prior systemic therapy.

Researchers randomly assigned 371 patients to nivolumab dosed at 240 mg IV every 2 weeks. The other 372 patients received sorafenib (Nexavar, Bayer) dosed at 400 mg twice daily. Treatment continued until disease progression or unacceptable toxicity.

Baseline characteristics were well-balanced between treatment groups.

OS served as the primary endpoint. Objective response rate and PFS by blinded independent central review, efficacy by PD-L1 expression, and safety served as additional endpoints.

Minimum follow-up was 22.8 months.

Patients assigned nivolumab achieved longer median OS (16.4 months vs. 14.7 months; HR = 0.85; 95% CI, 0.72-1.02), but the difference did not reach the predefined threshold of statistical significance (P = .0419).

A numerically higher percentage of nivolumab-treated patients survived 12 months (59.7% vs. 55.1%) and 24 months (36.8% vs. 33.1%).

OS analysis by predefined subsets showed greater benefit among patients from Asia (HR = 0.74; 95% CI, 0.56-0.98), those with Barcelona Clinic Liver Cancer stage C disease (HR = 0.78; 95% CI, 0.65-0.95), and those with vascular invasion and/or extrahepatic spread (HR = 0.74; 95% CI, 0.61-0.9).

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Researchers observed consistent treatment effect with nivolumab regardless of PD-L1 status, although they reported a trend toward improved OS among patients with PD-L1 expression of 1% or greater (median, 16.7 months vs. 15.2 months; HR = 0.84; 95% CI, 0.69-1.02).

Median PFS did not differ significantly between the nivolumab and sorafenib groups (3.7 months vs. 3.8 months; HR = 0.93; 95% CI, 0.79-1.1).

Researchers reported benefit with nivolumab with regard to ORR (OR = 2.41; 95% CI, 1.48-3.92), as well as rates of complete response (14% vs. 1%) and partial response (12% vs. 6%).

Nearly half of patients in both groups received subsequent therapy (49% for nivolumab and 53% for sorafenib), with 38% of those assigned nivolumab and 46% of those assigned sorafenib undergoing subsequent systemic therapy. Also, 20% of patients in the sorafenib group received subsequent immunotherapy.

The percentage of patients assigned sorafenib who received subsequent therapy may have contributed to the statistically negative trial results, Yau said.

Patients assigned sorafenib were more likely to experience grade 3/grade 4 treatment-related adverse events (49% vs. 22%) and discontinue therapy due to grade 3/grade 4 treatment-related adverse events (8% vs. 4%).

Sorafenib-treated patients also were more likely to experience skin events (any grade, 64% vs. 28%; grade 3/grade 4, 18% vs. 2%) and gastrointestinal events (any grade, 47% vs. 9%; grade 3/grade 4, 5% vs. 2%).

Researchers used FACT-Hep — a disease-specific questionnaire — to measure the effects of HCC and treatment on health care-related quality of life. Yau also reported “clinically meaningful differences” in favor of nivolumab through 113 weeks.

In addition, through 89 weeks, the rates of patients who reported experiencing worsening of treatment side effects was lower with nivolumab (range, 7% to 29%) than sorafenib (range, 32% to 53%).

“CheckMate 459 did not meet the predefined threshold of statistical significance for OS. However, nivolumab demonstrated clinically meaningful improvements in OS, ORR and complete response rate in first-line advanced HCC,” Yau said.

“Nivolumab demonstrated a favorable and manageable safety profile consistent with previous reports,” he added. “Improved quality of life and reduced treatment burden were observed for patients treated with nivolumab.” – by Mark Leiser

 

Reference: Yau T, et al. Abstract LBA38_PR. Presented at: European Society for Medical Oncology Congress; Sept. 27-Oct. 1, 2019; Barcelona, Spain.

 

Disclosures: Bristol-Myers Squibb funded this study. Yau reports a consultant/advisory role with and honoraria from Bristol-Myers Squibb. Please see the abstract for all other authors’ relevant financial disclosures.

    Perspective

    For many years, we didn’t talk about response in HCC because we didn’t see any response with systemic therapies. Only recently are we observing an increasing number of patients with response, and we’re able to start to correlate response to OS. This trend appears to continue in the CheckMate 459 study, as we saw an increase in responders with nivolumab compared with sorafenib, and these data are very much in line with previous studies with nivolumab, pembrolizumab (Keytruda, Merck) and other immuno-oncology agents in HCC.

    This is the longest OS we have ever seen in a phase 3 HCC study in the first-line setting. I think it is important to acknowledge that we do not see an early detrimental effect of nivolumab compared with sorafenib. If you look at later time points, you will see an increasing benefit, which we have seen before with nivolumab.

    Nevertheless, this negative. Should we be surprised to see a negative phase 3 study in first-line HCC? If we look at the last 10 years, we’ve had 14 trials. Two were positive with superiority compared with placebo, and one was positive with noninferiority compared with sorafenib.

    So no, we may not be surprised, but why did this one fail?

    The first question was, did we have a clear signal to proceed with nivolumab to phase 3? I think the answer is yes, because we did see durable responses and — in an early phase 1/phase 2 study — we saw promising median OS with nivolumab among patients with advanced HCC.

    The next question is, what has changed in recent years with regard to median OS in first-line phase 3 trials? OS has increased in first-line HCC but, interestingly, not only in the experimental arm. When we look at sorafenib data over time, median OS has increased from about 10.2 months to almost 15 months in CheckMate 459. Is sorafenib more active? Most likely not.

    So this raises the question of whether we are treating a different patient population. If this is the case, we need to ask what are the key prognostic parameters in first-line treatment of HCC? Also, what is the effect of subsequent therapy? The quantity and quality of second-line therapies have changed, and second-line treatment has an effect on the OS from first-line studies.

    In the REFLECT study, the most common second-line treatment after sorafenib was sorafenib. When we look at CheckMate 459, we not only have more patients receiving second-line but we have more tyrosine kinase inhibitors available, as well as immunotherapy.

    Of course, it’s not only about efficacy. It’s also about side effects and quality of life. In this trial, the side-effect profile clearly favors nivolumab, specifically with respect to fatigue, skin toxicity and diarrhea. Last but not least, I would also like to see the impact on liver function, because preservation of liver function is key to getting patients to second- and third-line therapy.

    It really is unfortunate that this is another negative phase 3 study, but I agree that we saw clinically meaningful safety and efficacy data. The efficacy is in line with previous second-line reports. We clearly have to acknowledge that median OS has increased in HCC, and the fact that the quantity and quality of subsequent therapies have improved is certainly good news. When we look at the total package — efficacy, safety and quality of life — there is a clear signal in favor of nivolumab. Nevertheless, the trial is negative. We need biomarkers to identify patients who benefit from immunotherapy monotherapy, and this needs to happen in the near future.

    • Arndt Vogel, MD, PhD
    • Hannover Medical School

    Disclosures: Vogel reports speaker or consultant/advisory roles with AstraZeneca, Bayer, Bristol-Myers Squibb, BTG, Eisai, Eli Lilly, Incyte, Ipsen, Janssen, Medac, Merck, Merck Sharpe & Dohme, Novartis, Pierre Fabre, Roche, Sanofi and Servier. He also reports research funding from Servier and a commercial medical education provider role with OncLive.

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