GI cancer

Immunotherapy has potential as first line treatment in HCC: CheckMate 459

The trial of the PD-1 inhibitor nivolumab as a first-line treatment in advanced hepatocellular carcinoma (HCC) did not meet its overall survival endpoint but showed ‘clinically meaningful’ efficacy and safety benefits, an expert has told ESMO 2019 congress.

Presenting data from the phase III CheckMate 459 trial in a late breaking session, Dr Thomas Yau, from the University of Hong Kong, China, told delegates that while the trial did not meet its predefined threshold of statistical significance (P=0.0419) for overall survival (OS), nivolumab demonstrated improvements in OS, objective response rate (ORR) and complete response (CR) compared to sorafenib, the current standard of care.

Furthermore, consistent OS benefit was observed regardless of PD-L1 status as well as across the majority of predefined sub groups including those with hepatitis infection and those with vascular invasion and/or extra-hepatic spread.

A favourable and manageable safety profile was also seen in patients with advanced HCC treated with first-line nivolumab, Dr Yau said.

“These results are important in the treatment of hepatocellular carcinoma, as there have been no significant advances over sorafenib in the first-line setting in more than a decade,” he said.

“HCC is often diagnosed in the advanced stage, where effective treatment options are limited. The encouraging efficacy and favourable safety profile seen with nivolumab demonstrates the potential benefit of immunotherapy as a first-line treatment for patients with this aggressive cancer.”

The clinically meaningful overall survival benefit was “particularly impactful” considering the high frequency of subsequent use of systemic therapy, including immunotherapy in the sorafenib arm, Dr Yau noted.

He added that the patient-reported findings suggested that patients in the nivolumab arm experienced better quality of life and further supported clinical data that demonstrated a treatment benefit for nivolumab versus sorafenib in advanced HCC.

Commenting on the study’s findings, Dr Angela Lamarca from the Christie NHS Foundation Trust, Manchester, UK, said the fact that the trial failed to meet its primary endpoint meant the results were unlikely to change the current standard of care. However, she said it was becoming more apparent that immunotherapy could have a role for the first-line treatment of advanced HCC.

She noted that the study had two possible limitations, namely the unselected population and the predefined threshold of statistical significance.

“In addition, the study design with a ‘high’ predefined threshold of statistical significance is generating confusion in the community with potentially beneficial therapies generating statistically negative studies,” she added.

Invited discussant Professor of Gastroenterology Arndt Vogel (pictured) from Hannover, Germany told congress delegates that despite its negative result, the 1st line phase III trial showed the longest median OS ever seen in HCC.

He added that it was also not surprising to see a negative phase III trial in 1st line HCC, since REFLECT had been the only trial in a long line of trials to show a positive result.

“The package [efficacy, safety and Qol] is in favour of nivolumab… but we need biomarkers to identify patients that benefit from nivolumab mono-therapy,” he concluded.

Crunching the numbers

The phase 3 CheckMate 459 study randomised 743 patients with advanced hepatocellular carcinoma to nivolumab or sorafenib as first-line treatment. Median overall survival was 16.4 months for nivolumab and 14.7 months for sorafenib (hazard ratio [HR] 0.85; 95% confidence interval [CI]: 0.72-1.02; p=0.0752).

The overall response rate was 15% for nivolumab (including 14 patients with complete response) and 7% for sorafenib (5 patients with complete response). Grade 3 / 4 treatment-related adverse were reported in 22% of patients in the nivolumab arm (81 patients) and in 49% of those given sorafenib (179 patients). These led to discontinuation in 4% (16) and 8% (29) patients, respectively.

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