ESMO19: Limitations highlighted in failed CheckMate -459 study of Bristol-Myers Squibb's Opdivo in first-line liver cancer

Detailed results from the CheckMate -459 study presented Friday at the European Society for Medical Oncology (ESMO) congress showed that firstline use of Bristol-Myers Squibb's Opdivo (nivolumab) in unresectable hepatocellular carcinoma (HCC) was linked to an increased response rate among patients with high PD-L1 levels. The company announced in June that the trial had failed to meet its primary endpoint of overall survival (OS), although researchers said Friday that this may have been due to limitations of the study.

Angela Lamarca, from the Christie NHS Foundation Trust, suggested that "the lack of a reliable biomarker may have contributed to the study's failure," and while PD-L1 "looks promising...we need a more reliable marker to select patients who will derive benefit." She also cited the significance threshold in CheckMate -459 as another possible limitation, saying study designs "with a 'high' predefined threshold of statistical significance is generating confusion in the community with potentially beneficial therapies generating statistically negative studies."

CheckMate -459 involved 743 patients with unresectable HCC who were randomised to receive either Opdivo or Bayer's Nexavar (sorafenib) as a first-line treatment until disease progression or unacceptable toxicity. In addition to the main goal of OS, secondary endpoints included progression-free survival, overall response rate (ORR) and the relationship between tumour PD-L1 expression and efficacy.

Results showed that after a minimum follow-up of 22.8 months, median OS was 16.4 months for Opdivo and 14.7 months for Nexavar. The 12-month OS rates in these groups were 59.7% and 55.1%, respectively, while the 24-month OS rates were 36.8% and 33.1%. In addition, ORR was 15% for Bristol-Myers Squibb's therapy, including 14 patients with complete responses, versus 7% for Bayer's drug, including five complete responses. 

Regarding PD-L1 expression, responses were observed in 12% of Opdivo-treated patients and 7% of Nexavar-treated patients with PD-L1 expression of less than 1%. Among those with PD-L1 expression of 1% or more, response rates in these two groups were 28% and 9%, respectively.

Study author Thomas Yau said "the primary analysis demonstrated a clinically meaningful OS benefit, which is particularly impactful considering the high frequency of subsequent use of systemic therapy, including immunotherapy in the Nexavar arm. Importantly, there was also a higher complete response rate with Opdivo compared to Nexavar." He also noted that the patient-reported findings suggest those in the Opdivo arm experienced better quality of life compared with Nexavar.

Meanwhile, Grade 3/4 treatment-related adverse were reported in 22% of patients given Opdivo, compared to 49% for Nexavar, leading to discontinuations in the two groups of 4% and 8%, respectively. "The favourable safety profile with Opdivo is of relevance," Lamarca noted, adding that this "becomes apparent in the form of less toxicity-related treatment discontinuation."

Opdivo was granted accelerated FDA approval in 2017 for the treatment of HCC in patients who were previously treated with Nexavar. Bristol Myers-Squibb reported in July that Opdivo sales in the second quarter had increased 12% year-on-year to $1.8 billion.

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