BMS' Bid For Opdivo In First-Line HCC Stymied
Executive Summary
Top-line results from a Phase III study testing Opdivo versus Nexavar in first-line liver cancer fail to meet OS target. Bristol points to positive numerical trend, but the results are a setback in the indication.
Bristol-Myers Squibb Co. missed in its effort to show PD-1 inhibitor Opdivo could improve upon standard-of-care Nexavar in first-line hepatic cell carcinoma (HCC), leaving the pharma to look for a combination regimen with CTLA-4 inhibitor Yervoy in previously treated patients, as well as monotherapy in adjuvant care.
On a day of dual surprises for investors, BMS revealed that CheckMate-459 did not demonstrate a statistically significant benefit on overall survival (OS) compared to Bayer AG/Amgen Inc.’s Nexavar (sorafenib), long the standard in first-line HCC. Separately, the US pharma announced that its pending merger with Celgene Corp. would be delayed while the companies sell off the latter’s psoriasis blockbuster Otezla (apremilast) in order to address concerns of the US Federal Trade Commission. (Also see "In Merger Plot Twist, BMS Needs A Buyer For Celgene's Otezla, Raising New Questions" - Scrip, 24 Jun, 2019.)
While BMS did not provide full data from CheckMate-459, it reported on 24 June that Opdivo (nivolumab) showed a positive numerical trend on OS compared to Nexavar but fell short of statistical significance (p=0.0752). Full results from the trial will be presented later at a medical meeting, the firm said. Opdivo obtained accelerated approval for second-line HCC from the US Food and Drug Administration in September 2017. (Also see "Bristol's Opdivo Diversifies Options In Liver Cancer" - Scrip, 25 Sep, 2017.)
Datamonitor Healthcare senior analyst Zachary McLellan told Scrip that these results are “a large blow to [Opdivo’s] prospects” in HCC. He added that a recent decision to pull a filing for second-line therapy in Europe with Opdivo seems “well-founded” – the European Medicines Agency expressed concern that the study used for approval in second-line treatment lacked a comparator.
“A path forward in the first-line setting where Nexavar remains the standard is now less clear. Combinations may be an answer, however,” McLellan said. At the recent American Society of Clinical Oncology conference, BMS presented data showing that an Opdivo/Yervoy combination regimen yielded better results than Opdivo monotherapy in patients previously treated with Nexavar, the analyst noted.
“A large Phase III may be needed to confirm this benefit, particularly in light of this recent setback, but BMS may forge ahead with another accelerated approval submission in post-Nexavar settings and may test the combination in the front-line setting,” McLellan added. “For now, we will have to wait and see.”
Nexavar stood as the unchallenged standard of care in the first-line setting for roughly a decade, before last summer’s approval of Eisai Co. Ltd./Merck & Co. Inc.’s Lenvima (lenvatinib). (Also see "First In 10 Years, But Lenvima's First-Line Liver Label Could Be Challenged Soon" - Scrip, 17 Aug, 2018.) Earlier this year, however, Merck experienced its own setback in HCC when Keytruda (pembrolizumab) failed the Phase III KEYNOTE-240 study in second-line HCC. (Also see "Merck's Keytruda Loss In Liver Cancer Could Be Gain For Rivals" - Scrip, 19 Feb, 2019.)
In a statement, BMS said it retains confidence in Opdivo’s potential for HCC treatment and will evaluate insights gained from CheckMate-459. More than 1,000 patients were enrolled in the trial, according to Biomedtracker, with treatment continuing until the disease progresses or there is unacceptable toxicity. Beyond the primary endpoint of OS, secondary endpoints included overall response rate, progression-free survival and relationship between patients’ expression of PD-L1 and efficacy – no data for those endpoints were disclosed.
Other Combo Regimens Pending
While HCC is the most common form of liver cancer and fastest-rising cause of cancer-related mortality in the US, Credit Suisse analyst Vamil Divan pointed out in a same-day note that HCC is a relatively small market, with about 11,000 patients in the US and 38,000 worldwide. BMS had seemed well-positioned to gain approval for the first-line setting based on its approval in second-line therapy, he wrote, but its failure to demonstrate an OS benefit with Opdivo monotherapy now opens a door for combination regimens being investigated by competitors including Merck, Roche and AstraZeneca PLC.
William Blair & Co. analyst Matt Phipps wrote on 24 June that the failure of CheckMate-459 places increased importance on other ongoing BMS trials, notably CheckMate-9LA, testing Opdivo with Yervoy and two lines of chemotherapy in first-line lung cancer. That study is expected to report out early in 2020.
Phipps also slashed his revenue estimates for Opdivo in HCC based on the trial miss. Blair now projects $212m in 2020, down from $477m; $179m in 2021, reduced from $666m; and $146m in 2022, rather than the previous estimate of $812m.
BMS noted that it still is testing Opdivo monotherapy in adjuvant HCC (CheckMate-9DX) and in combination with Yervoy (ipilimumab) versus Yervoy monotherapy in previously treated patients as part of the CheckMate-040 trial. Biomedtracker lists nine current Phase III programs in HCC, including AstraZeneca’s Phase III HIMALAYA study of anti-PD-L1 agent Imfinzi (durvalumab) and CTLA-4 inhibitor tremelimumab in first-line HCC. Data from that study are expected in 2020.
Meanwhile, Roche expects data before year’s end from the Phase III IMBrave150 study combining its anti-PD-L1 Tecentriq (atezolizumab) and chemotherapy agent Avastin (bevacizumab) in first-line HCC.