Bayer will this week claim an important prize for its multi-kinase inhibitor Stivarga as the new standard of care for second-line treatment of unresectable hepatocellular carcinoma.
The positive outcome of its Resorce trial will have important commercial implications for the group, especially given the approaching patent expiry on Nexavar. It might be savvy to conduct studies to move Stivarga up to the first-line setting, but here Bayer would face competition from Eisai’s Lenvima and Bristol-Myers Squibb’s Opdivo, which are both already in such trials (see tables below).
The German group yesterday disclosed the data it will present at the World Congress on Gastrointestinal Cancer on Thursday from Resorce, its pivotal study of Stivarga. These show that its drug conferred a statistically significant 2.8-month survival advantage in second-line HCC, with a 38% reduction in the risk of death.
|Resorce study results|
|Median OS*||10.6 months||7.8 months||HR=0.62 (p<0.001)|
|Median PFS||3.1 months||1.5 months||HR=0.44 (p<0.001)|
|Median TTP||3.2 months||1.5 months||HR=0.46 (p<0.001)|
|Disease control rate||65.2%||36.1%||p<0.001|
|Overall response rate||10.6%||4.1%||p=0.005|
This level of benefit should be sufficient to ensure that Stivarga becomes the new standard for patients failing on or intolerant to first-line HCC treatment, which is Bayer’s own Nexavar.
Bayer disclosed that the 573-patient Resorce study had rendered a positive outcome some two months ago, but it held the full data back for presenting fresh to oncologists this week. However, it managed to do so with such a lack of ballyhoo that few noticed, which was all the more remarkable given that the study had broken a decade-long run of negative results in HCC.
Of course Stivarga has already been launched for other indications – colorectal cancer and gastrointestinal stromal tumours – though sales are modest, reaching $347m last year. Given its commercial availability patients might get the drug ahead of a formal HCC approval, which will probably come in 2017.
If the Stivarga data do prompt a move into first-line use Bayer must keep an eye on two ongoing HCC studies in this setting: Eisai’s Reflect trial of Lenvima is to render results in December, while Bristol’s CheckMate-459 study of Opdivo is projected to report in May 2017.
Lenvima has shown very strong early results, with a median time to progression of 7.4 months and a median OS of 18.7 months in a single-arm phase I/II trial. At the recent Asco meeting Bristol presented updated findings from its phase II Checkmate-040 study, which showed a 15% overall response rate.
It also reported preliminary data from a dose expansion in 206 HCC patients, which showed an ORR of 9%, with 14% in non-HCV/HBV infected Nexavar-naive/intolerant patients, and 7% in uninfected Nexavar progressors.
|Phase III trials in advanced hepatocellular carcinoma|
|Project||Company||Trial name||Design||Trial ID||Data due|
|Localised first line|
|Therasphere||BTG||Yes-P||vs Nexavar||NCT01887717||Jun 2019|
|Therasphere||BTG||Stop-HCC||Nexavar +/-||NCT01556490||Jul 2019|
|Cometriq||Exelixis||Celestial||vs placebo||NCT01908426||Oct 2016|
|Lenvima||Eisai||Reflect||vs Nexavar||NCT01761266||Dec 2016|
|Opdivo||BMS||CheckMate 459||vs Nexavar||NCT02576509||May 2017|
|Pexastimogene devacirepvec||Sillagen/Transgene||Phocus||Nexavar +/-||NCT02562755||Oct 2017|
|Donafenib||Suzhou Zelgen||-||vs Nexavar||NCT02645981||Dec 2018|
|Tivantinib||Daiichi Sankyo/Arqule||Metiv-HCC||vs placebo||NCT01755767||Dec 2016|
|Tivantinib||Kyowa Hakko Kirin||Jet-HCC||vs placebo||NCT02029157||Dec 2016|
|Apatinib||Jiangsu HengRui||-||vs placebo||NCT02329860||Jan 2017|
|Livatag||Onxeo||Relive||vs BSC||NCT01655693||Jul 2017|
|Cyramza||Lilly||Reach-2||vs placebo||NCT02435433||Oct 2017|
As such a possible move of Stivarga to the first-line setting has benefits and risks for Bayer, but there are also perils from not doing anything. There are two agents in pivotal studies for second-line HCC that are due to read out this year: Exelixis’s Cometriq and Arqule’s tivantinib.
Exelixis will be looking to gain an additional indication for Cometriq after its recent success in renal cell carcinoma, while Arqule and its partners Kyowa Hakko Kirin and Daiichi Sankyo are targeting patients with high c-met.
EP Vantage had forecast that progress would come in the HCC field just a few months ago (Hopes rise for a liver cancer breakthrough in 2016, February 19, 2016). Perhaps more will follow.