Sirtex trial miss means beads could stay as back-up

Quality over quantity is a useful maxim, but not always when it comes to cancer patients’ survival. The radioactive microbeads developed by Sirtex Medical did not increase overall survival of hepatocellular carcinoma patients over the standard of care, Bayer’s Nexavar, in the phase III Sarah trial – but they did improve quality of life.

Certainly this will appeal to many patients. But it might not be enough to expand the beads’ US approval – they are currently indicated only for liver metastases from colorectal cancer – to include HCC, or to move them higher up the treatment sequence for liver mets. Sirtex intends to push towards both of these goals, but its shares fell 13% on the Australian exchange as investors mulled the prospect of a missed opportunity.

The 459-patient Sarah trial saw Sirtex aiming to show a superiority difference in overall survival with its SIR-Spheres, resin microspheres impregnated with yttrium-90, over Nexavar. But in the intent-to-treat population there was no significant difference between the two therapies on median overall survival – indeed, Nexavar showed a numerical benefit, at 9.9 months versus 8.0 months with the beads. In the per-protocol population survival was identical for both arms, at 9.9 months.

The tumours of patients treated with SIR-Spheres had a higher objective response than with Nexavar, though again this was not significant.

Sphere of influence

A hit on survival would have been a great advantage to Sirtex, particularly after the big miss in the Sirflox trial two years ago, which killed its chances of having a first-line therapy for metastatic colorectal cancer (Sirtex slips on its beads after trial miss, March 17, 2015).

In its absence the group is plugging the beads’ record on side effects, which is indeed better than Nexavar’s (see table). Sirtex’s therapy was a big hit with patients when it came to quality of life, with questionnaire responses at three month intervals heavily favouring the beads over Nexavar, which patients said caused “a significant and sustained decline” in quality of life. That said, there was one case of radiation-induced GI ulcer and one case of radiation pneumonitis with the SIR-Spheres.

Sarah data
SIR-Spheres Nexavar P value
OS (intent-to-treat) 8.0 months 9.9 months 0.18
OS (per-protocol) 9.9 months 9.9 months 0.92
Objective response  19.0% 11.6% 0.042
All side effects 77% 94% <0.001
Side-effects ≥ grade 3 41% 63% <0.001
Median number of side effects  5 10 <0.001
Fatigue 42% 65% <0.001
Nausea or vomiting 12% 23% <0.001
Treatment-related diarrhoea 13% 68% <0.001
Hand-foot skin reaction 0.4% 21% <0.001
Anorexia 13% 32% <0.001
Weight loss 6% 21% <0.001
Alopecia 0% 16% <0.001
Hypertension 3% 13% <0.001
Non-gastrointestinal haemorrhage 3% 10% 0.002
Infection 4% 11% 0.007
Abdominal pain 20% 29% 0.032
Gastrointestinal ulceration 2% 0.5% 0.37
Ascites 12% 11% 0.57
Hyperbilirubinemia 12% 13% 0.86
Radiation pneumonitis 0.4% 0% 0.46

Sarah’s principal investigator, Professor Valérie Vilgrain of the Hôpitaux de Paris, said that the quality of life advantages “should be a critical factor in selecting first-line treatment for this patient population in the future”. And Sirtex is going all out on this strategy, saying in a presentation yesterday that it will immediately commence sales and marketing activities on the Sarah results in Europe and other non-US regions. It will also file for US approval in HCC in the second half of this year.

Sirtex might be able to boost its chances of achieving regulatory and commercial expansion when new data come in a few weeks. Results of a parallel study in 360 Asia Pacific HCC patients, called Sirvenib, will be presented at the Asco meeting on June 4.

But it faces an uphill climb. Nexavar will soon go generic, and the cost implications will not favour SIR-Spheres even with quality-of-life data on their side. And Bayer has another ace up its sleeve, with Stivarga awaiting US approval for the second-line systemic treatment of HCC patients after a decent showing in phase III last year (Bayer quietly claims its liver cancer prize, June 29, 2016).

HCC is now a battleground for immuno-oncology too, with Bristol-Myers Squibb’s PD-1 inhibitor Opdivo showing promise when given first or second-line (Bristol looks to exploit Opdivo’s liver cancer advantage, January 23, 2017).

It is possible that, far from obtaining approval for first-line use in HCC, Sirtex’s approach might not even progress past the third line of therapy.

Study Trial ID
Sarah NCT01482442
Sirvenib NCT01135056

To contact the writer of this story email Elizabeth Cairns in London at elizabethc@epvantage.com or follow @LizVantage on Twitter

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