GSK’s Votrient expected to show noninferiority to Pfizer’s Sutent, no effect on front-line RCC uptake

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GlaxoSmithKline’s (NYSE:GSK) Votrient will likely be proven noninferior to Pfizer’s (NYSE:PFE) Sutent (sunitinib) in GSK’s COMPARZ trial in front-line metastatic renal cell carcinoma (RCC), experts told BioPharm Insight. Votrient’s uptake will nonetheless remain limited due to the continued dominance of Sutent in the front-line setting, they added.

The US Food and Drug Administration (FDA) approved Sutent in advanced RCC in 2006, while Votrient was approved for the same indication in 2009.

Despite the availability of multiple drugs in advanced RCC, including Pfizer’s Inlyta (axitinib) and Torisel (temsirolimus) and Novartis’ (NYSE:NVS) Afinitor (everolimus), Sutent remains the dominant drug in front-line RCC treatments, said Dr Phillippe Spiess, urologic oncologist, H. Lee Moffit Cancer Center, Florida. Around 70% of drug therapy in advanced RCC begins with Sutent, he estimated.

Sutent is also approved for select subtypes of gastrointestinal and pancreatic cancers, while Votrient is approved for advanced soft tissue sarcoma. Sutent’s 2011 global sales were USD 1.19bn compared to Votrient’s USD 157m, according to BioPharm Insight data.

GSK is also comparing Votrient and Sutent in a questionnaire-based patient-preference study called PISCES, but experts questioned its significance given the subjectivity of results.

Importance of noninferiority data

The 927-patient Phase III COMPARZ trial tested Votrient and Sutent head-to-head as front-line RCC therapies in a global, randomized trial. Results will be presented at the upcoming 2012 European Society of Medical Oncology (ESMO) conference in Vienna to be held 28 September to 2 October, according to a GSK spokesperson.

GSK declined to further elaborate on COMPARZ or PISCES trial progress before presenting data at ESMO, citing company policy.

The COMPARZ trial is designed to show noninferiority between Votrient and Sutent, and while it may be interesting from a marketing perspective for GSK, it will not likely show any clinical advantage for using Votrient, said Dr Robert Figlin, director, Division of Hematology/Oncology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai, California. Expected results from the COMPARZ trial will not likely influence current medical practice, and Sutent will remain the first choice for front-line RCC therapy for most physicians, he added.

Therefore, it is important for GSK that Votrient demonstrates favorable efficacy and side-effect profiles to differentiate it from Sutent, said Dr Lothar Bergmann, oncologist and director, Medical Clinic, University of Frankfurt Hospital. He does not, however, expect any major differences between the two drugs in terms of progression-free survival (PFS), the primary endpoint of the COMPARZ trial. PFS measures the amount of time a patient goes without his/her disease worsening.

Spiess feels while results will likely show equal PFS, it is still a meaningful endpoint for GSK. Figlin agreed but noted, unfortunately, results demonstrating noninferiority will not likely change prescription habits because physicians are looking more for differences in efficacy.

Sutent seems to have a higher response rate than Votrient, noted Bergmann, who added Sutent will remain the most effective front-line RCC drug. Drugs in front-line RCC are “pretty well-established,” Spiess said.

Potential of side-effect benefit

Bergmann feels, however, Votrient’s front-line uptake may increase if it can “clearly” show differences in tolerability. Sutent has skin toxicities and can cause severe hypertension in some patients that, according to clinical data, is not seen with Votrient, Spiess said. On the other hand, Votrient can cause gastrointestinal toxicity, which is “a bit worse” than Sutent, he added.

If GSK is to be believed, Figlin said, then Votrient seems in general to have a comparable or even better side-effect profile than Sutent. But the opinion of physicians who prescribe Votrient, and the patients who use it, is that there is no difference in side-effect profiles, he added.

Bergmann noted he is “a bit cautious” when explaining Votrient’s side effects, because the trial conducted to approve the drug was global and may have resulted in more favorable outcomes due to differences in practice between different countries. There was even a difference in how side effects were recorded between Northern and Southern Europe, he added. He agreed with Figlin’s skepticism of Votrient’s side effects, saying, in fact, from personal experience Votrient’s major side effects are “more than expected.”

PISCES’ subjectivity

In addition to the COMPARZ trial, GSK’s PISCES study used questionnaires to assess the differences in preference between Votrient and Sutent in 169 metastatic RCC patients. While patients seem to prefer Votrient over Sutent, the trial is highly subjective, Figlin said. Patient preference is important, but results from this study are difficult to assess due to its design and are not very conclusive, Spiess added.

In fact, many physicians have raised concerns about the trial design, as the timing of presenting the questionnaire to the patients is ambiguous, Bergmann said. Sutent, for example, is administered for four weeks followed by two weeks without drug therapy. If patients were questioned immediately after drug therapy, their answers to tolerance would be different than when they are questioned after the two weeks rest, Bergmann noted. The time point when the questionnaire is presented makes a difference, Spiess agreed, as side effects look worse near the beginning of the rest period.

Another issue with the PISCES trial is that almost 30%-40% of patients dropped out of the study, Bergmann said. Experts he has had discussions with concluded that the drop-out rate is high, given they were expecting only around 10% at most, he explained. While he did not know the exact cause of the high number of patients lost, he added physicians were cautious of drawing conclusions from this trial.

The National Cancer Institute estimates 64,770 new cases of kidney cancer in the US in 2012, and a vast majority will have RCC.

GSK’s current market cap is USD 114.1bn.

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