There are currently 7 agents (excluding cytokines) approved for use in renal cell carcinoma (RCC), 5 of which are approved for use in the first-line setting, of which 4 are VEGF pathway inhibitors. With so many options, and few definitively differentiating factors, how is a physician (or patient) to choose the best course of therapy? If efficacy is equal (which for many of these agents it has yet to be compared), toxicity is the next logical choice, as it can have a significant impact on treatment intensity and patient quality of life. So how does one (that is, a manufacturer with a new agent in RCC – or any other crowded market) go about demonstrating such differentiation?
Votrient (pazopanib, GlaxoSmithKline) was approved based on demonstrated superior progression-free survival (PFS) benefit compared to placebo in treatment-naïve or cytokine-pretreated RCC. This superiority was sufficient for regulatory approval, but the lack of comparison to other approved agents relegated Votrient to minimal market share, primarily in later lines of therapy. This was despite levels of efficacy that appeared comparable to the market leader, Sutent (sunitinib, Pfizer), and with an apparently improved safety profile. The key words here are “appeared” and “apparently.” In the absence of head-to-head data comparing Votrient with Sutent, physicians have been reticent to adopt Votrient upfront.
Perhaps in anticipation of this, GlaxoSmithKline took the bold move of initiating a patient preference study shortly after gaining regulatory approval for Votrient in advanced or metastatic RCC. The PISCES trial randomized patients to sequential treatment with Votrient (10 weeks) followed by Sutent (10 weeks) or the reverse order, and patients completed preference questionnaires at the end of each treatment period. This unique design allowed direct evaluation of drug preference among patients who had been equally exposed to both agents. The results, presented at today’s Oral Genitourinary Cancers session, were overwhelming – 70% of patients who completed both treatments and questionnaires preferred Votrient whereas only 22% preferred Sutent (8% stated no preference). Overall quality of life and all queried toxicities were cited as favoring Votrient with fatigue standing out from the patients’ perspective. Despite the overwhelming nature of these results favoring Votrient, the lack of head-to-head efficacy data still weighs on physicians minds, with Dr. Escudier and an audience member both commenting that they plan to wait on the results of the COMPARZ study (NCT00720941) before acting on the PISCES results. COMPARZ, a head-to-head study against the market leader, can be viewed as a bold move by GSK in retrospect given the positive results from PISCES. However, at the time COMPARZ was initiated, efficacy was viewed as the most important issue in RCC. However, with the results of PISCES, Votrient will likely be rewarded even if non-inferior efficacy is demonstrated in COMPARZ particularly with physicians who are already convinced that Votrient and Sutent have similar efficacy. Stay tuned for the COMPARZ data in late 2012 or 2013.
Recognizing your weaknesses and threats, and leveraging your strengths and opportunities is one of the first things taught in business school and should be incorporated into any strategic development plan. GSK is going out guns blazing in a valiant attempt to position Votrient as the preferred first-line agent for advanced RCC. How will other new entrants in this competitive field fare? Next in line for probable approval is tivozanib (AVEO/Astellas), for which the results of their pivotal Phase III TIVO-1 trial were presented immediately prior to the PISCES data. AVEO initially planned to position tivozanib as a preferred agent based on biology – greater affinity for VEGFR-1,-2, and -3 with a longer half-life were supposed to produce superior efficacy and better tolerability and allow it to penetrate the RCC market. Based on the data presented today, tivozanib is clearly superior to Nexavar in terms of both efficacy and tolerability – but is that enough? Tivozanib is clearly (upon regulatory approval) “an” option in advanced RCC, but it’s far from “the” option. Manufacturers attempting to enter the RCC could take a lesson from GSK in terms of boldness, innovation, and proactive behavior. At this point, manufacturers should consider a patient preference study similar to GSK’s PISCES. Regulatory approval does not guarantee market share – newer agents will need to demonstrate compelling benefits against appropriate standards of care that will convince physicians, patients, and payers alike that they are the drug to beat.
By Gordon Gochenauer, Director, Commercial Development, Kantar Health