Just five years ago, the treatment options for patients with advanced kidney cancer were limited, but today, the market for renal cell carcinoma drugs is one of the most crowded in the oncology field, with six targeted agents on the market and more on the way.

As the market for kidney cancer evolves to include a range of treatment options, many with similar mechanisms of action, it raises questions about what is next for the business area. Drug makers are looking for new growth opportunities amid a small - though growing - patient population, while payers, physicians and patients want to see comparative efficacy data to help guide decision-making.

The market is moving toward sequential and combination treatment in the hopes of extending the life of patients. But the biggest impact of existing therapies is on progression-free survival, not overall survival, and thus, the need for more effective treatments remains.

How the market will shake out following the launch of three additional drugs for RCC in 2009 remains to be seen, but in the absence of comparative data, physicians and patients are grappling with the different treatment options.

"In the short term," kidney cancer specialist Robert Figlin, MD, (City of Hope Comprehensive Cancer Center) said in an interview, the market "is going to be driven by the comfort of the physician delivering the drug, the comfort of the patient with the side effect profile, the consideration of co-morbid diseases that limit one versus the other and cost."

For Advanced RCC, A Tidal Wave Of New Drugs

FDA approval of Nexavar (sorafenib) in December 2005 marked the first new drug for metastatic renal cell carcinoma in a decade. Before that, the most common treatments were interleukin, interferon, chemotherapy and radiation, drugs with limited efficacy and harsh side effects. Following on the heels of Nexavar came Pfizer's Sutent (sunitinib) in January 2006, then Wyeth's (now Pfizer's) Torisel (temsirolimus) in 2007. In 2009, GlaxoSmithKline's Votrient (pazopanib) and Novartis' Afinitor (everolimus) joined the market, and Roche/Genentech's Avastin (bevacizumab) added a kidney cancer indication.

Nexavar, Sutent and Votrient are all multi-tyrosine kinase inhibitors targeting vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), while Torisel and Afinitor inhibit mammalian target of rapamycin (mTOR). Avastin targets VEGF.

RCC: A Small Fraction Of Big Oncology Market

Six drug launches in five years is a substantial number for a small market. The market for advanced kidney cancer drugs was only $452.5 million in the U.S. in 2008 and about $950 million for the U.S., Europe and Japan combined, according to Decision Resources. Kidney cancer is one of the smaller cancers in terms of prevalence, representing only about 3 percent of all adult cancers. Close to 58,000 new kidney cancers were diagnosed in the U.S. in 2009, according to the Kidney Cancer Association. Renal cell carcinoma is by far the most common form.

The primary treatment for kidney cancer, however, is surgery, and thus, drugs are used to treat just a fraction of the patient population, those with disease that has spread. Thirty percent of kidney cancer patients show signs of advanced RCC when diagnosed, meaning their tumor has spread outside of the kidney, according to the Kidney Cancer Association, while 15 to 20 percent of patients have metastatic disease at the time of diagnosis, meaning the cancer has spread to other parts of the body.

Five-year survival rates are dramatically different for the different patient groups. For those with local disease who undergo surgery, it is around 90 percent, whereas for those with metastatic disease it is only 9.9 percent, according to the American Cancer Society.

Despite its small size, RCC is a market that is expected to grow, driven by increased diagnosis, more treatment options that can be used in the second and third lines, and longer patient survival. The market is expected to grow close to 7 percent annually through 2013, then slow to about 3.8 percent until 2018, according to Decision Resources. The market research firm forecasts that the size of the RCC market will climb from $949 million in 2008 to $1.6 billion in 2018.

"When I look at the market now in the U.S., we have more patients receiving third-line treatment in 2009 than were receiving first-line treatment in 2005," Alison Ayers, VP of worldwide commercial development for Pfizer Oncology, said in an interview. "We have almost 80 percent of patients who start first-line therapy actually getting through to third-line, so we are seeing really durable treatment options that are allowing patients to have much extended life expectancy."

Sutent Leads Market, But Votrient Joins The Race

Pfizer's Sutent has emerged as the market leader in the first-line treatment setting, accounting for 61 percent of sales among angiogenesis inhibitors in 2008, Decision Resources said. Angiogenesis inhibitors accounted for 83 percent of the RCC treatment market.

Pfizer reported worldwide 2009 sales of Sutent of $964 million, though the drug is also approved for gastrointestinal stromal tumors. Sales of Nexavar for the year were $843 million, although Nexavar is also approved for hepatocellular carcinoma. The mTOR inhibitors are largely used in patients with poor prognosis or those who have progressed on VEGF-targeted therapy.

The availability of Votrient and Afinitor are expected to have a significant impact on the market. FDA approval of Votrient in October was supported by significant progression-free survival data, though the drug carries a "black box" warning on fatal hepatotoxicity. The Phase III data showed Votrient reduced the risk of tumor progression or death by 54 percent compared to placebo, regardless of prior treatment. Overall median PFS was 9.2 months with Votrient compared to 4.2 months with placebo (¹ Also see "GSK's Votrient Will Need To Show Efficacy Outweighs Black Box" - Pink Sheet, 20 October, 2009.

Afinitor was approved in March, supported by the RECORD-1 trial, which was halted early when results showed Afinitor more than doubled the time to tumor progression or death compared with placebo (4.9 months to 1.9 months) (² Also see "Afinitor Wins FDA Nod For Kidney Cancer" - Pink Sheet, 30 March, 2009.).

Afinitor has some other attributes that give it competitive distinction and mark the strategies that companies can take when they are late comers to a market. Afinitor has a convenience advantage in that it is an oral drug, whereas Torisel is an intravenous infusion. Afinitor was also approved with a label indicating it for use in patients with advanced RCC that have failed on Sutent or Nexavar - which provides data that is key information for physicians and payers.

The use of Afinitor after a tyrosine kinase inhibitor has been endorsed by the National Comprehensive Care Network, which issues treatment guidelines, with its highest level of recommendation. Category I recommendations have also been given to pazopanib, sunitinib and bevacizumab in combination with interferon in the first-line setting and to temsirolimus in poor-risk patients.

Still, the treatment guidelines are no assurance of market performance. Though it has a first-line recommendation from NCCN, GSK's Votrient has thus far had a minimal impact on the first-line market, Pfizer maintained. "Sutent remains by far the most widely used agent in first-line RCC, with Votrient picking up only a few percentage points of share," said Ayers. "Where we are seeing Votrient being used is in the third- and later-lines of treatment."

But that's typical of how new drug launches generally play out in the oncology market. Over time, Votrient could supplant Sutent as the market leader. Decision Resources predicts Votrient will eventually overtake Sutent and estimates peak sales of the drug could reach $500 million to $1 billion.

A Real Need: Comparative Effectiveness

But with no comparative data among the drugs, it's difficult for physicians and patients to ferret out which treatments are best for whom.

"The good news is the number of drugs," Figlin said. "The difficult news is we really do not have very much in the way of comparative effectiveness, so although we have a great deal of understanding of the benefit of individual drugs compared with controls...we don't have a comparator of these drugs to each other."

Payers, too, would like to see comparative efficacy data to better direct reimbursement decisions. Despite the fact the RCC market is so competitive, the cost of therapy remains expensive. The wholesale acquisition cost of Sutent is just under $5,100 per month, for example, while Votrient launched at $5,495 per month.

"The strategy employed by our competitors has not been to lower the price or go into a price war," Ayers said. "I think what you are seeing is that there is such advantage offered by the new treatments for renal cancer that they are offering value for money."

But payers would like to see more clear cut data demonstrating that value. "I don't think RCC is that different from statins," said Jacqueline Kosecoff, the CEO of UnitedHealth's Pharmacy Benefit Manager, Prescriptions Solutions. "It all starts with the question, are these drugs very similar in the way they work and act or are some of them very, very different, meaning do they produce different outcomes," she said. "If the answer is no, it's really hard to tell the difference among them from a scientific perspective."

"Comparative effectiveness studies would add great value for patients, clinicians and payers," added Medco's Milayna Subar, national practice leader for the PBM's Oncology Therapeutic Resource Center.

But given how small the advanced kidney cancer population is and the limits of the disease on life expectancy it's hardly the first market payers are looking at to crack down on spending, and with the limited data, payers aren't anxious to contract with just one or two drugs

"Kidney cancer is still a small player in a big disease called cancer, and a lot of the comparative efficacy is going to be generated by the bold companies that are willing to ask the questions and put their drugs up against others," Figlin said.

Indeed, some companies are doing just that, as drug makers look to better differentiate their products. GlaxoSmithKline, for example, has initiated a Phase III study comparing pazopanib head to head against sunitinib. The trial, which has begun enrolling patients, will evaluate the two drugs on progression-free survival and overall survival.

What's Next? Sequential/Combination Treatment

Plus, as the market moves toward sequential and combination treatment, drug makers are also trying to get a better handle on where in the treatment paradigm their therapies can offer the most benefit.

"The opinion leaders in renal cell are recognizing now the opportunity to develop a continuum of care approach," Ayers said. "This is very much what happens in colorectal cancer and breast cancer, where you have your first-line treatment and when you progress on that, there is something else that you try. I think eventually those things may be figured out, but the reality is that with the length of time that patients are surviving those trials are going to take a long time to do."

Pfizer, for example, is developing an investigational VEGF inhibitor, axitinib, as another treatment for metastatic RCC. The Phase III program is studying axitinib compared to Nexavar in patients including those that have progressed on Sutent.

Aveo Pharmaceuticals, in Cambridge, Mass., is developing a triple VEGF inhibitor for RCC, tivozanib, which it is studying in a Phase III trial head-to-head against Nexavar.

The outcome of those studies could have an impact on Nexavar in the RCC space over the long-term, but Onyx Chief Operating Officer Laura Brege commented on the ongoing trials in an interview. "I think it's great that there are trials taking a look at Nexavar as an important standard of care in kidney cancer and trying to figure out what another drug's position will be."

"I think it is an interesting mark of where a marketplace is when Nexavar and other drugs are considered important drugs to compare with," she added. Onyx is targeting the liver cancer area as a bigger growth driver for Nexavar, however, than kidney cancer.

The Adjuvant Setting: Another Opportunity

One opportunity in the RCC space is in the adjuvant setting, which represents the majority of patients and where there are currently no treatments approved. Both Pfizer and Bayer/Onyx are studying Sutent and Nexavar in the adjuvant setting, with the aim of preventing patients from progressing to metastatic disease after surgery.

"The big unmet medical need is the high-risk resective patients, and is there a [treatment] for these patients at risk for recurrence," Figlin said.

Pfizer has partnered with the genomic-based clinical laboratory services company Genomic Health to develop a genomic test to estimate the risk of recurrence following surgery for patients with Stage I-III renal carcinoma. Genomic Health has successfully developed such a test for breast cancer, Oncotype DX .

"What we will be able to offer to patients, assuming that Sutent is successful in this adjuvant trial, is a diagnostic test that will identify the patients who have the highest risk of recurrence, and then hopefully an active treatment that will help those patients delay or avoid recurrence," Ayers explained.

- Jessica Merrill ( ³ j.merrill@elsevier.com )

RCC Market Snapshot: In A Crowded Field, What's Next?

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