Another New Drug Approved For Kidney Cancer

Cancer Decisions ^ | 10.01.06 | Ralph Moss, Ph.D.

[Coleus]

In late July, the European Commission (EC) approved the drug Nexavar (sorafenib, formerly known as BAY 43-9006) for the treatment of advanced kidney cancer. Nexavar is classified as an oral multikinase inhibitor targeting tumors and their blood supply. It is similar in many ways to Pfizer's new drug Sutent. In December 2005, Nexavar was given "fast track" approval by the US Food and Drug Administration (FDA) for the same indication as Sutent. (A "fast track" review is aimed at speeding up the approval process for drugs designed to treat patients with serious or life-threatening diseases, where there is an unmet medical need.)  But once again - as with Sutent - the bottom line question is whether Nexavar has been proven to provide any real patient benefit. Does Nexavar actually enable patients to live longer and/or improve their quality of life? Or does it simply provide a temporary remission of the disease without any significant prolongation of life?

As yet, there have not to my knowledge been any phase III randomized controlled trials (RCTs) of Nexavar. There has, however, been an elaborate phase II, non-randomized trial that was organized by the University of Chicago. This trial evaluated the effect of Nexavar on tumor growth in patients with metastatic kidney cancer (also called renal cell carcinoma, or RCC).  This study had a complicated design. All patients in the study received an oral dose of 400 milligrams (mg) of Nexavar twice per day. After 12 weeks, patients whose tumors shrank by less than 25 percent were randomly assigned to receive Nexavar or a placebo for an additional 12 weeks. Patients whose tumors then exhibited a 25 percent or greater shrinkage continued with Nexavar, while those whose tumors actually continued to grow during this period discontinued treatment. The primary end point of the study was to see how many patients remained "progression-free" at 24 weeks after initiation of Nexavar (Ratain 2006).

Of 202 patients who were treated during the so-called run-in period (in which everyone got Nexavar), just 73 had tumor shrinkage equal or greater than 25 percent. Sixty-five patients with stable disease at 12 weeks were randomly assigned to get Nexavar or placebo. At 24 weeks, 50 percent of the Nexavar-treated patients were "progression free" vs. 18 percent of the placebo-treated patients. Median progression-free survival (PFS) was significantly longer in the Nexavar-treated patients (24 weeks) compared to those treated only with a placebo (6 weeks). The median overall PFS was 29 weeks for the entire patient population. The most common adverse effects were skin rash with desquamation (a condition in which the skin peels away), hand-foot skin reaction, and fatigue. Nine percent of the patients discontinued therapy because of such side effects, but at least no patients died from toxicity. The authors concluded that Nexavar "has significant disease-stabilizing activity in metastatic renal cell carcinoma and is tolerable with chronic daily therapy."

I presume that this elaborate study design would not have been necessary if Nexavar had any clear-cut effect on survival. But there is no mention of any impact on overall survival in this report. Does this matter, you may ask, when Nexavar so clearly prolongs progression-free survival in a select group of patients? Yes, it does. Overall survival and improved quality of life are the two main benefits one can hope for from an anticancer treatment. While progression-free survival ideally could offer a psychological lift to some patients, one can easily imagine situations in which hopes are raised by the temporary shrinkage of a tumor, only to be dashed when the tumor returns with even greater virulence later on. The most important issue remains unaddressed: what actual effect does this drug have on the lifespan of renal cell cancer patients? FDA's decision to approve an increasing number of drugs based on dubious indications of benefit has had the effect of flooding the market with new compounds, most of which offer no real improvement over existing, more established (and less costly) drugs.

"We're all going to have to have flash cards to remember all the names of these agents in the future," quipped Dr. Hope S. Rugo of the University of California, San Francisco, after presenting a lecture at the 2006 American Society of Clinical Oncology (ASCO) meeting. She was referring to sunitinib, axitinib, sorafenib, pazopanib, as well as other similar-acting (and similar-sounding) drugs (Pollack 2006).  But the money keeps rolling in for these various look-alike products. Onyx Pharma, manufacturer of Nexavar, has priced the new drug at a whopping $4,333 a month, or around $50,000 per year. This figure surprised even seasoned Wall St. stock analysts, but they did not sound at all displeased. "With approximately 2,100 patients currently on the drug, 2006 sales of approximately $35 million are basically in the bag," enthused Morgan Stanley analyst Steven Harr (Tomassi 2006). While industry, private-practice oncologists (who make a sizeable proportion of their income through selling and administering drugs in their offices - the so-called "chemotherapy concession") and even some patient advocates are enthusiastic about this latest in the parade of new ‘targeted' drugs, there are also reasons to be cautious.

Patients or their insurers will now have to pay $50,000 per year for a drug that only conveys the dubious benefit of some additional "progression-free survival." PFS is to overall survival as fool's gold is to real ingots. Whether the drug really benefits patients in terms of prolonging their survival is still an unproven hypothesis. But it should escape no one's attention that targeted anticancer drugs in general have not lived up to expectations: with few exceptions, they are far less effective and more toxic than anticipated. For that reason, it is best to look at all new entries in the targeted drug derby with a dose of skepticism, and to demand proof of actual life-prolongation before breaking out the champagne.

--Ralph W. Moss, Ph.D.

References:

Morgan G, Ward R, Barton M. The contribution of cytotoxic chemotherapy to 5-year survival in adult malignancies. Clin Oncol (R Coll Radiol). 2004;16(8):549-60.

Pollack, Andrew. New drugs for cancer could soon flood market. New York Times, June 4, 2006.

Ratain MJ, Eisen T, Stadler WM, et al. Phase II Placebo-Controlled Randomized Discontinuation Trial of Sorafenib in Patients With Metastatic Renal Cell Carcinoma. J Clin Oncol.2006;24:2505-2512.

Tomassi, Kate DuBose. Onyx Pharma set for strong first half, Forbes.com, Dec. 21, 2005, Available at: http://www.forbes.com/2005/12/21/onyx-pharmaceuticals-cancer-1221markets05.html?partner=msn

[pgkdan]

Do you have RCC?