Bayer/Onyx Nexavar Approved For Broad Advanced Kidney Cancer Indication

FDA's full approval of Bayer/Onyx' kidney cancer therapy Nexavar (sorafenib) covers both refractory and first-line use.

Although most patients in the clinical trials of Nexavar had been previously treated with conventional treatment, FDA approved sorafenib Dec. 20 for the broad indication of "treatment of patients with advanced renal cell carcinoma."

"FDA did not want patients to have to undergo relatively marginal treatment before receiving this drug. We were satisfied that there were a subset of patients, albeit small, that did not have prior treatment that had a similar treatment effect," Office of Oncology Drug Products Director Richard Pazdur said during a FDA teleconference announcing the approval.

"In oncology there is no agent that I'm aware of that has activity in a refractory population that does not have at least equal to or greater activity in a less heavily treated population," he added.

Additionally, under Bayer/Onyx' expanded access program for Nexavar, nearly half of the over 2,000 U.S. patients who received sorafenib therapy were first-line patients.

Bayer and partner Onyx are touting sorafenib as the "first oral multi-kinase inhibitor that targets serine/threonine and receptor tyrosine kinases in both the tumor cell and tumor vasculature."

In a randomized placebo-controlled Phase III trial, Nexavar 200 mg doubled progression-free survival from a median value of three months for advance renal cell carcinoma patients on placebo to six months for patients in the sorafenib arm (p-value <0.000001).

"If one takes a look at the log rank test...it has five zeros in front of it," Pazdur noted. "A very impressive result. Probably one of the most impressive results I've seen in clinical oncology."

Pazdur further added that the agency's acceptance of a progression-free survival endpoint illustrates the importance of the magnitude of a drug's benefit on a given endpoint and how it may relate to overall survival (see ¹ (Also see "Magnitude Of Effect, Not Survival, Is Key To Approval For Oncologic Nexavar" - Pink Sheet, 2 Jan, 2006.)).

In a planned interim analysis in April based on 220 deaths, overall survival was longer for Nexavar than placebo (hazard ratio of 0.72). However, the result was not statistically significant.

In a Dec. 20 conference call with investors, Onyx Chief Medical Officer Henry Fuchs explained that for the April interim analysis, the threshold for meeting statistical significance was a p-value of <0.0005.

By comparison, "the final analysis on 540 patients requires a p-value of 0.040 to be significant," Fuchs said. Bayer also plans a second interim analysis, but the company did not say when it would disclose those results.

Another issue that may have confounded the survival analysis was the crossover design of the placebo-controlled randomized study, Pazdur noted.

Pazdur was enthusiastic about the risk/benefit ratio of Nexavar, due to the drug's significantly improved toxicity profile over conventional therapies.

"There has been a sea change in the risk/benefit relationship with the treatment of renal cell carcinoma. We have an agent here that has a very favorable toxicity profile compared to conventional therapy of either [interleukin-2] or interferon," Pazdur said. "We believe that this represents truly - from a medical point of view - a major advance in the treatment of advanced renal cell carcinoma."

Sorafenib is the first drug approved in renal cell carcinoma in over ten years and the first and only kidney cancer therapy approved based on progression-free survival. In 1992, FDA approved Chiron's Proleukin (interleukin-2) for the treatment of metastatic melanoma and metastatic renal cell carcinoma based on a response rate of approximately 13%-15%.

Common adverse reactions associated with IL-2 include sepsis, capillary leakage syndrome and hypotension.

IL-2 "has considerable toxicity with toxic death associated at about 4% and myocardial infarctions and also acute renal failures," Pazdur said. He added that the dosing schedule for IL-2 frequently required either ICU administration or inpatient hospitalization.

Interferon, which is used off-label in cancer treatments, is "a very toxic therapy that really complicates one's quality of life, [causing] profound fatigue and flu-like syndromes," Pazdur said.

In Phase III studies, common adverse events for Nexavar were diarrhea, rash/desquamation, fatigue, hand-foot skin reaction, alopecia, nausea, pruritus, hypertension, vomiting and anorexia.

Grade III adverse events were reported in 31% of patients treated with sorafenib versus 22% of placebo-treated patients, and Grade IV events were reported in 7% of sorafenib patients and 6% of placebo patients.

In clinical trials of Nexavar, the incidence of treatment-emergent cardiac ischemia/infarction events was higher in the sorafenib arm (2.9%) than in the placebo group (0.4%).

Labeling also cautions about an increased risk of bleeding following Nexavar administration.

The Nexavar application (NDA 21-923) was part of FDA's continuous marketing application pilot 1 program, which allows sponsors of fast-track agents to submit NDAs in separate reviewable units. The last unit was submitted on July 11. The agency's approval following a priority review came ahead of the mid-January user fee deadline.

"Although we anticipate the kidney cancer market will be competitive, we believe that having this data set and a somewhat earlier-than-expected approval gives us a distinct competitive advantage," Onyx Chief Business Officer Edward Kenney said during the company's conference call.

Bayer and Onyx planned to have sorafenib available to patients within 24 hours of announcing its approval.

The company also launched the Resources for Expert Assistance and Care Helpline to address patient and healthcare provider questions regarding Nexavar treatment and reimbursement.

Bayer and Onyx "have multiple specialty pharmacies under contract and REACH will help in linking those patients to specialty pharmacies for direct product distribution," Kenney said.

"Based on formulary market research that was recently conducted, we anticipate the acceptance of Nexavar by most major private carriers as well as inclusion in the formularies of plan sponsors providing coverage under the new Medicare Part D," he added.

According to Onyx, the price of Nexavar for specialty pharmacies is $4,333 for a one-month supply; with mark-up, the price will be $5,416, Onyx said.

The drug is priced as one of the more expensive cancer therapies available.

Nexavar is significantly more expensive than other small molecule oral kinase inhibitors Tarceva (OSI's erlotinib) and Iressa (AstraZeneca's gefitinib), which have wholesale acquisition costs of $3,349/month and $2,127/month, respectively.

Sorafenib is still priced well below Bristol-Myers Squibb/ImClone's Erbitux and Genentech's Avastin . Aggressive pricing for the EGFR inhibitors in 2004 prompted public criticism from oncologists, including calls for price controls (² (Also see "Avastin, Erbitux Costs Invite Price Controls, Former NCI Deputy Says" - Pink Sheet, 21 Jun, 2004.), p. 25).

Tarceva may be the most informative pricing point comparator for Nexavar. Erlotinib is approved for the treatment of non-small cell lung cancer. Bayer and Onyx are planning to initiate a Phase III trial in non-small cell lung cancer in the first half of 2006 (³ (Also see "Bayer Nexavar Safety Profile Fuels Research In Multiple Cancer Indications" - Pink Sheet, 19 Dec, 2005.), p. 7).

Onyx and Bayer also intend to expand Nexavar's indication to liver and skin cancer.

The companies are conducting an international placebo-controlled Phase III trial of approximately 550 first-line liver cancer patients studying the primary endpoints of overall survival or time to symptom progression. A single-arm Phase II study of 137 first-line liver cancer patients reported a time to tumor progression of 4.2 months, with an overall survival time of 9.2 months.

There are two Phase III studies underway for Nexavar in metastatic melanoma, one sponsored by Bayer/Onyx and the other sponsored by the Eastern Cooperative Oncology Group. The studies are comparing Nexavar in combination with carboplatin and paclitaxel vs. carboplatin and paclitaxel alone.

The company-sponsored study will assess progression-free survival of 250 patients who have had one prior systemic chemotherapy regimen, while the ECOG study will assess overall survival of 800 patients without prior systemic chemotherapy.