Exelixis’ Cabozantinib Cleared For Kidney Cancer, With Competitive Labeling

Company plans to launch within two weeks, priced at a premium to competing drugs in kidney cancer.

Exelixis Inc.is set to launch its cabozantinib soon in renal cell cancer under the brand name Cabometyx, at a premium price and with labeling citing an overall survival benefit, but the firm faces a tough marketing battle against Bristol's Opdivo.

Cabozantinib is an oral drug that works on a number of targets, including VEGFR2, MET and RET. The drug was initially approved in 2013 for treating the very rare medullary thyroid cancer and branded as Cometriq (Also see "Cometriq Thyroid Approval May Open Door For Use In Prostate Cancer" - Pink Sheet, 10 Dec, 2012.). Company sales of $37.2m for 2015 were mainly driven by Cometriq.

The new approval, announced late April 25, covers treatment of patients with advanced renal cell carcinoma after anti-angiogenic therapy. The drug had breakthrough therapy status with FDA and was cleared ahead of the July 22 user fee date.

The filing was supported by the METEOR trial, in which the drug demonstrated superiority over Novartis AG’s Afinitor (everolimus) on the primary endpoint of progression-free survival, as well as demonstrating superior efficacy on secondary endpoints related to overall survival and objective response rate.

During an April 25 investor call, VP-Commercial PJ Haley said that the company is prepared to launch and anticipates shipping within two weeks.

Cabometyx will be sold in bottles of 30 tablets at 20 mg, 40 mg and 60 mg doses. The recommended dose is 60 mg once daily. All doses will be sold at the same price – a wholesale acquisition cost of $13,750 per bottle.

“This is competitive with other agents approved for advanced renal cell carcinoma. Importantly, it also reflects the value of Cabometyx, as demonstrated by the strength of the METEOR data with the unprecedented trifecta of improvement in overall survival, progression-free survival and objective response rate,” Haley said.

In an April 25 note, Leerink Partners analyst Michael Schmidt said that WAC pricing for Cabometyx of $13,750/month represents a premium over Afinitor as well as Pfizer Inc.’s Inlyta (axitinib), priced at $10,500, and $11,400 per month in 2015, respectively, and came in at about 20% higher than estimated.

The list price for the average kidney cancer patient taking the PD-1 inhibitor Opdivo (nivolumab) at the recommended dose is $12,700 per month, according toBristol-Myers Squibb Co.

Compared to Cabometyx, Cometriq is dosed differently, at strengths of 60 mg, 100 mg and 140 mg, and consequently winds up costing less in terms of the amount of drug provided. The recommended dose is 140 mg once-daily. The WAC for a bottle of 28 tablets for any dose of Cometriq was increased by 8.9% to $14,152 as of the start of the year, according to Exelixis.

Execs noted during the call that the label’s dosage and administration instructions stipulate: “Do NOT substitute Cabometyx tablets with cabozantinib capsules.”

Because the FDA-approved label states that the two products are not interchangeable, Haley said that the company expects patients with RCC will be treated with Cabometyx.

Survival Benefit Keeps Cabo Competitive

In the pivotal METEOR trial, median PFS was 7.4 months for Cabometyx vs. 3.8 months for Afinitor, a statistically significant 42% reduction in risk for progression.

However, overall survival matters a lot, particularly since Bristol’s Opdivo was approved in November 2015 for second-line RCC with a proven survival benefit (Also see "Bristol, Exelixis Trials Preview Changes In Kidney Cancer Market" - Pink Sheet, 20 Jul, 2015.). The drug has been performing well in kidney cancer and other indications and reached worldwide sales of $942m in 2015, its first year on the market (Also see "Among New Drug Launches, Oncology Scores Big While CV Lags" - Pink Sheet, 28 Mar, 2016.).

The first analysis of overall survival in the METEOR study showed a strong trend toward a benefit toward overall survival, which was confirmed as statistically significant in a second analysis, the company announced in February.

The drug demonstrated a 34% reduction in the rate of death – median OS was 21.4 months vs. 16.5 months for those receiving Afinitor – in the study.

Leerink’s Schmidt said that the approval had been expected but that the inclusion of overall survival data in labeling was a nice surprise.

“Cabo generated an impressive hazard ratio of 0.66 that compares well with that of recently approved Opdivo in similar patients (HR=0.73),” though numerically, results were better for Opdivo in the pivotal CHECKMATE-025 study, Schmidt noted.

Chief Medical Officer Gisela Schwab said that this is a first time that a tyrosine kinase inhibitor as a single agent has demonstrated an OS benefit in a large Phase III study in a second- or later-line advanced RCC population. There had been no upper limit on the number of prior therapies in METEOR.

Comparing To Opdivo

Like Opdivo, Cabometyx is already included with a high recommendation for use in National Comprehensive Cancer Network guidelines.

The objective response rate results look similar for the two drugs. In the METEOR trial, ORR was 17% for Cabometyx vs. 3% for Afinitor. That compares to 21.5% for Opdivo vs. 3.9% for Afinitor in the CheckMate-025 study.

However, Schmidt noted that while the data look very compelling, it will take an “aggressive marketing effort to compete with Opdivo” in second-line renal cell carcinoma and, consequently, Leerink’s modeling is based on capturing the third-line RCC market.

Morningstar Equity Research Analyst Stefan Quenneville commented that despite a slightly superior hazard ratio for Cabometyx, he expects that Opdivo will take the lead in second-line RCC patients because of its much milder safety profile.

“Nevertheless, we think both drugs have attractive opportunities in the indication, and there is the potential for them to be used in combination,” Quenneville wrote.

The warnings section of Cabometyx labeling cites hemorrhage, GI perforations, serious thrombotic events and severe diarrhea, among other adverse events. In the METEOR study, 60% of patients on Cabometyx needed a dose reduction vs. 24% for Afinitor due to adverse events. Grade 3/4 events occurring in at least 5% of patients included hypertension, diarrhea, fatigue, hyponatremia, anemia and hypokalemia.

Schwab said that clinicians are very familiar with using tyrosine kinase inhibitors and that the side effects were predictable and could be managed with dose reductions to help patients stay on therapy.

Holding On To Second-Line

CEO Mike Morrissey said that the company was not planning to concede second-line RCC. There are some 17,000 patients in the US in the second- or later-line setting who could be eligible for treatment with Cabometyx. Exelixis will be going after the broad population allowed in labeling.

“We think we've got very, very competitive data and we're going to fight for every patient, every script, every refill, every single day. And I'm thrilled with the commercial team and having now spent time with the entire sales organization last week at our launch meeting, I am very confident that they're going to get out there and just do a tremendous job of educating and selling the drug,” Morrissey said.

A seasoned team with more than 80 sales professionals exclusively focused on Cabometyx is in place and ready to compete in the RCC market with a “laser focus,” Haley said.

It will likely take from six to 12 months to secure formulary coverage on most plans, but the company doesn’t believe there will be significant barriers to coverage in the meantime.

“We were able to obtain excellent coverage for Cometriq in MTC and we will leverage that experience for Cabometyx,” Haley said.

The company will also be offering free drugs to uninsured patients, copay assistance and comprehensive reimbursement support services.

“The programs have been designed to be best-in-class, as ensuring patient access to our drugs is a top priority for Exelixis,” Haley said.