As buzz grows approaching the European Society for Medical Oncology (ESMO) meeting in Copenhagen this weekend, therapeutic prospects in first-line renal cell carcinoma (RCC) have drawn particular interest, with big pharma and biotech players waiting for data rollouts.

Last week, Wall Street nicked shares of Exelixis Inc. when ESMO abstracts were unveiled. Apparently at issue were updated data from a phase Ib trial to be highlighted at the meeting, with results showing that New York-based Pfizer Inc.'s Inlyta (axitinib) when combined with Keytruda (pembrolizumab) from Merck & Co. Inc., of Kenilworth, N.J., gained a 67 percent response rate in first-line RCC.

South San Francisco-based Exelixis has Cabometyx (cabozantinib), approved for second-line and third-line RCC, and ESMO will include results from the company's experiment called CABOSUN. Collaborators at the National Cancer Institute are sponsoring the randomized phase II trial comparing Cabometyx to Sutent (sunitinib, Pfizer Inc.) in first-line therapy of intermediate- or poor-risk RCC patients. The primary endpoint of the trial is progression-free survival (PFS), and the study achieved its target enrollment of 150 patients in March 2015. If the CABOSUN data pan out with clinically significant improvements in patients plus no new safety hitches, Cabometyx might get the approval nod in first-line because of the need for a therapy in that patient group, and because the drug has proved its mettle in later-stage experiments against second-line disease. (See BioWorld Today, April 26, 2016.)

Figuring out the odds of success, clinically or from a regulatory standpoint, is far from simple, but Leerink analyst Michael Schmidt took a shot in his Sept. 19 research report. He speculated that Cabometyx could garner a median PFS higher than 10 months, and noted that Sutent has generated 11 months on that measure in first-line RCC.

"Within intermediate-risk patients (56 percent), PFS was 11 months, and PFS was four months in the poor-risk group (6 percent of patients)," he wrote. "A second phase III trial comparing Sutent vs. Votrient [pazopanib, Glaxosmithkline plc] resulted in 9.5 months median PFS for the former, but the study included more poor-risk patients (58 percent intermediate-risk, 12 percent poor-risk). The median PFS for Cabometyx-treated patients in CABOSUN largely depends on the ratio of intermediate-risk to poor-risk patients in the study, but even with an unlikely 50/50 ratio, [the] median PFS for Cabometyx should be more than 10 months, given CABOSUN powering assumptions."

The study was powered at 85 percent, based on 123 events and a one-sided type I error rate of 0.12 (alpha) to detect a hazard ratio of 0.67. In all, 157 patients were randomized 1-to-1 to receive either Cabometyx (n=79) or Sutent (n=78). Secondary endpoints include overall survival (OS), and objective response rate. In May, Exelixis disclosed that Cabometyx achieved a statistically significant PFS benefit over Sutent in front-line RCC. Exelixis and Ipsen have slated an investor briefing at ESMO Monday.

Aiming to beat Sutent, major players in first-line RCC have late-stage combo trials ongoing. Those include one testing Opdivo (nivolumab, Ono Pharmaceutical Inc.) plus Yervoy (ipilimumab, Bristol-Myers Squibb Co.) vs. Sutent; Avastin (bevacizumab, Roche AG) plus Tecentriq (atezolizumab, Roche AG) vs. Sutent; and Inlyta plus avelumab – the programmed cell death ligand 1 (PD-L1) inhibitor partnered between Darmstadt, Germany-based Merck KGaA and Pfizer – vs. Sutent. Avelumab just began a phase III trial in July in combination with or as follow-on treatment to platinum-based chemotherapy in patients with metastatic, previously untreated epithelial ovarian cancer. (See BioWorld Today, July 7, 2016.)


Among the first-line RCC bids, "the probability of success (POS) for Opdivo plus Yervoy is highest and key opinion leaders (KOLs) expect a 'fair amount' of use in front-line (20-30 percent of patients), pending approval," in the view of Leerink's Schmidt. The trial is fully enrolled. If it does lead to marketing clearance, "this would 'free-up' incrementally more patients in second-line to use Cabometyx, since they wouldn't receive Opdivo monotherapy after Opdivo/Yervoy failure in first-line," he wrote. POS of the Roche compounds' trial is "only modest, according to one KOL, and OS needs to be superior vs. Opdivo-plus-Yervoy to see meaningful use of this combination," he added. The Pfizer experiment with avelumab only started in March, and thus "likely won't reach the market until 2019 at the earliest, assuming success. By then, Sutent could be an irrelevant comparator [in first-line RCC], posing additional commercial challenges. 'Nobody is using lenvatinib [Lenvima, Eisai Inc.],' based on our checks."

Earlier this year, Exelixis selected Paris-based Ipsen as its partner outside the U.S., Canada and Japan in an exclusive licensing deal to commercialize and develop Cabometyx in all indications.

The deal brought Exelixis $200 million up front plus regulatory milestone payments, including $60 million upon the approval of Cabometyx in Europe – that happened in September – to treat advanced RCC, and $50 million upon the filing and approval of Cabometyx in Europe to treat advanced hepatocellular carcinoma.

The pact included more regulatory milestone rewards for other potential indications and up to $545 million in would-be commercial milestones. Exelixis also found itself eligible for tiered royalties that start at 2 percent for the first $50 million in net Cabometyx sales by Ipsen in its territories and escalate after the initial period to a tiered royalty of 22 percent to 26 percent on annual net sales.

The arrangement gave Ipsen a transfer of rights outside the U.S. from existing partner Swedish Orphan Biovitrum AB, of Stockholm, for the capsule formulation of the drug, branded Cometriq, to treat adults with progressive, unresectable, locally advanced or metastatic medullary thyroid cancer (MTC). Exelixis retained exclusive commercial rights to in the U.S. – where the drug also is approved as Cometriq to treat MTC – as well as in Canada and in Japan, where the company said it planned to continue partnering discussions. (See BioWorld Today, March 2, 2016.)