Exelixis Makes The Case For Early Filing Of Cabozantinib In Frontline Kidney Cancer

Company recruited clinical experts to explain why Phase II CABOSUN should be enough for approval and why a Phase III study is now impractical.

Exelixis Inc.is gearing up to file cabozantinib for early FDA approval for frontline metastatic kidney cancer after releasing strong results in the Phase II CABOSUN study, but the market has the jitters about whether a Phase III study will be needed.

Exelixis released positive full results from the eagerly awaited Phase II CABOSUN first-line metastatic RCC study at the European Society for Medical Oncology meeting on Oct. 9 in Copenhagen, following a top-line release in May. (Also see "Exelixis' Strong Cabometyx Start Signals Changing Of Guard In Kidney Cancer Market" - Scrip, 5 Aug, 2016.) Cabozantinib is currently marketed as Cometriq for metastatic medullary thyroid cancer and is marketed as Cabometyx for renal cell carcinoma after prior antiangiogenic therapy. It is partnered with Ipsen outside of the US, Canada and Japan.

CABOSUN Results

The study included 157 previously untreated patients with intermediate or poor-risk disease and randomized patients to cabozantinib or Pfizer Inc.'s Sutent (sunitinib). Between 70% and 80% of the population have intermediate or poor-risk disease.

Cabozantinib was associated with a significant 31% reduction in risk of progression or death (8.2 months vs. 5.6 months). Benefits were seen across subgroups, including in patients with bone metastases. The company noted that the PFS for the comparator arm was similar to historical controls in the first-line setting for patients with a similar risk profile.

The drug was associated with a significantly better objective response rate of 46% versus 18% for Sutent. Researchers also noted a trend toward an improvement in median overall survival, with a hazard ratio of 0.80 (30.3 months versus 21.8 months).

Rates of adverse events and discontinuation rates were similar for cabozantinib and Sutent.

In an Oct. 11 note, Leerink Partners' analyst Michael Schmidt observed that in beating the standard-of-care Sutent in first-line renal cell carcinoma, cabozantinib achieved what no other agent has been able to do – including Novartis AG's Votrient (pazopanib) and Afinitor (everolimus), Pfizer's Inlyta (axitinib) and Aveo Pharmaceuticals Inc.'s tivozanib.

Comments from key opinion leaders suggest that this is "paradigm-shifting" and can be attributed to the drug's differentiated mechanism of action, that is inhibiting Met and Axl in addition to VEGF, Schmidt said.

Filing Timing Up In The Air

The company plans to file an sNDA based on the mid-stage data with FDA. During an Oct. 11 investor presentation, execs said that they were working to transfer data from the Alliance for Clinical Trials in Oncology, which sponsored the trial as part of Exelixis’ collaboration with the National Cancer Institute’s Cancer Therapy Evaluation Program (NCI-CTEP), to the company, which will corroborate the efficacy results through independent radiology review. This will allow the company to prepare a dataset for the supplemental NDA.

Timing for the supplemental NDA "depends on a variety of factors," so Exelixis is not providing a timeline yet, Gisela Schwab, chief medical officer, said during an Oct. 10 investor presentation.

Meanwhile, partner Ipsen is in discussions with the European Medicines Agency to define a regulatory path and submission simultaneously with Exelixis' efforts in the US, Schwab said.

Despite the strength of the data and plans for a filing, Exelixis’ stock price closed at closed at $12.61, down from $13.02, on Oct. 10 and as investors apparently fretted about the lack of significant overall survival benefit and the potential need for a Phase III study prior to approval.

The discussant at the ESMO meeting – Bernard Escudier, chairman of the renal cancer unit at Institut Gustave Roussy in France – suggested that a Phase III trial would be necessary for cabozantinib to get a first-line approval.

In an interview from the meeting in Copenhagen, Datamonitor Healthcare analyst Rachel Lloyd commented that that she doesn't think the results suggest that cabozantinib will automatically take over from sunitinib in first-line RCC.

"Although the PFS data were impressive (8.2 months versus 5.6 months), the hazard ratio wasn’t (0.69) and OS was not significant," she commented.

Leerink's Schmidt, however, thinks that there is a high likelihood of approval based on CABOSUN, based on the robustness of the results and the strength of Exelixis' Oct. 10 investor presentation.

The 31% reduction in risk of progression or death clearly meets criteria that are viewed as clinically meaningful by physicians, in his view. "PFS improvement was consistent across several subgroups and there were no enrollment imbalances in the trial," Schmidt added.

While the OS curves appeared to separate initially and then seemed to converge again, the OS data were still very immature and the trial was not powered to demonstrate an OS benefit, he said.

"PFS has been the historic approvable endpoint in 1L RCC," Schmidt pointed out.

Furthermore, the results in the METEOR study in the second-line population were "pretty remarkable," which would make it harder for FDA to decline to approve it in intermediate- and poor-risk 1L RCC, he said.

A New Standard Of Care?

During Exelixis' investor presentation, Nizar Tannir, professor and deputy chair of genitourinary medical oncology at the University of Texas' MD Anderson Cancer Center, described cabozantinib as "a new standard of care for first-line patients with clear cell RCC with poor risk and intermediate risk."

Tannir also questioned the wisdom of running a Phase III study testing cabozantinib against Sutent in hundreds of patients order to confirm the CABOSUN results, particularly when there was a nine-month numerical difference in overall survival, a secondary endpoint, though it hasn't crossed the threshold of significance yet.

Tannir said that he does not believe the data are ever going to show that cabozantinib is inferior to sunitinib, certainly not by PFS or response rate, nor that overall survival will "suddenly flip" and that patients on sunitinib would suddenly have a better outcome.

Performing a similar study would be a "waste of resources," he asserted.

Phase III trials of poor-to-intermediate risk patients are now going to be very challenging for newcomers because the bar is now higher at a median PFS of 8.2 months with cabozantinib, Tannir added.

Tannir also said that he believes that in the US, patient advocates will demand that insurance companies allow cabozantinib as a first-line treatment and that many physicians will prescribe the drug "without hesitation."