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Cabozantinib extends PFS in metastatic renal cell carcinoma
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COPENHAGEN, Denmark — Cabozantinib significantly prolonged PFS compared with sunitinib among poor- and intermediate-risk patients with metastatic renal cell carcinoma, according to results of the randomized phase 2 CABOSUN trial presented at the European Society for Medical Oncology Congress.
Cabozantinib (Cabometyx, Exelixis) also more than doubled the objective response rate.
“Cabozantinib is already approved in the second-line setting, and based on these data, I think there is real potential for the indication to expand to first line,” Toni Choueiri, MD, director of Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, told HemOnc Today.
Cabozantinib — a small molecule inhibitor of the MET and VEGFR2 tyrosine kinases — received FDA approval earlier this year for treatment of patients with advanced renal cell carcinoma who received prior antiangiogenic therapy.
Sunitinib (Sutent, Pfizer) — a small-molecule multitargeted receptor tyrosine kinase inhibitor — has long been the standard first-line treatment for metastatic renal cell carcinoma.
In the CABOSUN trial, Choueiri and colleagues compared cabozantinib with sunitinib for frontline treatment of patients with clear-cell metastatic renal cell carcinoma.
All patients had ECOG performance status of 0 to 2, and they were classified as intermediate (80.9%) or poor risk per International Metastatic Renal Cell Carcinoma Database Consortium criteria.
Researchers randomly assigned 79 patients to 60 mg cabozantinib daily. The other 78 patients received 50 mg sunitinib daily, administered on a 4-weeks-on, 2-weeks-off schedule.
Median follow-up was 20.8 months, at which time 13 patients (16.4%) assigned cabozantinib and two patients (2.5%) assigned sunitinib remained on therapy.
Cabozantinib-treated patients achieved significantly longer median PFS (8.2 months vs. 5.6 months; HR = 0.69; 95% CI, 0.48-0.98) and a considerably higher objective response rate (46% vs. 18%).
Cabozantinib also extended median OS (26.4 months vs. 23.5 months; adjusted HR = 0.87; 95% CI, 0.55-1.4), but the difference did not reach statistical significance.
Researchers reported similar rates of grade 3 or higher adverse events between treatment groups (cabozantinib, 70.5%; sunitinib, 72.2%). Sixteen patients in each group discontinued treatment due to toxicity.
Patients assigned cabozantinib experienced higher incidence of hypertension (28% vs. 22%) and palmar-plantar erythrodysesthesia (8% vs. 4%). Patients assigned sunitinib experienced higher incidence of diarrhea (11% vs. 10%), fatigue (15% vs. 6%) and hematologic events (22.2% vs. 2.6%).
Although the study did not include good-risk patients, there is no clinical or biological rationale that suggests they would not derive similar benefit from cabozantinib, Choueiri said.
Even if regulatory authorities expand the indication of cabozantinib to include frontline treatment, a shift toward combination regimens — such as cabozantinib plus nivolumab (Opdivo, Bristol-Myers Squibb), as well as cabozantinib plus nivolumab and ipilimumab (Yervoy, Bristol-Myers Squibb) — is underway, Choueiri said.
“I think the future is multiple pathways and multiple mechanisms of action at the same time,” Choueiri told HemOnc Today.
Several questions remain unanswered, according to Bernard Escudier, MD, chairman of the renal cancer unit at Institut Gustave-Roussy in France, who was not involved with the study.
These questions include whether the results are applicable to all patients with metastatic renal cell carcinoma, including those classified as good-risk patients; whether cabozantinib should be considered the new first-line standard of care; and how results of ongoing phase 3 trials designed with sunitinib as the control should be interpreted.
“While more mature data and additional studies using cabozantinib in the first-line setting will be required, this study raises a lot of new expectations for the treatment of metastatic renal cell carcinoma,” Escudier said in a press release. – by Mark Leiser
For more information: Choueiri TK, et al. Abstract LBA30_PR. Presented at: European Society for Medical Oncology Congress; Oct. 7-11, 2016; Copenhagen, Denmark.
Disclosure: Exelixis provided funding for this study. Choueiri reports institutional funding from Exelixis and Pfizer, as well as advisory board compensation from Pfizer. The other researchers report no relevant financial disclosures.
Editor's Note: On Oct. 12, we corrected the body of this article to indicate that cabozantinib improved PFS, response rate and OS compared with sunitinib. The Editors regret this error.
Perspective
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Sumanta K. Pal, MD
The CABOSUN data represent a potential game-changer for the frontline therapy of metastatic renal cell carcinoma. This is the first study in the frontline setting to establish the superiority of one VEGF–directed therapy over another. Other studies have come close. A phase 3 study that compared axitinib (Inlyta, Pfizer) with sorafenib (Nexavar, Bayer) showed a modest improvement in PFS with axitinib, but this difference was not statistically significant.There are elements of the CABOSUN data that may come under scrutiny. For instance, the primary endpoint of the trial was investigator-assessed PFS. Ideally, designation of progression events would be made via central review. Efforts are apparently underway to secure this information. However, it is rare to see a marked discordance in central and investigator review.
A second element of the study that has been challenged is the sample size. This randomized phase 2 study included 150 patients. A discussant for this study at ESMO proposed that a phase 3 study be done using a similar randomization, but this seems wasteful and fraught with challenge. Given the magnitude of benefit seen with cabozantinib (Cabometyx, Exelixis) in the CABOSUN trial, would patients be willing to undergo randomization to sunitinib (Sutent, Pfizer)?
Bear in mind that the activity of cabozantinib has further been established in the phase 3 METEOR trial, in which the agent was compared with everolimus (Afinitor, Novartis) in previously treated patients with advanced renal cell carcinoma. That study showed a significant benefit in PFS, response rate and OS. Further, recent experiences at the FDA have shown randomized phase 2 data to be sufficient for regulatory approval in advanced renal cell carcinoma. As one prominent example, the combination of lenvatinib (Lenvima, Eisai) and everolimus was approved on the basis of a randomized study with a little more than 50 patients per treatment arm.
The next generation of studies with cabozantinib should focus on combinations, perhaps with novel immunotherapeutic strategies. There are multiple trials in the frontline setting that compare sunitinib with combinations of VEGF–directed therapy with PD-1 inhibitors. However, with the results of CABOSUN, one must wonder whether sunitinib is an appropriate control arm.
Just ahead of presentation of the CABOSUN data at ESMO, Andrea B. Apolo, MD, investigator in the Genitourinary Malignancies Branch at NCI, outlined preliminary results from a phase 1 trial that combined cabozantinib and nivolumab (Opdivo, Bristol-Myers Squibb). No concerning safety signals were observed, and impressive activity was seen in an array of rare genitourinary malignancies.
Moving forward, a frontline trial of cabozantinib with or without immunotherapy might be envisioned. Another unique application of cabozantinib might be in the context of non-clear cell histologies. The SWOG 1500 trial, launched in April, will compare sunitinib, cabozantinib and two other putative MET inhibitors in patients with advanced papillary renal cell carcinoma. With cabozantinib reflecting a new frontline standard in advanced renal cell carcinoma, investigators will have to move quickly to investigate novel applications and combinations with this agent.
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