Dose equivalence
While cabozantinib in capsule formulation was approved for the treatment of medullary thyroid cancer (Cometriq), cabozantinib was reformulated into tablets with greater bioavailability, and this formulation (Cabometyx) was tested in the METEOR trial. When studying pharmacokinetics of cabozantinib tablet and capsule formulations in healthy adults, there are slight differences. A Phase I, randomized, open-label single-dose study in healthy individuals characterized the plasma pharmacokinetics of cabozantinib capsule, and tablet formulations showed a 19% increase in the Cmax of the tablet formulation compared to the capsule formulation following a single 140 mg dose. However, a <10% difference in the AUC was observed between cabozantinib tablet and capsule formulations. Thus, in pharmacokinetic studies, the tablet and capsule formulations failed to fulfill the bioequivalence study acceptance criteria.65 Though not a large difference in pharmacokinetic activity, the results suggest that patients with RCC should only be given the tablet form (Cabometyx) to ensure more accurate monitoring and the tablet form is not interchangeable with the capsule form.
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DISCUSSION
The advent of VEGF and mTOR inhibitors in RCC has significantly improved the prognosis for patients with metastatic RCC. In patients not eligible for IFNα or interleukin-2, VEGF TKIs have replaced cytokines as the standard of care in metastatic RCC. However, complete responses are rare (3%), and identifying agents effective in the setting of de novo or acquired resistance remains an important goal.10 The METEOR trial established cabozantinib as a choice for treatment in the second line and beyond, validating the preclinical work suggesting that MET acts as an alternative angiogenic pathway in the development of VEGF TKI resistance (Figure 4). As yet there are no known biomarkers to help with selection of patients for whom cabozantinib will be most effective; this has remained an elusive goal throughout the RCC therapeutic landscape.
Toxicity remains an important concern in the management of metastatic RCC, especially as more effective treatments result in longer durations of therapy. A meta-analysis recently drew attention to the high incidence and increased risk of developing hand–foot syndrome with cabozantinib, possibly in a dose-dependent manner.66 When comparing across trials, the approved starting dose of cabozantinb has similar and even less discontinuation due to adverse events compared to other TKIs. Proactive and aggressive management of this toxicity and others will be critical for maintaining the quality of life for RCC patients on cabozantinib. Dose reductions and discontinuations for the aforementioned trials are summarized in Tables 2 and 4.
(To view a larger version of Table 4, click here.)
FUTURE DIRECTIONS
Further studies are needed to delineate the optimal cabozantinib dose. Patients should be counseled on its toxicity profile prior to treatment. As clinicians, we may need to reassess current dosing strategies and can look at other TKIs for prospective adjustments in dosing. A 2 weeks-on and 1 week-off schedule of sunitinib has shown decreased toxicity in metastatic RCC patients who initially experience grade ≥3 toxicity on the 4/2 schedule and a 2/1 schedule can extend treatment duration considerably.67 In the RAINBOW trial, a large retrospective analysis of 208 patients found that switching sunitinib to an alternate 2 weeks on and 1 week off schedule without affecting dose density over a 6-week cycle was associated with improved outcomes and increased tolerability. The 2/1 schedule reduced overall incidence of grade 3–4 toxicities to 8.2% compared to 45.7% in the 4/2 schedule in the same patients and 29.4% in the control arm.68 Other studies have shown a lower incidence of dose interruption and similar outcomes compared with the standard dosing schedule of 4 weeks on and 2 weeks off.69–71
The sequence that cabozantinib should be used among the growing number of therapeutic options is also up for investigation. Though cabozantinib’s approval was based on patients with advanced RCC who had received prior anti-angiogenic therapy, there may be a role for the drug in treatment-naïve patients as a first-line therapy. The Phase II CABOSUN study will compare cabozantinib to a 4/2 schedule of sunitinib in the first-line setting and compare the tolerability of these regimens. Patients were randomized in a 1:1 ratio to 60 mg once daily of cabozantinib or 50 mg once daily (4 weeks on and 2 weeks off) of sunitinib with the primary outcome measured as PFS and OS, with the secondary endpoints including objective response rate. If the safety profile is similar to previously reported studies and shows improved PFS, OS, or ORR when compared with sunitinib, then cabozantinib could prove to be the new standard first-line therapy for untreated advanced RCC.64 In the second-line setting, cabozanitinib is considered a standard of care therapy in patients who have received prior antiangiogeneic therapy. Similar to other TKIs, cabozantinib can be given safely with careful adverse-event monitoring and appropriate dose reductions.
