Introduction
Cabozantinib is a tyrosine kinase inhibitor (TKI) targeting multiple receptor tyrosine kinases implicated in tumor angiogenesis, invasion, and metastasis, including MET (hepatocyte growth factor receptor), VEGFR2 (vascular endolethial growth factor receptor 2), AXL (GAS6 receptor), and RET (glial cell-derived neurotrophic factor receptor) [
1]. The cabozantinib capsule formulation (Cometriq
®) is approved at a dose of 140-mg-free base equivalents (FBE) daily in the USA for the treatment of progressive metastatic medullary thyroid cancer (MTC) and in the European Union (EU) for the treatment of progressive, unresectable locally advanced or metastatic MTC [
2,
3]. The cabozantinib tablet formulation (Cabometyx
™) was subsequently approved at a dose of 60-mg FBE daily in the USA for the treatment of renal cell carcinoma (RCC) following anti-angiogenic therapy and in the EU following prior VEGF-targeted therapy [
4,
5]. Cabozantinib tablets are also being evaluated in a pivotal clinical study in patients with hepatocellular carcinoma at a 60-mg FBE daily dose [
6].
The cabozantinib tablet formulation (Cabometyx) and capsule formulation (Cometriq) were not bioequivalent following a single 140-mg dose in HVs [
7]; the geometric least-squares mean (GLSM) for maximal plasma concentration (
Cmax) was 19% higher for the tablet formulation and the upper 90% confidence interval for the GLSM ratio for
Cmax (131.65%) slightly exceeded the 125% bioequivalence acceptance limit. However, the GLSM values for tablet and capsule formulations were similar (< 10% difference) for both area under the plasma concentration–time curve (AUC
0−t and AUC
0−∞) measures, and the 90% CIs were 100–115% around the GLSM ratios.
The 140-mg FBE cabozantinib capsule dose used in the pivotal phase III study in patients with MTC was based on the maximally tolerated dose identified in a phase I study of cabozantinib in patients with MTC and other solid tumors [
8]. In the pivotal phase III study, 79% of MTC patients (169 of 214) who received the 140-mg FBE cabozantinib capsule dose eventually dose-reduced [
9]. Two protocol-defined cabozantinib dose reductions were allowed: from 140- to 100-mg/day, and from 100- to 60-mg/day. Forty-two percent of MTC patients received 60-mg/day as their final dose [
10]. Exposure–response (ER) modeling suggested that the cabozantinib dose reductions from 140- to 100-mg and from 100- to 60-mg were not projected to result in a marked reduction in progression free survival (PFS) or in tumor lesion regrowth in patients with MTC [
11,
12].
The 60-mg FBE cabozantinib tablet dose evaluated in the phase III study in patients with RCC was based on findings from a phase I study in patients with RCC of improved tolerance to study drug and evidence of clinical activity in patients who had dose-reduced from 140- to 60-mg [
13]. Dose reductions to a 40- or a 20-mg daily dose were permitted in the pivotal phase III study in RCC patients to maintain treatment in response to drug-related adverse events (AEs). Although lower than the 140-mg capsule dose administered to MTC patients, the 60-mg cabozantinib tablet dose was associated with a high percentage of dose reductions in both the phase III study in RCC patients (62%; 206 of 330) [
14] and in a phase III study in patients with castrate-resistant prostate cancer (CRPC) (74%; 505 of 682) [
15]. ER modeling suggested cabozantinib exposures associated with a simulated 60-mg dose in RCC patients would result in slightly greater decreases in PFS, median percent change of tumor size from baseline, and best overall response rate (based on target lesion) relative to simulated 40- or 20-mg starting doses [
16].
A popPK analysis was previously performed on pooled data for 289 cabozantinib-treated cancer patients (including MTC) receiving daily administration of the cabozantinib capsule formulation at a dose of 140-mg FBE/day, except for five subjects that were dosed at 200-mg FBE/day [
11]. The data were adequately described by a 1-compartment model with first-order absorption and first-order elimination with a small lag time. The mean CL/
F and apparent volume of distribution of the central compartment (Vc/
F) values estimated for a typical White male subject were 4.42 [standard error (SE)%: 2.98%)] L/h and 349 (SE%: 2.73%) L, respectively, resulting in an estimated effective half-life of 55 h. The inter-subject variability (IIV) for CL/
F (CV%) was 35%.
A popPK analysis of cabozantinib was subsequently performed using data collected from 282 patients with RCC and 63 normal HVs following oral administration of doses of 20-, 40-, and 60-mg [
17]. A two-compartment disposition model with dual (fast and slow) lagged first-order absorption processes adequately characterized the concentration–time profile of cabozantinib in HVs and patients with RCC. The mean CL/
F and terminal-phase volume of distribution (
Vz) predicted for a typical White male subject were 2.23 L/h (90% CI 2.13, 2.34) and 319 L (SE%: 2.7%), respectively, resulting in an estimated terminal plasma half-life of approximately 99 h. The IIV for CL/
F was 46%. These popPK modeling analyses indicated that cabozantinib CL/
F was approximately twofold lower in RCC patients than in MTC patients, which is consistent with the comparable observed steady-state exposures (
Ctrough,ss) in RCC and CRPC patients administered a 60-mg tablet dose and in MTC patients administered a 140-mg capsule dose [
16]. Based on these apparent differences in cabozantinib PK observed across cancer patients with different tumor types, an integrated popPK model was developed with the pooled PK data from different patient populations and HVs to evaluate the potential impact of patient population, formulations, and doses on the PK of cabozantinib.
Discussion
Cabozantinib is a TKI approved for the treatment of MTC and RCC [
2‐
5]. Although the formulations and dosages are different for MTC (140-mg/day Cometriq) and RCC (60-mg/day Cabometyx) and dose adjustments and interruptions were allowed in the respective phase III studies, the resultant cabozantinib steady-state exposures in the pivotal phase III studies were comparable for the two patient populations [
16]. Findings from popPK analyses subsequently showed that cabozantinib CL/
F (CV%) in MTC patients [4.4 L/h (35%)] was twofold higher than in RCC patients [2.2 L/h (46%)] [
11,
17], suggesting an apparent difference in cabozantinib clearance in patients with different tumor types.
To examine the extent to which demographic covariates could explain heterogeneity in the PK parameters across cancer populations, an integrated population PK analysis of cabozantinib was conducted using exposure data from HVs and cancer patients with different types of malignancies (ie, MTC, RCC, CRPC, GB). This analysis included data from nine clinical studies (three phase I, two phase II and four phase III) for a total of 8072 cabozantinib concentration records from 1534 subjects. A two-compartment model with first-order elimination and a dual absorption (first-order + zero-order) process adequately described the observed cabozantinib PK data.
The FM model which incorporated demographic covariates (age, body weight, sex, and race) and type of cancer malignancy (RCC, CRPC, MTC, GB, and other malignancies) on cabozantinib CL/F and Vc/F was evaluated. While most covariate effects (including patient demographics) included in the FM model had small-to-moderate effects on cabozantinib PK parameters and exposure metrics, MTC cancer-type led to a > 90% increase in CL/F. Ad hoc analyses showed that the cabozantinib concentrations at day 29 were primarily driving the increase in CL/F in MTC patients in pivotal phase III study XL184-301. MTC patients had lower steady-state plasma concentrations at day 29 than anticipated for the given dose relative to patients with other cancer types or HVs and suggested that lower observed accumulation could be due to higher clearance in this patient population. Possible reasons for the large increase in cabozantinib clearance at steady state for MTC patients evident in the integrated popPK analysis were explored, including differences in treatment-emergent AEs, concomitant medications, and administered cabozantinib dose.
Diarrhea is a common treatment-related AE in cancer patients receiving cabozantinib [
8,
9,
13‐
15], and the 140-mg dose administered to MTC patients may be anticipated to result in a higher incidence and/or severity of diarrhea than a 60-mg dose given to RCC and CRPC subjects. As cabozantinib is considered to undergo enterohepatic recirculation [
21], a decrease in the absorption fraction of cabozantinib typically reabsorbed via enterohepatic reabsorption due to treatment-related diarrhea may result in an apparent increase in cabozantinib clearance. The severity of diarrhea and possible effect on clearance would be anticipated to be greater in MTC patients administered a higher cabozantinib dose (140-mg) than that given to patients with other tumor types (60-mg). However, there was no marked difference in Grade 3/4 diarrhea in the subjects enrolled in the cabozantinib arm of the pivotal MTC study administered a 140-mg dose [16% (34 of 214); [
9]] and in the cabozantinib arm of the pivotal RCC study administered a 60-mg dose [13% (43 of 311); [
14]].
In a separate popPK analysis [
26], MTC patients were reported to have higher (67% greater) oral clearance for another TKI (motesanib) relative to patients with differentiated thyroid cancer (DTC), in conjunction with a higher baseline incidence rate of diarrhea (68 and 6% in MTC and DTC cohorts, respectively). Similar to cabozantinib, patients’ disease type best accounted for inter-patient variability in motesanib CL/
F of all covariates tested. However, incorporating diarrhea into the popPK model did not result in a significant improvement in the model fit, after accounting for the patients’ disease type, and there was no difference in motesanib CL/
F among MTC patients with severe, moderate, and mild diarrhea. In addition, both the motesantib and cabozantinib popPK analyses showed a minimal effect on Vc/
F in MTC patients, whereas a reduction in oral bioavailability due to diarrhea would be expected to result in increases in both CL/
F and Vc/
F. The mechanistic basis for the difference in motesanib CL/
F between DTC and MTC patients was not identified.
Increased cabozantinib clearance in MTC patients at steady state could be related to treatment-emergent hypocalcemia, particularly in advanced MTC patients who undergo thyroidectomy when the parathyroid glands are also partially or completely removed resulting in decreased plasma parathyroid hormone levels. Hypocalcemia may affect drug clearance indirectly via stimulation of active vitamin D metabolite 1,25 dihydroxyvitamin D
3 (1,25(OH)
2D
3) synthesis, and subsequent induction of CYP3A4 by 1α,25(OH)
2D
3 [
27,
28]. Since cabozantinib is metabolized by CYP3A4 [
29], hypocalcemia was considered as a potential contributing factor in reducing cabozantinib clearance in MTC patients. Although clinical laboratory-defined hypocalcemia was identified in 52% of MTC patients receiving cabozantinib in the pivotal phase III study XL184-301 [
2], and in fewer MTC patients receiving placebo in the same study (27%), overall no evidence of altered calcium levels was noted in patients with MTC compared to other cancers to suggest that hypocalcemia was responsible for increased cabozantinib clearance in this population.
Differences in concomitant medication use, particularly administration of strong CYP3A4 inducers in MTC patients, could have resulted in the increased cabozantinib clearance observed in the MTC patient population. However, only 1.4% of patients (3 of 207 total) were reported to have used a concomitant strong CYP3A4 inducer in the MTC phase III study of cabozantinib [
11]. Cabozantinib is also a substrate of efflux transporter MRP2 [
25], so concomitant administration of an MRP2 inducer could potentially increase cabozantinib clearance by enhancing hepatic and/or intestinal drug MRP2-mediated transport activity. Although overall use of concomitant MRP2 inducers was not documented for MTC patients in study XL184-301, only 5.5% of MTC subjects (12 of 219) administered cabozantinib were reported to have received MRP2 inducer (and moderate CYP3A4 inducer) dexamethasone.
Cabozantinib plasma clearance (CL/
F) may also appear to be higher if oral bioavailability (
F) decreased with increasing cabozantinib dose. The approved cabozantinib dose for MTC patients (140-mg) is higher than the dose approved for RCC patients and dose generally administered to non-MTC patient populations (60-mg), and steady-state CL/
F in the MTC popPK analysis (4.4 L/h) was higher than that determined in the RCC popPK analysis (2.2 L/h). However, no decrease in cabozantinib oral bioavailability was evident in a cross-study analysis indicating generally dose-linear PK for tablet and capsule formulations over a broad dose range (20–140 mg) [
25]. In addition, lower cabozantinib exposures associated with higher relative CL/
F in MTC patients were only observed at steady state (day 29) and not at day 1.
Alternatively, estimates of CL/
F values from MTC subjects that tolerate a 140-mg daily cabozantinib dose may be higher than the overall study population if they reflect a sub-population that tolerates this higher dose at steady state based on a faster relative intrinsic clearance. In the MTC popPK analysis, high drop-out rate or early discontinuation was also considered to possibly explain the lower day 29 concentrations in MTC patients relative to HVs [
11]. If subjects with low clearance and higher exposures dropped out or discontinued the study early due to treatment-emergent AEs, only those subjects with higher clearances resulting in lower, more tolerable exposures would remain. This scenario is unlikely considering 79% of the patients in the MTC popPK analysis contributed PK samples on both days 1 and 29.
Finally, a more detailed PK sampling of the terminal elimination phase was included in the RCC popPK analysis (up to 504-h post-dose in HVs) than in the MTC popPK analysis where the final PK sample was taken at approximately 24-h post-dose. As cabozantinib has a relatively long plasma terminal half-life (HV mean: 118 h [
25]), plasma clearance could have been underestimated in the MTC popPK analysis based on a more limited PK data collection of terminal elimination phase. However, the integrated popPK model developed subsequently included exposure data from patients with different tumor types and HVs; the addition of all covariates, including demographic (age, weight sex, and race) and population (RCC, CRPC, MTC, GB, and advanced malignancies) on both CL/
F and Vc/
F resulted in an adequate fit to the data. The magnitude of most demographic and population-specific covariate effects on cabozantinib PK was small, except for MTC patient population who had a substantially larger estimated cabozantinib CL/
F. Thus, model-related and PK sampling differences do not appear to underlie the higher CL/
F values in MTC patients evident at steady state.