DOSING ANE TOXICITY
Initial studies showed that cabozantinib inhibits tumor growth in a dose-dependent manner, and dose escalation was evaluated. The maximum tolerated dose in the Phase I study specifically in medullary thyroid cancer patients was 175 mg daily with dose-limiting grade 3 or worse toxicities including fatigue (10%), elevation of lipase (9%), and amylase (5%), as well as diarrhea, weight loss, and transaminitis. For medullary thyroid cancer, a dose of 140 mg daily was chosen for the registration trial and became the FDA-approved dose for this indication.
A follow-up Phase III trial, EXAM, demonstrated substantial PFS prolongation with cabozantinib vs placebo in patients with medullary thyroid cancer. A total of 330 patients were administered cabozantinib in a 2:1 ratio either in 140 mg base form (219 patients) or placebo (111 patients). The most common grade 3/4 adverse events were diarrhea (cabozantinib 15.9% vs placebo 1.8%), hand–foot syndrome (cabozantinib 12.6% vs placebo 0%), fatigue (cabozantinib 9.3% vs placebo 2.8%), hypocalcemia (cabozantinib 9.3% vs placebo 0%), and hypertension (cabozantinib 7.9% vs placebo 0%). Notably, dose reductions occurred in 79% of patients and dose interruptions occurred in 65% patients in the cabozantinib arm. As a result of adverse events, 16% of patients treated with cabozantinib had the drug discontinued.59 The need for monitoring the adverse events on cabozantinib is supported by a recent meta-analysis of 22 publications looking at response and toxicity of TKIs in patients with thyroid carcinoma. In this meta-analysis, cabozantinib at 140 mg was found to be associated with the highest percentage of dose reductions and/or discontinuation among TKIs.60
Based on dosing used to treat medullary thyroid cancer, a Phase I trial on RCC was conducted with a dose of 140 mg of cabozantinib daily. The trial showed encouraging efficacy but considerable toxicity as previously mentioned. Comparable to the medullary thyroid cancer studies, treatment discontinuation occurred in 24% of patients due to adverse events. Dose reductions occurred in 80% of patients. The median average daily dose was 75.5 mg cabozantinib (range, 43.8–137.5 mg), and the median dose intensity percentage was 53.9% (range, 31.3%–98.2%).53
Due to the high toxicities seen in the 140 mg dose of cabozantinib, subsequent Phase II trials were conducted on lower doses of cabozantinib in other tumor types, including metastatic prostate cancer. In a Phase II randomized discontinuation study, 171 patients with metastatic castrate-resistant prostate cancer received cabozantinib 100 mg daily: 68% of them had partial or complete resolution of bone scans and 67% of patients with pain at baseline reported a decrease in pain. However, by week 12, dose reductions occurred in 51% of patients, with 12% discontinuing treatment due to adverse events. The most common grade 3 toxicities were fatigue, hypertension, and hand–foot syndrome. The most common serious adverse event was pulmonary embolism (6%).61 A follow-up study with 144 patients with metastatic prostate cancer investigated cabozantinib at daily starting doses of 100 vs 40 mg until disease progression or unacceptable toxicity. Though there was bone scan response and clinically meaningful pain relief in the majority of patients, in the 100 mg cohort, 84% of patients had at least one dose reduction and 25% discontinued treatment because of an adverse event. In the 40 mg cohort, 31% of patients had at least one dose reduction because of an adverse event and 18% of them discontinued treatment. Interestingly, the median average daily dose received in the 100 mg and 40 mg cohorts was 55 and 36 mg/d, respectively. As a result, the starting doses of ≤100 mg were thought to be advisable for follow-up studies due to tolerability concerns while having equivalent efficacy as the true difference in actual dose administered between the cohorts was not large.62
Subsequent studies in prostate cancer, the COMET program, utilized 60 mg as the starting dose. Phase II studies conducted on lower doses of 60 and 40 mg of cabozantinib resulted in less adverse events and continued clinical efficacy.63 COMET 1 and 2 were randomized, double blind, controlled trials completed for metastatic castrate-resistant prostate cancer at a starting dose of cabozantinib of 60 mg daily. Sixty percent of patients who received cabozantinib experienced at least one dose reduction.56 COMET 2 compared cabozantinib with mitoxantrone and prednisone (MP): 55% of the patients receiving cabozantinib experienced at least one dose reduction compared to 14% of the patients receiving MP. Seventy percent of the patients in the cabozantinib group had a grade 3/4 adverse event. However, fewer patients discontinued study treatment for adverse events in the cabozantinib arm (16% vs 26% for MP).57
In the METEOR trial, the 60 mg cabozantinib dose was used as the starting dose; notably dose reductions were still required in 60% of patients in the cabozantinib arm, most commonly due to diarrhea, plantar palmar dysesthesia, hypertension, and fatigue. The median average daily dose was 44 mg for cabozantinib and 9 mg for everolimus. Serious adverse events occurred equally in both the cabozantinib and everolimus groups (40% and 43%, respectively). Treatment discontinuation because of an adverse event not related to disease progression was recorded in 40 (12%) of 331 patients in the cabozantinib group and 34 (11%) of 322 patients in the everolimus group (Table 1). Death considered related to study treatment occurred in one patient in the cabozantinib group (death not otherwise specified) and in two patients in the everolimus group (aspergillosis and aspiration pneumonia).58
(To view a larger version of Table 1, click here.)
Importantly, cabozantinib at lower doses continues to have clinical efficacy, especially in medullary thyroid cancer and RCC with much improved tolerability. Previous meta-analysis showing cabozantinib to have a highest percentage of discontinuation among TKIs was studied with a starting dose of 140 mg much higher than the approved 60 mg dose in RCC.60 When comparing across trials, the 60 mg dose has a similar discontinuation rate to sorafinib, which is lower than other TKIs (Table 2). The median average daily dose in the METEOR trial was 43 mg for cabozantinib and suggests that the toxicity threshold may be slightly >40 mg rather than the starting dose of 60 mg. Analysis of the CABOSUN study, where cabozantinib is being compared with sunitinib for previously untreated patients with advanced intermediate- or poor-risk RCC renal cancer, will provide more data on comparative toxicity and tolerability and also raise the possibility of its use as a first-line drug.64 This trial and other ongoing trials are summarized in Table 3.
(To view a larger version of Table 2, click here.)
(To view a larger version of Table 3, click here.)