FDA Approved Uses of Cabozantinib

Metastatic medullary thyroid carcinoma with signifi cant amyloid stroma

The Food and Drug Administration (FDA) recently approved cabozantinib for the treatment of hepatocellular carcinoma in patients who previously received sorafenib.

Cabozantinib (Cometriq [capsule] or Cabometyx [tablet]) is an oral tyrosine kinases inhibitor of MET, VEGFR, and AXL.[1] Receptor tyrosine kinases play important roles in both normal cellular function and pathologic processes, including oncogenesis, metastasis, tumor angiogenesis, and tumor microenvironment maintenance.[2]

The FDA first approved cabozantinib for treatment of medullary thyroid cancer. Later, the FDA approved its use in renal cell carcinoma.

Medullary Thyroid Cancer

The FDA approved cabozantinib (Cometriq) to treat metastatic medullary thyroid cancer (MTC) in November 2012. It was based on results from an international, multicenter, randomized, double-blind, controlled trial including 330 subjects. Participants needed to exhibit progressive disease within 14 months before study entry, which was confirmed via an independent radiology review committee or the treating physician.

Patients were randomized to receive either cabozantinib 140 mg or placebo orally once daily until progressive disease or intolerable toxicity. Randomization was stratified according to age < 65 years vs > 65 years and previous utilization of a tyrosine kinase inhibitor.

Primary endpoints were progression-free survival (PFS), objective response (OR), and response duration employing modified RECIST criteria. Patients in the cabozantinib group had prolonged PFS compared to those receiving placebo (P < .0001). Specifically, median PFS in the cabozantinib arm was 11.2 months and median PFS in the placebo arm was 4.0 months.

Only patients taking cabozantinib experienced a partial response (27% vs 0; P < .0001). Furthermore, the median duration of OR was 14.7 months for those treated with the drug. No significant differences in overall survival were observed between arms.[2]

In a 2019 meta- and economic analysis evaluating the utility of cabozantinib and vandetanib in patients of England’s National Health Service, Tappenden et al. concluded:[3]

“The identified trials suggest that cabozantinib and vandetanib improve PFS more than the placebo; however, significant OS benefits were not demonstrated. The economic analyses indicate that within the EU-label population, the ICERs [incremental cost-effectiveness ratios] for cabozantinib and vandetanib are > £138,000 per QALY (quality-adjusted life year) gained. Within the restricted EU (European Union)-label population, the ICER for vandetanib is expected to be > £66,000 per QALY gained.”

Advanced Renal Cell Carcinoma With History of Anti-Angiogenic Therapy

In April 2016, the FDA approved cabozantinib tablets for the treatment of patients with advanced renal cell carcinoma (RCC) who had received previous anti-angiogenic therapy. This approval came on the heels of the drug receiving Fast Track and Breakthrough Therapy designations by the FDA.

At the time, Toni Choueiri, MD, Clinical Director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute and lead author of the METEOR trial, stated that “The efficacy profile demonstrated by Cabometyx in the METEOR trial, now complemented by the overall survival benefit, is highly compelling. Cabometyx is distinct from other approved treatment options, as it targets multiple tyrosine kinases involved in the development of RCC, including MET, AXL and three VEGF receptors. At the same time, physicians are very familiar with this class of drug and how to use dose adjustments to balance safety and efficacy. The approval of Cabometyx is wonderful news for physicians who are looking for a new option for their previously treated patients with advanced kidney cancer.”[4]

METEOR[1] was an open-label, randomized phase 3 trial, in which patients ≥ 18 years were randomly assigned (1:1) to receive 60 mg cabozantinib daily (n=330) or 10 mg everolimus (Afinitor) daily (n=328). Participants had advanced or metastatic clear-cell RCC, harbored measurable disease, and were previously treated with one or more VEGFR tyrosine-kinase inhibitors.

The primary outcome was PFS assessed by an independent radiology review committee, and secondary outcomes included OS and objective response. Safety measures were analyzed in all patients who received at least one dose of study drug.

Median duration of follow-up for OS and safety in participants taking cabozantinib was 18.7 months (IQR 16.1–21.1) vs 18.8 months (16.0–21.2) in those taking everolimus. Median OS in patients taking cabozantinib was 21.4 months (95% confidence interval [CI], 18.7–not estimable) vs 16.5 months (14.7–18.8) in those taking everolimus (hazard ratio [HR] 0.66 [95% CI 0.53–0.83]; P = .00026). Cabozantinib treatment was associated with improved PFS (HR 0.51 [95% CI 0.41–0.62]; P < .0001) and objective response (17% [13–22] with cabozantinib vs 3% [2–6] with everolimus; P < .0001) per independent review.

The most frequent grade 3 or 4 adverse events in the study were hypertension, diarrhea, fatigue, palmar-plantar erythrodysesthesia, anemia, hyperglycemia, and hypomagnesemia. Severe adverse events (grade 3 or more) were observed in 130 patients (39%) taking cabozantinib vs 129 patients (40%) taking everolimus. One treatment-related death was observed in the cabozantinib group and two were observed in the everolimus group.

“The improvements in progression-free survival, overall survival, and objective response suggest that cabozantinib should be considered as a new treatment for previously treated patients with advanced renal cell carcinoma,” the authors concluded. “Recently, the immune checkpoint inhibitor nivolumab also improved overall survival compared with everolimus in this population, but without improving progression-free survival.”[1]

Advanced RCC

In December 2017, the FDA approved cabozantinib tablets for first-line treatment of advanced RCC based on results of the CABOSUN trial. In CABOSUN, cabozantinib use was associated with extended PFS and improved objective response rate (ORR) compared with sunitinib in patients judged intermediate or poor risk per International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria.

In total, 157 patients aged ≥ 18 years without prior systemic treatment were randomized 1:1 to cabozantinib (n=79) 60 mg orally daily or sunitinib (n=78) 50 mg orally daily for 4 weeks followed by 2 weeks off; treatment continued until disease progression or intolerable toxicity. Patients were stratified per IMDC risk group and bone metastases. PFS and objective response rate (ORR) were assessed using subgroups of baseline characteristics and determined by an independent radiology committee

In general, cabozantinib treatment was related to better PFS and ORR compared with sunitinib across subgroups (eg, defined by IMDC risk, bone metastases, age, and tumor burden). Estimated median PFS for patients taking cabozantinib was 8.6 months (95% CI, 6.8- 14.0) vs 5.3 months (95% CI, 3.0, 8.2) for patients administered sunitinib (HR 0.48; 95% CI, 0.31, 0.74; P = .0008).

The most common grade 3-4 adverse reactions (≥ 5%) in those taking cabozantinib were hypertension, diarrhea, hyponatremia, hypophosphatemia, palmar-plantar erythrodysesthesia, fatigue, increased ALT, decreased appetite, stomatitis, pain, hypotension, and syncope.[5,6]

“The treatment landscape for first-line RCC is rapidly evolving, with approval of the combination of nivolumab and ipilimumab for patients with advanced RCC of intermediate or poor IMDC risk and ongoing trials of VEGF pathway and checkpoint inhibitor combinations,” wrote George et al., authors of the CABOSUN trial.

Although results of the trial were intended to be hypothesis-generating, the authors noted that “the positive MET status may be associated with a greater treatment benefit with cabozantinib versus sunitinib, although patients benefited with cabozantinib irrespective of MET status.”[6]

Hepatocellular Carcinoma

In January 2019, the FDA approved cabozantinib tablets for patients with hepatocellular carcinoma (HCC) previously treated with sorafenib. The approval was based on results from the CELESTIAL trial.

In the randomized (2:1), double-blind, placebo-controlled, multicenter trial, patients were randomized to cabozantinib 60 mg orally once daily (n=470) or placebo (n=237) until the time of disease progression or unacceptable toxicity.

The primary endpoint was OS. PFS and ORR , assessed by investigators using RECIST 1.1, were also measured. Cabozantinib use was associated with a median OS of 10.2 months (95% CI: 9.1-12.0) vs 8 months (95% CI: 6.8-9.4) for those receiving placebo (HR 0.76; 95% CI: 0.63, 0.92; P = .0049). Median PFS was 5.2 months (4.0-5.5) in the cabozantinib arm compared with 1.9 months (1.9-1.9) in the placebo arm (HR 0.44; 95% CI, 0.36, 0.52; P < .001). The ORR was 4% (95% CI, 2.3, 6.0) in those taking cabozantinib vs 0.4% (95% CI, 0.0, 2.3) in those taking placebo.[7]

Grade 3 or 4 adverse events were higher in patients taking cabozantinib (68%) than in those taking placebo (36%).

Authors of the CELESTIAL trial concluded with the following: “Among patients with previously treated advanced hepatocellular carcinoma, treatment with cabozantinib resulted in longer overall survival and progression-free survival than placebo. The rate of high-grade adverse events in the cabozantinib group was approximately twice that observed in the placebo group.”[8]

Disclosures:

References:

1. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2016;17: 917–27.

2.srtrong CenterWatch. Cometriq (cabozantinib). Available at: https://www.centerwatch.com/drug-information/fda-approved-drugs/drug/1237/cometriq-cabozantinib/?mp Accessed August 28, 2019.

3. Tappenden P, Carroll C, Hamilton J, et al. Cabozantinib and vandetanib for unresectable locally advanced or metastatic medullary thyroid cancer: a systematic review and economic model. Health Technol Assess. 2019;23:1-144.

4. Exelixis. Press release. Exelixis Announces FDA Approval of CABOMETYX™ (Cabozantinib) Tablets for Patients with Advanced Renal Cell Carcinoma Who Have Received Prior Anti-Angiogenic Therapy. Available at: https://ir.exelixis.com/news-releases/news-release-details/exelixis-announces-fda-approval-cabometyxtm-cabozantinib-tablets Accessed August 28, 2019.

5. US Food and Drug Administration. FDA grants regular approval to Cabometyx for first-line treatment of advanced renal cell carcinoma. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-cabometyx-first-line-treatment-advanced-renal-cell-carcinoma Accessed August 28, 2019.

6. George DJ, Hessel C, Halabi S, et al. Cabozantinib versus sunitinib for untreated patients with advanced renal cell carcinoma of intermediate or poor risk: subgroup analysis of the Alliance A031203 CABOSUN trial. Oncologist. 2019;24:1–5.

7. US Food and Drug Administration. FDA approves cabozantinib for hepatocellular carcinoma. Available at: https://www.fda.gov/drugs/fda-approves-cabozantinib-hepatocellular-carcinoma Accessed August 28, 2019.

8. Abou-Alfa GK, Meyer T, Cheng AL, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018;379:54-63.