Regulatory Decision Summary for Cabometyx

This Supplement to a New Drug Submission (SNDS) was filed to expand the Cabometyx (cabozantinib) indication to include adult patients who have received prior therapy versus the previous indication that included only those who have received prior vascular endothelial growth factor (VEGF)-targeted therapy.

In this submission, the results of two real world evidence (RWE) studies along with sub-group analyses from the previously reviewed Phase III Study (METEOR), served as the basis for the evaluation of cabozantinib in this treatment setting.

A two-arm retrospective, observational cohort Study CLIN-60000-455 ONTADA (n = 485) using United States Oncology Network electronic health record (EHR) data compared real-world treatment outcomes of cabozantinib with those treated with other VEGF-targeted tyrosine kinase inhibitors (TKIs) (e.g. sunitinib, pazopanib and axitinib) in patients with advanced and/or metastatic renal cell carcinoma (a/mRCC) progressing on prior immune checkpoint inhibitor (CPI) therapy. The RWE data revealed that in the routine care for a/mRCC 68.2% of participants in the study received cabozantinib compared to 31.8% who received other TKIs in the post CPI treatment.

The RWE cabozantinib data demonstrated improvements in the effectiveness parameters, including 6-month and objective response rates, when compared with other TKIs: Inverse Probability of Treatment Weighting (IPTW)-adjusted real world Objective Response Rate (rwORR): 62.4% for cabozantinib versus 49.4% for non-cabozantinib TKIs.

A higher percentage of participants receiving cabozantinib than non-cabozantinib TKIs demonstrated partial (61.1% versus 46.0%) and complete responses (1.3% versus 0%). Participants receiving cabozantinib also had a significantly longer time to drug discontinuation (TTD) compared to those receiving other TKIs (adjusted median TTD: cabozantinib, 6.9 months; non-cabozantinib TKI, 4.0 months; Hazard Ratio (HR): 0.7 (95% confidence interval [CI]: 0.6, 0.8); log-rank p = 0.0005).

The median adjusted real-world Progression Free Survival (rwPFS) for those who received cabozantinib was 7.9 months (95% CI: 6.7, 9.9), and was not statistically different from those who received non-cabozantinib TKI treatment with a median of 9.2 months (95% CI: 6.8, 12.2) and HR of 1.0 (95% CI: 0.8, 1.2) and log-rank p = 0.8751.

The median adjusted overall survival (OS) for participants receiving cabozantinib was not significantly different from those receiving non-cabozantinib TKI (19.2 months [95% CI: 15.9, 20.7] vs. 19.1 months [95% CI: 13.9, 25.9]; log-rank p-value = 0.7353).

The overall limitations of the study included missing data, a smaller than anticipated sample size, an imbalance between cohorts, and data were not collected for research purposes.

This RWE suggested that more patients received cabozantinib (as compared to other TKIs) for mRCC after having progressed on prior CPI. There was limited information on the comparative effectiveness of those regimens.

Study CLIN-60000-453 CABOSEQ was a retrospective, observational cohort study of mRCC patients included in the International mRCC Database Consortium (IMDC). Patients initiated 2L cabozantinib or sunitinib after progressing on 1L Ipi+Nivo. This study was designed and analyzed in accordance with the target trial emulation framework. Study endpoints were pre-specified in the protocol: OS and time to treatment failure (TTF) were the primary endpoints, with ORR as a secondary endpoint.

The results from 120 and 121 patients who received cabozantinib or sunitinib after 1L Ipi+Nivo, respectively are summarised below:

Median TTF was 8.5 months (95% CI: 6.9-12.9) for cabozantinib and 4.5 months (95% CI: 3.7-5.8) for sunitinib; unadjusted median OS was 21.4 months (95% CI: 17.9-NA) from initiation of cabozantinib and 10.1 months (95% CI: 7.6-17.7) for sunitinib; and adjusted HR for OS between cabozantinib versus sunitinib was 0.44 (95% CI: 0.22-0.86).

It is recognised that despite adjustments for the key variables, the RWE data were still prone to unobservable differences, potentially not accounted for in the analysis. The primary limitation of the study was a potential bias due to residual confounding.

Overall, the positive treatment effect of Cabometyx observed in the RWE studies, combined with the results of the subgroup analysis in the previously conducted METEOR Study (that showed efficacy gains in the small subgroup of patients who received prior CPI), the efficacy of Cabometyx in patients who received prior CPI can be supported. This is also in line with the United States Food and Drug Administratin (FDA) approved expanded indication for Cabometyx for patients with advanced renal cell carcinoma irrespective of the line of treatment or previous 1L therapy (either VGFR-I or CPI).

The cabozantinib safety profile was based on the previously conducted clinical studies such as Study XL184-308 (METEOR) and Study A031203 (CABOSUN) and post-marketing real world data.

The most frequent adverse events (AE) associated with cabozantinib typically include diarrhea, fatigue, nausea, decreased appetite, palmar-plantar erythrodysesthesia syndrome (PPES), hypertension, vomiting, decreased weight, constipation, dysgeusia, stomatitis, hypothyroidism, and dysphonia.

The most frequent serious AEs include abdominal pain, pleural effusion, diarrhea, nausea, anemia, back pain, dyspnea, fatigue, pneumonia, pulmonary embolism, vomiting, and pain. Less frequent, but medically important AEs, such as gastrointestinal (GI) perorations, fistulas, hemorrhages, venous and arterial thrombosis, proteinuria, and wound complications may also be observed. No new safety signals were identified.

The Risk Management Plan (RMP) is acceptable and no follow-up is required.

It is concluded that the effectiveness of cabozantinib observed in the RWE datasets, combined with the results of the subgroup analysis in the METEOR Study provides sufficient evidence for Cabometyx to be considered a treatment option for mRCC patients after the 1L therapies (irrespective of whether the 1L regimen included a VEGF targeted therapy or CPI).

The product monograph (PM) of Cabometyx was revised to reflect this expanded Cabometyx indication (i.e., for the treatment of adult patients with advanced Renal Cell Carcinoma (RCC) who have received prior therapy).

The cabozantinib benefit/risk profile remains positive with the expanded indication.

For further details about Cabometyx, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.