Cabozantinib – a new option for medullary thyroid patients with progressive disease
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| Jun 4, 2012
Cabozantinib (XL184, Exelixis) is an inhibitor of multiple receptor tyrosine kinases (RTKs), including RET, c-MET and VEGFR2. Mutations in the RET proto-oncogene play an important role in the development of medullary thyroid cancer (MTC), and cabozantinib has shown activity against the common mutant forms of RET and MET. In June 2008, Exelixis initiated a pivotal Phase III EXAM study to confirm the activity of cabozantinib observed in an earlier Phase I trial. The EXAM study evaluated cabozantinib monotherapy versus placebo in patients with unresectable, locally advanced or metastatic MTC with documented RECIST progression within 14 months of screening as determined by an independent radiology committee (IRC). In October 2011, the company announced via a press release that the drug improved progression-free survival (PFS) in the EXAM trial. Based on the positive data, a New Drug Application (NDA) was submitted to the U.S. regulatory agency in May 2012. The full data from the EXAM trial were presented this morning at the Targeting Therapeutics for Thyroid Cancers oral session (Abstract 5508).
Baseline patient characteristics showed that prior systemic therapy was administered in 37% of enrolled patients on the cabozantinib arm (20% of whom had received a TKI, and 46% were positive for RET mutation) and 42% of patients on the placebo arm (of whom 22% had received a TKI, and 52% were positive for RET mutation). Cabozantinib improved PFS from 4.0 months for placebo to 11.2 months (HR 0.28, p < 0.0001), 1-year PFS from 7.2% to 47.3%, and objective response rate (ORR) from 0% to 28% (p<0.0001), respectively. Median duration of response was 14.6 months. Patients previously treated with other targeted agents such as Caprelsa® (vandetanib, AstraZeneca), a RET / VEGFR2 / EGFR TKI also indicated for MTC, also benefited. Interim overall survival data was not mature at the time of presentation, and final analysis will be conducted after 217 events. However, no difference in overall survival was observed at the time of interim analysis conducted in June 2011. A biomarker analysis showed a correlation between changes in serum calcitonin (and CEA) and target lesions.
In terms of safety, common Grade 3 toxicities in the cabozantinib versus placebo arm included diarrhea (16% vs 2%), hand foot skin reaction (13% vs 0%) and fatigue (9% vs 3%). Death for reasons other than progressive disease occurred in 5.6% patients on the cabozantinib arm (of which 1.9% were from causes typically associated with VEGF inhibition versus 2.8% in the placebo arm). No data was reported on the percentage of patients who required dose reductions.
With the positive data, cabozantinib will clearly represent a new treatment option for MTC patients when it gets approved. But how will it be used by physicians? Will it compete with Caprelsa which earned its MTC regulatory approval in the U.S. in 2011 based on the results of ZETA Phase III trial, or will it be used after patients progress on Caprelsa?
In the ZETA trial, Caprelsa improved PFS from 19.3 months for the placebo arm to 30.5 months. The difficulty in making the comparison of cabozantinib versus Caprelsa is that the control arms performed so differently (4.0 months in the EXAM trial compared to 19 months in the ZETA trial). Clearly, the patient characteristics were very different. Unlike Caprelsa, the EXAM trial enrolled patients with documented worsening of disease at screening compared with a previous CT scan or MRI done within 14 months of screening. The presence of progressive disease would explain why the PFS was so short for these patients. This patient population was not previously evaluated in a Phase III trial, and it is unclear whether the strategy of Exelixis was to get an approval in a patient population with a high unmet need or to create a new patient segment that would help them differentiate from Caprelsa competition. Given such specific inclusion criteria of progressive disease, it will be interesting to see whether physicians will choose to utilize cabozantinib before Caprelsa or after patients progress on Caprelsa. Even if relegated to post-Caprelsa setting, the good news for cabozantinib is that it showed activity in patients previously treated with a TKI (which included sunitinib or Caprelsa), although the magnitude of the benefit is currently unknown as no data was presented specifically for the Caprelsa-treated patient population.
Tolerability will also likely come into play when choosing between Caprelsa and cabozantinib, although the toxicity profiles appear fairly similar. Regardless of how physicians will choose to adopt and utilize these two agents in MTC, cabozantinib did demonstrate efficacy in a patient population with rapidly progressing disease and limited treatment options, and will undoubtedly enjoy adoption into clinical practice.