EXAM

Background

Phase III double-blind RCT (EXAM). N=330 patients with documented radiographic progression of metastatic medullary thyroid cancer (MTC), ECOG PS 0–2. Enrolled 2008–2011 at 147 global sites. Randomized 2:1 (cabozantinib:placebo). Cabozantinib is an oral multikinase inhibitor targeting MET, VEGFR2, and RET — the oncogenic driver in hereditary and ~50% of sporadic MTC. First phase III trial to demonstrate PFS benefit in progressive MTC.

Interventions and follow up

Arm A: Cabozantinib 140 mg oral daily until PD or unacceptable toxicity
Arm B: Placebo
Primary endpoint: PFS
mFollow up: Not specified (event-driven)

Results

mPFS: 11.2 months (cabozantinib) vs 4.0 months (placebo), HR 0.28 (95% CI 0.19–0.40), P<.001
ORR: 28% vs 0%
1-year PFS rate: 47.3% vs 7.2%
OS: Trend favoring cabozantinib in RET M918T-mutant subgroup but not in overall population

Adverse events

Main adverse events: Most common grade 3–4: diarrhea 16%, palmar-plantar erythrodysesthesia 13%, fatigue 9%, hypertension 8%, weight loss. Dose reductions required in 79% of cabozantinib patients; treatment holds in 65%; discontinuation for AEs in 16%. Toxicity profile is substantial at 140 mg.

Conclusions

Cabozantinib dramatically improved PFS (HR 0.28, median 11.2 vs 4.0 months) and achieved a 28% ORR in progressive MTC regardless of RET mutation status. EXAM led to FDA approval of cabozantinib for progressive MTC in 2012, establishing it as a standard treatment option alongside vandetanib.

Key Limitations

Key Limitations: No OS benefit demonstrated in the overall population. At 140 mg daily, cabozantinib has a high dose-reduction rate (79%) and significant toxicity burden; the approved dose in MTC (140 mg) is higher than the 60 mg dose used in other indications. OS benefit was suggested only in the RET M918T-mutant subgroup (sporadic MTC). Vandetanib (ZETA trial) provided comparable PFS benefit. RET-selective inhibitors (selpercatinib, pralsetinib) now show superior ORR (>69%) with less toxicity in RET-mutant MTC.

Clinical Context

FDA approved cabozantinib 140 mg for progressive, metastatic MTC in November 2012. Alongside vandetanib (ZETA), cabozantinib was the standard for progressive MTC until the selective RET inhibitors emerged. NCCN now recommends selpercatinib or pralsetinib as preferred first-line therapy for RET-mutant MTC due to superior ORR and tolerability. Cabozantinib (140 mg) and vandetanib remain standard options for RET-wild-type or RET-unknown MTC, or when RET inhibitors are unavailable.

References

References: Elisei R et al, JCO 2013 (primary)