PAPMET

Background

Phase II, open-label, randomized multi-arm trial. 152 patients with advanced papillary RCC (type 1 or 2, with or without MET alterations). Four arms: cabozantinib vs sunitinib vs crizotinib vs savolitinib (MET-selective). The largest prospective RCT specifically addressing treatment of papillary RCC, a non-clear cell histology without approved targeted therapy at the time.

Interventions and follow up

Arm A: Cabozantinib 60mg/day orally (multi-kinase VEGFR/MET/AXL/RET inhibitor)
Arm B: Sunitinib 50mg/day (4 wks on / 2 wks off) orally
Arm C: Crizotinib 250mg twice daily (MET/ALK inhibitor)
Arm D: Savolitinib 600mg/day (MET-selective inhibitor)
Primary endpoint: PFS (cabozantinib vs sunitinib primary comparison)
mFollow up: 14.9 mo

Results

PFS (cabozantinib vs sunitinib): 9.0 vs 5.6 mo, HR 0.60, P=.019
ORR (cabozantinib): 23% vs 4% (sunitinib)
PFS (savolitinib vs sunitinib): 7.0 vs 5.6 mo, HR 0.71 — not significant
PFS (crizotinib vs sunitinib): HR 0.83 — not significant

Adverse events

Overall grade ≥3: cabozantinib 68% vs sunitinib 58%
Cardiovascular: hypertension (Cabo 26%)
GI: diarrhea grade ≥3 (Cabo 12%)
Dermatologic: hand-foot skin reaction (Cabo 15%)
Constitutional: fatigue grade ≥3 (Cabo 8%)
Discontinuation due to AEs: Cabo 32%, Sunitinib 18%

Conclusions

Cabozantinib significantly improved PFS over sunitinib in advanced papillary RCC, establishing cabozantinib as the preferred VEGF-TKI in this non-clear cell histology. MET-selective agents (savolitinib, crizotinib) did not significantly outperform sunitinib in unselected papillary RCC, though MET-driven cases may still benefit from targeted MET inhibition.

Key Limitations

Key Limitations: Phase II design with modest sample size limits statistical power for OS and subgroup analyses. MET alteration status (amplification, mutation) was not a pre-specified selection criterion — MET-selective agents may have outperformed in MET-driven tumors. Papillary RCC is heterogeneous (Type 1: MET-driven, indolent; Type 2: FH-mutated, aggressive) and outcomes differed by subtype. Updated guidelines now recommend MET testing and immunotherapy (pembrolizumab + lenvatinib from KEYNOTE-B61) rather than sunitinib as first-line alternatives.

Clinical Context

PAPMET established cabozantinib as the preferred TKI in papillary RCC, and it remains widely used. However, the treatment landscape has evolved: pembrolizumab + lenvatinib (KEYNOTE-B61, single-arm phase 2) showed ORR ~49% in non-clear cell RCC including papillary histology, and is increasingly used first-line. For MET-exon-14-skipping or MET-amplified papillary RCC, MET-targeted agents remain a rational option. Savolitinib + osimertinib studies ongoing in MET-driven papillary RCC.

References

References: Pal SK et al, Lancet 2021