Table 2.
Results of completed phase II MET/hepatocyte growth factor targeted therapy clinical trials
| Trial name | Endpoint | Sample size | Major conclusions | Side effects | Reference |
|---|---|---|---|---|---|
| ARQ197-209 (NCT00777309) | Primary: PFS Secondary: OS, ORR, safety | ET, n = 84; EP, n = 83 | 1. In ITT patients: PFS was better in ET (median 3.8 m vs 2.3 m, P = 0.24; planned multivariable Cox regression HR 0.68, P < 0.05) 2. OS: no difference between ET and EP (median 8.5 m vs 6.9 m, adjusted HR 0.87, P = 0.5) 3 ORR (PR only): 7/74 (10%) in ET and 5/72 (7%) in EP 4. Planned exploratory analysis: • PFS was better in the ET arm in KRAS mutant group (median 2.3 m vs 1.0 m, P = 0.006, n = 10 and n = 5) • Patients with nonsquamous histology (n = 117) showed benefit from ET in both PFS (adjusted HR 0.61, P = 0.04) and OS (adjusted HR 0.58, P = 0.04), by applying the proportional hazards model generated for ITT population • Patients with EGFR wild-type tumors (n = 99) demonstrated a trend towards a benefit from ET in PFS (HR 0.70; P = 0.12) and OS (HR 0.76, P = 0.25) • Among the ITT population, median time to new metastatic lesions was longer in ET (7.3 m vs 3. 6 m, HR 0.49, P < 0.01). This effect was more pronounced in patients with nonsquamous histology |
Rash, diarrhea, fatigue, and anemia were similar in two groups | 34 |
| XL184-202 Phase Ib/II study of cabozantinib (XL184) with or without erlotinib in NSCLC with acquired erlotinib resistance (NCT00596648) | Objectives: safety, pharmacokinetics, MTD, and ORR | 54 in phase Ib; 36 patients assessable for response | 1. The overall safety and tolerability profile of cabozantinib and erlotinib appear acceptable 2. Three patients with prior erlotinib therapy had ≥30% reduction in tumor measurements on at least one postbaseline scan, including three with a complete or PR 3. Prolonged SD ≥4 months has been observed in some patients including one patient for ≥9 months and one patient with EGFR T790M |
Diarrhea (26%), fatigue (15%), dyspnea (12%), and hypoxia (9%) | 86 |
| Randomized discontinuation trial of cabozantinib (XL184) (NCT00940225) | Primary: ORR, safety | 398/483 enrolled patients; nine types of solid tumor were evaluable for the lead-in stage | 1. Soft tissue ORR 9% in 8/9 indications, 10% in NSCLC. ODC (PR or SD) at week twelve of 40% or higher were observed in six different solid tumors, including NSCLC. 69% with at least one postbaseline scan had tumor regression 2. Complete or partial resolution of bone scan lesions was observed in 59/68 (86.8%) patients with prostate or breast cancer or melanoma |
Most common related AEs grade ≥3: fatigue (9%), hand-foot syndrome (8%), and hypertension (5%) | 87 |
| OAM4558 g (NCT00854308) | Primary: PFS Secondary: OS, safety | ME, n = 64; Placebo plus erlotinib, n = 64 | 1. 54% of patients had MET IHC expression and associated with a worse outcome (OS HR 2.52) 2. In MET IHC 2+/3+ group: improved PFS (median 3.0 m vs 1.5 m, HR 0.47, P = 0.01) and OS (median 12.6 m vs 4.6 m, HR 0.37, P = 0.002) in ME group 3. In MET IHC −/1+ group: worse OS in ME group (HR 3.02, P = 0.021) 4. An OS benefit from ME was observed in MET FISH+ as well as in FISH−/IHC+; removing patients with EGFR mutation did not alter results |
Erlotinib-related toxicities were comparable between treatment arms | 96 |
Abbreviations: AE, adverse effect; EP, erlotinib plus placebo; ET, erlotinib plus tivantinib; FISH, fluorescence in situ hybridization; HR, hazard ratio; IHC, immunohistochemistry; ITT, intention-to-treat; m, month; ME, MetMAb plus erlotinib; MTD, maximum tolerated dose; NSCLC, nonsmall cell lung cancer; ODC, overall disease control; ORR, overall response rate; OS, overall survival; PFS, progression free survival; PR, partial response; SD, stable disease; vs, versus.