Background
Phase 3 RCT; N=571 recurrent advanced NSCLC (squamous and non-squamous) progressing after one prior chemotherapy regimen. Non-inferiority design comparing pemetrexed vs docetaxel.
Interventions and follow up
Arm A: Pemetrexed 500 mg/m2 IV day 1 q21d
Arm B: Docetaxel 75 mg/m2 IV day 1 q21d
Primary endpoint: overall survival (non-inferiority)
mFollow up: NR
Arm B: Docetaxel 75 mg/m2 IV day 1 q21d
Primary endpoint: overall survival (non-inferiority)
mFollow up: NR
Results
mOS: 8.3mo vs 7.9mo, pemetrexed vs docetaxel; not significant
mPFS: 2.9mo vs 2.9mo
ORR: 9.1% vs 8.8%
Pooled histology analysis (Scagliotti, Oncologist 2009, PMID 19221167):
Non-squamous mOS: 9.3mo vs 8.0mo, HR 0.78, 95%CI 0.61-1.00
Squamous mOS: 6.2mo vs 7.4mo, HR 1.56, 95%CI 1.08-2.26
mPFS: 2.9mo vs 2.9mo
ORR: 9.1% vs 8.8%
Pooled histology analysis (Scagliotti, Oncologist 2009, PMID 19221167):
Non-squamous mOS: 9.3mo vs 8.0mo, HR 0.78, 95%CI 0.61-1.00
Squamous mOS: 6.2mo vs 7.4mo, HR 1.56, 95%CI 1.08-2.26
Adverse events
Hematologic: Grade ≥3 neutropenia 5% vs 40%; febrile neutropenia 2% vs 13%; G-CSF use 3% vs 19%
Other: alopecia 6% vs 38%
Other: alopecia 6% vs 38%
Conclusions
Pemetrexed is non-inferior to docetaxel in 2L advanced NSCLC with a markedly better hematologic toxicity profile; benefit is confined to non-squamous histology.
Key Limitations
Non-inferiority design; histology-by-treatment interaction was a retrospective/pooled analysis, not pre-specified in the original trial.
Clinical Context
Established pemetrexed as a 2L option (FDA approved 2004) and seeded the histology-driven restriction to non-squamous NSCLC; pemetrexed is now largely used 1L with platinum ± immunotherapy in non-squamous disease.