Background
Phase III noninferiority RCT, N=1,725, chemo-naive stage IIIB (not curable) or IV NSCLC, ECOG 0-1, CrCl >45 mL/min. Excluded grade >1 neuropathy, brain mets, uncontrolled third-spacing.
Interventions and follow up
Arm A: Cisplatin 75 mg/m2 + pemetrexed 500 mg/m2 d1 q3wk up to 6 cycles
Arm B: Cisplatin 75 mg/m2 d1 + gemcitabine 1,250 mg/m2 d1, d8 q3wk up to 6 cycles
Both arms: dexamethasone 4 mg PO BID day before/of/after each d1 treatment
Primary endpoint: OS (ITT, noninferiority)
Arm B: Cisplatin 75 mg/m2 d1 + gemcitabine 1,250 mg/m2 d1, d8 q3wk up to 6 cycles
Both arms: dexamethasone 4 mg PO BID day before/of/after each d1 treatment
Primary endpoint: OS (ITT, noninferiority)
Results
mOS all patients: 10.3 vs 10.3 mo (A vs B); HR 0.94, 95%CI 0.84-1.05 (noninferiority met)
mOS adenocarcinoma: 12.6 vs 10.9 mo; HR 0.84, 95%CI 0.71-0.99; P=.03
mOS large cell: 10.4 vs 6.7 mo; HR 0.67, 95%CI 0.48-0.96; P=.03
mOS squamous cell: 9.4 vs 10.8 mo; HR 1.23, 95%CI 1.00-1.51; P=.05
mOS adenocarcinoma: 12.6 vs 10.9 mo; HR 0.84, 95%CI 0.71-0.99; P=.03
mOS large cell: 10.4 vs 6.7 mo; HR 0.67, 95%CI 0.48-0.96; P=.03
mOS squamous cell: 9.4 vs 10.8 mo; HR 1.23, 95%CI 1.00-1.51; P=.05
Adverse events
Hematologic gr3-4 (A vs B): neutropenia 15% vs 27%; anemia 6% vs 10%; thrombocytopenia 4% vs 13%; febrile neutropenia 1% vs 4% (P=.002)
GI gr3-4: nausea 7% vs 4% (P=.004)
Other: alopecia 12% vs 21% (P=.001)
GI gr3-4: nausea 7% vs 4% (P=.004)
Other: alopecia 12% vs 21% (P=.001)
Conclusions
Cisplatin/pemetrexed was noninferior to cisplatin/gemcitabine overall with less toxicity, but the histology interaction (worse OS in squamous, better in nonsquamous) established pemetrexed as a nonsquamous-only agent. Squamous tumors express higher thymidylate synthase (and Skp2) than adenocarcinoma (P<.0001, Ceppi et al).
Key Limitations
Histology subgroups were not pre-stratified primary endpoints (hypothesis-generating). Predates molecular subtyping and immunotherapy; chemotherapy-only comparator.
Clinical Context
Landmark trial establishing histology-directed chemotherapy: pemetrexed is restricted to nonsquamous NSCLC. ESMO/ASCO guidance reflects this; pemetrexed remains a backbone of nonsquamous platinum doublets (now combined with pembrolizumab per KEYNOTE-189).