Erlotinib +/- Bevacizumab trials

Background

Group of first-line RCTs of erlotinib +/- bevacizumab in EGFR-mutant advanced NSCLC. JO25567: phase II, N=154, treatment-naive stage IIIB/IV or postoperative recurrent. NEJ026: phase III, N=228. ACCRU (US): phase II, N=88.

Interventions and follow up

Arm A: Erlotinib 150 mg PO daily + bevacizumab 15 mg/kg IV q21d
Arm B: Erlotinib 150 mg PO daily
Primary endpoint: PFS

Results

JO25567 mPFS: 16.4 mo vs 9.7 mo; HR 0.52 (95%CI 0.35–0.76); P=.0005
JO25567 mOS: 47.0 mo vs 47.4 mo; HR 0.81 (95%CI 0.53–1.23); P=.3267
NEJ026 mPFS: 16.9 mo vs 13.9 mo; HR 0.61 (95%CI 0.42–0.88); P=.016
NEJ026 mOS: 50.7 mo vs 46.2 mo; HR 1.00 (95%CI 0.68–1.5); P=.973
ACCRU mPFS: 17.9 mo vs 13.5 mo; HR 0.81 (95%CI 0.50–1.31); P=.39
ACCRU mOS: 32.4 mo vs 50.6 mo; HR 1.41 (95%CI 0.71–2.81); P=.33

Adverse events

Skin: rash 99% vs 99%; skin eruption (NEJ026) 26% vs 16%
GI: diarrhea 81% vs 79% (NEJ026 9% vs 13%)
Cardiovascular: hypertension 79% vs 14% (grade ≥3 61% vs 12%); NEJ026 HTN 40% vs 20%
Skin/nail: paronychia 79% vs 65%
Renal: proteinuria (NEJ026) 12% vs 0%

Conclusions

Adding bevacizumab to erlotinib improved PFS but not OS in first-line EGFR-mutant NSCLC; consistent with the class pattern that EGFR+VEGF combinations improve PFS only, at the cost of added toxicity.

Key Limitations

No OS benefit; added hypertension/proteinuria toxicity; smaller/phase II trials (JO25567, ACCRU); comparator was erlotinib (not osimertinib); ACCRU underpowered with numerically worse OS.

Clinical Context

Erlotinib + bevacizumab FDA approved first-line for EGFR ex19del/L858R metastatic NSCLC (2020). ESMO/ASCO list it as an option but osimertinib is preferred first-line; combination reserved for selected patients given toxicity and PFS-only benefit.

References