Avelumab not superior to chemotherapy as first-line treatment of advanced PD-L1 positive NSCLC
The phase III JAVELIN Lung 100 trial compared first-line avelumab monotherapy in two dose schedules vs. platinum-based doublet chemotherapy in patients with previously untreated PD-L1 positive advanced non-small cell lung cancer (NSCLC). Unfortunately, the trial did not meet its primary objective of demonstrating superior overall survival or progression-free survival with avelumab in patients with high expression of PD-L1 on tumour cells (≥ 80% of tumour cells).
Avelumab is an anti–PD-L1 antibody that is approved worldwide as monotherapy for the treatment of locally advanced or metastatic urothelial carcinoma (first-line maintenance) and metastatic Merkel cell carcinoma, as well as in combination with axitinib for advanced renal cell carcinoma. In the phase I JAVELIN Solid Tumor trial, avelumab showed antitumour activity and an acceptable safety profile in patients with NSCLC. While post hoc analyses in the phase III JAVELIN Lung 200 trial showed longer overall survival (OS) and progression-free survival (PFS) and higher objective response rates (ORRs) in subgroups with higher levels of PD-L1 expression, avelumab did not statistically significantly prolong OS vs. docetaxel in patients with platinum-treated PD-L1+ NSCLC. At WCLC 2022, Prof. Reck reported results from the primary analysis of the phase III JAVELIN Lung 100 trial, which compared avelumab (administered in two different dosing schedules) vs. platinum-based doublet chemotherapy as first-line treatment for patients with PD-L1+ advanced NSCLC.
Study design
JAVELIN Lung 100 was an open-label, multicentre, phase III trial that enrolled adult patients with previously untreated metastatic or recurrent stage IV PD-L1+ (PD-L1 expression on ≥1% of tumour cells determined by Dako PD-L1 IHC 73-10 pharmDx) and EGFR/ALK-wild-type NSCLC. Patients were initially randomised 1:1 to receive avelumab 10 mg/kg every 2 weeks (Q2W) or platinum-based doublet chemotherapy every 3 weeks (Q3W) intravenously, stratified by histology. Following a protocol amendment based on pharmacokinetics/exposure analyses, patients were randomised 1:2:2 to receive avelumab 10 mg/kg Q2W, platinum-based doublet chemotherapy Q3W, or avelumab 10 mg/kg weekly (QW) for 12 weeks and Q2W thereafter, stratified by histology and PD-L1 expression cut-offs (high, ≥80%; moderate, ≥50%; and any, ≥1% of tumour cells). Primary endpoints were OS and PFS per independent review committee (IRC) in patients with high-expression PD-L1+ tumours (≥80% of tumour cells).
Results
In total, 1,214 patients with PD-L1+ tumours (≥1% of tumour cells) were randomised to the avelumab Q2W (N= 366), chemotherapy (N= 526), or avelumab QW (N= 322) arms. The baseline characteristics were well-balanced among the treatment arms in patients with high PD-L1 expression. At data cut-off (October 2021), median follow-up was >41 months in all arms. OS analyses favoured avelumab vs. chemotherapy but differences were not statistically significant (median 20.1 vs. 14.9 months and HR[95%CI]: 0.85[0.67-1.09], p= 0.1032 for avelumab Q2W and median 19.3 vs. 15.3 months with HR[95%CI]: 0.79[0.59-1.07], p= 0.0630 for avelumab QW). Also the PFS analyses for avelumab Q2W and QW favoured avelumab vs. chemotherapy but differences were again not statistically significant (median 8.4 vs. 5.6 months with HR[95%CI] : 0.71[0.54-1.93], p= 0.0070 and median 7.5 vs. 5.6 months with HR[95%CI]: 0.72[0.52-0.98], p= 0.0196, respectively). The ORR was 37.7% for avelumab Q2W, 34.6% for avelumab QW and 30.1% for chemotherapy. Also the median duration of response favoured avelumab vs. chemotherapy (35.9 months, 19.4 months and 8.4 months, respectively).
Among patients with high-expression PD-L1+ tumours, 5.3% and 1.5 % of patients in the avelumab Q2W and QW arms vs. 30-35% of patients in the chemotherapy arms received post-study anti-PD-(L)1 treatment. Among all treated patients in the avelumab Q2W, avelumab QW, and chemotherapy arms, treatment-related adverse events (TRAEs) occurred in 67.3%, 70.4% and 86.0%, including grade ≥3 TRAEs in 16.6%, 13.8% and 46.0% respectively.
Conclusion
JAVELIN Lung 100 did not meet its primary objective of demonstrating superior OS or PFS by IRC with first-line avelumab (Q2W or QW) vs. platinum-based doublet chemotherapy in patients with high-expression PD-L1+ tumours. The safety profile of avelumab was even though consistent with previous studies of avelumab monotherapy and no new safety signals were observed. Efficacy and safety results were similar in the avelumab Q2W and QW arms.
Reference
Reck M, Barlesi F, Yang J, et al. Avelumab vs Chemotherapy for First-line Treatment of Advanced PD-L1+ NSCLC: Primary Analysis from JAVELIN Lung 100. Presented at IASLC WCLC 2022; Abstract OA15.03.
