The phase 3 JAVELIN Lung did not produce statistically significant overall or progression-free survival benefit with avelumab for non–small cell lung cancer.
Despite longer progression-free and overall survival (OS) observed in patients with PD-L1–positive non–small cell lung cancer who were treated with avelumab (Bavencio) vs platinum-based chemotherapy, results failed to reach statistical significance in the phase 3 JAVELIN Lung 100 trial (NCT02576574).
Results, which were presented during the 2022 World Conference on Lung Cancer, showed that the median OS with avelumab (n = 151) given every 2 weeks was 20.1 months (95% CI, 15.0-24.3) vs 14.9 months (95% CI, 11.8-18.6) with chemotherapy (n = 216) in the high PD-L1–positive populations (HR, 0.85; 95% CI, 0.67-1.09; 1-sided P = .1032), missing the significance threshold of P = .0019. The median progression-free survival (PFS) in the investigative and control arms was 8.4 months (95% CI, 5.4-12.6) and 5.6 months (95% CI, 5.4-6.8), respectively (HR, 0.71; 95% CI, 0.54-1.93; 1-sided P = .0070; significance threshold, P = .0039).
The median OS with weekly avelumab (n = 130) was 19.3 months (95% CI, 14.0-28.1) vs 15.3 months (95% CI, 11.6-19.1) with chemotherapy (n = 129) in this population (HR, 0.79; 95% CI, 0.59-1.07; 1-sided P = .0630); here, the significance threshold was P = .0057. The median PFS in the investigative arm was 7.5 months (95% CI, 4.2-1.1) vs 5.6 months (95% CI, 5.0-6.8) in the control arm (HR, 0.72; 95% CI, 0.52-0.98; 1-sided P = .0196; significance threshold, P = .0103).
“Factors that may have contributed to these results were that significant changes [were made] to the study design, including changes to the primary analysis population, primary end points, and addition of the [once weekly] arm, that led to multiple hypothesis testing and splitting of the α across end points,” said Martin Reck, MD, PhD, of the Airway Research Center North, German Center for Lung Research, LungenClinic, in a presentation of the data. “[Moreover, it is important to note] the evolution of the second-line treatment for advanced NSCLC during the study, and [that] many patients in the chemotherapy arm received subsequent immune checkpoint inhibitor therapy.”
The JAVELIN Lung 100 trial enrolled patients with metastatic or recurrent stage IV NSCLC without EGFR mutations or ALK rearrangements who had PD-L1 expression in 1% or more of tumor cells. Moreover, patients were required to have measurable disease per RECIST v1.1 criteria and an ECOG performance status of 0 or 1.
Before the protocol amendment, patients were first randomly assigned 1:1 to receive intravenous avelumab every 2 weeks at a dose of 10 mg/kg (n = 205) or platinum-based doublet chemotherapy every 3 weeks (n = 205). Patients were stratified by disease histology.
Following the amendment, patients were randomly assigned 1:2:2, where they received avelumab every 2 weeks at 10 mg/kg (n = 161), platinum-based doublet chemotherapy every 3 weeks (n = 321), or avelumab weekly at 10 mg/kg (n = 322). They were stratified based on histology and PD-L1 expression.
The primary end points of the trial were OS and PFS in patients with high PD-L1–expressing tumors. Important secondary end points comprised PFS and OS in those with moderate-to-high PD-L1–expressing tumors, best overall response (BOR), duration of response (DOR), and safety.
Because data from preliminary efficacy-exposure analyses from the phase 1 JAVELIN Solid Tumor trial (NCT01772004) suggested a link between greater exposure to avelumab and higher objective response rates (ORRs) in patients with NSCLC, investigators hypothesized that more weekly dosing of avelumab would lead to increased exposure of the drug vs every 2 weeks. As such, weekly avelumab was given for the first 12 weeks, followed by every 2 weeks from week 13 onwards.
Per the hierarchical testing procedure, the PFS and OS achieved with avelumab every 2 weeks or weekly was compared with chemotherapy in those with high PD-L1 expression (defined as 80% or high expression on tumor cells; step 1), followed by those with moderate to high PD-L1 expression (defined as 50% or higher expression on tumor cells; step 2). OS alone was then evaluated in those with any PD-L1 expression (defined as 1% or higher expression on tumor cells; step 3). Steps 2 and 3 were tested only if the null hypothesis in step 1 was rejected, Reck noted.
The median age of participants, spanning arms, was 63.8 years, with a range of 25 years to 85 years. Most patients were male, had an ECOG performance status of 1, were White, had stage V disease at study entry, a history of smoking, nonsquamous histology, and visceral metastases.
Additional data from the trial showed that the 12-month OS rate reported with avelumab, given every 2 weeks, was 64.7% vs 56.9% with chemotherapy; the 24-month OS rates were 42.5% and 36.5%, respectively. The 12-month PFS rates in the investigative and control arms were 42.5% and 21.0%, respectively; the 24-month rates were 29.6% and 11.2%, respectively.
When avelumab was given weekly, the 12-month OS rate was 63.0% vs 58.2% with chemotherapy; the 24-month OS rates were 43.7% and 35.0%, respectively. The 12-month PFS rate with avelumab was 40.6% vs 16.8% with chemotherapy; the 24-month PFS rates were 22.6% and 9.0%, respectively.
Subgroup analyses revealed that OS favored avelumab given every 2 weeks compared with chemotherapy in the high PD-L1–positive population. OS findings were comparable by subgroup for weekly avelumab vs chemotherapy.
When avelumab was administered every 2 weeks, the agent elicited an ORR of 37.7% (95% CI, 30.0%-46.0%) by IRC assessment vs 30.1% (95% CI, 24.1%-46.0%) with chemotherapy. In the avelumab arm, the confirmed BOR was a complete response (CR) in 3.3% of patients, partial response (PR) in 34.4% of patients, and stable disease (SD) in 23.8% of patients; progressive disease occurred in 17.9% of patients, and 20.5% were not evaluable. The median DOR with avelumab every 2 weeks was 35.9 months (95% CI, 14.6–not reached [NR]) vs 8.4 months (95% CI, 5.0-15.1).
Weekly avelumab elicited an ORR of 34.6% (95% CI, 26.5%-43.5%) compared with 30.2% (95% CI, 22.5%-38.9%) with chemotherapy. Here, the BOR with avelumab was a CR, PR, and SD in 3.1%, 31.5%, and 23.1% of patients, respectively; 22.3% experienced disease progression and 20.0% were not evaluable. The median DOR in the investigative arm was 19.4 months (95% CI, 10.8-NR) vs 8.4 months (95% CI, 4.4-11.1) in the control arm.
Of those who received avelumab every 2 weeks, 41.1% received subsequent anticancer therapy vs 52.3% of those who had received chemotherapy; 5.3% and 30.6% of patients, respectively, received subsequent immune checkpoint inhibition.
Of those who received weekly avelumab, 37.7% received subsequent anticancer treatment vs 58.1% of those who had received chemotherapy; rates of those who received subsequent immunotherapy were 1.5% and 34.9% of patients, respectively.
The safety profile of avelumab proved to be consistent with what has previously been reported with the agent, with no new signals observed.
Any-grade adverse effects (AEs) occurred in 95.8% of those who received avelumab every 2 weeks, 96.9% of those who received the agent weekly, and 96.8% of those who were given chemotherapy (n = 500); these effects were grade 3 or higher in 60.1%, 56.9%, and 64.8% of patients, respectively. Treatment-related AEs occurred in 67.3%, 70.4%, and 86.0% of patients, respectively, and they were grade 3 or higher in 16.6%, 13.8%, and 46.0% of patients, respectively.
Treatment-related toxicities resulted in treatment discontinuation for 12.2% of those who received avelumab every 2 weeks, 8.5% of those who were given weekly avelumab, and 15.2% of those who received chemotherapy. Treatment-related deaths occurred in 3 patients who received avelumab every 2 weeks, 1 patient who received the agent weekly, and 6 patients who received chemotherapy.
Reck M, Barlesi F, Yang JC-H, et al. Avelumab vs chemotherapy for first-line treatment of advanced PD-L1+ NSCLC: primary analysis from JAVELIN Lung 100. Presented at: International Association for the Study of Lung Cancer 2022 World Conference on Lung Cancer; August 6-9, 2022; Vienna, Austria. Abstract OA15.03