Avelumab for patients with previously treated metastatic or recurrent non-small-cell lung cancer (JAVELIN Solid Tumor): dose-expansion cohort of a multicentre, open-label, phase 1b trial

Abstract

Background Avelumab, a fully human IgG1 immune checkpoint inhibitor targeting programmed death ligand 1 (PD-L1), has shown antitumour activity and an acceptable safety profile in patients with advanced solid tumours. Here, we assessed avelumab treatment in patients with advanced, platinum-treated non-small cell lung cancer (NSCLC). Methods In this dose-expansion cohort of a multicentre, open-label, phase 1 study, patients with progressive or platinum-resistant metastatic or recurrent NSCLC were enrolled at 58 sites in the United States. Eligible patients had confirmed stage IIIB or IV NSCLC with squamous or nonsquamous histology, measurable disease by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), tumour biopsy or archival sample for biomarker assessment, and Eastern Cooperative Oncology Group performance status 0 or 1, among other criteria. Patient selection was not based on PD-L1 expression or other biomarkers, including EGFR or KRAS mutation or ALK translocation status. Patients received avelumab monotherapy 10 mg/kg every 2 weeks until disease progression or toxicity. The primary endpoint was safety and tolerability. Secondary endpoints included best overall response, progression-free survival, overall survival, and clinical activity associated with PD-L1 expression. Responses were evaluated using RECIST v1.1, and analyses of antitumour activity and safety were performed in all patients who received at least one dose of avelumab. This trial is registered with ClinicalTrials.gov (NCT01772004); enrolment in this cohort is closed and the trial is ongoing. Findings Between 10 September 2013 and 24 June 2014, 184 patients were enrolled and initiated treatment with avelumab. Median follow-up duration was 8·8 months (interquartile range [first and third quartiles], 7·2–11·9 months). The most common treatment-related adverse events of any grade were fatigue (n=46; 25%), infusion-related reaction (n=38; 21%), and nausea (n=23; 13%). Grade ≥3 treatment-related adverse events occurred in 23 of 184 patients (13%); the most common were infusion-related reaction (n=4; 2%), elevated lipase (n=3; 2%), constipation (n=2; 1%), and dyspnoea (n=2; 1%). 16 of 184 patients (9%) had a serious adverse event related to treatment with avelumab, with infusion-related reaction (4 [2%]) and dyspnoea (2 [1%]) occurring in more than one patient. Immune-related treatment-related events occurred in 22 patients (12%). The confirmed objective response rate, regardless of PD-L1 status, was 12% (95% CI, 8–18), including one complete response and 21 partial responses. Seventy patients had stable disease, for an overall disease-control rate of 50%. Interpretation Avelumab showed an acceptable safety profile and antitumour activity in patients with progressive or resistant NSCLC, providing a rationale for additional studies of avelumab in this disease setting. Funding Merck KGaA, Darmstadt, Germany and Pfizer, Inc, New York, USA.

Avelumab: another active immune checkpoint inhibitor in non-small cell lung cancer

“…Most of the infusion reactions occurred after the first two infusions and were mild to moderate in severity. They did not lead to treatment discontinuation with modern supportive care (9). This observation is perhaps due to the unique construct of avelumab which will be further characterized in large ongoing phase 3 trials.…”

“…It was recently approved for patients with chemotherapy-refractory metastatic Merkel cell carcinoma (8). In a recent issue of Lancet Oncology, Gulley and colleagues reported a multicenter, open-label, phase 1b trial of avelumab for patients with previously treated metastatic or recurrent NSCLC (9). This was a dose-expansion cohort of a dose-escalation phase 1a trial (JAVELIN solid tumor) after avelumab demonstrated antitumor activity with an acceptable adverse event profile in patients with advanced solid tumors (10).…”

“…In the present study, a novel anti-PD-L1 rabbit monoclonal antibody clone 73-10 was used to evaluate PD-L1 expression on tumor cells and tumor-associated immune cells. Patients were categorized into subgroups with a grading system composed of three different cutoff points 1%, 5%, or 25% for PD-L1 positivity of tumor cells and 10% cutoff for tumor-associated immune cells (9). Exploratory post-hoc subgroup analyses demonstrated essentially similar response rates and survival independent of patient characteristics, number of previous lines of therapy, PD-L1 expression on either tumor cells or tumor-associated immune cell.…”

“…Perhaps, clone 73-10 is more sensitive compared to other analytically similar clones 22C3, 28-8, and SP263 (14). Thus, the heterogeneity of PD-L1 expression assays makes the interpretation of statistically significant longer median progression-free survival observed in the PD-L1 ≥1% group more difficult when compared across the studies (9).…”

Tumor-associated macrophages—additional effectors at anti-PD-1/PD-L1 therapy?

“…Monoclonal antibody drugs that target the interaction between PD-1 and PD-L1 have shown dramatic and/or durable responses in a subset of NSCLC patients (3)(4)(5)(6), leading to FDA approvals of three agents (nivolumab, pembrolizumab, and atezolizumab) for treatment of metastatic NSCLC patients. Other agents that also target this pathway, such as durvalumab (7) and avelumab (8), are currently under clinical development.…”