Elsevier

The Lancet Oncology

Volume 18, Issue 5, May 2017, Pages 599-610
The Lancet Oncology

Articles
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

https://doi.org/10.1016/S1470-2045(17)30240-1Get rights and content

Summary

Background

Avelumab, a human Ig-G1 monoclonal antibody targeting PD-L1 and approved in the USA for the treatment of metastatic Merkel cell carcinoma, has shown antitumour activity and an acceptable safety profile in patients with advanced solid tumours in a dose-escalation phase 1a trial. In this dose-expansion cohort of that trial, we assess avelumab treatment in a cohort of 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 cancer treatment centres and academic hospitals in the USA. Eligible patients had confirmed stage IIIB or IV NSCLC with squamous or non-squamous 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 expression of other biomarkers, including EGFR or KRAS mutation or ALK translocation status. Patients received infusional avelumab monotherapy 10 mg/kg every 2 weeks until disease progression or toxicity. The primary objective was to assess safety and tolerability. This trial is registered with ClinicalTrials.gov, number NCT01772004; enrolment in this cohort is closed and the trial is ongoing.

Findings

Between Sept 10, 2013, and June 24, 2014, 184 patients were enrolled and initiated treatment with avelumab. Median follow-up duration was 8·8 months (IQR 7·2–11·9). The most common treatment-related adverse events of any grade were fatigue (46 [25%] of 184 patients), infusion-related reaction (38 [21%]), and nausea (23 [13%]). Grade 3 or worse treatment-related adverse events occurred in 23 (13%) of 184 patients; the most common (occurring in more than two patients) were infusion-related reaction (four [2%] patients) and increased lipase level (three [2%]). 16 (9%) of 184 patients had a serious adverse event related to treatment with avelumab, with infusion-related reaction (in four [2%] patients) and dyspnoea (in two [1%]) occurring in more than one patient. Serious adverse events irrespective of cause occurred in 80 (44%) of 184 patients. Those occurring in more than five patients (≥3%) were dyspnoea (ten patients [5%]), pneumonia (nine [5%]), and chronic obstructive pulmonary disease (six [3%]). Immune-related treatment-related events occurred in 22 patients (12%). Of 184 patients, 22 (12% [95% CI 8–18]) achieved a confirmed objective response, including one complete response and 21 partial responses. 70 (38%) had stable disease. Overall, 92 (50%) of 184 patients achieved disease control (they had a confirmed response or stable disease as their best overall response). One patient was initially thought to have died from grade 5 radiation pneumonitis during the study; however, this adverse event was subsequently regraded to grade 3 and the death was attributed to disease progression.

Interpretation

Avelumab showed an acceptable safety profile and antitumour activity in patients with progressive or treatment-resistant NSCLC, providing a rationale for further studies of avelumab in this disease setting.

Funding

Merck KGaA and Pfizer.

Introduction

Lung cancer is the leading cause of cancer deaths worldwide.1 Most patients present with stage IV disease, which has a median overall survival of 8–10 months and a 5-year relative survival of about 4%.2, 3, 4 First-line treatment for patients with non-small-cell lung cancer (NSCLC) without any actionable mutation is generally based on platinum-doublet chemotherapy. Until recently, eligible patients with progressive disease following first-line therapy typically received chemotherapy with docetaxel or pemetrexed, which has been associated with a 1-year survival of about 30%.5 In eligible subsets of patients with specific tumour biomarkers, such as EGFR mutations or ALK or protein kinase ROS1 rearrangements, targeted therapy with tyrosine kinase inhibitors has shown clinical efficacy, but resistance eventually develops.6, 7

Research in context

Evidence before this study

Because the field of immunotherapy with anti-PD-L1 or anti-PD-1 immune checkpoint inhibitors has expanded rapidly in recent years, we did a 5-year systematic search of the English language literature using both PubMed and selected annual congresses (American Society of Clinical Oncology, European Society for Medical Oncology, European Cancer Congress, and World Conference on Lung Cancer). Search dates were between Jan 1, 2011, and Aug 22, 2016, and terms included “PD-1” and “PD-L1,” in addition to relevant generic and investigational drug names of immune checkpoint inhibitors (“nivolumab”, “BMS-936558”, “pembrolizumab”, “lambrolizumab”, “MK-3475”, “atezolizumab”, “MPDL3280A”, “durvalumab”, “MEDI4736”, “avelumab”, and “MSB0010718A”). Most clinical studies were published after 2013. Additional search terms were used to identify literature about patients with advanced non-small-cell lung cancer (NSCLC). Recent evidence from phase 2 and phase 3 trials indicates that anti-PD-L1 and anti-PD-1 antibodies have efficacy and are well tolerated in patients with squamous and non-squamous histological subtypes of NSCLC. Tumour PD-L1 expression might have predictive value for efficacy of anti-PD-1 antibodies in non-squamous NSCLC. Avelumab is a human anti-PD-L1 IgG1 antibody that is approved in the USA for the treatment of metastatic Merkel cell carcinoma and has shown promising antitumour activity and a manageable safety profile in several other tumour types. Unlike other anti-PD-L1 or anti-PD-1 antibodies approved or in advanced clinical development, avelumab has been shown to mediate antibody-dependent cellular cytotoxicity in vitro. Based on safety, pharmacokinetic, target occupancy, and preliminary efficacy data obtained during a dose-escalation study of avelumab, the dose of 10 mg/kg given as a 1-h intravenous infusion every 2 weeks was selected for phase 1 dose expansion in various tumours.

Added value of this study

We report the safety and antitumour activity of avelumab monotherapy in a large phase 1 cohort of patients with progressive or platinum-resistant metastatic or recurrent NSCLC. Eligible patients in this cohort were not preselected based on NSCLC histology, PD-L1 expression status, or EGFR or ALK status. Clinical activity was recorded independent of PD-L1 expression, or squamous versus non-squamous histology. This is the largest cohort of patients studied in a phase 1 trial of avelumab and further characterises its clinical attributes.

Implications of all the available evidence

Avelumab had a manageable safety profile and promising clinical activity in a population of patients with progressive, platinum-treated, metastatic, or recurrent NSCLC. Responses occurred irrespective of PD-L1 expression status and in squamous and non-squamous tumours. These findings support the therapeutic benefit of anti-PD-L1 antibodies in patients with previously treated NSCLC. These results with avelumab have provided the rationale for an ongoing phase 3 trial in the second-line NSCLC population and underscore the potential benefits of immunotherapy for patients with this difficult-to-treat disease.

NSCLC tumours can evade immune activity through several mechanisms, including the expression of molecules (immune checkpoints) that inhibit T-cell activation. In particular, PD-L1 expression is often upregulated in immunogenic tumours, including NSCLC,8, 9 and binding of PD-L1 to its receptor on T cells, PD-1, inhibits tumour immunity by suppressing T-cell activation,8, 10, 11 enabling tumours to escape T-cell surveillance. PD-L1–PD-1 axis blockade might stimulate a patient's antitumour immune response by promoting T-cell reactivity against tumour neoantigens.12 Patients with recurrent or metatstatic NSCLC have few therapeutic options. However, recently, PD-L1–PD-1-targeted immune checkpoint inhibitors have been shown to increase overall survival versus docetaxel in patients with previously treated advanced NSCLC, leading to regulatory approval of three anti-PD-L1–PD-1 therapies (atezolizumab, nivolumab, and pembrolizumab) in this setting.13, 14, 15, 16 These agents might therefore be able to address a major unmet need. Correlative and translational studies in NSCLC and other tumour types suggest that the clinical benefits of immune checkpoint inhibition might be affected by tumour histology, mutational load, molecular drivers of disease, and expression of PD-L1 by tumours, although responses have been achieved independently of these factors.9, 17, 18 However, patient selection and stratification based on such factors are important characteristics to consider in clinical study design and prespecified subgroup analyses.

Avelumab (MSB0010718C) is a human anti-PD-L1 IgG1 antibody that has been approved in the USA for the treatment of metastatic Merkel cell carcinoma. Avelumab inhibits PD-L1–PD-1 interactions but leaves the PD-L2–PD-1 pathway intact. By contrast with other PD-L1–PD-1 drugs assessed in clinical trials so far, avelumab binding to the surface of tumour cells via PD-L1 has the potential to induce natural killer cell-mediated antibody-dependent cellular cytotoxicity (ADCC) of tumour cells, as shown by preclinical models, which might contribute to its clinical activity.19, 20 A large, multicohort, phase 1 dose-escalation and dose-expansion trial is being done21 to assess the safety and activity of avelumab in patients with a range of advanced solid tumours. In the phase 1a dose-escalation part of the study, avelumab was safely given by intravenous infusion every 2 weeks, had a predictable pharmacokinetic profile at doses up to 20 mg/kg, and showed preliminary evidence of antitumour activity, including durable responses and stable disease.21, 22 The 10 mg/kg dose, which has a half-life of about 4 days, was selected for further study in dose-expansion cohorts in a range of tumour types. Here, we present phase 1b results from this study in a cohort of patients with advanced NSCLC whose disease has progressed after platinum-based chemotherapy and are unselected for PD-L1 expression.

Section snippets

Study design and participants

JAVELIN Solid Tumor is an ongoing, international, multicentre, phase 1, open-label trial that includes several expansion cohorts. This trial included a dose-escalation part (phase 1a), the results of which are reported separately, and a dose-expansion part (phase 1b) comprising 16 different cohorts. In the dose-expansion cohort reported here, eligible patients had histologically or cytologically confirmed stage IIIB or IV NSCLC, with squamous or non-squamous histology, which had progressed

Results

Between Sept 10, 2013, and June 24, 2014, 288 patients were screened and 184 eligible patients with locally advanced or metastatic measurable disease that had relapsed following treatment with a platinum-based doublet therapy were enrolled at 58 cancer treatment centres and academic hospitals in the USA (appendix pp 6, 7) and received avelumab (figure 1). Because of high interest in the study and subsequent acceleration of recruitment by investigators at the end of the enrolment period, planned

Discussion

In this large cohort of patients with metastatic NSCLC that had progressed following chemotherapy with a platinum-containing doublet, avelumab monotherapy showed an acceptable safety profile and encouraging clinical activity. Confirmed responses, which generally occurred early and were durable, were recorded in some patients, and more than a third of patients achieved stable disease. The time to response observed with avelumab is similar to median time to response reported for chemotherapy

References (33)

  • F Fossella et al.

    Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group

    J Clin Oncol

    (2003)
  • N Hanna et al.

    Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy

    J Clin Oncol

    (2004)
  • D Jackman et al.

    Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer

    J Clin Oncol

    (2010)
  • H Isozaki et al.

    Mechanisms of acquired resistance to ALK inhibitors and the rationale for treating ALK-positive lung cancer

    Cancers

    (2015)
  • H Dong et al.

    Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion

    Nat Med

    (2002)
  • SL Topalian et al.

    Safety, activity, and immune correlates of anti-PD-1 antibody in cancer

    N Engl J Med

    (2012)
  • Cited by (0)

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