Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial - PubMed (original) (raw)

Clinical Trial

doi: 10.1016/S1470-2045(17)30900-2. Epub 2017 Dec 5.

John Ellerton 2, Jeffrey R Infante 3, Manish Agrawal 4, Michael Gordon 5, Raid Aljumaily 6, Carolyn D Britten 7, Luc Dirix 8, Keun-Wook Lee 9, Mathew Taylor 10, Patrick Schöffski 11, Ding Wang 12, Alain Ravaud 13, Arnold B Gelb 14, Junyuan Xiong 14, Galit Rosen 14, James L Gulley 15, Andrea B Apolo 16

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Clinical Trial

Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial

Manish R Patel et al. Lancet Oncol. 2018 Jan.

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Abstract

Background: The approval of anti-programmed death ligand 1 (PD-L1) and anti-programmed death 1 agents has expanded treatment options for patients with locally advanced or metastatic urothelial carcinoma. Avelumab, a human monoclonal anti-PD-L1 antibody, has shown promising antitumour activity and safety in this disease. We aimed to assess the safety profile in patients (both post-platinum therapy and cisplatin-naive) treated with avelumab and to assess antitumour activity of this drug in post-platinum patients.

Methods: In this pooled analysis of two cohorts from the phase 1 dose-expansion JAVELIN Solid Tumor study, patients aged 18 years and older with histologically or cytologically confirmed locally advanced or metastatic urothelial carcinoma that had progressed after at least one previous platinum-based chemotherapy were enrolled from 80 cancer treatment centres or hospitals in the USA, Europe, and Asia. Eligible patients had adequate end-organ function, an Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, and at least one measurable lesion. Cisplatin-ineligible patients who might have been previously treated in the perioperative setting, including platinum-naive patients, were also eligible. Patients unselected for PD-L1 expression received avelumab (10 mg/kg, 1 h intravenous infusion) every 2 weeks until confirmed disease progression, unacceptable toxicity, or other criterion for withdrawal. The primary endpoint for this efficacy expansion cohort was confirmed best overall response (according to RECIST version 1.1), adjudicated by independent review. Safety analysis was done in all patients who received at least one dose of avelumab. Antitumour activity was assessed in post-platinum patients who received at least one dose of avelumab. This trial is registered with ClinicalTrials.gov, number NCT01772004; enrolment in this cohort of patients with metastatic urothelial carcinoma is closed and the trial is ongoing.

Findings: Between Sept 3, 2014, and March 15, 2016, 329 patients with advanced metastatic urothelial carcinoma were screened for enrolment into this study; 249 patients were eligible and received treatment with avelumab for a median of 12 weeks (IQR 6·0-19·7) and followed up for a median of 9·9 months (4·3-12·1). Safety and antitumour activity were evaluated at data cutoff on June 9, 2016. In 161 post-platinum patients with at least 6 months of follow-up, a best overall response of complete or partial response was recorded in 27 patients (17%; 95% CI 11-24), including nine (6%) complete responses and 18 (11%) partial responses. The most frequent treatment-related adverse events (any grade in ≥10% patients) were infusion-related reaction (73 [29%]; all grade 1-2) and fatigue (40 [16%]). Grade 3 or worse treatment-related adverse events occurred in 21 (8%) of 249 patients, the most common of which were fatigue (four [2%]), and asthenia, elevated lipase, hypophosphataemia, and pneumonitis in two (1%) patients each. 19 (8%) of 249 patients had a serious adverse event related to treatment with avelumab, and one treatment-related death occurred (pneumonitis).

Interpretation: Avelumab showed antitumour activity in the treatment of patients with platinum-refractory metastatic urothelial carcinoma; a manageable safety profile was reported in all avelumab-treated patients. These data provide the rationale for therapeutic use of avelumab in metastatic urothelial carcinoma and it has received accelerated US FDA approval in this setting on this basis.

Funding: Merck KGaA, and Pfizer Inc.

Copyright © 2018 Elsevier Ltd. All rights reserved.

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Figures

Figure 1:

Figure 1:

Trial profile

Figure 2:

Figure 2:. Antitumour activity of avelumab

(A) Time and duration of confirmed responses in patients with at least 6 months of follow-up (27 confirmed responses as of data cutoff). (B) Change in size of target lesions from baseline in evaluable patients with at least 6 months of follow-up (n=130) with programmed death ligand 1 (PD-L1) expression status indicated (based on a ≥5% expression staining threshold on tumour cells; non-evaluable specimens [n=16] included those that were missing, of poor quality, or otherwise not available to provide results). The upper dotted line represents progression at 20% increase in size of target lesions and the lower dotted line represents the Response Evaluation Criteria In Solid Tumors (RECIST) boundary for complete response or partial response at 30% decrease in size of target lesions. (C) Percentage change in sum of target lesion diameters from baseline over time for all assessable patients with at least 6 months of follow-up (n=130), defined as those patients with baseline tumour assessments and at least one post-baseline assessment. The upper dotted line represents progression at 20% increase in size of target lesions and the lower dotted line represents the RECIST boundary for complete response or partial response at 30% decrease in size of target lesions.

Figure 3:

Figure 3:. Subgroup analyses of responses based on patient and disease characteristics at baseline

(A) Objective responses by subgroup for select patient characteristics in patients with at least 6 months of follow-up. Plotted points represent % objective responses in each patient subgroup; error bars show 95% CIs. Vertical dashed line represents response rate in the n=161 population (17%). (B) Association of best overall response with tumour mutation based on RNAseq in patients with evaluable samples (n=29). ECOG=Eastern Cooperative Oncology Group. PD-L1=programmed death ligand 1.

Figure 4:

Figure 4:. Progression-free survival (A) and overall survival (B) in patients with at least 6 months of follow-up (n=161) and according to PD-L1 expression status

PD-L1 expression based on a 5% expression staining threshold (n=139 evaluable). PD-L1=programmed death ligand 1.

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