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, John Ellerton, Jeffrey R. Infante, Manish Agrawal, Michael Gordon, Raid Aljumaily, Carolyn D. Britten, Luc Dirix, Keun Wook Lee, Mathew Taylor, Patrick Schöffski, Ding Wang, Alain Ravaud, Arnold B. Gelb, Junyuan Xiong, Galit Rosen, James L. Gulley, Andrea B. Apolo

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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.

    LanguageEnglish (US)
    Pages51-64
    Number of pages14
    JournalThe Lancet Oncology
    Volume19
    Issue number1
    DOIs
    StatePublished - Jan 1 2018

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    Platinum
    Carcinoma
    Neoplasms
    Safety
    avelumab
    Therapeutics
    Ligands
    Cisplatin
    Fatigue
    Pneumonia
    Asthenia
    Therapeutic Uses

    ASJC Scopus subject areas

    • Oncology

    Cite this

    Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor) : pooled results from two expansion cohorts of an open-label, phase 1 trial. / Patel, Manish R.; Ellerton, John; Infante, Jeffrey R.; Agrawal, Manish; Gordon, Michael; Aljumaily, Raid; Britten, Carolyn D.; Dirix, Luc; Lee, Keun Wook; Taylor, Mathew; Schöffski, Patrick; Wang, Ding; Ravaud, Alain; Gelb, Arnold B.; Xiong, Junyuan; Rosen, Galit; Gulley, James L.; Apolo, Andrea B.

    In: The Lancet Oncology, Vol. 19, No. 1, 01.01.2018, p. 51-64.

    Research output: Contribution to journalArticle

    Patel, MR, Ellerton, J, Infante, JR, Agrawal, M, Gordon, M, Aljumaily, R, Britten, CD, Dirix, L, Lee, KW, Taylor, M, Schöffski, P, Wang, D, Ravaud, A, Gelb, AB, Xiong, J, Rosen, G, Gulley, JL & Apolo, AB 2018, 'Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial' The Lancet Oncology, vol. 19, no. 1, pp. 51-64. https://doi.org/10.1016/S1470-2045(17)30900-2
    Patel, Manish R. ; Ellerton, John ; Infante, Jeffrey R. ; Agrawal, Manish ; Gordon, Michael ; Aljumaily, Raid ; Britten, Carolyn D. ; Dirix, Luc ; Lee, Keun Wook ; Taylor, Mathew ; Schöffski, Patrick ; Wang, Ding ; Ravaud, Alain ; Gelb, Arnold B. ; Xiong, Junyuan ; Rosen, Galit ; Gulley, James L. ; Apolo, Andrea B. / Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor) : pooled results from two expansion cohorts of an open-label, phase 1 trial. In: The Lancet Oncology. 2018 ; Vol. 19, No. 1. pp. 51-64.
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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.",
    author = "Patel, {Manish R.} and John Ellerton and Infante, {Jeffrey R.} and Manish Agrawal and Michael Gordon and Raid Aljumaily and Britten, {Carolyn D.} and Luc Dirix and Lee, {Keun Wook} and Mathew Taylor and Patrick Sch{\"o}ffski and Ding Wang and Alain Ravaud and Gelb, {Arnold B.} and Junyuan Xiong and Galit Rosen and Gulley, {James L.} and Apolo, {Andrea B.}",
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    T1 - Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor)

    T2 - The Lancet Oncology

    AU - Patel, Manish R.

    AU - Ellerton, John

    AU - Infante, Jeffrey R.

    AU - Agrawal, Manish

    AU - Gordon, Michael

    AU - Aljumaily, Raid

    AU - Britten, Carolyn D.

    AU - Dirix, Luc

    AU - Lee, Keun Wook

    AU - Taylor, Mathew

    AU - Schöffski, Patrick

    AU - Wang, Ding

    AU - Ravaud, Alain

    AU - Gelb, Arnold B.

    AU - Xiong, Junyuan

    AU - Rosen, Galit

    AU - Gulley, James L.

    AU - Apolo, Andrea B.

    PY - 2018/1/1

    Y1 - 2018/1/1

    N2 - 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.

    AB - 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.

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