Abstract
Background: The combination of an immune checkpoint inhibitor and a VEGF pathway inhibitor to treat patients with advanced renal-cell carcinoma might increase the clinical benefit of these drugs compared with their use alone. Here, we report preliminary results for the combination of avelumab, an IgG1 monoclonal antibody against the programmed cell death protein ligand PD-L1, and axitinib, a VEGF receptor inhibitor approved for second-line treatment of advanced renal-cell carcinoma, in treatment-naive patients with advanced renal-cell carcinoma. Methods: The JAVELIN Renal 100 study is an ongoing open-label, multicentre, dose-finding, and dose-expansion, phase 1b study, done in 14 centres in the USA, UK, and Japan. Eligible patients were aged 18 years or older (≥20 years in Japan) and had histologically or cytologically confirmed advanced renal-cell carcinoma with clear-cell component, life expectancy of at least 3 months, an Eastern Cooperative Oncology Group performance status of 1 or less, received no previous systemic treatment for advanced renal cell carcinoma, and had a resected primary tumour. Patients enrolled into the dose-finding phase received 5 mg axitinib orally twice daily for 7 days, followed by combination therapy with 10 mg/kg avelumab intravenously every 2 weeks and 5 mg axitinib orally twice daily. Based on the pharmacokinetic data from the dose-finding phase, ten additional patients were enrolled into the dose-expansion phase and assigned to this regimen. The other patients in the dose-expansion phase started taking combination therapy directly. The primary endpoint was dose-limiting toxicities in the first 4 weeks (two cycles) of treatment with avelumab plus axitinib. Safety and antitumour activity analyses were done in all patients who received at least one dose of avelumab or axitinib. This trial is registered with ClinicalTrials.gov, number NCT02493751. Findings: Between Oct 30, 2015, and Sept 30, 2016, we enrolled six patients into the dose-finding phase and 49 into the dose-expansion phase of the study. One dose-limiting toxicity of grade 3 proteinuria due to axitinib was reported among the six patients treated during the dose-finding phase. At the cutoff date (April 13, 2017), six (100%, 95% CI 54–100) of six patients in the dose-finding phase and 26 (53%, 38–68) of 49 patients in the dose-expansion phase had confirmed objective responses (32 [58%, 44–71] of all 55 patients). 32 (58%) of 55 patients had grade 3 or worse treatment-related adverse events, the most frequent being hypertension in 16 (29%) patients and increased concentrations of alanine aminotransferase, amylase, and lipase, and palmar-plantar erythrodysaesthesia syndrome in four (7%) patients each. Six (11%) of 55 patients died before data cutoff, five (9%) due to disease progression and one (2%) due to treatment-related autoimmune myocarditis. At the end of the dose-finding phase, the maximum tolerated dose established for the combination was avelumab 10 mg/kg every 2 weeks and axitinib 5 mg twice daily. Interpretation: The safety profile of the combination avelumab plus axitinib in treatment-naive patients with advanced renal-cell carcinoma seemed to be manageable and consistent with that of each drug alone, and the preliminary data on antitumour activity are encouraging. A phase 3 trial is assessing avelumab and axitinib compared with sunitinib monotherapy. Funding: Pfizer and Merck.
Original language | English |
---|---|
Pages (from-to) | 451-460 |
Number of pages | 10 |
Journal | The Lancet Oncology |
Volume | 19 |
Issue number | 4 |
DOIs | |
Publication status | Published - 2018 Apr |
ASJC Scopus subject areas
- Oncology
Access to Document
Other files and links
Fingerprint
Dive into the research topics of 'Preliminary results for avelumab plus axitinib as first-line therapy in patients with advanced clear-cell renal-cell carcinoma (JAVELIN Renal 100): an open-label, dose-finding and dose-expansion, phase 1b trial'. Together they form a unique fingerprint.Cite this
- APA
- Standard
- Harvard
- Vancouver
- Author
- BIBTEX
- RIS
Preliminary results for avelumab plus axitinib as first-line therapy in patients with advanced clear-cell renal-cell carcinoma (JAVELIN Renal 100) : an open-label, dose-finding and dose-expansion, phase 1b trial. / Choueiri, Toni K.; Larkin, James; Oya, Mototsugu et al.
In: The Lancet Oncology, Vol. 19, No. 4, 04.2018, p. 451-460.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Preliminary results for avelumab plus axitinib as first-line therapy in patients with advanced clear-cell renal-cell carcinoma (JAVELIN Renal 100)
T2 - an open-label, dose-finding and dose-expansion, phase 1b trial
AU - Choueiri, Toni K.
AU - Larkin, James
AU - Oya, Mototsugu
AU - Thistlethwaite, Fiona
AU - Martignoni, Marcella
AU - Nathan, Paul
AU - Powles, Thomas
AU - McDermott, David
AU - Robbins, Paul B.
AU - Chism, David D.
AU - Cho, Daniel
AU - Atkins, Michael B.
AU - Gordon, Michael S.
AU - Gupta, Sumati
AU - Uemura, Hirotsugu
AU - Tomita, Yoshihiko
AU - Compagnoni, Anna
AU - Fowst, Camilla
AU - di Pietro, Alessandra
AU - Rini, Brian I.
N1 - Funding Information: Avelumab combined with axitinib as first-line treatment in patients with advanced renal-cell carcinoma had a manageable safety profile and showed encouraging antitumour activity. The maximum tolerated dose established in the dose-finding phase was avelumab 10 mg/kg every 2 weeks plus axitinib 5 mg twice daily, but further assessment of this dose (ie, clinical feasibility of long-term administration) will inform the recommended phase 2 dose. Although cross-trial comparisons of safety profiles are complicated by differences in study design and reporting (eg, all-cause vs treatment-related events), the adverse events observed with combination therapy in this study were largely consistent with the known safety profiles of avelumab 16 and axitinib 23 when used alone or combined with pembrolizumab and axitinib in phase 1/2 studies. 18 No new toxicities were reported. The frequencies of all-grade and grade 3 or 4 events of increased alanine aminotransferase concentrations were slightly higher than those previously reported 23 in a larger set of patients with advanced renal-cell carcinoma treated with axitinib (all grades 29% vs 22%; grade 3 or 4 7% [with no grade 4 events] vs <1%). The frequencies, types, and severities of immune-related adverse events in this trial were consistent with those reported for other monoclonal antibodies inhibiting PD-L1 and PD-1 interactions, 3 including rare autoimmune myocarditis. 23 Infusion-related reactions were mostly mild to moderate, and occurred mainly at the first infusion. One patient discontinued treatment because of an infusion-related reaction, and the proportion of patients who had axitinib dose reductions was higher than that reported in a previous study of axitinib monotherapy (56% vs 25%). 24 The antitumour activity observed with the combination of avelumab and axitinib was encouraging, with most patients experiencing early and durable responses. The proportion of patients with confirmed objective responses was 58% (95% CI 44–71), which was higher than that seen with axitinib alone, and was consistent with response data from other phase 1/2 studies of monoclonal antibodies inhibiting interactions between PD-L1 and PD-1 combined with angiogenesis inhibitors. For instance, in a study of single-agent axitinib treatment in previously untreated patients with advanced renal-cell carcinoma, an objective response was seen 62 (32%) of 192 patients. 24 Preliminary results from a phase 1b study of axitinib combined with pembrolizumab as first-line therapy for advanced renal-cell carcinoma showed objective responses in 37 (71%) of 52 patients. 18 In a phase 2 study of bevacizumab combined with atezolizumab compared with sunitinib monotherapy in treatment-naive patients with advanced renal-cell carcinoma, objective responses were seen in 32% and 29% of patients, respectively. 21 Multiple combinations are currently under investigation in phase 3 trials. 3 In a randomised phase 3 trial that compared the combination of the immune checkpoint inhibitors nivolumab and ipilimumab (a CTLA-4 inhibitor) with sunitinib alone, objective responses were seen in 42% (95% CI 37–47) versus 27% (22–31), and an overall survival improvement was seen with combined therapy for patients in the poor-risk and intermediate-risk categories. 10 The clinical benefit observed in patients with advanced renal cell carcinoma classified into poor-risk and intermediate-risk categories in this study indicates potential for a shift away from single-agent TKIs as preferred first-line standard-of-care treatment. PD-L1 is often expressed in the tumour microenvironment in patients with renal-cell carcinoma. 25 In our study, PD-L1 expression was assessed on tumour and immune cells, and there seemed to be a correlation between intratumour PD-L1 expression and the likelihood of achieving an objective response after receiving avelumab plus axitinib. Similarly, in the IMmotion 150 trial, 21 the number of patients with objective responses among patients who received bevacizumab and atezolizumab was higher among those with PD-L1 expressed on at least 1% of the tumour-infiltrated immune cells than in those who had PD-L1 expression on less than 1% of the immune infiltrates. In addition, clinical activity in the CheckMate-214 study, 10 which investigated the combination of nivolumab and ipilimumab in patients with renal-cell carcinoma, was substantially higher in patients with tumours positive for PD-L1 than in those without PD-L1 expression. Although in this study we noted an association between objective response and high PD-L1 tumour expression, we did not formally test the predictive value of PD-L1 expression in patients with advanced renal-cell carcinoma treated with avelumab plus axitinib. This trial had several limitations. It is a single-arm trial with no monotherapy comparator groups, which prevents the direct comparison of the combination treatment with the respective drugs used alone in this population. Additionally, progression-free and overall survival data were not mature at the time of data cutoff because the minimum follow-up time for this analysis was 27·6 weeks and most patients were still receiving treatment. Longer follow-up will aid in further describing the antitumour activity of combined avelumab and axitinib in patients with advanced clear-cell renal-cell carcinoma. In conclusion, the combination of avelumab and axitinib in treatment-naive patients with advanced renal-cell carcinoma had a manageable safety profile consistent with the profiles of the individual agents when administered as monotherapy, and antitumour activity was encouraging. The JAVELIN Renal 101, randomised, phase 3 trial comparing avelumab and axitinib versus sunitinib monotherapy for first-line treatment of patients with advanced renal-cell carcinoma is ongoing. 26 Contributors TKC, MM, TP, PBR, MBA, SG, AC, CF, AdP, and BIR conceived and designed the study. TKC, JL, MM, PN, TP, DM, PBR, DDC, DC, MBA, MSG, SG, HU, YT, AC, AdP, and BIR collected and assembled the data. TKC, JL, MM, PN, DM, PBR, DDC, DC, MBA, MSG, SG, HU, YT, AC, CF, AdP, and BIR analysed and interpreted the data. All authors were involved in writing the Article and approved the final version. Declaration of interests TKC has received grants and personal fees from AstraZeneca, Bristol-Myers Squibb, Eisai, Exelixis, GlaxoSmithKline, Merck, Novartis, Pfizer, Peloton, and Roche/Genentech, personal fees from Bayer, Cerulean, Corvus, Foundation Medicine, and Prometheus Laboratories, and grants from Tracon. JL has received grants and personal fees from Bristol-Myers Squibb, Merck, Novartis, and Pfizer, personal fees from Eisai, EUSA Pharma, GlaxoSmithKline, Kymab, Pierre Fabre, Roche/Genentech, and Secarna. MO has received grants and personal fees from Asahi Kasei Pharma, Astellas Pharma, Novartis Pharma, Ono Pharmaceutical, and Pfizer Japan, grants from ASKA Pharmaceutical, and personal fees from AstraZeneca, Bayer Yakuhin, Boston Scientific Corp, Bristol-Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Hisamitsu Pharmaceutical, Janssen Pharmaceutical, Meiji Seika Pharma, Merck, Nihon Medi-Physics, Nippon Kayaku, Nippon Shinyaku, Kissei Pharmaceutical, Kyorin Pharmaceutical, Kyowa Hakko Kirin, Sanofi, Shionogi, Sumitomo Dainippon Pharmaceutical, Taiho Pharmaceutical, Takeda Pharmaceutical, Teijin Pharma, and Tsumura. FT has received grants from Bristol-Myers Squibb and Novartis. MM, AC, CF, and AdP are employees of Pfizer. MM and AdP have a pending patent (WO2016205277). PN has received personal fees from Merck. TP has received personal fees from AstraZeneca, Merck, Novartis, Pfizer, and Roche, and grants from AstraZeneca and Roche. DM has received personal fees from Array BioPharm, Bristol-Myers Squibb, Eisai, Exelixis, Genentech BioOncology, Merck, Novartis, and Pfizer, and grants from Prometheus Laboratories. PBR was an employee of Pfizer during the trial, has been an employee of AstraZeneca, and has pending patents (anti-PD-L1 and anti-CTLA-4 antibodies for treating solid tumours; anti-B7-H1 antibodies for treating tumours; and antibodies and methods of detection of an immune modulator). DDC has received personal fees from Exelixis and Karyopharm. DC has received personal fees from Bristol-Myers Squibb, Exelixis, Genentech, Pfizer, and Prometheus Laboratories. MBA has received grants and personal fees from Pfizer and personal fees from Bristol-Myers Squibb, Exelixis, Eisai, Merck, Novartis, and Roche. SG's institution received funding from Bristol-Myers Squibb, Five Prime, Hoosier, Incyte, Merck, Novartis, Pfizer, Rexahn, and Viralytics, and SG's spouse holds stock in Salarius. YT has received grants from Astellas, AstraZeneca, Bristol-Myers Squibb, Ono Pharmaceutical, Pfizer, and personal fees from Astellas, AstraZeneca, Ono Pharmaceutical, and Pfizer. BIR has received grants and personal fees from Pfizer. The other authors declare no competing interests. Acknowledgments We thank the patients and their families and the investigators, co-investigators, and study teams at each of the participating centres and at Pfizer, Milan, Italy. The full list of participating study sites and principal investigators is shown in the appendix (p 4) . This trial was sponsored by Pfizer, New York, NY, USA, and is part of an alliance with Merck, Darmstadt, Germany. Medical writing support was provided by Shaun Rosebeck at ClinicalThinking, Hamilton, NJ, USA, and was funded by Pfizer, and Merck. Publisher Copyright: © 2018 Elsevier Ltd
PY - 2018/4
Y1 - 2018/4
N2 - Background: The combination of an immune checkpoint inhibitor and a VEGF pathway inhibitor to treat patients with advanced renal-cell carcinoma might increase the clinical benefit of these drugs compared with their use alone. Here, we report preliminary results for the combination of avelumab, an IgG1 monoclonal antibody against the programmed cell death protein ligand PD-L1, and axitinib, a VEGF receptor inhibitor approved for second-line treatment of advanced renal-cell carcinoma, in treatment-naive patients with advanced renal-cell carcinoma. Methods: The JAVELIN Renal 100 study is an ongoing open-label, multicentre, dose-finding, and dose-expansion, phase 1b study, done in 14 centres in the USA, UK, and Japan. Eligible patients were aged 18 years or older (≥20 years in Japan) and had histologically or cytologically confirmed advanced renal-cell carcinoma with clear-cell component, life expectancy of at least 3 months, an Eastern Cooperative Oncology Group performance status of 1 or less, received no previous systemic treatment for advanced renal cell carcinoma, and had a resected primary tumour. Patients enrolled into the dose-finding phase received 5 mg axitinib orally twice daily for 7 days, followed by combination therapy with 10 mg/kg avelumab intravenously every 2 weeks and 5 mg axitinib orally twice daily. Based on the pharmacokinetic data from the dose-finding phase, ten additional patients were enrolled into the dose-expansion phase and assigned to this regimen. The other patients in the dose-expansion phase started taking combination therapy directly. The primary endpoint was dose-limiting toxicities in the first 4 weeks (two cycles) of treatment with avelumab plus axitinib. Safety and antitumour activity analyses were done in all patients who received at least one dose of avelumab or axitinib. This trial is registered with ClinicalTrials.gov, number NCT02493751. Findings: Between Oct 30, 2015, and Sept 30, 2016, we enrolled six patients into the dose-finding phase and 49 into the dose-expansion phase of the study. One dose-limiting toxicity of grade 3 proteinuria due to axitinib was reported among the six patients treated during the dose-finding phase. At the cutoff date (April 13, 2017), six (100%, 95% CI 54–100) of six patients in the dose-finding phase and 26 (53%, 38–68) of 49 patients in the dose-expansion phase had confirmed objective responses (32 [58%, 44–71] of all 55 patients). 32 (58%) of 55 patients had grade 3 or worse treatment-related adverse events, the most frequent being hypertension in 16 (29%) patients and increased concentrations of alanine aminotransferase, amylase, and lipase, and palmar-plantar erythrodysaesthesia syndrome in four (7%) patients each. Six (11%) of 55 patients died before data cutoff, five (9%) due to disease progression and one (2%) due to treatment-related autoimmune myocarditis. At the end of the dose-finding phase, the maximum tolerated dose established for the combination was avelumab 10 mg/kg every 2 weeks and axitinib 5 mg twice daily. Interpretation: The safety profile of the combination avelumab plus axitinib in treatment-naive patients with advanced renal-cell carcinoma seemed to be manageable and consistent with that of each drug alone, and the preliminary data on antitumour activity are encouraging. A phase 3 trial is assessing avelumab and axitinib compared with sunitinib monotherapy. Funding: Pfizer and Merck.
AB - Background: The combination of an immune checkpoint inhibitor and a VEGF pathway inhibitor to treat patients with advanced renal-cell carcinoma might increase the clinical benefit of these drugs compared with their use alone. Here, we report preliminary results for the combination of avelumab, an IgG1 monoclonal antibody against the programmed cell death protein ligand PD-L1, and axitinib, a VEGF receptor inhibitor approved for second-line treatment of advanced renal-cell carcinoma, in treatment-naive patients with advanced renal-cell carcinoma. Methods: The JAVELIN Renal 100 study is an ongoing open-label, multicentre, dose-finding, and dose-expansion, phase 1b study, done in 14 centres in the USA, UK, and Japan. Eligible patients were aged 18 years or older (≥20 years in Japan) and had histologically or cytologically confirmed advanced renal-cell carcinoma with clear-cell component, life expectancy of at least 3 months, an Eastern Cooperative Oncology Group performance status of 1 or less, received no previous systemic treatment for advanced renal cell carcinoma, and had a resected primary tumour. Patients enrolled into the dose-finding phase received 5 mg axitinib orally twice daily for 7 days, followed by combination therapy with 10 mg/kg avelumab intravenously every 2 weeks and 5 mg axitinib orally twice daily. Based on the pharmacokinetic data from the dose-finding phase, ten additional patients were enrolled into the dose-expansion phase and assigned to this regimen. The other patients in the dose-expansion phase started taking combination therapy directly. The primary endpoint was dose-limiting toxicities in the first 4 weeks (two cycles) of treatment with avelumab plus axitinib. Safety and antitumour activity analyses were done in all patients who received at least one dose of avelumab or axitinib. This trial is registered with ClinicalTrials.gov, number NCT02493751. Findings: Between Oct 30, 2015, and Sept 30, 2016, we enrolled six patients into the dose-finding phase and 49 into the dose-expansion phase of the study. One dose-limiting toxicity of grade 3 proteinuria due to axitinib was reported among the six patients treated during the dose-finding phase. At the cutoff date (April 13, 2017), six (100%, 95% CI 54–100) of six patients in the dose-finding phase and 26 (53%, 38–68) of 49 patients in the dose-expansion phase had confirmed objective responses (32 [58%, 44–71] of all 55 patients). 32 (58%) of 55 patients had grade 3 or worse treatment-related adverse events, the most frequent being hypertension in 16 (29%) patients and increased concentrations of alanine aminotransferase, amylase, and lipase, and palmar-plantar erythrodysaesthesia syndrome in four (7%) patients each. Six (11%) of 55 patients died before data cutoff, five (9%) due to disease progression and one (2%) due to treatment-related autoimmune myocarditis. At the end of the dose-finding phase, the maximum tolerated dose established for the combination was avelumab 10 mg/kg every 2 weeks and axitinib 5 mg twice daily. Interpretation: The safety profile of the combination avelumab plus axitinib in treatment-naive patients with advanced renal-cell carcinoma seemed to be manageable and consistent with that of each drug alone, and the preliminary data on antitumour activity are encouraging. A phase 3 trial is assessing avelumab and axitinib compared with sunitinib monotherapy. Funding: Pfizer and Merck.
UR - http://www.scopus.com/inward/record.url?scp=85043381916&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85043381916&partnerID=8YFLogxK
U2 - 10.1016/S1470-2045(18)30107-4
DO - 10.1016/S1470-2045(18)30107-4
M3 - Article
C2 - 29530667
AN - SCOPUS:85043381916
VL - 19
SP - 451
EP - 460
JO - The Lancet Oncology
JF - The Lancet Oncology
SN - 1470-2045
IS - 4
ER -