Munich, Germany, 21 October 2018 - A combination of the immune checkpoint blocker, avelumab, plus the tyrosine kinase inhibitor (TKI), axitinib, significantly improves progression-free survival (PFS) in previously untreated patients with advanced renal cell carcinoma (RCC) in a phase 3 study, according to results presented at ESMO 2018 Congress.
Median PFS was 13.8 versus 7.2 months in the combination arm compared to the sunitinib arm (HR = 0.61; p < .0001) in the patients with programmed cell death-ligand 1 positive (PD-L1+) tumours, while median PFS in patients irrespective of PD-L1 expression was 13.8 versus 8.4 months (HR = 0.69; p = .0001) respectively. Confirmed objective response rate was 55.2 (CI 95%: 49.9, 61.2) and 25.5 (CI 95%: 20.6, 30.9) respectively.
"JAVELIN Renal 101 is the first positive phase 3 study combining an immune checkpoint blocker with a TKI compared to TKI alone in the first line treatment of advanced RCC," remarked Dr Robert Motzer, presenter and study lead from Memorial Sloan Kettering Cancer Center, New York City, US. "The findings support the potential of avelumab plus axitinib as a new treatment approach for patients with advanced RCC. The combination benefit was shown in all subgroups of patients, by independent review as well as by investigators, and whether tumour cells stained positive for PD-L1 or not," he continued.
Despite available therapies, the outlook for patients with advanced RCC remains poor with less than 10% of patients surviving at five years post-diagnosis.
New treatment options are needed. Avelumab is an IgG1 monoclonal antibody against the programmed cell death protein ligand PD-L1 (checkpoint blocker), while axitinib is a TKI, and TKIs have been the mainstay of treatment. "TKIs, and checkpoint blockers like avelumab, both may have potential immune-modulating functions that, when combined, may provide clinical benefit in patients with advanced RCC that exceeds the effects of the respective drugs alone, without compromising toxicity," said Motzer.
In the JAVELIN Renal 101 global, randomised trial, 886 kidney cancer patients with all MSKCC (Memorial Sloan Kettering Cancer Center/Motzer score used for selection of mRCC patients for trial inclusion) prognostic subgroups (good, intermediate, and poor risk) were enrolled and were administered therapy as first-line treatment. Avelumab was administered to 442 patients at 10 mg/kg intravenously (IV) every two weeks in combination with axitinib, 5 mg orally twice daily. The comparator group of 444 patients received sunitinib given at 50 mg orally once a day on a schedule of four weeks on followed by two weeks off (4/2). The primary outcomes were PFS in PD-L1+ patients (up to 30 months); and overall survival in PD-L1+ patients up to five years.
Treatment-emergent adverse events of grade 3 and over were experienced by 71.2% versus 71.5% of patients in the combination versus sunitinib arms respectively, and led to discontinuation of drug in 22.8% versus 13.4% respectively.
Prof. Thomas Powles, consultant oncologist at Barts Health NHS Trust, London, UK, commented on the results. "The results are eye catching. The response rates are twice as good as previous standards of care, and progression-free survival is entering into very impressive territory for a randomised trial. This approach involves giving combinations of most active agents upfront, therefore there is uncertainty around whether this will translate into a similarly impressive survival signal, as seen with other immunotherapy combinations."
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1 Abstract LBA6_PR 'JAVELIN Renal 101: A randomized, phase III study of avelumab + axitinib vs sunitinib as first-line treatment of advanced renal cell carcinoma (aRCC)' will be presented by Robert Motzer during Presidential Symposium 2 on Sunday 21 October, 16:30 to 18:10 (CEST) in Room 18 - Hall A2. Annals of Oncology, Volume 29 Supplement 8 October 2018
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LBA6_PR - JAVELIN Renal 101: A randomized, phase III study of avelumab + axitinib vs sunitinib as first-line treatment of advanced renal cell carcinoma (aRCC)
R.J. Motzer1, K. Penkov2, J.B.A.G. Haanen3, B.I. Rini4, L. Albiges5, M.T. Campbell6, C.K. Kollmannsberger7, S. Negrier8, M. Uemura9, J.L. Lee10, H. Gurney11, R. Berger12, M. Schmidinger13, J. Larkin14, M.B. Atkins15, J. Wang16, P.B. Robbins17, A. Chudnovsky18, A. Di Pietro19, T.K. Choueiri20
1Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA, 2Medical Oncology, Private Medical Institution "Euromedservice", St. Petersburg, Russian Federation, 3Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, Netherlands, 4Medical Oncology, Cleveland Clinic, Cleveland, OH, USA, 5Department of Cancer Medicine, Institut Gustave Roussy, Villejuif, France, 6Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, 7Medical Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada, 8D'Oncologie Medicale, Centre Leon Berard, Lyon, France, 9Medical Oncology, Osaka University Hospital, Osaka, Japan, 10Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea, 11Medicine and Health Sciences, Macquarie University, Macquarie Park, Australia, 12Institute of Onocology and Radiotherapy, Chaim Sheba Medical Center, Ramat Gan, Israel, 13Department of Medicine I, Clinical Division of Oncology and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria, 14Department of Medical Oncology, Royal Marsden NHS Foundation Trust, London, UK, 15Oncology & Medicine, Georgetown-Lombardi Comprehensive Cancer Center, Washington DC, USA, 16Oncology, Pfizer, Cambridge, MA, USA, 17Translational Oncology, Pfizer, San Diego, CA, USA, 18Immuno-Oncology, Pfizer, Cambridge, MA, USA, 19Immuno-Oncology, Pfizer, Milan, Italy, 20Medical Oncology, The Lank Center for Genitourinary Oncology Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA, USA
Background: In a phase 1b trial, 1L A + Ax had encouraging antitumor activity for patients (pts) with aRCC (Lancet Oncol. 2018;19:451).
Methods: Eligible pts with clear-cell aRCC, ECOG less than or equal to 1, and no prior systemic therapy were randomized 1:1 (stratified by ECOG and geographic region) to receive A 10 mg/kg IV Q2W + Ax 5 mg PO BID in 6-wk cycles or S 50 mg PO QD on schedule 4/2; all prognostic risk groups were included. Primary endpoints were progression-free survival (PFS; by blinded independent central review [BICR] per RECIST v1.1) and overall survival (OS) in pts with PD-L1+ tumors (greater than or equal to 1% of immune cells). Secondary endpoints included PFS by BICR and OS irrespective of PD-L1 expression, objective response (OR), and safety.
Results: As of 20 Jun 2018, 886 pts were randomized (A + Ax: N = 442; S: N = 444); of these, 21%/62%/16% had favorable/intermediate/poor IMDC risk criteria (not reported in < 1%). In 560 pts (63.2%) with PD-L1+ tumors, median PFS was 13.8 vs 7.2 mo in A + Ax vs S arms, respectively (HR = 0.61; p < .0001; Table). Median PFS in pts irrespective of PD-L1 expression was 13.8 vs 8.4 mo (HR = 0.69; p = .0001). PFS and OR results favored A + Ax in pts irrespective of PD-L1 expression and in all MSKCC/IMDC prognostic risk groups. OS data were immature at data cutoff (< 16% of pts with events). In A + Ax vs S arms, grade ?3 treatment-emergent adverse events occurred in 71.2% vs 71.5% of pts and led to discontinuation of any study drug in 22.8% vs 13.4%; deaths due to study treatment toxicity occurred in 0.7% vs 0.2% of pts.
Conclusions: This randomized phase 3 trial met its primary objective of significantly improving PFS in pts with PD-L1+ aRCC treated with A + Ax vs S. PFS and OR benefit was also observed in pts irrespective of PD-L1 expression and across all prognostic risk groups. The safety profiles were consistent with those of prior studies of each drug. These results support A + Ax as a potential new 1L standard-of-care for pts with aRCC.
Clinical trial identification: NCT02684006
Editorial Acknowledgement: Medical writing support was provided by ClinicalThinking Inc., Hamilton, NJ, USA
Legal entity responsible for the study: Pfizer, Inc
Funding: This trial was sponsored by Pfizer and is part of an alliance between Pfizer and Merck KGaA, Darmstadt, Germany
Disclosure: R.J. Motzer: Financial interest: Pfizer, Bristol Myers Squibb, Novartis, Eisai, Exelixis, Genentech/Roche, Merck.
K. Penkov: Financial interest: the private medical institution Euromedservice.
B.I. Rini: Financial interest: Novartis, BMS, Pfizer, Merck, Astra-Zeneca.
L. Albiges: Financial interest: Bristol-Myers Squibb, Pfizer, Novartis, Ipsen, Roche, Astellas Pharma, Merck, Amgen.
M.T. Campbell: Financial interest: Pfizer, Genentech, Apricity, AstraZeneca, Eisai, EMD Serono.
S. Negrier: Financial interest: Pfizer, Ipsen, BMS, Novartis, EUSA Pharma.
H. Gurney: Financial interest: Bristol-Myers Squibb, Ipsen, Merck Sharp & Dohme, AstraZeneca, Astellas Pharma, Roche, Pfizer.
M. Schmidinger: Financial interest: Pfizer, Roche, Novartis, BMS, Ipsen, Exelixis, Eisai, Astellas.
J. Larkin: Financial interest: BMS, MSD, Novartis, Pfizer, Eisai, GSK, Kymab, Roche/Genentech, Roche, Secarna, Pierre Fabre, EUSA Pharma.
M.B. Atkins: Financial interest: BMS, Merck, Novartis, Genentech/Roche, Pfizer, Exelixis, Eisai, AstraZeneca, Array.
J. Wang: Employment at and stock ownership in Pfizer, Inc.
P.B. Robbins: Financial interest: Pfizer, AstraZeneca, Merck, BMS.
A. Chudnovsky: Financial interest: Pfizer.
A. Di Pietro: Dr. di Pietro reports financial interest from Pfizer.
T.K. Choueiri: Financial interest: AstraZeneca, Bayer, BMS, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Corvus, Ipsen, Tracon.
All other authors have declared no conflicts of interest.