Background: Ramucirumab—an IgG1 vascular endothelial growth factor receptor 2 antagonist—plus docetaxel was previously reported to improve progression-free survival in platinum-refractory, advanced urothelial carcinoma. Here, we report the secondary endpoint of overall survival results for the RANGE trial. Methods: We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 investigative sites (hospitals, clinics, and academic centres) in 23 countries. Previous treatment with one immune checkpoint inhibitor was permitted. Patients were randomly assigned (1:1) using an interactive web response system to receive intravenous ramucirumab 10 mg/kg or placebo 10 mg/kg volume equivalent followed by intravenous docetaxel 75 mg/m2 (60 mg/m2 in Korea, Taiwan, and Japan) on day 1 of a 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met. Randomisation was stratified by geographical region, Eastern Cooperative Oncology Group performance status at baseline, and visceral metastasis. Progression-free survival (the primary endpoint) and overall survival (a key secondary endpoint) were assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT02426125; patient enrolment is complete and the last patient on treatment is being followed up for safety issues. Findings: Between July 20, 2015, and April 4, 2017, 530 patients were randomly allocated to ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267) and comprised the intention-to-treat population. At database lock (March 21, 2018) for the final overall survival analysis, median follow-up was 7·4 months (IQR 3·5–13·9). In our sensitivity analysis of investigator-assessed progression-free survival at the overall survival database lock, median progression-free survival remained significantly improved with ramucirumab compared with placebo (4·1 months [95% CI 3·3–4·8] vs 2·8 months [2·6–2·9]; HR 0·696 [95% CI 0·573–0·845]; p=0·0002). Median overall survival was 9·4 months (95% CI 7·9–11·4) in the ramucirumab group versus 7·9 months (7·0–9·3) in the placebo group (stratified HR 0·887 [95% CI 0·724–1·086]; p=0·25). Grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients and with an incidence more than 2% higher with ramucirumab than with placebo were febrile neutropenia (24 [9%] of 258 patients in the ramucirumab group vs 16 [6%] of 265 patients in the placebo group) and neutropenia (17 [7%] of 258 vs six [2%] of 265). Serious adverse events were similar between groups (112 [43%] of 258 patients in the ramucirumab group vs 107 [40%] of 265 patients in the placebo group). Adverse events related to study treatment and leading to death occurred in eight (3%) patients in the ramucirumab group versus five (2%) patients in the placebo group. Interpretation: Additional follow-up supports that ramucirumab plus docetaxel significantly improves progression-free survival, without a significant improvement in overall survival, for patients with platinum-refractory advanced urothelial carcinoma. Clinically meaningful benefit might be restricted in an unselected population. Funding: Eli Lilly and Company.
|Number of pages||16|
|Journal||The Lancet Oncology|
|Publication status||Published - 2020 Jan|
Bibliographical noteFunding Information:
Eli Lilly and company will provide access to all individual participant data collected during the trial, after anonymisation, except for pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the USA and EU and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data have been made available. Access to data will be provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, and blank or annotated case report forms, will be provided in a secure data sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org . Acknowledgments This study was funded by Eli Lilly and Company. We thank the patients, their families, and the study personnel across all sites for participating in this study. We thank the independent data monitoring committee, and the entire RANGE clinical trial team. Susan P Whitman, an employee of Eli Lilly and Company, provided medical writing support. Ling Gao, an employee of Eli Lilly and Company, contributed to pharmacokinetic schedule design, data analysis, and interpretation. Ryan Rhodes, formerly employed by Eli Lilly and Company, contributed to biomarker data generation and analysis.
To our knowledge, ramucirumab is the only angiogenesis inhibitor, in combination with docetaxel, to show significant improvement in progression-free survival compared with placebo plus docetaxel in a phase 3 trial of platinum-refractory urothelial carcinoma. Platinum-refractory urothelial carcinoma is a challenging disease with typically short overall survival, poor achievement of overall response, and multiple failed trials. To our knowledge, pembrolizumab is the only therapy to achieve a statistically significant improvement in overall survival compared with chemotherapy in this population. 1 The RANGE trial was designed to test the primary efficacy endpoint of progression-free survival, which was achieved. The progression-free survival benefit was maintained with longer follow-up in the intention-to-treat sensitivity analysis (HR 0·696 [95% CI 0·573–0·845]). The proportion of patients with an objective response also remained consistent with that in the intention-to-treat sensitivity analysis, with an almost doubling of responses in the ramucirumab group compared with the placebo group. Duration of response was also longer in the ramucirumab group than in the placebo group. The higher proportion of patients with a response and duration of response probably contributed to the longer progression-free survival we observed in the ramucirumab group compared with the placebo group. Our safety and quality of life findings were also consistent with previously reported results. 20 No new safety issues emerged with longer follow-up, and quality of life was maintained. Overall survival was not significantly improved with the addition of ramucirumab to docetaxel compared with placebo plus docetaxel in the intention-to-treat population. Post-discontinuation therapies, including use of immune therapies, were similar between the treatment groups and unlikely to have contributed to any overall survival differences observed. The overall survival endpoint was designed to test a clinically meaningful improvement with an assumed HR of 0·75 and a 3-month improvement in overall survival from 9 months to 12 months with the addition of ramucirumab to docetaxel. RANGE did not meet this endpoint in the intention-to-treat population. Since pembrolizumab has previously shown a statistically significant overall survival benefit in a similar population compared with taxane monotherapy or vinflunine in a randomised phase 3 trial, 1 pembrolizumab could be accepted over ramucirumab as a preferred standard of care. Atezolizumab did not show superiority versus chemotherapy in a randomised phase 3 study 2 but is still used to treat patients with locally advanced or metastatic urothelial carcinoma after progression with platinum-based chemotherapy. Given the few treatment options for platinum-refractory disease and the potential use of PD-1 and PD-L1 agents in frontline combinations, pending the results of several key phase 3 trials (eg, pembrolizumab with or without standard chemotherapy [ NCT02853305 ], atezolizumab with or without platinum-based chemotherapy [ NCT02807636 ], and durvalumab with or without tremelimumab [ NCT02516241 ]), our trial results are important for treatment decisions in the second-line setting. The pre-specified subgroup overall survival analyses in RANGE, although exploratory in nature, warrant further consideration. We observed an almost 3-month improvement in overall survival with the addition of ramucirumab for patients with a primary bladder tumour, but found no difference for patients with non-bladder primary tumours ( appendix p 24 ). A similar finding was reported in the randomised phase 3 EORTC Intergroup study, which evaluated the addition of paclitaxel to cisplatin and gemcitabine. 26 Paclitaxel has been reported to have potential anti-angiogenic effects, which raises the question of whether the tumour site of origin within urothelial carcinoma might result in a variable response to anti-angiogenic therapy. 27 In the RANGE study, patients from east Asia had no overall survival benefit with ramucirumab compared with patients not from east Asia. Patients from east Asia also had a lower proportion of bladder primary tumours (42% in the ramucirumab group and 49% in the placebo group) compared with patients from other geographical regions (where bladder primary tumours ranged from 67–76%). Genomic and molecular characterisation of upper urinary tract and lower urinary tract tumours, and knowledge of how different urinary carcinoma molecular classifications might respond to chemotherapy, is evolving. 28–30 The molecular alterations and relative proportions of different genomic subgroups might vary between upper-tract and lower-tract disease. Biomarker research to explore potential genomic drivers of response to ramucirumab and the differences seen in upper-tract versus lower-tract tumours in the RANGE trial is ongoing. We enrolled a population that was characteristic of patients with platinum-refractory urothelial carcinoma; however, this might have been a limitation of the study. The short median follow-up duration of 7·4 months (IQR 3·5–13·9) reflects the poor prognosis of the patients enrolled in this study, with many patients succumbing to their disease within a few months. Approxiately a quarter of patients enrolled in the study died in the first 4·5 months of the study, which might have restricted our ability to see any treatment effects. The RANGE team has previously reported that overall survival varies with clinical characteristics, with median overall survival in the placebo group ranging from 6·1 months to 10·5 months, depending on baseline characteristics, and ramucirumab having the greatest overall survival effect in patients with more favourable clinical characteristics. 31 We plan to report pharmacokinetic analysis of exposure response in a future publication. Enrolling a broad population might dilute the effect of anti-angiogenic treatment if only a small group of patients truly benefit; this might also have affected the results of CALGB 90601, 32 which also did not show a significant improvement in overall survival and only a modest improvement in progression-free survival with the addition of bevacizumab to frontline platinum treatment in patients with metastatic urothelial carcinoma. To date, to our knowledge, a selection strategy to identify patients who are most likely to benefit from anti-angiogenic therapy has not been successful in any solid tumour. Biomarker analysis in specimens obtained from patients in the RANGE trial is ongoing. Standard-of-care therapy has evolved since the initial design and enrolment of the RANGE trial, with five immune checkpoint inhibitors targeting PD-1 or PD-L1 approved for platinum-refractory urothelial carcinoma in various regions. The RANGE trial allowed previous immune checkpoint inhibitor therapy, although such patients represented a small subgroup given the availability of these agents during trial enrolment. Efficacy results in this subgroup were consistent with the intention-to-treat population. 33 In our exploratory analysis of PD-L1 expression and efficacy, a higher proportion of patients achieving an objective response was seen in the ramucirumab group than in the placebo group, regardless of PD-L1 expression. Progression-free survival and overall survival had substantially improved HRs in patients with a PD-L1 combined positive score of 10 or higher. These results are hypothesis-generating and warrant exploration of the potential effects of ramucirumab on the tumour immune microenvironment. We used the combined positive scoring system for this analysis because a previous trial of pembrolizumab, the only therapy approved in platinum-refractory urothelial carcinoma based on phase 3 data showing a statistical overall survival benefit, used this approach. 1 We also obtained tumour cell and immune cell scores and ongoing analyses of these will be presented in a future manuscript. The VEGF axis has been implicated in immune suppression. 34 Dual blockade of PD-L1 and VEGF pathways has been shown to increase intratumoural CD8 T cells, MHC class 1 molecules, Th1 cells, and T-effector markers and significantly improve progression-free survival compared with PD-L1 monotherapy in PD-L1-positive patients with renal cell carcinoma. 35,36 Given the results of the RANGE trial for patients with a PD-L1 combined positive score of 10 or higher, combining ramucirumab with PD-1 or PD-L1 therapy in the appropriate patients warrants evaluation. Results from a phase 1b study across select tumour types, including urothelial carcinoma, were recently published. 37 In that study, molecular subtypes and ramucirumab exposures achieved were unknown. 37 A more thorough understanding of the interaction between clinical factors, exposure response, molecular subtypes, and PD-L1 status of the tumour and microenvironment will help to identify patients who are most likely to benefit from a combined ramucirumab and PD-1-directed or PD-L1-directed therapy combination. Such analyses are ongoing and will be reported separately. In conclusion, our results support the progression-free survival benefit of the addition of an anti-VEGFR2 antibody to standard chemotherapy in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy and represent, to our knowledge, the first positive randomised phase 3 data to evaluate anti-angiogenic therapy in patients with urothelial carcinoma. Appropriately designed trials testing the hypotheses derived from our subgroup and exploratory analyses are warranted. Contributors DPP, RdW, KNC, CNS, HN, and TP were members of the scientific council and contributed to study design, data collection, data interpretation, and drafting, critical review, and approval of the submitted manuscript. AML, RAW, OH, AHZ, and KMB-M contributed to study design, data analysis, data interpretation, and drafting, critical review, and approval of the submitted report. FR, RRH, and SW contributed to data analysis, data interpretation, and drafting, critical review and approval of the submitted report. BA, IJP, FL, AR-V, AB, HSC, MT, GT, XGdM, HH, DC, SAH, EYY, IC, AD, AF, MSvdH, NM, AN, Y-CO, W-PS, J-LL, AS, SS, LG, JB, GG, AP, STT, UV, and JBA-C contributed to data collection, data interpretation, critical review, and approval of the submitted report. Declaration of interests DPP reports grants from Eli Lilly and Company, during the conduct of the study; and consultant fees from Ada Cap, Amgen, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Eli Lilly, Exelixis, Incyte, Janssen, Pfizer, Pharmacyclics, Roche Laboratories, Seattle Genetics, and Urogen, grants from Ada Cap, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Clovis, Eli Lilly, Endocyte, Genentech, Innocrin, MedImmune, Merck, Novartis, Pfizer, Progenics, Roche Laboratories, Sanofi Aventis, and Seattle Genetics, and ownership interest or investments in Bellicum and Tyme, outside the submitted work. RdW reports personal fees from Eli Lilly and Company, during the conduct of the study; and grants (paid to institution) from Sanofi and personal fees from Merck, Roche, Bayer, Janssen, Clovis, and Sanofi, outside the submitted work. KNC reports institutional funding from Eli Lilly and Company, during the conduct of the study. AD reports travel reimbursements from Eli Lilly and Company, consulting fees from Bristol-Myers Squibb, travel and consulting fees from AstraZeneca, and equity in Kynan Pharma, Allogene, and Urogen, outside the submitted work. CNS reports personal fees from Eli Lilly and Company, Bristol-Myers Squibb, Merck/Pfizer, and Clovis, outside the submitted work. SAH reports personal fees from Roche, Merck, AstraZeneca, Pierre Fabre, Sotio, Pfizer, Janssen, and Bayer, outside the submitted work. AF reports honoraria from AstraZeneca, Merck Sharp & Dohme, and Roche, outside the submitted work. AB reports personal fees from AstraZeneca and Bristol-Myers Squibb, and grants and personal fees from Roche, outside the submitted work. EYY reports grants and personal fees from Eli Lilly, during the conduct of the study; and grants and personal fees from Agensys, Astellas, Bayer, Dendreon, Genentech/Roche, Merck, and Seattle Genetics and personal fees from AstraZeneca, Churchill Pharmaceuticals, EMD Serono, Ferring, Janssen, Medivation, Sanofi, Tolmar, Tokai, QED, Amgen, Pharmacyclics, and InCyte, outside the submitted work. MSvdH reports grants (paid to institution) from Roche and AstraZeneca and consultation and grant support (both to institute) from Bristol-Myers Squibb, outside the submitted work. NM reports research grants from Janssen, AstraZeneca, Merck Sharp & Dohme, Bayer, Lilly, Roche, and Taiho, outside the submitted work. AN reports grants, personal fees, and non-financial support from Roche, grants and personal fees from Merck and AstraZeneca, and personal fees from Seattle Genetics and Bayer, during the conduct of the study. JB reports grants from Eli Lilly and Company, during the conduct of the study; and personal fees from AstraZeneca, Astellas, and Eusa Pharma and grants and personal fees from Bristol-Myers Squibb, Eisai, Ipsen, Merck Sharp & Dohme, Novartis, Roche, and Pfizer, and personal fees from Eusa Pharma, outside the submitted work. J-LL reports grants, personal fees, and advisory board fees from Pfizer Korea and Ipsen Korea, personal fees and advisory board fees from Janssen, Astellas Korea, Bristol-Myers Squibb Korea, and Sanofi Aventis, and personal fees from Novartis Korea, outside the submitted work. MT reports personal fees from Astellas, Sanofi, Bayer, and Janssen, outside the submitted work. AP reports consultant fees from Merck Sharp & Dohme, Bayer, Bristol-Myers Squibb, Janssen, Astellas, Novartis, Roche, AstraZeneca, and Pfizer, outside the submitted work. XGdM reports personal fees from Pfizer, Bristol-Myers Squibb, Eli Lilly and Company, Pharmamar, Novartis, Ipsen, and Roche, outside the submitted work. AR-V reports grants from Takeda, grants and personal fees from Merck Sharp and Dohme, and grants and personal fees from Pfizer, Janssen, Astellas, Roche, Bristol-Myers Squibb, Clovis, Bayer, and Sanofi-Aventis, outside the submitted work. STT reports institutional research support from Eli Lilly during the conduct of the study, and prior honoraria from Sanofi; and consulting and advisory roles for Medivation, Astellas Pharma, Dendreon, Janssen, Bayer, Genentech, Sanofi, Endocyte, Immunomedics, Karyopharm Therapeutics, Abbvie, Tolmark, QED, institutional research support from Janssen, Astellas Pharma, Progenics, Millennium, Amgen, Bristol-Myers Squibb, Dendreon, Rexahn Pharmaceuticals, Bayer, Genentech, Newlink Genetics, Inovio Pharmaceuticals, AstraZeneca, Immunomedics, Novartis, AVEO, Boehringer Ingelheim, Merck Sharp & Dohme, Stem CentRx, Karyopharm Therapeutics, Abbvie, Medivation, Endocyte, Exelixis, and Clovis Oncology, and travel, accommodations, and expenses received from Sanofi and Amgen, outside the submitted work. UV reports personal fees (honoraria) and other (consulting, advisory, or speaker bureau payments) from Bayer and Sanofi, grants, personal fees, and consulting, advisory, or speaker bureau payments from Bristol-Myers Squibb, Exelixis, and Pfizer, and grants and consulting or advisory role payments from Astellas Pharma, outside the submitted work. JBA-C reports personal fees from Bristol-Myers Squibb, Sanofi, Janssen, and EMD Serono outside the submitted work. OH and FR were employees of Eli Lilly and Company during the conduct of the study and are shareholders at Eli Lilly and Company. AML, SW, RRH, AHZ, and KMB-M are employees and shareholders at Eli Lilly and Company. RAW is an employee, shareholder, and has patents pending at Eli Lilly and Company. TP reports strategic or advisory fees and grants from Roche, strategic or advisory and consultant or honoraria fees from Pfizer, Bristol-Myers Squibb, and AstraZeneca, and consultant or honoraria fees from Exelexis, Incyte, Ipsen, Merck, and Seattle Genetics, all outside the submitted work. All other authors declare no competing interests.
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