Abstract
Patients with metastatic renal cell carcinoma with sarcomatoid features (sRCC) have a poor prognosis and have shown limited responsiveness to inhibition of the VEGF pathway. We conducted a prespecified analysis of the randomised, phase 3 IMmotion151 trial in previously untreated patients with advanced or metastatic RCC to assess the effectiveness of atezolizumab + bevacizumab versus sunitinib in a subgroup of patients with sarcomatoid features. Patients whose tumour had any component of sarcomatoid features were included and received atezolizumab + bevacizumab (n = 68) or sunitinib (n = 74). Baseline characteristics were similar between the groups. Median progression-free survival was significantly longer in the group receiving atezolizumab + bevacizumab overall (8.3 vs 5.3 mo; hazard ratio [HR] 0.52 95% confidence interval [CI] 0.34–0.79) and in the subset of patients with PD-L1–positive tumours (8.6 vs 5.6 mo; HR 0.45, 95% CI 0.26–0.77). More patients receiving atezolizumab + bevacizumab achieved an objective response (49% vs 14%), including complete responses (10% vs 3%), and reported greater symptom improvements versus sunitinib. Safety was consistent with the known profiles of each drug and with that reported in the overall safety-evaluable population of IMmotion151. This analysis supports enhanced activity of atezolizumab + bevacizumab in patients with sRCC.
Patient summary:
In this report, we looked at patients with a specific type of kidney cancer (tumours with sarcomatoid features) that has been hard to treat. A treatment with two drugs (atezolizumab and bevacizumab) appeared to help patients live longer without the disease getting worse than another drug (sunitinib) that is often used. Patients who took the two drugs also said they were better able to carry out their everyday activities than patients who took sunitinib. The combination of these two drugs may work better in patients with this type of advanced kidney cancer.
Keywords: metastatic renal cell carcinoma, sarcomatoid, RCC, sRCC, IMmotion151, atezolizumab, bevacizumab
Advanced or metastatic renal cell carcinoma with sarcomatoid features (sRCC) is characterised by the presence of spindle-shaped malignant epithelial cells and associated with multiple histological subtypes of renal cell carcinoma (RCC) and an aggressive phenotype [1–4]. Only 10–20% of patients with RCC have sarcomatoid features, but these patients have a particularly poor prognosis and limited response to inhibition of the VEGF pathway [5–8].
IMmotion151 was a randomised, open-label, phase 3 study evaluating the efficacy and safety of atezolizumab + bevacizumab versus sunitinib in patients with previously untreated, inoperable RCC [9]. Atezolizumab + bevacizumab prolonged progression-free survival (PFS) versus sunitinib, particularly for patients with PD-L1–positive disease (median PFS 11.2 vs 7.7 mo; hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.57–0.96; p = 0.0217). We conducted a prespecified subgroup analysis to assess the effectiveness of atezolizumab + bevacizumab versus sunitinib in patients whose tumours had sarcomatoid features.
The design, methods, and primary findings from IMmotion151 have been reported previously [9]. In brief, patients with unresectable RCC with clear cell histology and/or a component of sarcomatoid carcinoma were randomised to receive atezolizumab 1200 mg + bevacizumab 15 mg/kg once every 3 wk (n = 454) or sunitinib 50 mg once daily (n = 461; 4 wk on, 2 wk off). Patients with RCC and any component of high-grade malignant spindle cells consistent with sarcomatoid histology per local pathology review were eligible. The co-primary endpoints were investigator-assessed PFS for patients with ≥ 1% immune cells expressing PD-L1 (PD-L1+) and overall survival (OS) in the intent-to-treat (ITT) population. In the ITT population, the PD-L1+ patients receiving atezolizumab + bevacizumab showed longer PFS (median 11.2 vs 7.7 mo; HR 0.74, 95% CI 0.57–0.96; p = 0.02). The interim OS analysis did not show a significant difference between the groups. The secondary endpoints of investigator-assessed PFS and OS for patients with sarcomatoid features are reported here along with investigator-assessed objective response rate (ORR), safety, biomarker evaluations, and patient-reported outcomes (PROs) related to symptoms and functionality.
Patients were included in this prespecified subgroup analysis if their tumour had any evidence of sarcomatoid features as reported by the investigator according to the local pathology report. The clinical cutoff date for PFS, ORR, PRO, and safety outcomes was September 29, 2017, with a median follow-up of 13 mo. The clinical cutoff for OS was August 13, 2018, with a median follow-up of 17 mo. The median follow-up time for those who were alive was 27 mo. Descriptive statistics were used to compare outcomes between the treatment groups. The safety-evaluable population of IMmotion151 and this subgroup analysis were defined as patients who received any amount of study drug.
A total of 142 patients with sRCC (81% had clear cell RCC, 19% had non–clear cell RCC) received atezolizumab + bevacizumab (n = 68) or sunitinib (n = 74); baseline demographic and clinical characteristics are shown in Supplementary Table 1. Fewer patients who received atezolizumab + bevacizumab were male (59% vs 74%) and fewer had tumours expressing PD-L1 (53% vs 68%), while more had poor Memorial Sloan Kettering Cancer Center (MSKCC) risk category (25% vs 14%). Compared with the ITT population, more patients whose tumours had sarcomatoid features also had PD-L1+ disease (61% vs 40%) and intermediate or poor risk (MSKCC category, 92% vs 80%).
Efficacy was evaluated for all patients with sarcomatoid features and for a subset of patients with sarcomatoid features and PD-L1+ expression. PFS was longer and ORR was higher among patients receiving atezolizumab + bevacizumab in the overall sarcomatoid features group and among those with PD-L1+ tumours, including complete responses (Table 1 and Fig.1). Kaplan-Meier curves for OS in the overall and PD-L1+ sarcomatoid features groups are available in Supplementary Fig. 1.
Table 1 –
Summary of efficacy in the sRCC sarcomatoid features and ITT populations.
| ITT | Sarcomatoid features | ITT with PD-L1 + | Sarcomatoid features with PD-L1 + | |||||
|---|---|---|---|---|---|---|---|---|
|
|
|
|
|
|||||
| Atezo + bev (n = 454) | Sunitinib (n = 461) | Atezo + bev (n = 68) | Sunitinib (n = 74) | Atezo + bev (n = 178) | Sunitinib (n = 184) | Atezo + bev (n = 36) | Sunitinib (n = 50) | |
|
| ||||||||
| Median PFS (95% CI), mo a | 11.2 (9.6, 13.3) | 8.4 (7.5, 9.7) | 8.3 (5.4,12.9) | 5.3 (3.3, 6.7) | 11.2 (8.9,15.0) | 7.7 (6.8, 9.7) | 8.6 (3.9, 15.3) | 5.6 (3.3, 6.7) |
| Stratified HR (95% CI) | 0.83 (0.70, 0.97) | 0.52 (0.34, 0.79) | 0.74 (0.57, 0.96) | 0.45 (0.26, 0.77) | ||||
| ORR (95% CI), %a | 37 (32, 41) | 33 (29, 38) | 49 (36, 61) | 14 (7, 23) | 43 (35, 50) | 35 (28, 42) | 56 (38, 72) | 12 (5, 24) |
| Ongoing responses, % | 65 | 59 | 52 | 30 | 65 | 53 | 45 | 0 |
| Complete response, % | 5 | 2 | 10 | 3 | 9 | 4 | 14 | 4 |
| Median OS (95% CI), mo b | 33.6 (29.0, NE) | 34.9 (27.8, NE) | 21.7 (15.3, NE) | 15.4 (10.4, 19.5) | 34.0 (28.6, NE) | 32.7 (23.3, NE) | 19.3 (14.8, NE) | 15.0 (8.4, 19.5) |
| Stratified HR (95% CI) | 0.93 (0.76,1.14) | 0.64 (0.41, 1.01) | 0.84 (0.62, 1.15) | 0.61 (0.35,1.08) | ||||
Atezo, atezolizumab; bev, bevacizumab; HR, hazard ratio; ITT, intention to treat; NE, not estimable; ORR, objective response rate; OS, overall survival; PD-L1, programmed death-ligand 1; PFS, progression-free survival; sRCC, advanced or metastatic renal cell carcinoma with sarcomatoid features.
Investigator-assessed ORR. Clinical cutoff date: September 29, 2017.
Clinical cutoff date: August 13, 2018.
Fig. 1 –
PFS in the overall and PD-L1+ sarcomatoid histology groups from patients in IMmotion151.
Atezo = atezolizumab; bev = bevacizumab; CI = confidence interval; PFS = progression-free survival; Sarc = sarcomatoid.
Safety outcomes for patients with sarcomatoid tumours receiving atezolizumab + bevacizumab were generally consistent with the known safety profile of each treatment component and with those reported for the overall safety-evaluable population of IMmotion151 (Supplementary Table 2) [9].
Patients with sarcomatoid features treated with atezolizumab + bevacizumab reported a longer median time to clinically meaningful deterioration of symptoms and interference with daily functioning than those treated with sunitinib (Supplementary Fig. 2).
This analysis of patients with sRCC enrolled in IMmotion151 suggests greater clinical efficacy with atezolizumab + bevacizumab than with sunitinib. Patients with sarcomatoid features treated with atezolizumab + bevacizumab had significantly longer PFS and OS and higher ORR than those who received sunitinib. A high proportion of patients with sarcomatoid features also achieved a complete response. Observed clinical benefits were notable in the subset of sarcomatoid patients with PD-L1+ disease. Patients receiving atezolizumab + bevacizumab reported a longer time to interference of symptoms with their daily functioning. Owing to the small sample size, the imbalance of confounders between treatment arms was not accounted for to eliminate potential bias, which is a limitation associated with the statistical analysis. The safety profile observed with atezolizumab + bevacizumab was consistent with those of the individual agents and with that of the overall safety-evaluable population of IMmotion151. No new safety signals were observed. Although exploratory, these results appear to support the enhanced activity of atezolizumab + bevacizumab in patients with RCC and sarcomatoid differentiation.
Data sharing
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Supplementary Material
Acknowledgments:
The authors thank Kate Faber and Kenji Hashimoto for their contributions to the study. Patients treated at Memorial Sloan Kettering Cancer Center were supported in part by Memorial Sloan Kettering Cancer Center Support Grant/Core Grant (P30 CA008748). Support for third-party writing assistance for this manuscript, furnished by Jeff Frimpter of Health Interactions, was provided by F. Hoffmann–La Roche Ltd.
Financial disclosures: Brian I. Rini certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Brian I. Rini has received institutional research funding from Pfizer, Merck, BMS, AVEO, Genentech, and AstraZeneca; held leadership roles for SITC, ASCO, and KCA; received honoraria on a personal basis from and acted in a consulting or advisory role for Pfizer, Merck, BMS, AVEO, Genentech, Synthorx, Surface Oncology, and 3D Medicines; holds a shareholder or stockholder interest in PTC Therapeutics; and received travel, accommodation, and other expenses from Pfizer, Merck, and BMS. Robert J. Motzer has received institutional research funding from Pfizer, Merck, Genentech/Roche, Eisai, Exelixis, and BMS; and acted in a consulting or advisory role for Pfizer, Merck, Genentech/Roche, Eisai, Exelixis, Lilly Oncology, and Novartis. Thomas Powles has received institutional research funding from AstraZeneca, Roche, BMS, Exelixis, Ipsen, Merck/MSD, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, and Eisai; received honoraria from AstraZeneca, BMS, Exelixis, Incyte, Ipsen, Merck/MSD, Novartis, Pfizer, Seattle Genetics, Merck Serono, Astellas, Johnson & Johnson, Eisai, and Roche on a personal basis; and received travel, accommodation, and other expenses from Roche, Pfizer, MSD, AstraZeneca, and Ipsen. David F. McDermott has received institutional research funding from BMS, Pfizer, Merck, Alkermes, Genentech, Exelixis, and X4 Pharma; and received honoraria from BMS, Pfizer, Merck, Alkermes, EMD Serono, Lilly, Iovance, and Eisai on a personal basis. Bernard Escudier has received honoraria on a personal basis from and acted in a consulting or advisory role for Pfizer, BMS, Ipsen, AVEO, and Oncorena; and received travel, accommodation, and other expenses from BMS and Ipsen. Frede Donskov has received personal research funding from Pfizer, Ipsen, and MSD. Robert Hawkins has received honoraria from BMS, Pfizer, Novartis, and Ipsen on a personal basis; and received royalties or licensing fees for patents for an MRC phage antibody. Sergio Bracarda has acted in a consulting or advisory role for Bayer, Astellas, AAA, Janssen, Pfizer, BMS, Roche, Ipsen, MSD, Merck, and AstraZeneca; and received travel, accommodation, and other expenses from Astellas, Roche, Ipsen, MSD, Pfizer, and Janssen. Jens Bedke has received institutional research funding from AstraZeneca, Astellas, BMS, Eisai, Ipsen, MSD, Novartis, Nektar, Pfizer, Roche, and Seattle Genetics; and received honoraria from BMS and MSD on an institutional basis and from AstraZeneca, Astellas, BMS, Eisai, EUSA Pharma, Ipsen, MSD, Merck Serono, Novartis, Pfizer, and Roche on a personal basis. Ugo De Giorgi has received institutional research funding from AstraZeneca, Roche, and Sanofi; acted in a consulting or advisory role for Astellas, Bayer, BMS, Ipsen, Janssen, Merck, Pfizer, and Sanofi; and received travel, accommodation, and other expenses from BMS, Ipsen, Janssen, and Pfizer. Camillo Porta has acted in a consulting or advisory role for MSD, BMS, AstraZeneca, Pfizer, Ipsen, EUSA, Novartis, Eisai, Janssen, and General Electric; provided expert testimony/speaker bureau services for MSD, BMS, AstraZeneca, Pfizer, Ipsen, EUSA, Eisai, and General Electric; and received travel, accommodation, and other expenses from Roche. Alain Ravaud has received institutional research funding from Pfizer and Merck KGaA; received honoraria from Pfizer, BMS, and Ipsen on a personal basis; and acted in a consulting or advisory role for and received travel, accommodation, and other expenses from Pfizer, Merck KGaA, Novartis, Ipsen, AstraZeneca, BMS, and Roche. Francis Parnis has received travel, accommodation, and other expenses from Astellas. Enrique Grande has received institutional research funding from Pfizer, AstraZeneca, MTEM/Threshold, Roche, Ipsen, Lexicon, and Astellas; held leadership roles for ENETS, GETNE and GETHI; received honoraria on a personal basis from and acted in a consulting or advisory role for Pfizer, BMS, Ipsen, Roche, Eisai, EUSA Pharma, MSD, Sanofi-Genzyme, Adacap, Novartis, Pierre Fabre, Lexicon, Celgene, Janssen, Bayer, Astellas, Lilly, and AstraZeneca; and received travel, accommodation, and other expenses from Pfizer, Ipsen, Roche, and Janssen. Wei Zhang is an employee of Genentech. Mahrukh Huseni is an employee of Genentech/Roche. Susheela Carroll is an employee of Calithera Biosciences and former employee of Genentech/Roche; holds a shareholder or stockholder interest in Calithera Biosciences and former shareholder or stockholder interest in Roche; and disclosed a relationship with Ultragenyx through her spouse’s employment as a contractor. Roxana Sufan is an employee of Genentech. Christina Schiff is an employee of and holds a shareholder or stockholder interest in Genentech/Roche. Michael B. Atkins has received institutional research funding from BMS; received honoraria from Genentech/Roche on an institutional basis; and acted in a consulting or advisory role for Genentech/Roche, BMS, Merck, Pfizer, Novartis, Exelixis, Eisai, and Arrowhead.
Funding/Support and role of the sponsor:
This study was sponsored by F Hoffmann–La Roche Ltd. and Genentech Inc., a member of the Roche Group. The sponsors played a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript.
Footnotes
Appendix A. Supplementary data
Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.eururo.2020.06.021.
References
- [1].Delahunt B Sarcomatoid renal carcinoma: the final common dedifferentiation pathway of renal epithelial malignancies. Pathology 1999;31:185–90. [DOI] [PubMed] [Google Scholar]
- [2].Störkel S, Eble JN, Adlakha K, et al. Classification of renal cell carcinoma: workgroup No. 1. Cancer 1997;80:987–9. [DOI] [PubMed] [Google Scholar]
- [3].Shuch B, Bratslavsky G, Linehan WM, Srinivasan R. Sarcomatoid renal cell carcinoma: a comprehensive review of the biology and current treatment strategies. Oncologist 2012;17:46–54. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [4].Shuch B, Amin A, Armstrong AJ, et al. Understanding pathologic variants of renal cell carcinoma: distilling therapeutic opportunities from biologic complexity. Eur Urol 2015;67:85–97. [DOI] [PubMed] [Google Scholar]
- [5].Escudier B, Droz JP, Rolland F, et al. Doxorubicin and ifosamide in patients with metastatic sarcomatoid renal cell carcinoma: a phase II study of the Genitourinary Group of the French Federation of Cancer Centers. J Urol 2002;168:959–61. [DOI] [PubMed] [Google Scholar]
- [6].Shuch B, Said J, La Rochelle JC, et al. Cytoreductive nephrectomy for kidney cancer with sarcomatoid histology—is up-front resection indicated and, if not, is it avoidable? J Urol 2009;182:2164–71. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [7].Joseph RW, Millis SZ, Carballido EM, et al. PD-1 and PD-L1 expression in renal cell carcinoma with sarcomatoid differentiation. Cancer Immunol Res 2015;3:1303–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [8].Golshayan AR, George S, Heng DY, et al. Metastatic sarcomatoid renal cell carcinoma treated with vascular endothelial growth factor-targeted therapy. J Clin Oncol 2009;27:235–41. [DOI] [PubMed] [Google Scholar]
- [9].Rini BI, Powles T, Atkins MB, et al. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicenter, open-label, phase 3, randomized controlled trial. Lancet 2019;393:2404–15. [DOI] [PubMed] [Google Scholar]
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