- Email: [email protected]
Nivolumab: The New Second Line Treatment for Advanced Renal-cell Carcinoma Commentary on: Nivolumab Versus Everolimus in Advanced Renal-cell Carcinoma
Accepted Manuscript Title: Nivolumab – the New Second Line Treatment for Advanced Renal-Cell Carcinoma Author: Edmund CP Chedgy, Peter C Black PII: DOI: Reference:
S0090-4295(15)01108-5 http://dx.doi.org/doi: 10.1016/j.urology.2015.12.003 URL 19503
To appear in:
Urology
Please cite this article as: Edmund CP Chedgy, Peter C Black, Nivolumab – the New Second Line Treatment for Advanced Renal-Cell Carcinoma, Urology (2015), http://dx.doi.org/doi: 10.1016/j.urology.2015.12.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
15-02344
Nivolumab – the new second line treatment for Advanced Renal-Cell Carcinoma Edmund CP Chedgy, MD & Peter C Black, MD Vancouver Prostate Centre, University of British Columbia
Commentary on: Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma1 R.J. Motzer, B. Escudier, D.F. McDermott, S. George, H.J. Hammers, S. Srinivas, S.S. Tykodi, J.A. Sosman, G. Procopio, E.R. Plimack, D. Castellano, T.K. Choueiri, H. Gurney, F. Donskov, P. Bono, J. Wagstaff, T.C. Gauler, T. Ueda, Y. Tomita, F.A. Schutz, C. Kollmannsberger, J. Larkin, A. Ravaud, J.S. Simon, L.-A. Xu, I.M. Waxman, and P. Sharma, for the CheckMate 025 Investigators N Engl J Med November 5, 2015 Vol. 373 No. 19, 1803-1813. Correspondence: Peter Black MD, FACS, FRCSC Vancouver Prostate Centre Department of Urologic Sciences University of British Columbia Level 6, 2775 Laurel St Vancouver, BC V5Z 1M9 Canada Tel:(604) 875-4301 Email: [email protected]
Summary This phase 3 open labelled trial randomized 821 patients with advanced or metastatic clear cell renal cell carcinoma (RCC), who had progressed or failed prior treatment with an antiangiogenic agent, to receive either 10 mg everolimus PO daily or nivolumab 3mg/kg IV every 2 weeks. Nivolumab, an IgG4 programmed cell death inhibitor, is an immune checkpoint inhibitor. All patients had been treated with either 1 or 2 different prior antiangiogenic therapies but less than 3 systemic therapies overall and had progressed during or within 6 months of their last treatment. The primary endpoint was overall survival,
Page 1 of 3
with secondary endpoints of objective response rate (ORR), progression-free survival (PFS), tumor expression of PD-L1 and incidences of adverse events. This trial reached its pre-specified superiority criteria early and was terminated as a result of its interim analysis. There was a minimum follow up of 14 months with 70% of patients terminating treatment as a result of disease progression during follow up. Nivolumab demonstrated a median 5.4 month improved overall survival over everolimus, with a hazard ratio of 0.73 (98.5%CI, 0.57-0.93; P=0.002). Patients receiving nivolumab had a median overall survival of 25 months. The benefit of nivolumab was consistent in sub-group analyses based on MSKCC prognostic score, age and gender. PFS was equivalent between the two treatment groups (HR 0.88; 95%CI, 0.75-1.03; P=0.11). However, an ad-hoc sensitivity analysis of PFS in patients who had not progressed or died at 6 months demonstrated a statistically significant delay in progression with nivolumab (HR 0.64; 95%CI, 0.47-0.88). Nivolumab had an ORR of 25% whilst everolimus had an ORR of 5% (OR 5.98; 95% CI, 3.68 to 9.72; P<0.001). Only four patients in the nivolumab group and two in the everolimus group had complete responses to therapy. The median time to response and duration of response was similar in the two groups (3.5 vs 3.7 months and 12 months, respectively). 31% in the nivolumab group and 27% in the everolimus group had treatment responses lasting longer than 12 months. There was no statistically significant difference in treatment outcomes related to degree of PD-L1 expression. Nivolumab was better tolerated than everolimus with a longer median duration of treatment (5.5 mo vs 2.7 mo) and fewer adverse events (79% vs 88%). 8% of patients receiving nivolumab and 13% of those receiving everolimus discontinued their treatment as a result of adverse events. Nivolumab had a lower percentage of grade 3/4 adverse events compared to everolimus (19% vs. 37%). Discussion This study has demonstrated a clear median overall survival benefit of 5.4 months for patients receiving nivolumab. Furthermore, nivolumab showed a significantly higher ORR than everolimus, and it was very well tolerated. As a result, nivolumab has recently been approved by the FDA2 and is now the new standard agent for second line therapy after failure of a VEGF-targeted therapy in patients with advanced clear cell RCC. The European Association of Urology (EAU) has recently updated their guidelines to accommodate this change3. A second trial comparing cabozantinib and everolimus in a similar patient cohort has also recently been published4. In this study cabozantinib demonstrated a 42% reduction in risk of progression or death and a higher response rate (21% vs 58%) compared to everolimus. There was a significant overall survival benefit, (HR 0.67; 95% CI, 0.51 to 0.89; P = 0.005), but there was also a high risk of significant toxicity. 68% of patients in the cabozantinib group experienced high-grade adverse events. As a result, cabozantinib has also been adopted in the EAU guidelines as an option for second-line therapy after failed VEGFR-targeted therapy, but the safety profile will certainly favor use of nivolumab in this setting3. The nivolumab trial highlights the limitations of PFS as an endpoint for immunotherapy. Similar observations were made for Sipuleucel-T in the context of metastatic castrate resistant prostate cancer5. Delayed efficacy may mean that a patient progresses by standard imaging criteria but subsequently has a benefit with respect to overall survival. It has therefore been argued that PFS is not a sensitive enough
Page 2 of 3
measure to detect a benefit of treatment and that time between episodes of progression may be a more accurate reflection of drug activity6. Alternatively, in the case of nivolumab and clear cell RCC, the late separation of PFS curves may be due to selective responses in patients with an, as yet unidentified, molecularly different subtype of tumor. Only a small number of patients (1%) demonstrated a complete response to treatment with nivolumab. This is in contrast to previous studies with interleukin-2 in which 8.4% of patients demonstrated durable complete responses to treatment7. Nevertheless the survival benefit was clear. It would appear that complete response to nivolumab is unnecessary to achieve longer term benefits. Further exploration to determine optimal patient selection and possible utilization of combination therapies may extend and expand the utility of nivolumab. The optimal duration of nivolumab therapy is not clear from this study. Should treatment be continued after progression? Can treatment be safely stopped after demonstrating a significant objective response? These are both questions that need answering and future trials will need to be designed to take into account different episodes of progression and to identify alternate molecular markers to predict treatment response. Cost-effectiveness studies are also warranted.
References 1. 2.
3. 4. 5. 6. 7.
Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in Advanced RenalCell Carcinoma. The New England Journal of Medicine. Nov 5 2015;373(19):1803-1813. Administration FaD. FDA approves Opdivo to treat advanced form of kidney cancer. 2015; http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm473971.htm. Accessed 27 November 2015, 2015. Powles T, Staehler M, Ljungberg B, et al. Updated EAU Guidelines for Clear Cell Renal Cancer Patients Who Fail VEGF Targeted Therapy. European Urology. Oct 24 2015. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. The New England Journal of Medicine. Nov 5 2015;373(19):1814-1823. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. The New England Journal of Medicine. Jul 29 2010;363(5):411-422. Di Lorenzo G, Ferro M, Buonerba C. Sipuleucel-T (Provenge(R)) for castration-resistant prostate cancer. BJU Int. Jul 2012;110(2 Pt 2):E99-104. McDermott DF, Regan MM, Clark JI, et al. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. Journal of Clinical Oncology. Jan 1 2005;23(1):133-141.
Page 3 of 3
S0090-4295(15)01108-5 http://dx.doi.org/doi: 10.1016/j.urology.2015.12.003 URL 19503
To appear in:
Urology
Please cite this article as: Edmund CP Chedgy, Peter C Black, Nivolumab – the New Second Line Treatment for Advanced Renal-Cell Carcinoma, Urology (2015), http://dx.doi.org/doi: 10.1016/j.urology.2015.12.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
15-02344
Nivolumab – the new second line treatment for Advanced Renal-Cell Carcinoma Edmund CP Chedgy, MD & Peter C Black, MD Vancouver Prostate Centre, University of British Columbia
Commentary on: Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma1 R.J. Motzer, B. Escudier, D.F. McDermott, S. George, H.J. Hammers, S. Srinivas, S.S. Tykodi, J.A. Sosman, G. Procopio, E.R. Plimack, D. Castellano, T.K. Choueiri, H. Gurney, F. Donskov, P. Bono, J. Wagstaff, T.C. Gauler, T. Ueda, Y. Tomita, F.A. Schutz, C. Kollmannsberger, J. Larkin, A. Ravaud, J.S. Simon, L.-A. Xu, I.M. Waxman, and P. Sharma, for the CheckMate 025 Investigators N Engl J Med November 5, 2015 Vol. 373 No. 19, 1803-1813. Correspondence: Peter Black MD, FACS, FRCSC Vancouver Prostate Centre Department of Urologic Sciences University of British Columbia Level 6, 2775 Laurel St Vancouver, BC V5Z 1M9 Canada Tel:(604) 875-4301 Email: [email protected]
Summary This phase 3 open labelled trial randomized 821 patients with advanced or metastatic clear cell renal cell carcinoma (RCC), who had progressed or failed prior treatment with an antiangiogenic agent, to receive either 10 mg everolimus PO daily or nivolumab 3mg/kg IV every 2 weeks. Nivolumab, an IgG4 programmed cell death inhibitor, is an immune checkpoint inhibitor. All patients had been treated with either 1 or 2 different prior antiangiogenic therapies but less than 3 systemic therapies overall and had progressed during or within 6 months of their last treatment. The primary endpoint was overall survival,
Page 1 of 3
with secondary endpoints of objective response rate (ORR), progression-free survival (PFS), tumor expression of PD-L1 and incidences of adverse events. This trial reached its pre-specified superiority criteria early and was terminated as a result of its interim analysis. There was a minimum follow up of 14 months with 70% of patients terminating treatment as a result of disease progression during follow up. Nivolumab demonstrated a median 5.4 month improved overall survival over everolimus, with a hazard ratio of 0.73 (98.5%CI, 0.57-0.93; P=0.002). Patients receiving nivolumab had a median overall survival of 25 months. The benefit of nivolumab was consistent in sub-group analyses based on MSKCC prognostic score, age and gender. PFS was equivalent between the two treatment groups (HR 0.88; 95%CI, 0.75-1.03; P=0.11). However, an ad-hoc sensitivity analysis of PFS in patients who had not progressed or died at 6 months demonstrated a statistically significant delay in progression with nivolumab (HR 0.64; 95%CI, 0.47-0.88). Nivolumab had an ORR of 25% whilst everolimus had an ORR of 5% (OR 5.98; 95% CI, 3.68 to 9.72; P<0.001). Only four patients in the nivolumab group and two in the everolimus group had complete responses to therapy. The median time to response and duration of response was similar in the two groups (3.5 vs 3.7 months and 12 months, respectively). 31% in the nivolumab group and 27% in the everolimus group had treatment responses lasting longer than 12 months. There was no statistically significant difference in treatment outcomes related to degree of PD-L1 expression. Nivolumab was better tolerated than everolimus with a longer median duration of treatment (5.5 mo vs 2.7 mo) and fewer adverse events (79% vs 88%). 8% of patients receiving nivolumab and 13% of those receiving everolimus discontinued their treatment as a result of adverse events. Nivolumab had a lower percentage of grade 3/4 adverse events compared to everolimus (19% vs. 37%). Discussion This study has demonstrated a clear median overall survival benefit of 5.4 months for patients receiving nivolumab. Furthermore, nivolumab showed a significantly higher ORR than everolimus, and it was very well tolerated. As a result, nivolumab has recently been approved by the FDA2 and is now the new standard agent for second line therapy after failure of a VEGF-targeted therapy in patients with advanced clear cell RCC. The European Association of Urology (EAU) has recently updated their guidelines to accommodate this change3. A second trial comparing cabozantinib and everolimus in a similar patient cohort has also recently been published4. In this study cabozantinib demonstrated a 42% reduction in risk of progression or death and a higher response rate (21% vs 58%) compared to everolimus. There was a significant overall survival benefit, (HR 0.67; 95% CI, 0.51 to 0.89; P = 0.005), but there was also a high risk of significant toxicity. 68% of patients in the cabozantinib group experienced high-grade adverse events. As a result, cabozantinib has also been adopted in the EAU guidelines as an option for second-line therapy after failed VEGFR-targeted therapy, but the safety profile will certainly favor use of nivolumab in this setting3. The nivolumab trial highlights the limitations of PFS as an endpoint for immunotherapy. Similar observations were made for Sipuleucel-T in the context of metastatic castrate resistant prostate cancer5. Delayed efficacy may mean that a patient progresses by standard imaging criteria but subsequently has a benefit with respect to overall survival. It has therefore been argued that PFS is not a sensitive enough
Page 2 of 3
measure to detect a benefit of treatment and that time between episodes of progression may be a more accurate reflection of drug activity6. Alternatively, in the case of nivolumab and clear cell RCC, the late separation of PFS curves may be due to selective responses in patients with an, as yet unidentified, molecularly different subtype of tumor. Only a small number of patients (1%) demonstrated a complete response to treatment with nivolumab. This is in contrast to previous studies with interleukin-2 in which 8.4% of patients demonstrated durable complete responses to treatment7. Nevertheless the survival benefit was clear. It would appear that complete response to nivolumab is unnecessary to achieve longer term benefits. Further exploration to determine optimal patient selection and possible utilization of combination therapies may extend and expand the utility of nivolumab. The optimal duration of nivolumab therapy is not clear from this study. Should treatment be continued after progression? Can treatment be safely stopped after demonstrating a significant objective response? These are both questions that need answering and future trials will need to be designed to take into account different episodes of progression and to identify alternate molecular markers to predict treatment response. Cost-effectiveness studies are also warranted.
References 1. 2.
3. 4. 5. 6. 7.
Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in Advanced RenalCell Carcinoma. The New England Journal of Medicine. Nov 5 2015;373(19):1803-1813. Administration FaD. FDA approves Opdivo to treat advanced form of kidney cancer. 2015; http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm473971.htm. Accessed 27 November 2015, 2015. Powles T, Staehler M, Ljungberg B, et al. Updated EAU Guidelines for Clear Cell Renal Cancer Patients Who Fail VEGF Targeted Therapy. European Urology. Oct 24 2015. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. The New England Journal of Medicine. Nov 5 2015;373(19):1814-1823. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. The New England Journal of Medicine. Jul 29 2010;363(5):411-422. Di Lorenzo G, Ferro M, Buonerba C. Sipuleucel-T (Provenge(R)) for castration-resistant prostate cancer. BJU Int. Jul 2012;110(2 Pt 2):E99-104. McDermott DF, Regan MM, Clark JI, et al. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. Journal of Clinical Oncology. Jan 1 2005;23(1):133-141.
Page 3 of 3