Maria-Victoria Mateos1, Hilary Blacklock2, Fredrik Schjesvold3, Albert Oriol4, David Simpson5, Anupkumar George6, Hartmut Goldschmidt7, Alessandra Larocca8, Asher Chanan-Khan9, Daniel Sherbenou10, Irit Avivi11, Noam Benyamini12, Shinsuke Iida13, Morio Matsumoto14, Kenshi Suzuki15, Vincent Ribrag16, Saad Z Usmani17, Sundar Jagannath18, Enrique M Ocio19, Paula Rodriguez-Otero20, Jesus San Miguel20, Uma Kher21, Mohammed Farooqui21, Jason Liao21, Patricia Marinello21, Sagar Lonial22. 1. Complejo Asistencial Universitario de Salamanca/IBSAL, Salamanca, Spain. Electronic address: mvmateos@usal.es. 2. Middlemore Hospital, Auckland, New Zealand. 3. Oslo Myeloma Center, Oslo University Hospital and KG Jebsen Center for B-Cell Malignancies, University of Oslo, Oslo, Norway. 4. Institut Català d'Oncologia and Institut Josep Carreras, Hospital Germans Triasi Pujol, Barcelona, Spain. 5. North Shore Hospital, Auckland, New Zealand. 6. Wellington Blood and Cancer Center, Wellington, New Zealand. 7. University Hospital Heidelberg and National Center of Tumor Diseases in Heidelberg, Heidelberg, Germany. 8. Myeloma Unit, Division of Hematology, University of Torino, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy. 9. Mayo Clinic, Jacksonville, FL, USA. 10. University of Colorado Cancer Center, Denver, CO, USA. 11. Sourasky Medical Center, Haifa, Israel. 12. Rambam Health Care Campus, HaAliya HaShniya, Israel. 13. Nagoya City University Graduate School of Medical Sciences, Mizuho-cho, Mizuho-ku, Nagoya, Japan. 14. National Hospital Organization, Shibukawa Medical Center, Shibukawa, Gunma, Japan. 15. Japanese Red Cross, Tokyo, Japan. 16. Institut Gustave Roussy, Villejuif, France. 17. Levine Cancer Institute/Atrium Health, Charlotte, NC, USA. 18. The Mount Sinai Medical Hospital, New York, NY, USA. 19. Hospital Universitario Marqués de Valdecilla (IDIVAL), Universidad de Cantabria, Santander, Spain. 20. Clinica Universidad de Navarra, CIMA, IDISNA, CIBERONC, Pamplona, Spain. 21. Merck & Co, Kenilworth, NJ, USA. 22. Winship Cancer Institute, Emory University, Atlanta, GA, USA.
Abstract
BACKGROUND:Pomalidomide and dexamethasone is a standard of care for patients with multiple myeloma in whombortezomib and lenalidomide treatment has failed. KEYNOTE-183 assessed efficacy and safety of pomalidomide and dexamethasone with or without pembrolizumab in patients with relapsed or refractory multiple myeloma. Here, we present the findings of an unplanned, ad-hoc interim analysis at the request of the US Food and Drug Administration (FDA). METHODS: KEYNOTE-183 was a randomised, open-label, phase 3 trial done at 97 medical centres across 11 countries (Australia, Canada, France, Germany, Israel, Italy, Japan, New Zealand, Norway, Spain, and USA). Patients aged at least 18 years with multiple myeloma, an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, previously treated with at least two lines of therapy (excluding pomalidomide) and refractory to the last line were randomly assigned 1:1 to the pembrolizumab plus pomalidomide and dexamethasone group or the pomalidomide and dexamethasone group via an interactive voice response or integrated web response system. Patients received oral pomalidomide 4 mg daily on days 1-21 and oral low-dose dexamethasone 40 mg on days 1, 8, 15, and 22 in 28-day cycles, with or without intravenous pembrolizumab 200 mg every 3 weeks. The dual primary endpoints were progression-free survival and overall survival. Efficacy was assessed in all randomly assigned patients and safety was assessed in patients who received at least one dose of study treatment. The trial is registered at ClinicalTrials.gov, number NCT02576977, and it is closed for accrual. FINDINGS:Between Jan 18, 2016, and June 7, 2017, 249 patients were randomly assigned to either the pembrolizumab plus pomalidomide and dexamethasone group (n=125) or the pomalidomide and dexamethasone group (n=124). On July 3, 2017, the FDA established that risks associated with the triple combination outweighed benefits and halted the study. Median follow-up was 8·1 months (IQR 4·5-10·9). Median progression-free survival was 5·6 months (95% CI 3·7-7·5) in the pembrolizumab plus pomalidomide and dexamethasone group versus 8·4 months (5·9-not reached) in the pomalidomide and dexamethasone group; progression-free survival estimates at 6 months were 48% (95% CI 37-58) versus 60% (49-69) at 6 months (hazard ratio [HR] 1·53; 95% CI 1·05-2·22; p=0·98). Median overall survival was not reached (95% CI 12·9-not reached) versus 15·2 months (12·7-not reached; HR 1·61; 95% CI 0·91-2·85; p=0·95); overall survival estimates at 6 months were 82% (95% CI 74-88) versus 90% (82-95). Serious adverse events occurred in 75 (63%) of 120 patients in the pembrolizumab plus pomalidomide and dexamethasone group versus 56 (46%) of 121 patients in the pomalidomide and dexamethasone group. Four (3%) treatment-related deaths occurred in the pembrolizumab plus pomalidomide and dexamethasone group (one each of unknown cause, neutropenic sepsis, myocarditis, and Stevens-Johnson syndrome); myocarditis and Stevens-Johnson syndrome were considered related to pembrolizumab. No treatment-related deaths were reported in the pomalidomide and dexamethasone group. INTERPRETATION: The results from this unplanned, FDA-requested, interim analysis showed that the benefit-risk profile of pembrolizumab plus pomalidomide and dexamethasone is unfavourable for patients with relapsed or refractory multiple myeloma. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co (Kenilworth, NJ, USA).
RCT Entities:
BACKGROUND:Pomalidomide and dexamethasone is a standard of care for patients with multiple myeloma in whom bortezomib and lenalidomide treatment has failed. KEYNOTE-183 assessed efficacy and safety of pomalidomide and dexamethasone with or without pembrolizumab in patients with relapsed or refractory multiple myeloma. Here, we present the findings of an unplanned, ad-hoc interim analysis at the request of the US Food and Drug Administration (FDA). METHODS: KEYNOTE-183 was a randomised, open-label, phase 3 trial done at 97 medical centres across 11 countries (Australia, Canada, France, Germany, Israel, Italy, Japan, New Zealand, Norway, Spain, and USA). Patients aged at least 18 years with multiple myeloma, an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, previously treated with at least two lines of therapy (excluding pomalidomide) and refractory to the last line were randomly assigned 1:1 to the pembrolizumab plus pomalidomide and dexamethasone group or the pomalidomide and dexamethasone group via an interactive voice response or integrated web response system. Patients received oral pomalidomide 4 mg daily on days 1-21 and oral low-dose dexamethasone 40 mg on days 1, 8, 15, and 22 in 28-day cycles, with or without intravenous pembrolizumab 200 mg every 3 weeks. The dual primary endpoints were progression-free survival and overall survival. Efficacy was assessed in all randomly assigned patients and safety was assessed in patients who received at least one dose of study treatment. The trial is registered at ClinicalTrials.gov, number NCT02576977, and it is closed for accrual. FINDINGS: Between Jan 18, 2016, and June 7, 2017, 249 patients were randomly assigned to either the pembrolizumab plus pomalidomide and dexamethasone group (n=125) or the pomalidomide and dexamethasone group (n=124). On July 3, 2017, the FDA established that risks associated with the triple combination outweighed benefits and halted the study. Median follow-up was 8·1 months (IQR 4·5-10·9). Median progression-free survival was 5·6 months (95% CI 3·7-7·5) in the pembrolizumab plus pomalidomide and dexamethasone group versus 8·4 months (5·9-not reached) in the pomalidomide and dexamethasone group; progression-free survival estimates at 6 months were 48% (95% CI 37-58) versus 60% (49-69) at 6 months (hazard ratio [HR] 1·53; 95% CI 1·05-2·22; p=0·98). Median overall survival was not reached (95% CI 12·9-not reached) versus 15·2 months (12·7-not reached; HR 1·61; 95% CI 0·91-2·85; p=0·95); overall survival estimates at 6 months were 82% (95% CI 74-88) versus 90% (82-95). Serious adverse events occurred in 75 (63%) of 120 patients in the pembrolizumab plus pomalidomide and dexamethasone group versus 56 (46%) of 121 patients in the pomalidomide and dexamethasone group. Four (3%) treatment-related deaths occurred in the pembrolizumab plus pomalidomide and dexamethasone group (one each of unknown cause, neutropenic sepsis, myocarditis, and Stevens-Johnson syndrome); myocarditis and Stevens-Johnson syndrome were considered related to pembrolizumab. No treatment-related deaths were reported in the pomalidomide and dexamethasone group. INTERPRETATION: The results from this unplanned, FDA-requested, interim analysis showed that the benefit-risk profile of pembrolizumab plus pomalidomide and dexamethasone is unfavourable for patients with relapsed or refractory multiple myeloma. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co (Kenilworth, NJ, USA).
Authors: Adam D Cohen; Noopur Raje; Jessica A Fowler; Khalid Mezzi; Emma C Scott; Madhav V Dhodapkar Journal: Clin Cancer Res Date: 2019-10-31 Impact factor: 12.531
Authors: Konstantin Byrgazov; Thomas Lind; Annica J Rasmusson; Claes Andersson; Ana Slipicevic; Fredrik Lehmann; Joachim Gullbo; Håkan Melhus; Rolf Larsson; Mårten Fryknäs Journal: Bone Rep Date: 2021-06-07