Caroline Robert1, Wen-Jen Hwu2, Omid Hamid3, Antoni Ribas4, Jeffrey S Weber5, Adil I Daud6, F Stephen Hodi7, Jedd D Wolchok8, Tara C Mitchell9, Peter Hersey10, Roxana Dronca11, Richard W Joseph12, Celine Boutros13, Le Min14, Georgina V Long15, Jacob Schachter16, Igor Puzanov17, Reinhard Dummer18, Jianxin Lin19, Nageatte Ibrahim20, Scott J Diede21, Matteo S Carlino22, Anthony M Joshua23. 1. Department of Oncology, Service of Dermatology, Institut de Cancérologie Gustave Roussy, 114 Rue Edouard Vaillant, Gustave Roussy, Villejuif, 94805, France; Paris-Saclay University, CNRS UMR 3348, Orsay, France. Electronic address: caroline.robert@gustaveroussy.fr. 2. Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA. Electronic address: hwu.wenjen@gmail.com. 3. Department of Hematology/Oncology, The Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, 11800 Wilshire Blvd Suite 300, Los Angeles, CA, 90025, USA. Electronic address: ohamid@theangelesclinic.org. 4. Department of Medicine and the Jonsson Comprehensive Cancer Center, University of California, Los Angeles (UCLA), 11-934 Factor bldg., Los Angeles, CA, 90095, USA. Electronic address: aribas@mednet.ucla.edu. 5. Department of Medicine, Laura and Isaac Perlmutter Cancer Center at NYU Langone Health, 522 First Avenue, 1310 Smilow Building, New York, NY, 10016, USA. Electronic address: Jeffrey.Weber@nyulangone.org. 6. Department of Medicine, University of California San Francisco, 1600 Divisadero St, San Francisco, CA, 94158, USA. Electronic address: adaud@medicine.ucsf.edu. 7. Melanoma Center and Center for Immuno-Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, USA. Electronic address: Stephen_Hodi@dfci.harvard.edu. 8. Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY, 10065, USA. Electronic address: wolchokj@mskcc.org. 9. Division of Hematology and Oncology, Abramson Cancer Center, University of Pennsylvania, 3400 Civic Center Blvd South Pavilion, Flr 10, Philadelphia, PA, 19104, USA. Electronic address: tara.mitchell@uphs.upenn.edu. 10. Department of Medicine, The University of Sydney, Camperdown, NSW, 2006, Australia; Centenary Institute, Misendon Rd, Bldg 93, Camperdown, NSW, 2050, Australia; Melanoma Institute Australia, The University of Sydney, 40 Rocklands Rd, Wollstonecraft, NSW, 2065, Australia. Electronic address: peter.hersey@sydney.edu.au. 11. Department of Hematology/Oncology, Mayo Clinic, 200 1st St. SW, Rochester, MN, 55905, USA. Electronic address: Dronca.Roxana@mayo.edu. 12. Division of Cancer Medicine, Mayo Clinic Cancer Center-Florida, 4500 San Pablo Rd, Jacksonville, FL, 32224, USA. Electronic address: joseph.richard@mayo.edu. 13. Department of Oncology, Service of Dermatology, Institut de Cancérologie Gustave Roussy, 114 Rue Edouard Vaillant, Gustave Roussy, Villejuif, 94805, France. Electronic address: celine.boutros@gustaveroussy.fr. 14. Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, MA, 02115, USA. Electronic address: lmin@bwh.harvard.edu. 15. Melanoma Institute Australia, The University of Sydney, 40 Rocklands Rd, Wollstonecraft, NSW, 2065, Australia; Royal North Shore Hospital, Reserve Road, St Leonards, NSW, 2065, Australia; Mater Hospital, Wollstonecraft, NSW, 2065, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2006, Australia. Electronic address: Georgina.Long@melanoma.org.au. 16. Division of Oncology, Level 2 Cancer Center, Sheba Medical Center, Tel HaShomer Hospital, Emek HaEla Street 1, Tel HaShomer, Ramat Gan, 52621, Israel. Electronic address: jacob.schachter@sheba.health.gov.il. 17. Melanoma Section Department of Medicine, Roswell Park Comprehensive Cancer Center, 915 CSC Building, Elm & Carlton Streets, Buffalo, NY, 14263, USA. Electronic address: Igor.Puzanov@RoswellPark.org. 18. Department of Dermatology, University Hospital Zürich, University of Zurich, Rämistrasse 100, Zürich, 8091, Switzerland. Electronic address: reinhard.Dummer@usz.ch. 19. Department of Clinical Oncology, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ, 07033, USA. Electronic address: jianxin_lin@merck.com. 20. Department of Clinical Oncology, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ, 07033, USA. Electronic address: nageatte.ibrahim@merck.com. 21. Department of Clinical Oncology, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ, 07033, USA. Electronic address: scott.diede@merck.com. 22. Department of Medicine, The University of Sydney, Camperdown, NSW, 2006, Australia; Melanoma Institute Australia, The University of Sydney, 40 Rocklands Rd, Wollstonecraft, NSW, 2065, Australia; Department of Medical Oncology, The Crown Princess Mary Cancer Centre, Westmead Hospital, 12 Moris Road, Westmead, NSW, 2145, Australia; Blacktown Hospital, 18 Blacktown Road, Blacktown, NSW, 2148, Australia. Electronic address: matteo.carlino@sydney.edu.au. 23. Melanoma Institute Australia, The University of Sydney, 40 Rocklands Rd, Wollstonecraft, NSW, 2065, Australia; Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, 610 University Ave, Toronto, ON, M5G2C1, Canada; The Kinghorn Cancer Centre at St Vincent's Hospital, 370 Victoria St, Darlinghurst, NSW, 2010, Australia; St Vincent's Clinical School, UNSW Sydney, Victoria St, Darlinghurst, NSW, 2010, Australia. Electronic address: Anthony.joshua@svha.org.au.
Abstract
OBJECTIVE: Long-term safety of pembrolizumab in melanoma was analyzed in KEYNOTE-001, KEYNOTE-002, and KEYNOTE-006. PATIENTS AND METHODS: Analysis involved patients who received ≥1 pembrolizumab dose. Lead-time bias was addressed via landmark analyses in patients who were progression-free before day 147. RESULTS: Adverse events (AEs) were analyzed for 1567 patients (median follow-up, 42.4 months). Most AEs were mild/moderate; grade 3/4 treatment-related AEs occurred in 17.7% of patients. Two pembrolizumab-related deaths occurred. Any-grade immune-mediated AEs (imAEs) occurred in 23.0%, most commonly hypothyroidism (9.1%), pneumonitis (3.3%), and hyperthyroidism (3.0%); grade 3/4 imAEs occurred in 6.9% of patients. Most imAEs occurred within 16 weeks of treatment. In landmark analysis, patients who did (n = 79) versus did not (n = 384) develop imAEs had similar objective response rates (ORRs) (64.6% versus 63.0%); median time to response (TTR), 5.6 months for both; median duration of response (DOR), 20.0 versus 25.3 months; median progression-free survival (PFS), 17.0 versus 17.7 months; median overall survival (OS), not reached (NR) versus 43 months (p = 0.1104). Patients who did (n = 17) versus did not (n = 62) receive systemic corticosteroids had similar ORRs (70.6% vs. 62.9%) and median TTR (6.4 vs. 5.6 months) but numerically shorter median PFS (9.9 vs. 17.0 months); median DOR, 14.2 months versus NR; median OS, NR for both. CONCLUSIONS: These results enhance the knowledge base for pembrolizumab in advanced melanoma, with no new toxicity signals after lengthy follow-up of a large population. In landmark analyses, pembrolizumab efficacy was similar regardless of imAEs or systemic corticosteroid use. CLINICAL TRIAL REGISTRY: NCT01295827, NCT01704287, NCT01866319.
OBJECTIVE: Long-term safety of pembrolizumab in melanoma was analyzed in KEYNOTE-001, KEYNOTE-002, and KEYNOTE-006. PATIENTS AND METHODS: Analysis involved patients who received ≥1 pembrolizumab dose. Lead-time bias was addressed via landmark analyses in patients who were progression-free before day 147. RESULTS: Adverse events (AEs) were analyzed for 1567 patients (median follow-up, 42.4 months). Most AEs were mild/moderate; grade 3/4 treatment-related AEs occurred in 17.7% of patients. Two pembrolizumab-related deaths occurred. Any-grade immune-mediated AEs (imAEs) occurred in 23.0%, most commonly hypothyroidism (9.1%), pneumonitis (3.3%), and hyperthyroidism (3.0%); grade 3/4 imAEs occurred in 6.9% of patients. Most imAEs occurred within 16 weeks of treatment. In landmark analysis, patients who did (n = 79) versus did not (n = 384) develop imAEs had similar objective response rates (ORRs) (64.6% versus 63.0%); median time to response (TTR), 5.6 months for both; median duration of response (DOR), 20.0 versus 25.3 months; median progression-free survival (PFS), 17.0 versus 17.7 months; median overall survival (OS), not reached (NR) versus 43 months (p = 0.1104). Patients who did (n = 17) versus did not (n = 62) receive systemic corticosteroids had similar ORRs (70.6% vs. 62.9%) and median TTR (6.4 vs. 5.6 months) but numerically shorter median PFS (9.9 vs. 17.0 months); median DOR, 14.2 months versus NR; median OS, NR for both. CONCLUSIONS: These results enhance the knowledge base for pembrolizumab in advanced melanoma, with no new toxicity signals after lengthy follow-up of a large population. In landmark analyses, pembrolizumab efficacy was similar regardless of imAEs or systemic corticosteroid use. CLINICAL TRIAL REGISTRY: NCT01295827, NCT01704287, NCT01866319.
Authors: John A McCulloch; Diwakar Davar; Richard R Rodrigues; Jonathan H Badger; Jennifer R Fang; Alicia M Cole; Ascharya K Balaji; Marie Vetizou; Stephanie M Prescott; Miriam R Fernandes; Raquel G F Costa; Wuxing Yuan; Rosalba Salcedo; Erol Bahadiroglu; Soumen Roy; Richelle N DeBlasio; Robert M Morrison; Joe-Marc Chauvin; Quanquan Ding; Bochra Zidi; Ava Lowin; Saranya Chakka; Wentao Gao; Ornella Pagliano; Scarlett J Ernst; Amy Rose; Nolan K Newman; Andrey Morgun; Hassane M Zarour; Giorgio Trinchieri; Amiran K Dzutsev Journal: Nat Med Date: 2022-02-28 Impact factor: 87.241
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Authors: Douglas G McNeel; Jens C Eickhoff; Ellen Wargowski; Laura E Johnson; Christos E Kyriakopoulos; Hamid Emamekhoo; Joshua M Lang; Mary Jane Brennan; Glenn Liu Journal: J Immunother Cancer Date: 2022-03 Impact factor: 13.751