Long-term safety of pembrolizumab monotherapy and relationship with clinical outcome: A landmark analysis in patients with advanced melanoma

Caroline Robert; Wen-Jen Hwu; Omid Hamid; Antoni Ribas; Jeffrey S Weber; Adil I Daud; F Stephen Hodi; Jedd D Wolchok; Tara C Mitchell; Peter Hersey; Roxana Dronca; Richard W Joseph; Celine Boutros; Le Min; Georgina V Long; Jacob Schachter; Igor Puzanov; Reinhard Dummer; Jianxin Lin; Nageatte Ibrahim; Scott J Diede; Matteo S Carlino; Anthony M Joshua

doi:10.1016/j.ejca.2020.11.010

Long-term safety of pembrolizumab monotherapy and relationship with clinical outcome: A landmark analysis in patients with advanced melanoma

Eur J Cancer. 2021 Feb:144:182-191. doi: 10.1016/j.ejca.2020.11.010. Epub 2020 Dec 24.

Authors

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

Affiliations

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.

Keywords: Advanced melanoma; Corticosteroid use; Immune-checkpoint inhibitors; Immune-related adverse events; Immunomodulating drugs; PD-1 inhibitors; Pembrolizumab.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Aged, 80 and over
Antibodies, Monoclonal, Humanized / adverse effects*
Antineoplastic Agents, Immunological / adverse effects*
Clinical Trials as Topic / statistics & numerical data*
Drug-Related Side Effects and Adverse Reactions / etiology
Drug-Related Side Effects and Adverse Reactions / pathology*
Female
Follow-Up Studies
Humans
Male
Melanoma / drug therapy*
Melanoma / pathology
Meta-Analysis as Topic
Middle Aged
Prognosis
Young Adult

Substances

Antibodies, Monoclonal, Humanized
Antineoplastic Agents, Immunological
pembrolizumab

Associated data

ClinicalTrials.gov/NCT01295827
ClinicalTrials.gov/NCT01866319
ClinicalTrials.gov/NCT01704287

Grants and funding

P30 CA008748/CA/NCI NIH HHS/United States