TY - JOUR
T1 - Ipilimumab alone or ipilimumab plus anti-PD-1 therapy in patients with metastatic melanoma resistant to anti-PD-(L)1 monotherapy
T2 - a multicentre, retrospective, cohort study
AU - Pires da Silva, Ines
AU - Ahmed, Tasnia
AU - Reijers, Irene L.M.
AU - Weppler, Alison M.
AU - Betof Warner, Allison
AU - Patrinely, James Randall
AU - Serra-Bellver, Patricio
AU - Allayous, Clara
AU - Mangana, Joanna
AU - Nguyen, Khang
AU - Zimmer, Lisa
AU - Trojaniello, Claudia
AU - Stout, Dan
AU - Lyle, Megan
AU - Klein, Oliver
AU - Gerard, Camille L.
AU - Michielin, Olivier
AU - Haydon, Andrew
AU - Ascierto, Paolo A.
AU - Carlino, Matteo S.
AU - Lebbe, Celeste
AU - Lorigan, Paul
AU - Johnson, Douglas B.
AU - Sandhu, Shahneen
AU - Lo, Serigne N.
AU - Blank, Christian U.
AU - Menzies, Alexander M.
AU - Long, Georgina V.
N1 - Funding Information:
ABW is supported by the National Cancer Institute Cancer Center Core (P30-CA008748). AMM is supported by a Cancer Institute NSW Fellowship and Melanoma Institute Australia. GVL is supported by National Health and Medical Research Council Practitioner Fellowship and the University of Sydney Medical Foundation and Melanoma Institute Australia. Support for the study from the Ainsworth Foundation and Lady Fairfax Charitable Trust is gratefully acknowledged.
Funding Information:
ABW is supported by the National Cancer Institute Cancer Center Core (P30-CA008748). AMM is supported by a Cancer Institute NSW Fellowship and Melanoma Institute Australia. GVL is supported by National Health and Medical Research Council Practitioner Fellowship and the University of Sydney Medical Foundation and Melanoma Institute Australia. Support for the study from the Ainsworth Foundation and Lady Fairfax Charitable Trust is gratefully acknowledged.
Funding Information:
IPdS reports personal fees from Bristol Myers Squibb, Merck Sharp & Dohme, and Roche, outside the submitted work. ABW reports personal fees from Shanghai Jo'Ann Medical Technology, Nanobiotix, Novartis, LG Chem Life Sciences, and Iovance, outside the submitted work. CA reports personal fees from Roche, Amgen, and Bristol Myers Squibb, outside the submitted work. JM reports grants, personal fees, and travel grants from Bristol Myers Squibb and Merck Sharp & Dohme; personal fees from Merck Sharp & Dohme, Pfizer, Sanofi, Amgen, and Novartis; personal fees and travel grants from Pierre Fabre; and travel grants from Ultrasun and Loreal, outside the submitted work. LZ reports personal fees, advisory board participation, and travel grants from Bristol Myers Squibb, Merck Sharp & Dohme, Pierre Fabre, Roche, and Novartis; and advisory board participation and travel grants from Sanofi and Amgen, outside the submitted work. ML reports personal fees from Bristol Myers Squibb, Novartis, Roche, and Merck Sharp & Dohme, outside the submitted work. OK and AH report personal fees from Bristol Myers Squibb and Merck Sharp & Dohme, outside the submitted work. OM reports grants and personal fees from Bristol Myers Squibb, Merck Sharp & Dohme, Pierre-Fabre, and Amgen; personal fees from Roche, Novartis, and GlaxoSmithKline; and grants from Merck Sharp & Dohme, outside the submitted work. PAA reports grants and personal fees from Bristol Myers Squibb, Roche, Array BioPharma, and Sanofi; personal fees from Merck Sharp & Dohme, Novartis, Merck Serono, Pierre Fabre, Incyte, Medimmune, AstraZeneca, Syndax, Sun Pharma, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Boehringer Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, and Lunaphore; and uncompensated consultant service from Takis, outside the submitted work. MSC reports personal fees from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Amgen, Sanofi, Merck Serono, Pierre Fabre, Roche, Ideaya, Regeneron, Nektar, Eisai, Qbiotics, and Oncosec, outside the submitted work. CL reports grants and personal fees from Bristol Myers Squibb and Roche; personal fees from Merck Sharp & Dohme, Novartis, Amgen, Avantis Medical Systems, Pierre Fabre, Pfizer, Incyte, Merck Serono, and Sanofi, outside the submitted work. PL reports personal fees and support for travel from Merck Sharp & Dohme and Novartis; personal fees from Amgen, Nektar, and Pierre Fabre; and grants, personal fees, and support for travel from Bristol Myers Squibb, outside the submitted work. DBJ reports being part of advisory boards and consulting for Array Biopharma, Catalyst, Iovance, Jansen, Merck Sharp & Dohme, Novartis, and Oncosec; grants and other research funding from Bristol Myers Squibb; and grants from Incyte, outside the submitted work. SS reports grants from Novartis, AstraZeneca, Merck Sharp & Dohme, and Genentech; and personal fees from AstraZeneca, Merck Sharp & Dohme, and Bristol Myers Squibb, outside the submitted work. CUB reports grants from an advisory role in Bristol Myers Squibb, Merck Sharp & Dohme, Roche, Novartis, GlaxoSmithKline, AstraZeneca, Pfizer, Lilly, GenMab, Pierre Fabre, and Third Rock Ventures; research funding from Bristol Myers Squibb, Novartis, and NanoString; stock ownership in Uniti cars; and is a cofounder of Immagene, outside the submitted work. AMM reports personal fees from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, and QBiotics, outside the submitted work. GVL reports personal fees from Amgen, Array Biopharma, Boehringer Ingelheim, Bristol Myers Squibb, Hexal, Highlight Therapeutics, Merck Sharp & Dohme, Novartis, Pierre Fabre, QBiotics, Regeneron Pharmaceuticals, and Specialised Therapeutics Australia, outside the submitted work. TA, ILMR, AMW, JRP, PS-B, KN, CT, DS, CLG, and SNL declare no competing interests.
Publisher Copyright:
© 2021 Elsevier Ltd
PY - 2021
Y1 - 2021
N2 - Background: Anti-PD-1 therapy (hereafter referred to as anti-PD-1) induces long-term disease control in approximately 30% of patients with metastatic melanoma; however, two-thirds of patients are resistant and will require further treatment. We aimed to determine the efficacy and safety of ipilimumab plus anti-PD-1 (pembrolizumab or nivolumab) compared with ipilimumab monotherapy in patients who are resistant to anti-PD-(L)1 therapy (hereafter referred to as anti-PD-[L]1). Methods: This multicentre, retrospective, cohort study, was done at 15 melanoma centres in Australia, Europe, and the USA. We included adult patients (aged ≥18 years) with metastatic melanoma (unresectable stage III and IV), who were resistant to anti-PD-(L)1 (innate or acquired resistance) and who then received either ipilimumab monotherapy or ipilimumab plus anti-PD-1 (pembrolizumab or nivolumab), based on availability of therapies or clinical factors determined by the physician, or both. Tumour response was assessed as per standard of care (CT or PET–CT scans every 3 months). The study endpoints were objective response rate, progression-free survival, overall survival, and safety of ipilimumab compared with ipilimumab plus anti-PD-1. Findings: We included 355 patients with metastatic melanoma, resistant to anti-PD-(L)1 (nivolumab, pembrolizumab, or atezolizumab), who had been treated with ipilimumab monotherapy (n=162 [46%]) or ipilimumab plus anti-PD-1 (n=193 [54%]) between Feb 1, 2011, and Feb 6, 2020. At a median follow-up of 22·1 months (IQR 9·5–30·9), the objective response rate was higher with ipilimumab plus anti-PD-1 (60 [31%] of 193 patients) than with ipilimumab monotherapy (21 [13%] of 162 patients; p<0·0001). Overall survival was longer in the ipilimumab plus anti-PD-1 group (median overall survival 20·4 months [95% CI 12·7–34·8]) than with ipilimumab monotherapy (8·8 months [6·1–11·3]; hazard ratio [HR] 0·50, 95% CI 0·38–0·66; p<0·0001). Progression-free survival was also longer with ipilimumab plus anti-PD-1 (median 3·0 months [95% CI 2·6–3·6]) than with ipilimumab (2·6 months [2·4–2·9]; HR 0·69, 95% CI 0·55–0·87; p=0·0019). Similar proportions of patients reported grade 3–5 adverse events in both groups (59 [31%] of 193 patients in the ipilimumab plus anti-PD-1 group vs 54 [33%] of 162 patients in the ipilimumab group). The most common grade 3–5 adverse events were diarrhoea or colitis (23 [12%] of 193 patients in the ipilimumab plus anti-PD-1 group vs 33 [20%] of 162 patients in the ipilimumab group) and increased alanine aminotransferase or aspartate aminotransferase (24 [12%] vs 15 [9%]). One death occurred with ipilimumab 26 days after the last treatment: a colon perforation due to immune-related pancolitis. Interpretation: In patients who are resistant to anti-PD-(L)1, ipilimumab plus anti-PD-1 seemed to yield higher efficacy than ipilimumab with a higher objective response rate, longer progression-free, and longer overall survival, with a similar rate of grade 3–5 toxicity. Ipilimumab plus anti-PD-1 should be favoured over ipilimumab alone as a second-line immunotherapy for these patients with advanced melanoma. Funding: None.
AB - Background: Anti-PD-1 therapy (hereafter referred to as anti-PD-1) induces long-term disease control in approximately 30% of patients with metastatic melanoma; however, two-thirds of patients are resistant and will require further treatment. We aimed to determine the efficacy and safety of ipilimumab plus anti-PD-1 (pembrolizumab or nivolumab) compared with ipilimumab monotherapy in patients who are resistant to anti-PD-(L)1 therapy (hereafter referred to as anti-PD-[L]1). Methods: This multicentre, retrospective, cohort study, was done at 15 melanoma centres in Australia, Europe, and the USA. We included adult patients (aged ≥18 years) with metastatic melanoma (unresectable stage III and IV), who were resistant to anti-PD-(L)1 (innate or acquired resistance) and who then received either ipilimumab monotherapy or ipilimumab plus anti-PD-1 (pembrolizumab or nivolumab), based on availability of therapies or clinical factors determined by the physician, or both. Tumour response was assessed as per standard of care (CT or PET–CT scans every 3 months). The study endpoints were objective response rate, progression-free survival, overall survival, and safety of ipilimumab compared with ipilimumab plus anti-PD-1. Findings: We included 355 patients with metastatic melanoma, resistant to anti-PD-(L)1 (nivolumab, pembrolizumab, or atezolizumab), who had been treated with ipilimumab monotherapy (n=162 [46%]) or ipilimumab plus anti-PD-1 (n=193 [54%]) between Feb 1, 2011, and Feb 6, 2020. At a median follow-up of 22·1 months (IQR 9·5–30·9), the objective response rate was higher with ipilimumab plus anti-PD-1 (60 [31%] of 193 patients) than with ipilimumab monotherapy (21 [13%] of 162 patients; p<0·0001). Overall survival was longer in the ipilimumab plus anti-PD-1 group (median overall survival 20·4 months [95% CI 12·7–34·8]) than with ipilimumab monotherapy (8·8 months [6·1–11·3]; hazard ratio [HR] 0·50, 95% CI 0·38–0·66; p<0·0001). Progression-free survival was also longer with ipilimumab plus anti-PD-1 (median 3·0 months [95% CI 2·6–3·6]) than with ipilimumab (2·6 months [2·4–2·9]; HR 0·69, 95% CI 0·55–0·87; p=0·0019). Similar proportions of patients reported grade 3–5 adverse events in both groups (59 [31%] of 193 patients in the ipilimumab plus anti-PD-1 group vs 54 [33%] of 162 patients in the ipilimumab group). The most common grade 3–5 adverse events were diarrhoea or colitis (23 [12%] of 193 patients in the ipilimumab plus anti-PD-1 group vs 33 [20%] of 162 patients in the ipilimumab group) and increased alanine aminotransferase or aspartate aminotransferase (24 [12%] vs 15 [9%]). One death occurred with ipilimumab 26 days after the last treatment: a colon perforation due to immune-related pancolitis. Interpretation: In patients who are resistant to anti-PD-(L)1, ipilimumab plus anti-PD-1 seemed to yield higher efficacy than ipilimumab with a higher objective response rate, longer progression-free, and longer overall survival, with a similar rate of grade 3–5 toxicity. Ipilimumab plus anti-PD-1 should be favoured over ipilimumab alone as a second-line immunotherapy for these patients with advanced melanoma. Funding: None.
UR - http://www.scopus.com/inward/record.url?scp=85107026441&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85107026441&partnerID=8YFLogxK
U2 - 10.1016/S1470-2045(21)00097-8
DO - 10.1016/S1470-2045(21)00097-8
M3 - Article
C2 - 33989557
AN - SCOPUS:85107026441
JO - The Lancet Oncology
JF - The Lancet Oncology
SN - 1470-2045
ER -