Efficacy of anti-PD-1 and ipilimumab alone or in combination in acral melanoma

Prachi Bhave; Tasnia Ahmed; Serigne N. Lo; Alexander Shoushtari; Anne Zaremba; Judith M. Versluis; Joanna Mangana; Michael Weichenthal; Lu Si; Thierry Lesimple; Caroline Robert; Claudia Trojanello; Alexandre Wicky; Richard Heywood; Lena Tran; Kathleen Batty; Florentia Dimitriou; Anna Stansfeld; Clara Allayous; Julia K. Schwarze; Meghan J. Mooradian; Oliver Klein; Inderjit Mehmi; Rachel Roberts-Thomson; Andrea Maurichi; Hui Ling Yeoh; Adnan Khattak; Lisa Zimmer; Christian U. Blank; Egle Ramelyte; Katharina C. Kähler; Severine Roy; Paolo A. Ascierto; Olivier Michielin; Paul C. Lorigan; Douglas B. Johnson; Ruth Plummer; Celeste Lebbe; Bart Neyns; Ryan Sullivan; Omid Hamid; Mario Santinami; Grant A. McArthur; Andrew M. Haydon; Georgina V. Long; Alexander M. Menzies; Matteo S. Carlino

doi:10.1136/jitc-2022-004668

Efficacy of anti-PD-1 and ipilimumab alone or in combination in acral melanoma

Prachi Bhave
, Tasnia Ahmed
, Serigne N. Lo
, Alexander Shoushtari
, Anne Zaremba
, Judith M. Versluis
, Joanna Mangana
, Michael Weichenthal
, Lu Si
, Thierry Lesimple
, Caroline Robert
, Claudia Trojanello
, Alexandre Wicky
, Richard Heywood
, Lena Tran
, Kathleen Batty
, Florentia Dimitriou
, Anna Stansfeld
, Clara Allayous
, Julia K. Schwarze

Meghan J. Mooradian, Oliver Klein, Inderjit Mehmi, Rachel Roberts-Thomson, Andrea Maurichi, Hui Ling Yeoh, Adnan Khattak, Lisa Zimmer, Christian U. Blank, Egle Ramelyte, Katharina C. Kähler, Severine Roy, Paolo A. Ascierto, Olivier Michielin, Paul C. Lorigan, Douglas B. Johnson, Ruth Plummer, Celeste Lebbe, Bart Neyns, Ryan Sullivan, Omid Hamid, Mario Santinami, Grant A. McArthur, Andrew M. Haydon, Georgina V. Long, Alexander M. Menzies, Matteo S. Carlino^*

^*Corresponding author for this work

Division of Cancer Sciences (L5)

University of Melbourne
Westmead Hospital
Melanoma Institute Australia
Memorial Sloan Kettering Cancer Center
University Hospital Essen
Netherlands Cancer Institute
UniversitatsSpital Zurich (University Hospital of Zurich)
Universitatsklinikum Schleswig Holstein
Beijing Cancer Hospital
Centre Eugène Marquis Rennes
Institut de Cancerlogie Gustave Roussy
Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale"
Lausanne University Hospital
University of Manchester (UOM)
Vanderbilt University Medical Center
Freeman Hospital Laboratory
APHP Hôpital Saint-Louis
Universitair Ziekenhuis Brussel
Massachusetts General Hospital
Austin Health
Warrnambool Hospital
Peninsula Health
Cedars-Sinai Medical Center
The Queen Elizabeth Hospital, North Western Adelaide Health Service
Fondazione IRCCS
The Alfred Hospital
Fiona Stanley Hospital
APC - AstroParticule et Cosmologie
University of Sydney

Research output: Contribution to journal › Article › peer-review

Abstract

Background Acral melanoma is a rare melanoma subtype with poor prognosis. Importantly, these patients were not identified as a specific subgroup in the landmark melanoma trials involving ipilimumab and the anti-programmed cell death protein-1 (PD-1) agents nivolumab and pembrolizumab. There is therefore an absence of prospective clinical trial evidence regarding the efficacy of checkpoint inhibitors (CPIs) in this population. Acral melanoma has lower tumor mutation burden (TMB) than other cutaneous sites, and primary site is associated with differences in TMB. However the impact of this on the effectiveness of immune CPIs is unknown. We examined the efficacy of CPIs in acral melanoma, including by primary site. Methods Patients with unresectable stage III/IV acral melanoma treated with CPI (anti-PD-1 and/or ipilimumab) were studied. Multivariable logistic and Cox regression analyses were conducted. Primary outcome was objective response rate (ORR); secondary outcomes were progression-free survival (PFS) and overall survival (OS). Results In total, 325 patients were included: 234 (72%) plantar, 69 (21%) subungual and 22 (7%) palmar primary sites. First CPI included: 184 (57%) anti-PD-1, 59 (18%) anti-PD-1/ipilimumab combination and 82 (25%) ipilimumab. ORR was significantly higher with initial anti-PD-1/ipilimumab compared with anti-PD-1 (43% vs 26%, HR 2.14, p=0.0004) and significantly lower with ipilimumab (15% vs 26%, HR 0.49, p=0.0016). Landmark PFS at 1 year was highest for anti-PD-1/ipilimumab at 34% (95% CI 24% to 49%), compared with 26% (95% CI 20% to 33%) with anti-PD-1 and 10% (95% CI 5% to 19%) with ipilimumab. Despite a trend for increased PFS, anti-PD-1/ipilimumab combination did not significantly improve PFS (HR 0.85, p=0.35) or OS over anti-PD-1 (HR 1.30, p=0.16), potentially due to subsequent therapies and high rates of acquired resistance. No outcome differences were found between primary sites. Conclusion While the ORR to anti-PD-1/ipilimumab was significantly higher than anti-PD-1 and PFS numerically higher, in this retrospective cohort this benefit did not translate to improved OS. Future trials should specifically include patients with acral melanoma, to help determine the optimal management of this important melanoma subtype.

Original language	English
Article number	e004668
Journal	Journal for ImmunoTherapy of Cancer
Volume	10
Issue number	7
DOIs	https://doi.org/10.1136/jitc-2022-004668
Publication status	Published - 1 Jul 2022

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

CTLA-4 Antigen
Immunotherapy
Melanoma
Programmed Cell Death 1 Receptor

Research Highlights, Institutes and Platforms

Manchester Cancer Research Centre

Access to Document

10.1136/jitc-2022-004668

Cite this

Bhave, P., Ahmed, T., Lo, S. N., Shoushtari, A., Zaremba, A., Versluis, J. M., Mangana, J., Weichenthal, M., Si, L., Lesimple, T., Robert, C., Trojanello, C., Wicky, A., Heywood, R., Tran, L., Batty, K., Dimitriou, F., Stansfeld, A., Allayous, C., ... Carlino, M. S. (2022). Efficacy of anti-PD-1 and ipilimumab alone or in combination in acral melanoma. Journal for ImmunoTherapy of Cancer, 10(7), Article e004668. https://doi.org/10.1136/jitc-2022-004668

@article{4bf9fc525f264238b2e2bc90f7581938,

title = "Efficacy of anti-PD-1 and ipilimumab alone or in combination in acral melanoma",

abstract = "Background Acral melanoma is a rare melanoma subtype with poor prognosis. Importantly, these patients were not identified as a specific subgroup in the landmark melanoma trials involving ipilimumab and the anti-programmed cell death protein-1 (PD-1) agents nivolumab and pembrolizumab. There is therefore an absence of prospective clinical trial evidence regarding the efficacy of checkpoint inhibitors (CPIs) in this population. Acral melanoma has lower tumor mutation burden (TMB) than other cutaneous sites, and primary site is associated with differences in TMB. However the impact of this on the effectiveness of immune CPIs is unknown. We examined the efficacy of CPIs in acral melanoma, including by primary site. Methods Patients with unresectable stage III/IV acral melanoma treated with CPI (anti-PD-1 and/or ipilimumab) were studied. Multivariable logistic and Cox regression analyses were conducted. Primary outcome was objective response rate (ORR); secondary outcomes were progression-free survival (PFS) and overall survival (OS). Results In total, 325 patients were included: 234 (72\%) plantar, 69 (21\%) subungual and 22 (7\%) palmar primary sites. First CPI included: 184 (57\%) anti-PD-1, 59 (18\%) anti-PD-1/ipilimumab combination and 82 (25\%) ipilimumab. ORR was significantly higher with initial anti-PD-1/ipilimumab compared with anti-PD-1 (43\% vs 26\%, HR 2.14, p=0.0004) and significantly lower with ipilimumab (15\% vs 26\%, HR 0.49, p=0.0016). Landmark PFS at 1 year was highest for anti-PD-1/ipilimumab at 34\% (95\% CI 24\% to 49\%), compared with 26\% (95\% CI 20\% to 33\%) with anti-PD-1 and 10\% (95\% CI 5\% to 19\%) with ipilimumab. Despite a trend for increased PFS, anti-PD-1/ipilimumab combination did not significantly improve PFS (HR 0.85, p=0.35) or OS over anti-PD-1 (HR 1.30, p=0.16), potentially due to subsequent therapies and high rates of acquired resistance. No outcome differences were found between primary sites. Conclusion While the ORR to anti-PD-1/ipilimumab was significantly higher than anti-PD-1 and PFS numerically higher, in this retrospective cohort this benefit did not translate to improved OS. Future trials should specifically include patients with acral melanoma, to help determine the optimal management of this important melanoma subtype. ",

keywords = "CTLA-4 Antigen, Immunotherapy, Melanoma, Programmed Cell Death 1 Receptor",

author = "Prachi Bhave and Tasnia Ahmed and Lo, \{Serigne N.\} and Alexander Shoushtari and Anne Zaremba and Versluis, \{Judith M.\} and Joanna Mangana and Michael Weichenthal and Lu Si and Thierry Lesimple and Caroline Robert and Claudia Trojanello and Alexandre Wicky and Richard Heywood and Lena Tran and Kathleen Batty and Florentia Dimitriou and Anna Stansfeld and Clara Allayous and Schwarze, \{Julia K.\} and Mooradian, \{Meghan J.\} and Oliver Klein and Inderjit Mehmi and Rachel Roberts-Thomson and Andrea Maurichi and Yeoh, \{Hui Ling\} and Adnan Khattak and Lisa Zimmer and Blank, \{Christian U.\} and Egle Ramelyte and K{\"a}hler, \{Katharina C.\} and Severine Roy and Ascierto, \{Paolo A.\} and Olivier Michielin and Lorigan, \{Paul C.\} and Johnson, \{Douglas B.\} and Ruth Plummer and Celeste Lebbe and Bart Neyns and Ryan Sullivan and Omid Hamid and Mario Santinami and McArthur, \{Grant A.\} and Haydon, \{Andrew M.\} and Long, \{Georgina V.\} and Menzies, \{Alexander M.\} and Carlino, \{Matteo S.\}",

note = "Funding Information: This study was presented in part as a poster presentation at the virtual ESMO Congress 16th {\textendash} 21st September 2021. PB: NHMRC Postgraduate Scholarship. GL: NHMRC Investigator Grant and, the University of Sydney Medical Foundation. AM: Cancer Institute NSW Fellowship and Melanoma Institute, Australia. Publisher Copyright: {\textcopyright} Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.",

year = "2022",

month = jul,

day = "1",

doi = "10.1136/jitc-2022-004668",

language = "English",

volume = "10",

journal = "Journal for ImmunoTherapy of Cancer",

issn = "2051-1426",

publisher = "Springer Nature",

number = "7",

}

Bhave, P, Ahmed, T, Lo, SN, Shoushtari, A, Zaremba, A, Versluis, JM, Mangana, J, Weichenthal, M, Si, L, Lesimple, T, Robert, C, Trojanello, C, Wicky, A, Heywood, R, Tran, L, Batty, K, Dimitriou, F, Stansfeld, A, Allayous, C, Schwarze, JK, Mooradian, MJ, Klein, O, Mehmi, I, Roberts-Thomson, R, Maurichi, A, Yeoh, HL, Khattak, A, Zimmer, L, Blank, CU, Ramelyte, E, Kähler, KC, Roy, S, Ascierto, PA, Michielin, O, Lorigan, PC, Johnson, DB, Plummer, R, Lebbe, C, Neyns, B, Sullivan, R, Hamid, O, Santinami, M, McArthur, GA, Haydon, AM, Long, GV, Menzies, AM & Carlino, MS 2022, 'Efficacy of anti-PD-1 and ipilimumab alone or in combination in acral melanoma', Journal for ImmunoTherapy of Cancer, vol. 10, no. 7, e004668. https://doi.org/10.1136/jitc-2022-004668

TY - JOUR

T1 - Efficacy of anti-PD-1 and ipilimumab alone or in combination in acral melanoma

AU - Bhave, Prachi

AU - Ahmed, Tasnia

AU - Lo, Serigne N.

AU - Shoushtari, Alexander

AU - Zaremba, Anne

AU - Versluis, Judith M.

AU - Mangana, Joanna

AU - Weichenthal, Michael

AU - Si, Lu

AU - Lesimple, Thierry

AU - Robert, Caroline

AU - Trojanello, Claudia

AU - Wicky, Alexandre

AU - Heywood, Richard

AU - Tran, Lena

AU - Batty, Kathleen

AU - Dimitriou, Florentia

AU - Stansfeld, Anna

AU - Allayous, Clara

AU - Schwarze, Julia K.

AU - Mooradian, Meghan J.

AU - Klein, Oliver

AU - Mehmi, Inderjit

AU - Roberts-Thomson, Rachel

AU - Maurichi, Andrea

AU - Yeoh, Hui Ling

AU - Khattak, Adnan

AU - Zimmer, Lisa

AU - Blank, Christian U.

AU - Ramelyte, Egle

AU - Kähler, Katharina C.

AU - Roy, Severine

AU - Ascierto, Paolo A.

AU - Michielin, Olivier

AU - Lorigan, Paul C.

AU - Johnson, Douglas B.

AU - Plummer, Ruth

AU - Lebbe, Celeste

AU - Neyns, Bart

AU - Sullivan, Ryan

AU - Hamid, Omid

AU - Santinami, Mario

AU - McArthur, Grant A.

AU - Haydon, Andrew M.

AU - Long, Georgina V.

AU - Menzies, Alexander M.

AU - Carlino, Matteo S.

N1 - Funding Information: This study was presented in part as a poster presentation at the virtual ESMO Congress 16th – 21st September 2021. PB: NHMRC Postgraduate Scholarship. GL: NHMRC Investigator Grant and, the University of Sydney Medical Foundation. AM: Cancer Institute NSW Fellowship and Melanoma Institute, Australia. Publisher Copyright: © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

PY - 2022/7/1

Y1 - 2022/7/1

N2 - Background Acral melanoma is a rare melanoma subtype with poor prognosis. Importantly, these patients were not identified as a specific subgroup in the landmark melanoma trials involving ipilimumab and the anti-programmed cell death protein-1 (PD-1) agents nivolumab and pembrolizumab. There is therefore an absence of prospective clinical trial evidence regarding the efficacy of checkpoint inhibitors (CPIs) in this population. Acral melanoma has lower tumor mutation burden (TMB) than other cutaneous sites, and primary site is associated with differences in TMB. However the impact of this on the effectiveness of immune CPIs is unknown. We examined the efficacy of CPIs in acral melanoma, including by primary site. Methods Patients with unresectable stage III/IV acral melanoma treated with CPI (anti-PD-1 and/or ipilimumab) were studied. Multivariable logistic and Cox regression analyses were conducted. Primary outcome was objective response rate (ORR); secondary outcomes were progression-free survival (PFS) and overall survival (OS). Results In total, 325 patients were included: 234 (72%) plantar, 69 (21%) subungual and 22 (7%) palmar primary sites. First CPI included: 184 (57%) anti-PD-1, 59 (18%) anti-PD-1/ipilimumab combination and 82 (25%) ipilimumab. ORR was significantly higher with initial anti-PD-1/ipilimumab compared with anti-PD-1 (43% vs 26%, HR 2.14, p=0.0004) and significantly lower with ipilimumab (15% vs 26%, HR 0.49, p=0.0016). Landmark PFS at 1 year was highest for anti-PD-1/ipilimumab at 34% (95% CI 24% to 49%), compared with 26% (95% CI 20% to 33%) with anti-PD-1 and 10% (95% CI 5% to 19%) with ipilimumab. Despite a trend for increased PFS, anti-PD-1/ipilimumab combination did not significantly improve PFS (HR 0.85, p=0.35) or OS over anti-PD-1 (HR 1.30, p=0.16), potentially due to subsequent therapies and high rates of acquired resistance. No outcome differences were found between primary sites. Conclusion While the ORR to anti-PD-1/ipilimumab was significantly higher than anti-PD-1 and PFS numerically higher, in this retrospective cohort this benefit did not translate to improved OS. Future trials should specifically include patients with acral melanoma, to help determine the optimal management of this important melanoma subtype.

AB - Background Acral melanoma is a rare melanoma subtype with poor prognosis. Importantly, these patients were not identified as a specific subgroup in the landmark melanoma trials involving ipilimumab and the anti-programmed cell death protein-1 (PD-1) agents nivolumab and pembrolizumab. There is therefore an absence of prospective clinical trial evidence regarding the efficacy of checkpoint inhibitors (CPIs) in this population. Acral melanoma has lower tumor mutation burden (TMB) than other cutaneous sites, and primary site is associated with differences in TMB. However the impact of this on the effectiveness of immune CPIs is unknown. We examined the efficacy of CPIs in acral melanoma, including by primary site. Methods Patients with unresectable stage III/IV acral melanoma treated with CPI (anti-PD-1 and/or ipilimumab) were studied. Multivariable logistic and Cox regression analyses were conducted. Primary outcome was objective response rate (ORR); secondary outcomes were progression-free survival (PFS) and overall survival (OS). Results In total, 325 patients were included: 234 (72%) plantar, 69 (21%) subungual and 22 (7%) palmar primary sites. First CPI included: 184 (57%) anti-PD-1, 59 (18%) anti-PD-1/ipilimumab combination and 82 (25%) ipilimumab. ORR was significantly higher with initial anti-PD-1/ipilimumab compared with anti-PD-1 (43% vs 26%, HR 2.14, p=0.0004) and significantly lower with ipilimumab (15% vs 26%, HR 0.49, p=0.0016). Landmark PFS at 1 year was highest for anti-PD-1/ipilimumab at 34% (95% CI 24% to 49%), compared with 26% (95% CI 20% to 33%) with anti-PD-1 and 10% (95% CI 5% to 19%) with ipilimumab. Despite a trend for increased PFS, anti-PD-1/ipilimumab combination did not significantly improve PFS (HR 0.85, p=0.35) or OS over anti-PD-1 (HR 1.30, p=0.16), potentially due to subsequent therapies and high rates of acquired resistance. No outcome differences were found between primary sites. Conclusion While the ORR to anti-PD-1/ipilimumab was significantly higher than anti-PD-1 and PFS numerically higher, in this retrospective cohort this benefit did not translate to improved OS. Future trials should specifically include patients with acral melanoma, to help determine the optimal management of this important melanoma subtype.

KW - CTLA-4 Antigen

KW - Immunotherapy

KW - Melanoma

KW - Programmed Cell Death 1 Receptor

UR - https://www.scopus.com/pages/publications/85133618181

U2 - 10.1136/jitc-2022-004668

DO - 10.1136/jitc-2022-004668

M3 - Article

C2 - 35793872

AN - SCOPUS:85133618181

SN - 2051-1426

VL - 10

JO - Journal for ImmunoTherapy of Cancer

JF - Journal for ImmunoTherapy of Cancer

IS - 7

M1 - e004668

ER -

Efficacy of anti-PD-1 and ipilimumab alone or in combination in acral melanoma

Abstract

UN SDGs

Keywords

Research Highlights, Institutes and Platforms

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