Survival and biomarker analyses from the OpACIN-neo and OpACIN neoadjuvant immunotherapy trials in stage III melanoma

doi:10.1038/s41591-020-01211-7

Clinical Trial

. 2021 Feb;27(2):256-263.

doi: 10.1038/s41591-020-01211-7. Epub 2021 Feb 8.

Survival and biomarker analyses from the OpACIN-neo and OpACIN neoadjuvant immunotherapy trials in stage III melanoma

E A Rozeman¹, E P Hoefsmit^#², I L M Reijers^#¹, R P M Saw^{3

4

5}, J M Versluis¹, O Krijgsman^{2

6}, P Dimitriadis², K Sikorska⁷, B A van de Wiel⁸, H Eriksson^{9

10}, M Gonzalez³, A Torres Acosta⁷, L G Grijpink-Ongering⁷, K Shannon^{3

5}, J B A G Haanen^{1

2}, J Stretch^{3

4

5}, S Ch'ng^{3

4

5}, O E Nieweg^{3

4

5}, H A Mallo¹, S Adriaansz¹, R M Kerkhoven¹¹, S Cornelissen¹², A Broeks¹², W M C Klop¹³, C L Zuur¹³, W J van Houdt¹³, D S Peeper^{2

6}, A J Spillane^{3

4

14}, A C J van Akkooi¹³, R A Scolyer^{3

15}, T N M Schumacher^{2

6}, A M Menzies^{3

16}, G V Long^{3

16}, C U Blank^{17

18}

Affiliations

¹ Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
² Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
³ Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.
⁴ Department of Surgery, Mater Hospital, Sydney, New South Wales, Australia.
⁵ Department of Surgery, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
⁶ Oncode Institute, Utrecht, the Netherlands.
⁷ Department of Biometrics, Netherlands Cancer Institute, Amsterdam, the Netherlands.
⁸ Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
⁹ Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
¹⁰ Department of Oncology/Skin Cancer Center, Theme Cancer, Karolinska University Hospital, Stockholm, Sweden.
¹¹ Genomics Core Facility, Netherlands Cancer Institute, Amsterdam, the Netherlands.
¹² Core Facility Molecular Pathology and Biobanking, Netherlands Cancer Institute, Amsterdam, the Netherlands.
¹³ Department of Surgical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
¹⁴ Breast and Melanoma Surgery Unit, Royal North Shore hospital, Sydney, New South Wales, Australia.
¹⁵ Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and New South Wales Health Pathology, Sydney, New South Wales, Australia.
¹⁶ Department of Medical Oncology, Royal North Shore and Mater Hospitals, Sydney, New South Wales, Australia.
¹⁷ Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands. c.blank@nki.nl.
¹⁸ Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands. c.blank@nki.nl.

^# Contributed equally.

PMID: 33558721
DOI: 10.1038/s41591-020-01211-7

Clinical Trial

Survival and biomarker analyses from the OpACIN-neo and OpACIN neoadjuvant immunotherapy trials in stage III melanoma

E A Rozeman et al. Nat Med. 2021 Feb.

. 2021 Feb;27(2):256-263.

doi: 10.1038/s41591-020-01211-7. Epub 2021 Feb 8.

Authors

Affiliations

¹ Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
² Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
³ Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia.
⁴ Department of Surgery, Mater Hospital, Sydney, New South Wales, Australia.
⁵ Department of Surgery, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
⁶ Oncode Institute, Utrecht, the Netherlands.
⁷ Department of Biometrics, Netherlands Cancer Institute, Amsterdam, the Netherlands.
⁸ Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
⁹ Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
¹⁰ Department of Oncology/Skin Cancer Center, Theme Cancer, Karolinska University Hospital, Stockholm, Sweden.
¹¹ Genomics Core Facility, Netherlands Cancer Institute, Amsterdam, the Netherlands.
¹² Core Facility Molecular Pathology and Biobanking, Netherlands Cancer Institute, Amsterdam, the Netherlands.
¹³ Department of Surgical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
¹⁴ Breast and Melanoma Surgery Unit, Royal North Shore hospital, Sydney, New South Wales, Australia.
¹⁵ Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and New South Wales Health Pathology, Sydney, New South Wales, Australia.
¹⁶ Department of Medical Oncology, Royal North Shore and Mater Hospitals, Sydney, New South Wales, Australia.
¹⁷ Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands. c.blank@nki.nl.
¹⁸ Department of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands. c.blank@nki.nl.

^# Contributed equally.

PMID: 33558721
DOI: 10.1038/s41591-020-01211-7

Abstract

Neoadjuvant ipilimumab plus nivolumab showed high pathologic response rates (pRRs) in patients with macroscopic stage III melanoma in the phase 1b OpACIN ( NCT02437279 ) and phase 2 OpACIN-neo ( NCT02977052 ) studies^1,2. While the results are promising, data on the durability of these pathologic responses and baseline biomarkers for response and survival were lacking. After a median follow-up of 4 years, none of the patients with a pathologic response (n = 7/9 patients) in the OpACIN study had relapsed. In OpACIN-neo (n = 86), the 2-year estimated relapse-free survival was 84% for all patients, 97% for patients achieving a pathologic response and 36% for nonresponders (P < 0.001). High tumor mutational burden (TMB) and high interferon-gamma-related gene expression signature score (IFN-γ score) were associated with pathologic response and low risk of relapse; pRR was 100% in patients with high IFN-γ score/high TMB; patients with high IFN-γ score/low TMB or low IFN-γ score/high TMB had pRRs of 91% and 88%; while patients with low IFN-γ score/low TMB had a pRR of only 39%. These data demonstrate long-term benefit in patients with a pathologic response and show the predictive potential of TMB and IFN-γ score. Our findings provide a strong rationale for a randomized phase 3 study comparing neoadjuvant ipilimumab plus nivolumab versus standard adjuvant therapy with antibodies against the programmed cell death protein-1 (anti-PD-1) in macroscopic stage III melanoma.

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Comment in

Pathological correlates and predictive biomarkers for neoadjuvant ICIs in melanoma.
Killock D. Killock D. Nat Rev Clin Oncol. 2021 Apr;18(4):193. doi: 10.1038/s41571-021-00488-y. Nat Rev Clin Oncol. 2021. PMID: 33627793 No abstract available.

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References

1. Blank, C. U. et al. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. Nat. Med. 24, 1655–1661 (2018). - DOI
1. Rozeman, E. A. et al. Identification of the optimal combination dosing schedule of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma (OpACIN-neo): a multicentre, phase 2, randomised, controlled trial. Lancet Oncol. 20, 948–960 (2019). - DOI
1. Hauschild, A. et al. Longer follow-up confirms relapse-free survival benefit with adjuvant dabrafenib plus trametinib in patients with resected BRAF^V600-mutant stage III melanoma. J. Clin. Oncol. https://doi.org/10.1200/JCO.18.01219 (2018).
1. Eggermont, A. M. M. et al. Longer follow-up confirms recurrence-free survival benefit of adjuvant pembrolizumab in high-risk stage III Melanoma: updated results from the EORTC 1325-MG/KEYNOTE-054 Trial. J. Clin. Oncol. https://doi.org/10.1200/jco.20.02110 (2020).
1. Ascierto, P. A. et al. Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. https://doi.org/10.1016/s1470-2045(20)30494-0 (2020).

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[1] Blank, C. U. et al. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. Nat. Med. 24, 1655–1661 (2018). - DOI

[2] Blank, C. U. et al. Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. Nat. Med. 24, 1655–1661 (2018). - DOI

[3] Rozeman, E. A. et al. Identification of the optimal combination dosing schedule of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma (OpACIN-neo): a multicentre, phase 2, randomised, controlled trial. Lancet Oncol. 20, 948–960 (2019). - DOI

[4] Rozeman, E. A. et al. Identification of the optimal combination dosing schedule of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma (OpACIN-neo): a multicentre, phase 2, randomised, controlled trial. Lancet Oncol. 20, 948–960 (2019). - DOI

[5] Hauschild, A. et al. Longer follow-up confirms relapse-free survival benefit with adjuvant dabrafenib plus trametinib in patients with resected BRAF^V600-mutant stage III melanoma. J. Clin. Oncol. https://doi.org/10.1200/JCO.18.01219 (2018).

[6] Hauschild, A. et al. Longer follow-up confirms relapse-free survival benefit with adjuvant dabrafenib plus trametinib in patients with resected BRAF^V600-mutant stage III melanoma. J. Clin. Oncol. https://doi.org/10.1200/JCO.18.01219 (2018).

[7] Eggermont, A. M. M. et al. Longer follow-up confirms recurrence-free survival benefit of adjuvant pembrolizumab in high-risk stage III Melanoma: updated results from the EORTC 1325-MG/KEYNOTE-054 Trial. J. Clin. Oncol. https://doi.org/10.1200/jco.20.02110 (2020).

[8] Eggermont, A. M. M. et al. Longer follow-up confirms recurrence-free survival benefit of adjuvant pembrolizumab in high-risk stage III Melanoma: updated results from the EORTC 1325-MG/KEYNOTE-054 Trial. J. Clin. Oncol. https://doi.org/10.1200/jco.20.02110 (2020).

[9] Ascierto, P. A. et al. Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. https://doi.org/10.1016/s1470-2045(20)30494-0 (2020).

[10] Ascierto, P. A. et al. Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial. Lancet Oncol. https://doi.org/10.1016/s1470-2045(20)30494-0 (2020).

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Survival and biomarker analyses from the OpACIN-neo and OpACIN neoadjuvant immunotherapy trials in stage III melanoma

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Survival and biomarker analyses from the OpACIN-neo and OpACIN neoadjuvant immunotherapy trials in stage III melanoma

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