Neoadjuvant immunotherapy with nivolumab and ipilimumab induces major pathological responses in patients with head and neck squamous cell carcinoma

Joris L. Vos; Joris B.W. Elbers; Oscar Krijgsman; Joleen J.H. Traets; Xiaohang Qiao; Anne M. van der Leun; Yoni Lubeck; Iris M. Seignette; Laura A. Smit; Stefan M. Willems; Michiel W.M. van den Brekel; Richard Dirven; M. Baris Karakullukcu; Luc Karssemakers; W. Martin C. Klop; Peter J.F.M. Lohuis; Willem H. Schreuder; Ludi E. Smeele; Lilly Ann van der Velden; I. Bing Tan; Suzanne Onderwater; Bas Jasperse; Wouter V. Vogel; Abrahim Al-Mamgani; Astrid Keijser; Vincent van der Noort; Annegien Broeks; Erik Hooijberg; Daniel S. Peeper; Ton N. Schumacher; Christian U. Blank; Jan Paul de Boer; John B.A.G. Haanen; Charlotte L. Zuur

doi:10.1038/s41467-021-26472-9

Neoadjuvant immunotherapy with nivolumab and ipilimumab induces major pathological responses in patients with head and neck squamous cell carcinoma

Joris L. Vos, Joris B.W. Elbers, Oscar Krijgsman, Joleen J.H. Traets, Xiaohang Qiao, Anne M. van der Leun, Yoni Lubeck, Iris M. Seignette, Laura A. Smit, Stefan M. Willems, Michiel W.M. van den Brekel, Richard Dirven, M. Baris Karakullukcu, Luc Karssemakers, W. Martin C. Klop, Peter J.F.M. Lohuis, Willem H. Schreuder, Ludi E. Smeele, Lilly Ann van der Velden, I. Bing TanSuzanne Onderwater, Bas Jasperse, Wouter V. Vogel, Abrahim Al-Mamgani, Astrid Keijser, Vincent van der Noort, Annegien Broeks, Erik Hooijberg, Daniel S. Peeper, Ton N. Schumacher, Christian U. Blank, Jan Paul de Boer, John B.A.G. Haanen, Charlotte L. Zuur^*

^*Corresponding author for this work

Radiotherapy

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

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Abstract

Surgery for locoregionally advanced head and neck squamous cell carcinoma (HNSCC) results in 30‒50% five-year overall survival. In IMCISION (NCT03003637), a non-randomized phase Ib/IIa trial, 32 HNSCC patients are treated with 2 doses (in weeks 1 and 3) of immune checkpoint blockade (ICB) using nivolumab (NIVO MONO, n = 6, phase Ib arm A) or nivolumab plus a single dose of ipilimumab (COMBO, n = 26, 6 in phase Ib arm B, and 20 in phase IIa) prior to surgery. Primary endpoints are feasibility to resect no later than week 6 (phase Ib) and primary tumor pathological response (phase IIa). Surgery is not delayed or suspended for any patient in phase Ib, meeting the primary endpoint. Grade 3‒4 immune-related adverse events are seen in 2 of 6 (33%) NIVO MONO and 10 of 26 (38%) total COMBO patients. Pathological response, defined as the %-change in primary tumor viable tumor cell percentage from baseline biopsy to on-treatment resection, is evaluable in 17/20 phase IIa patients and 29/32 total trial patients (6/6 NIVO MONO, 23/26 COMBO). We observe a major pathological response (MPR, 90‒100% response) in 35% of patients after COMBO ICB, both in phase IIa (6/17) and in the whole trial (8/23), meeting the phase IIa primary endpoint threshold of 10%. NIVO MONO’s MPR rate is 17% (1/6). None of the MPR patients develop recurrent HSNCC during 24.0 months median postsurgical follow-up. FDG-PET-based total lesion glycolysis identifies MPR patients prior to surgery. A baseline AID/APOBEC-associated mutational profile and an on-treatment decrease in hypoxia RNA signature are observed in MPR patients. Our data indicate that neoadjuvant COMBO ICB is feasible and encouragingly efficacious in HNSCC.

Original language	English
Article number	7348
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-26472-9
Publication status	Published - 22 Dec 2021

Bibliographical note

Acknowledgements:
We thank all patients and their families for their participation in the study. We thank our
colleagues from the NKI Core Facility Molecular Pathology & Biobanking (D. Peters, S.
Cornelissen, W. Hoefakker, M. Alkemade, L. Borghuis, and I. Hofland) for supplying lab
support; the Radiology & Nuclear Medicine department (A. Paape, A. van Raamsdonk,
and C. Vroonland) and the OR personnel (R. van Rossum, J. Hogenboom, J. Peerenboom, and S. Hermans) for their support in planning the various trial procedures; the
NKI Laboratory department (T. Korse, E. Platte, and M. Lucas) for PBMC acquisition
and isolation; the NKI scientific administration (A. Keijser, L. Ruiter, and E. van
Schaffelaar) for data management; the department of Medical Oncology (M. Tesselaar,
H. van Thienen, S. Wilgenhof, and M. Chalabi) and the Head and Neck Surgery and
Oncology nurse practitioners (H. Tefsen and M. Kroon) and residents for (outpatient)
clinical care; the members of the Tumor Biology & Immunology and Molecular
Oncology & Immunology departments for valuable discussions; S. Vanhoutvin for
financial management and legal support; and Bristol-Myers Squibb for scientific input
and financial support. This study was funded by the BMS International ImmunoOncology Network and the Riki Foundation, while the NKI was the study’s sponsor.
Both funding sources had no role in design and execution of the study, data analysis or
writing of the manuscript.

Publisher Copyright: © 2021, The Author(s).

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Vos, J. L., Elbers, J. B. W., Krijgsman, O., Traets, J. J. H., Qiao, X., van der Leun, A. M., Lubeck, Y., Seignette, I. M., Smit, L. A., Willems, S. M., van den Brekel, M. W. M., Dirven, R., Baris Karakullukcu, M., Karssemakers, L., Klop, W. M. C., Lohuis, P. J. F. M., Schreuder, W. H., Smeele, L. E., van der Velden, L. A., ... Zuur, C. L. (2021). Neoadjuvant immunotherapy with nivolumab and ipilimumab induces major pathological responses in patients with head and neck squamous cell carcinoma. Nature Communications, 12(1), Article 7348. https://doi.org/10.1038/s41467-021-26472-9

@article{3e57276ce6444abe978f74b082900f8c,

title = "Neoadjuvant immunotherapy with nivolumab and ipilimumab induces major pathological responses in patients with head and neck squamous cell carcinoma",

abstract = "Surgery for locoregionally advanced head and neck squamous cell carcinoma (HNSCC) results in 30‒50% five-year overall survival. In IMCISION (NCT03003637), a non-randomized phase Ib/IIa trial, 32 HNSCC patients are treated with 2 doses (in weeks 1 and 3) of immune checkpoint blockade (ICB) using nivolumab (NIVO MONO, n = 6, phase Ib arm A) or nivolumab plus a single dose of ipilimumab (COMBO, n = 26, 6 in phase Ib arm B, and 20 in phase IIa) prior to surgery. Primary endpoints are feasibility to resect no later than week 6 (phase Ib) and primary tumor pathological response (phase IIa). Surgery is not delayed or suspended for any patient in phase Ib, meeting the primary endpoint. Grade 3‒4 immune-related adverse events are seen in 2 of 6 (33%) NIVO MONO and 10 of 26 (38%) total COMBO patients. Pathological response, defined as the %-change in primary tumor viable tumor cell percentage from baseline biopsy to on-treatment resection, is evaluable in 17/20 phase IIa patients and 29/32 total trial patients (6/6 NIVO MONO, 23/26 COMBO). We observe a major pathological response (MPR, 90‒100% response) in 35% of patients after COMBO ICB, both in phase IIa (6/17) and in the whole trial (8/23), meeting the phase IIa primary endpoint threshold of 10%. NIVO MONO{\textquoteright}s MPR rate is 17% (1/6). None of the MPR patients develop recurrent HSNCC during 24.0 months median postsurgical follow-up. FDG-PET-based total lesion glycolysis identifies MPR patients prior to surgery. A baseline AID/APOBEC-associated mutational profile and an on-treatment decrease in hypoxia RNA signature are observed in MPR patients. Our data indicate that neoadjuvant COMBO ICB is feasible and encouragingly efficacious in HNSCC.",

author = "Vos, {Joris L.} and Elbers, {Joris B.W.} and Oscar Krijgsman and Traets, {Joleen J.H.} and Xiaohang Qiao and {van der Leun}, {Anne M.} and Yoni Lubeck and Seignette, {Iris M.} and Smit, {Laura A.} and Willems, {Stefan M.} and {van den Brekel}, {Michiel W.M.} and Richard Dirven and {Baris Karakullukcu}, M. and Luc Karssemakers and Klop, {W. Martin C.} and Lohuis, {Peter J.F.M.} and Schreuder, {Willem H.} and Smeele, {Ludi E.} and {van der Velden}, {Lilly Ann} and {Bing Tan}, I. and Suzanne Onderwater and Bas Jasperse and Vogel, {Wouter V.} and Abrahim Al-Mamgani and Astrid Keijser and {van der Noort}, Vincent and Annegien Broeks and Erik Hooijberg and Peeper, {Daniel S.} and Schumacher, {Ton N.} and Blank, {Christian U.} and {de Boer}, {Jan Paul} and Haanen, {John B.A.G.} and Zuur, {Charlotte L.}",

note = "Acknowledgements: We thank all patients and their families for their participation in the study. We thank our colleagues from the NKI Core Facility Molecular Pathology & Biobanking (D. Peters, S. Cornelissen, W. Hoefakker, M. Alkemade, L. Borghuis, and I. Hofland) for supplying lab support; the Radiology & Nuclear Medicine department (A. Paape, A. van Raamsdonk, and C. Vroonland) and the OR personnel (R. van Rossum, J. Hogenboom, J. Peerenboom, and S. Hermans) for their support in planning the various trial procedures; the NKI Laboratory department (T. Korse, E. Platte, and M. Lucas) for PBMC acquisition and isolation; the NKI scientific administration (A. Keijser, L. Ruiter, and E. van Schaffelaar) for data management; the department of Medical Oncology (M. Tesselaar, H. van Thienen, S. Wilgenhof, and M. Chalabi) and the Head and Neck Surgery and Oncology nurse practitioners (H. Tefsen and M. Kroon) and residents for (outpatient) clinical care; the members of the Tumor Biology & Immunology and Molecular Oncology & Immunology departments for valuable discussions; S. Vanhoutvin for financial management and legal support; and Bristol-Myers Squibb for scientific input and financial support. This study was funded by the BMS International ImmunoOncology Network and the Riki Foundation, while the NKI was the study{\textquoteright}s sponsor. Both funding sources had no role in design and execution of the study, data analysis or writing of the manuscript. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

day = "22",

doi = "10.1038/s41467-021-26472-9",

language = "English",

volume = "12",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Vos, JL, Elbers, JBW, Krijgsman, O, Traets, JJH, Qiao, X, van der Leun, AM, Lubeck, Y, Seignette, IM, Smit, LA, Willems, SM, van den Brekel, MWM, Dirven, R, Baris Karakullukcu, M, Karssemakers, L, Klop, WMC, Lohuis, PJFM, Schreuder, WH, Smeele, LE, van der Velden, LA, Bing Tan, I, Onderwater, S, Jasperse, B, Vogel, WV, Al-Mamgani, A, Keijser, A, van der Noort, V, Broeks, A, Hooijberg, E, Peeper, DS, Schumacher, TN, Blank, CU, de Boer, JP, Haanen, JBAG & Zuur, CL 2021, 'Neoadjuvant immunotherapy with nivolumab and ipilimumab induces major pathological responses in patients with head and neck squamous cell carcinoma', Nature Communications, vol. 12, no. 1, 7348. https://doi.org/10.1038/s41467-021-26472-9

TY - JOUR

T1 - Neoadjuvant immunotherapy with nivolumab and ipilimumab induces major pathological responses in patients with head and neck squamous cell carcinoma

AU - Vos, Joris L.

AU - Elbers, Joris B.W.

AU - Krijgsman, Oscar

AU - Traets, Joleen J.H.

AU - Qiao, Xiaohang

AU - van der Leun, Anne M.

AU - Lubeck, Yoni

AU - Seignette, Iris M.

AU - Smit, Laura A.

AU - Willems, Stefan M.

AU - van den Brekel, Michiel W.M.

AU - Dirven, Richard

AU - Baris Karakullukcu, M.

AU - Karssemakers, Luc

AU - Klop, W. Martin C.

AU - Lohuis, Peter J.F.M.

AU - Schreuder, Willem H.

AU - Smeele, Ludi E.

AU - van der Velden, Lilly Ann

AU - Bing Tan, I.

AU - Onderwater, Suzanne

AU - Jasperse, Bas

AU - Vogel, Wouter V.

AU - Al-Mamgani, Abrahim

AU - Keijser, Astrid

AU - van der Noort, Vincent

AU - Broeks, Annegien

AU - Hooijberg, Erik

AU - Peeper, Daniel S.

AU - Schumacher, Ton N.

AU - Blank, Christian U.

AU - de Boer, Jan Paul

AU - Haanen, John B.A.G.

AU - Zuur, Charlotte L.

N1 - Acknowledgements: We thank all patients and their families for their participation in the study. We thank our colleagues from the NKI Core Facility Molecular Pathology & Biobanking (D. Peters, S. Cornelissen, W. Hoefakker, M. Alkemade, L. Borghuis, and I. Hofland) for supplying lab support; the Radiology & Nuclear Medicine department (A. Paape, A. van Raamsdonk, and C. Vroonland) and the OR personnel (R. van Rossum, J. Hogenboom, J. Peerenboom, and S. Hermans) for their support in planning the various trial procedures; the NKI Laboratory department (T. Korse, E. Platte, and M. Lucas) for PBMC acquisition and isolation; the NKI scientific administration (A. Keijser, L. Ruiter, and E. van Schaffelaar) for data management; the department of Medical Oncology (M. Tesselaar, H. van Thienen, S. Wilgenhof, and M. Chalabi) and the Head and Neck Surgery and Oncology nurse practitioners (H. Tefsen and M. Kroon) and residents for (outpatient) clinical care; the members of the Tumor Biology & Immunology and Molecular Oncology & Immunology departments for valuable discussions; S. Vanhoutvin for financial management and legal support; and Bristol-Myers Squibb for scientific input and financial support. This study was funded by the BMS International ImmunoOncology Network and the Riki Foundation, while the NKI was the study’s sponsor. Both funding sources had no role in design and execution of the study, data analysis or writing of the manuscript. Publisher Copyright: © 2021, The Author(s).

PY - 2021/12/22

Y1 - 2021/12/22

N2 - Surgery for locoregionally advanced head and neck squamous cell carcinoma (HNSCC) results in 30‒50% five-year overall survival. In IMCISION (NCT03003637), a non-randomized phase Ib/IIa trial, 32 HNSCC patients are treated with 2 doses (in weeks 1 and 3) of immune checkpoint blockade (ICB) using nivolumab (NIVO MONO, n = 6, phase Ib arm A) or nivolumab plus a single dose of ipilimumab (COMBO, n = 26, 6 in phase Ib arm B, and 20 in phase IIa) prior to surgery. Primary endpoints are feasibility to resect no later than week 6 (phase Ib) and primary tumor pathological response (phase IIa). Surgery is not delayed or suspended for any patient in phase Ib, meeting the primary endpoint. Grade 3‒4 immune-related adverse events are seen in 2 of 6 (33%) NIVO MONO and 10 of 26 (38%) total COMBO patients. Pathological response, defined as the %-change in primary tumor viable tumor cell percentage from baseline biopsy to on-treatment resection, is evaluable in 17/20 phase IIa patients and 29/32 total trial patients (6/6 NIVO MONO, 23/26 COMBO). We observe a major pathological response (MPR, 90‒100% response) in 35% of patients after COMBO ICB, both in phase IIa (6/17) and in the whole trial (8/23), meeting the phase IIa primary endpoint threshold of 10%. NIVO MONO’s MPR rate is 17% (1/6). None of the MPR patients develop recurrent HSNCC during 24.0 months median postsurgical follow-up. FDG-PET-based total lesion glycolysis identifies MPR patients prior to surgery. A baseline AID/APOBEC-associated mutational profile and an on-treatment decrease in hypoxia RNA signature are observed in MPR patients. Our data indicate that neoadjuvant COMBO ICB is feasible and encouragingly efficacious in HNSCC.

AB - Surgery for locoregionally advanced head and neck squamous cell carcinoma (HNSCC) results in 30‒50% five-year overall survival. In IMCISION (NCT03003637), a non-randomized phase Ib/IIa trial, 32 HNSCC patients are treated with 2 doses (in weeks 1 and 3) of immune checkpoint blockade (ICB) using nivolumab (NIVO MONO, n = 6, phase Ib arm A) or nivolumab plus a single dose of ipilimumab (COMBO, n = 26, 6 in phase Ib arm B, and 20 in phase IIa) prior to surgery. Primary endpoints are feasibility to resect no later than week 6 (phase Ib) and primary tumor pathological response (phase IIa). Surgery is not delayed or suspended for any patient in phase Ib, meeting the primary endpoint. Grade 3‒4 immune-related adverse events are seen in 2 of 6 (33%) NIVO MONO and 10 of 26 (38%) total COMBO patients. Pathological response, defined as the %-change in primary tumor viable tumor cell percentage from baseline biopsy to on-treatment resection, is evaluable in 17/20 phase IIa patients and 29/32 total trial patients (6/6 NIVO MONO, 23/26 COMBO). We observe a major pathological response (MPR, 90‒100% response) in 35% of patients after COMBO ICB, both in phase IIa (6/17) and in the whole trial (8/23), meeting the phase IIa primary endpoint threshold of 10%. NIVO MONO’s MPR rate is 17% (1/6). None of the MPR patients develop recurrent HSNCC during 24.0 months median postsurgical follow-up. FDG-PET-based total lesion glycolysis identifies MPR patients prior to surgery. A baseline AID/APOBEC-associated mutational profile and an on-treatment decrease in hypoxia RNA signature are observed in MPR patients. Our data indicate that neoadjuvant COMBO ICB is feasible and encouragingly efficacious in HNSCC.

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U2 - 10.1038/s41467-021-26472-9

DO - 10.1038/s41467-021-26472-9

M3 - Article

C2 - 34937871

AN - SCOPUS:85121506311

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 7348

ER -

Neoadjuvant immunotherapy with nivolumab and ipilimumab induces major pathological responses in patients with head and neck squamous cell carcinoma

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