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 |
| Pages (from-to) | 7348 |
| Journal | Nature Communications |
| Volume | 12 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 22 Dec 2021 |
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In: Nature Communications, Vol. 12, No. 1, 7348, 22.12.2021, p. 7348.
Research output: Contribution to journal › Article › Academic › peer-review
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 - Funding Information: Study oversight. This study was an investigator-initiated trial with the NKI as sponsor. The NKI designed the study, collected and analyzed data, and wrote the manuscript. Funding was provided by Bristol-Myers Squibb through the International Immuno-Oncology Network and by the Riki Foundation. The trial protocol and its amendments were reviewed and approved by the Medical Research Ethics Committee of the Netherlands Cancer Institute—Antoni van Leeuwenhoek Hospital (MREC AVL, https://english.ccmo.nl/mrecs/accredited-mrecs/mrec-netherlands-cancer-institute-the-antoni-van-leeuwenhoek-hospital), under file number NL57794.031.16. The study’s design and conduct were in accordance with all relevant regulations regarding the use of human study participants and the 1964 Helsinki declaration, and was consistent with Good Clinical Practice guidelines as formulated by the International Conference on Harmonization. All patients provided written informed consent prior to enrollment. The authors affirm that the patient of whom clinical photography is shown in Fig. 1c provided additional informed consent for publication of the images. The patient depicted in Supplementary Fig. 2 had died at time of writing, and additional informed consent for the publication of the photographs was obtained from the patient’s partner. Funding Information: J.L.V., J.B.W.E., J.J.H.T., X.Q., A.vd.L., Y.L., I.S., L.S., S.O., B.J., W.V.V., A.A.M., V.vd.N., A.K., E.H., A.B., R.D., L.K., M.B.K., P.J.F.M.L., W.H.S., W.M.C.K., L.vd.V., and I.B.T. declare no competing interests. C.L.Z. reports receiving institutional research financial support from BMS to fund the present trial. M.W.M.vd.B. reports, outside the submitted work, institutional research funding from ATOS Medical. S.M.W. reports, all outside the submitted work: institutional research funding from Roche, Pfizer, MSD, Bayer, Amgen, BMS, AstraZeneca, Lilly and Nextcure. O.K. is employed at Neogene Therapeutics B.V., though at time of analysis and writing his employment was at the NKI. O.K. further reports, outside the submitted work, a pending patent application (title: “Gene signatures and method for predicting response to pd-1 antagonists and ctla-4 antagonists, and combination thereof”, number: WO2020005068A8). D.S.P. reports, all outside the submitted work, a pending patent application (title: “Gene signatures and method for predicting response to pd-1 antagonists and ctla-4 antagonists, and combination thereof”, number: WO2020005068A8) and a role as co-founder, shareholder and advisor of Immagene. J.P.d.B. reports, all outside the submitted work: institutional research funding from Merck KGaA; institutional honoraria for an advisory role for MSD. T.N.M.S. reports, all outside the submitted work: advisory roles for Adaptive Biotechnologies, AIMM Therapeutics, Allogene Therapeutics, Merus, Neogene Therapeutics, Neon Therapeutics and Scenic Biotech; research support from Merck KGaA; stockholdership of AIMM Therapeutics, Allogene Therapeutics, Merus, BioNTech, Neogene Therapeutics, and Scenic Biotech. C.U.B. reports, all outside the submitted work: institutional research funding from BMS, Novartis and Nanostring; institutional honoraria for advisory roles for BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, Genmab and Pierre Fabre; personal honoraria for an advisory role for Third Rock Ventures; stock ownership of Uniti Cars and Immagene. J.B.A.G.H. reports, all outside the submitted work: institutional honoraria for advisory roles for AIMM, Amgen, BioNTech, BMS, GSK, Ipsen, MSD, Merck Serono, Molecular Partners, Neogene Therapeutics, Novartis, Pfizer, Roche/Genentech, Sanofi, Seattle Genetics, Third Rock Ventures, Vaximm; stock option ownership of Neogene Therapeutics; Institutional research funding from Amgen, BioNTech, BMS, MSD, Novartis. 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.
UR - http://www.scopus.com/inward/record.url?scp=85121506311&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-26472-9
DO - 10.1038/s41467-021-26472-9
M3 - Article
C2 - 34937871
SN - 2041-1723
VL - 12
SP - 7348
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 7348
ER -