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. 2024 May;19(5):829-838.
doi: 10.1016/j.jtho.2023.12.022. Epub 2023 Dec 27.

Initial Chemotherapy for Locally Advanced and Metastatic NUT Carcinoma

Jia Luo  1 , Michelle Sanchez  2 , Elinton Lee  2 , Hans Hertzler  3 , Nhi Luong  3 , Emanuele Mazzola  4 , Bryanna Finstein  2 , Rubii Tamen  2 , Gifty Brisbane  2 , Tom Nguyen  2 , Paul K Paik  5 , Jamie E Chaft  5 , Michael L Cheng  1 , Hassan Khalil  6 , Sarina A Piha-Paul  7 , Lynette M Sholl  3 , Mizuki Nishino  8 , Pasi A Jänne  1 , Steven G DuBois  9 , Glenn J Hanna  10 , Geoffrey I Shapiro  11 , Christopher A French  12
Affiliations

Initial Chemotherapy for Locally Advanced and Metastatic NUT Carcinoma

Jia Luo et al. J Thorac Oncol. 2024 May.

Abstract

Introduction: NUT carcinoma (NC) is an underdiagnosed and aggressive poorly differentiated or squamous cell cancer. A subset of NC is sensitive to chemotherapy, but the optimal regimen is unknown. Experts have recommended platinum- and ifosfamide-based therapy based on case reports.

Methods: Patients with pathologically confirmed NC with known survival outcomes after chemotherapy and consented to participate in a worldwide registry were studied. Results were summarized using descriptive methods.

Results: The study included 118 patients with NC. Median age was 34 (range: 1-82) years, 39% were women, and 61% harbored a BRD4::NUTM1 fusion. Patients received platinum (74%) or ifosfamide (26%, including regimens with both, 13%). Of 62 patients with nonmetastatic disease, 40% had a thoracic primary. Compared with platinum-based chemotherapy, patients who received ifosfamide-based chemotherapy had nominally higher progression-free survival (12 mo: 59% [95% CI: 32-87] versus 37% [95% CI: 22-52], hazard ratio = 0.68 [0.32, 1.42], p = 0.3) but not overall survival (OS). Among the 56 patients with metastatic disease, 80% had a thoracic primary. Ifosfamide had an objective response rate (ORR) of 75% (six of eight) and platinum had an ORR of 31% (11 of 36). Nevertheless, there was no difference in progression-free survival or OS. The 3-year OS of the entire cohort was 19% (95% CI: 10%-28%). Of the 11 patients alive greater than 3 years, all presented with nonmetastatic and operable or resectable disease.

Conclusion: There is a numerically higher ORR for ifosfamide-based therapy compared with platinum-based therapy, with limited durability. OS at 3 years is only 19%, and development of effective therapies is an urgent unmet need for this patient population.

Keywords: Chemotherapy; Long term responders; NUT carcinoma; Poorly differentiated carcinoma; Squamous cell carcinoma.

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Conflict of interest statement

Disclosure Dr. Luo reports receiving research support to her institution from Erasca, Genentech, Kronos Bio, Novartis, and Revolution Medicines; receiving honoraria from Targeted Oncology, Physicians’ Education Resource, VJ Oncology, Cancer GRACE, and Community Cancer Education, Inc.; having advisory board participation from Astellas, AstraZeneca, and Amgen; receiving personal fees from Erasca, Blueprint Medicines, and Daiichi Sankyo; and having a pending patent filed by Memorial Sloan Kettering related to multimodal features to predict response to immunotherapy (PCT/US2023/115872). Dr. Paik receives compensation for consulting or advisory board participation from Bicara Therapeutics, Inc., EMD Serono, Inc., Novartis, Mirati Therapeutics, and Janssen; and receives honoraria for participation in CME educational programs from IDEOlogy, Excerpta Medica, PeerVoice, Physicians Education Resource, Medscape, Agile, Axis Medical Education, Aptitude Health, MJH, Annenberg Center, Cardinal Health, and Touch Independent Medical Education Ltd. Dr. Chaft has served as a consultant for AstraZeneca, Bristol-Myers Squib, Genentech, Merck, Flame Biosciences, Novartis, Regeneron-Sanofi, Guardant Health, and Janssen; and has received research funding to her institution from AstraZeneca, Bristol-Myers Squib, Genentech, and Merck. Dr. Cheng reports receiving honoraria from Lynx Group, WebMD, and Potomac Center for Medical Education; having consulting or advisory role for AstraZeneca, Boehringer Ingelheim, Mirati Therapeutics, Cepheid, Janssen, and Pfizer; receiving research funding from Palleon Pharmaceuticals (Inst); and receiving travel, accommodations, and expenses from Daiichi Sankyo, AstraZeneca, and Genzyme. Dr. Piha-Paul reports receiving clinical trial research support/grant funding through the institution from AbbVie, Inc., ABM Therapeutics, Inc., Acepodia, Inc., Alkermes, Aminex Therapeutics, BioMarin Pharmaceutical, Inc., Boehringer Ingelheim, Bristol-Myers Squib, Cerulean Pharma, Inc., Chugai Pharmaceutical Co., Ltd., Curis, Inc., Cyclacel Pharmaceuticals, Daiichi Sankyo, Eli Lilly, ENB Therapeutics, Epigenetix Inc., Five Prime Therapeutics, F-Star Beta Limited, F-Star Therapeutics, Gene Quantum, Genmab A/S, Gilead Sciences, Inc., GlaxoSmithKline, Helix BioPharma Corp., Hengrui Pharmaceuticals, Co., Ltd., HiberCell, Inc., Immorna Biotherapeutics, Inc., Immunomedics, Inc., Incyte Corp., Jacobio Pharmaceuticals Co., Ltd., Jiangsu Simcere Pharmaceutical Co., Ltd., Loxo Oncology, Inc., Lytix Biopharma AS, Medimmune, LLC, Medivation, Inc., Merck Sharp and Dohme Corp., Nectin Therapeutics, Ltd., Novartis Pharmaceuticals, Nurix, Pieris Pharmaceuticals, Inc., Pfizer, Phanes Therapeutics, Principia Biopharma, Inc., Puma Biotechnology, Inc., Purinomia Biotech, Inc., Rapt Therapeutics, Inc., Replimune, Roche/Blueprint, Seattle Genetics, Silverback Therapeutics, Shasqi, Inc., Synlogic Therapeutics, Taiho Oncology, Tesaro, Inc., Theradex Oncology, Toragen Therapeutics, Inc., TransThera Bio, Xencor, Inc., ZielBio, Inc., NCI/NIH, and P30CA016672 – Core Grant (CCSG Shared Resources); and having consulting for CRC Oncology. Dr. Sholl reports receiving research support to her institution from Genentech; and consulting from GV20 Therapeutics, Genentech, and Lilly. Dr. Nishino reports having consulting for AstraZeneca; and receiving research grants to the institution from Canon Medical Systems, AstraZeneca, Daiichi Sankyo, and Konica-Minolta. Dr. Jänne reports receiving grants from The Mark Foundation for Cancer Research and the American Cancer Society during the conduct of the study; personal fees outside of submitted work from Boehringer Ingelheim, Pfizer, Roche/Genentech, Chugai Pharmaceuticals, Ignyta, LOXO Oncology, Eli Lilly, SFJ Pharmaceuticals, Voronoi, Daiichi Sankyo, Biocartis, Novartis, Sanofi, Takeda Oncology, Transcenta, Silicon Therapeutics, Syndax, Nuvalent, Bayer, Esai, and Mirati Therapeutics; and grants outside the submitted work from Boehringer Ingelheim, Eli Lilly, Daiichi Sankyo, Takeda Oncology, PUMA, Astellas Pharmaceuticals, and Revolution Medicines. Dr. DuBois reports receiving honoraria or having advisory board participation from Amgen, Bayer, and Jazz Pharmaceuticals; and receiving travel expenses from LOXO Oncology, Roche, and Salarius, all outside the submitted work. Dr. Hanna reports receiving grants/contracts outside the submitted work from ACCRF, Actuate Therapeutics, ASCO CCF, Bicara, Bristol-Myers Squibb, Elevar Therapeutics, Exicure, Gateway for Cancer Research, Genentech, GlaxoSmithKline, ImmunityBio, Kartos, Kite, KSQ, Kura Oncology, Regeneron, Repertoire, Sanofi Genzyme, Secura Bio, and V Foundation; and having advisory role and/or receiving honoraria outside the submitted work from Bicara, Bio-Rad, Boxer Capital, Bristol-Myers Squibb, Coherus, Elevar, Exicure, General Catalyst, Guardian Bio, KSQ, Kura Oncology, Massachusetts Medical Society, Merck, Naveris, Nextech, Prelude, Rain, Regeneron, Remix, Replimune, Sanofi Genzyme, SIRPant, and Surface Oncology. Dr. Shapiro reports receiving personal fees from Merck KGaA/EMD-Serono, Bicycle Therapeutics, Cybrexa Therapeutics, Boehringer Ingelheim, Bayer, ImmunoMet, Concarlo Holdings, Syros, Zentalis, CytomX Therapeutics, Blueprint Medicines, Kymera Therapeutics, Janssen, Xinthera, and Artios; receiving grants from Merck KGaA/EMD-Serono, Tango, Bristol-Myers Squibb, Pfizer, and Eli Lilly; and having a patent for “Dosage regimen for sapacitabine and seliciclib” issued to Cyclacel Pharmaceuticals and GIS and a patent for “Compositions and methods for predicting response and resistance to CDK4/6 inhibition” issued to Liam Cornell and GIS. Dr. French reports receiving research funding from Boehringer Ingelheim and consultant fees from Boehringer Ingelheim. The remaining authors declare no conflict of interest.

Figures

Figure 1.
Figure 1.. Baseline characteristics of patients with NUT carcinoma
A. Distribution of primary site of disease in patients with NUT carcinoma in the registry who received chemotherapy with known outcomes. * indicates other primaries observed: n=2 thyroid primary, n=1 skin/soft tissue primary. B. Distribution of NUTM1 fusion oncogene partner in individuals with known fusion partner (n=74) either through validated FISH or NGS testing. ^ indicates other fusion partners observed: BRD2, n=1 and ZNF532, n=1. C. Flow diagrams for non-metastatic (n=62) and metastatic (n=56) patients of the primary site of disease and known fusion oncogene partner. The height of each bar is proportional to the number of patients with each baseline feature. D. Survival of patients who received chemotherapy starting from the start of platinum- or ifosfamide-based therapy by the Kaplan Meier method. Bands depict vertical 95% CI E. Survival of patients with metastatic disease (navy) and non-metastatic disease (blue) by the Kaplan Meier method Bands depict vertical 95% CI F. Survival of patients with thoracic (rose) and non-thoracic (olive) primary disease by the Kaplan Meier method. Bands depict vertical 95% CI
Figure 2.
Figure 2.. Outcomes to platinum- and ifosfamide-based chemotherapy in non-metastatic and metastatic disease
A. Survival outcomes of patients with non-metastatic disease defined by disease-free survival and event-free survival (left) and overall survival (right) by the Kaplan Meier method. Comparisons are shown between those who received a platinum-based treatment (olive) and ifosfamide based treatment (purple) and all patients (black) PFS = progression-free survival B. Best overall response in patients with metastatic disease per investigator determined RECIST comparing platinum-based and ifosfamide based treatment. *Not Evaluable: n=2 did not have an on-treatment scan and discontinued to pursue the next line of therapy; 1 patient was on platinum-based therapy for 42 days and alive for 67 days after; 1 patient was on platinum-based therapy for 24 days and alive for 46 days after C. Survival outcomes of patients with metastatic disease defined by progression-free survival (left) and overall survival (right) by the Kaplan Meier method. Comparisons are shown between those who received a platinum-based treatment (olive) and ifosfamide based treatment (purple) and all patients (black), dashed lines further separate ifosfamide (blue) and ifosfamide+platinum (rose) sub-cohorts of patients
Figure 3.
Figure 3.. Greater than three-year long-term survivors to multi-modal therapy in NC
Swimmers of the 11 patients (9%) with known survival beyond 3 years after the start of systemic therapy. Boxes on the left show baseline features of interest. Table below specifies platinum and/or ifosfamide based regimen patient received. Three patients received additional systemic therapy beyond platinum- and ifosfamide-based treatment (* = cyclophosphamide, ** = BET bromodomain inhibitor, and *** = PD-1 blockade immunotherapy). Abbreviations: platinum = platinum, ifosfamide = ifosfamide, cRT = concurrent chemotherapy and radiation, PFS = progression-free survival, rx = treatment, PD = progressive disease, diff = differentiation, VAI-PAI: vincristine, doxorubicin, ifosfamide – cisplatin, doxorubicin, ifosfamide
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