Clinical Trial

. 2024 Dec;25(12):1576-1588.

doi: 10.1016/S1470-2045(24)00507-2. Epub 2024 Nov 14.

Radiotherapy with cetuximab or durvalumab for locoregionally advanced head and neck cancer in patients with a contraindication to cisplatin (NRG-HN004): an open-label, multicentre, parallel-group, randomised, phase 2/3 trial

Loren K Mell¹, Pedro A Torres-Saavedra², Stuart J Wong³, Julie A Kish⁴, Steven S Chang⁵, Richard C Jordan⁶, Tian Liu⁷, Minh Tam Truong⁸, Eric W Winquist⁹, Vinita Takiar¹⁰, Trisha Wise-Draper¹¹, Jared R Robbins¹², Cristina P Rodriguez¹³, Musaddiq J Awan¹⁴, Beth M Beadle¹⁵, Christina Henson¹⁶, Samir Narayan¹⁷, Sharon A Spencer¹⁸, Steven Powell¹⁹, Neal Dunlap²⁰, Assuntina G Sacco²¹, Kenneth Shung Hu²², Henry S Park²³, Julie E Bauman²⁴, Jonathan Harris²⁵, Sue S Yom²⁶, Quynh-Thu Le¹⁵

Affiliations

¹ Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, USA. Electronic address: lmell@ucsd.edu.
² Biometric Research Program, Division of Cancer Treatment and Diagnosis, NCI, Bethesda, MD, USA.
³ Division of Hematology Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
⁴ Division of Hematology Oncology, Department of Medicine, Moffitt Cancer Center, Tampa, FL, USA.
⁵ Department of Otorhinolaryngology, Henry Ford Health System, Detroit, MI, USA.
⁶ NRG Oncology Biospecimen Bank, University of California San Francisco, San Francisco, CA, USA.
⁷ Department of Radiation Oncology, Emory University, Atlanta, GA, USA.
⁸ Department of Radiation Oncology, Boston Medical Center, Boston, MA, USA.
⁹ Department of Oncology, London Regional Cancer Program, London, ON, Canada.
¹⁰ Department of Radiation Oncology, University of Cincinnati, Cincinnati, OH, USA.
¹¹ Division of Hematology Oncology, University of Cincinnati, Cincinnati, OH, USA.
¹² Department of Radiation Oncology, University of Arizona College of Medicine, Tucson, AZ, USA.
¹³ Division of Hematology Oncology, University of Washington, Seattle, WA, USA.
¹⁴ Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, USA.
¹⁵ Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA.
¹⁶ Department of Radiation Oncology, University of Oklahoma, Oklahoma City, OK, USA.
¹⁷ Department of Radiation Oncology, Trinity Health Ann Arbor, Ann Arbor, MI, USA.
¹⁸ Department of Radiation Oncology, University of Alabama Birmingham, Birmingham, AL, USA.
¹⁹ Sanford USD Medical Center, Sioux Falls, SD, USA.
²⁰ Department of Radiation Oncology, University of Louisville, Louisville, KY, USA.
²¹ Division of Hematology Oncology, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
²² Department of Radiation Oncology, New York University Langone Medical Center, New York, NY, USA.
²³ Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, USA.
²⁴ Division of Hematology/Oncology, Department of Medicine, George Washington University and George Washington Cancer Center, Washington, DC, USA.
²⁵ NRG Oncology Statistics and Data Management Center, American College of Radiology, Philadelphia, PA, USA.
²⁶ Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA.

PMID: 39551064
PMCID: PMC11726348
DOI: 10.1016/S1470-2045(24)00507-2

Clinical Trial

Radiotherapy with cetuximab or durvalumab for locoregionally advanced head and neck cancer in patients with a contraindication to cisplatin (NRG-HN004): an open-label, multicentre, parallel-group, randomised, phase 2/3 trial

Loren K Mell et al. Lancet Oncol. 2024 Dec.

. 2024 Dec;25(12):1576-1588.

doi: 10.1016/S1470-2045(24)00507-2. Epub 2024 Nov 14.

Authors

Affiliations

¹ Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, USA. Electronic address: lmell@ucsd.edu.
² Biometric Research Program, Division of Cancer Treatment and Diagnosis, NCI, Bethesda, MD, USA.
³ Division of Hematology Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
⁴ Division of Hematology Oncology, Department of Medicine, Moffitt Cancer Center, Tampa, FL, USA.
⁵ Department of Otorhinolaryngology, Henry Ford Health System, Detroit, MI, USA.
⁶ NRG Oncology Biospecimen Bank, University of California San Francisco, San Francisco, CA, USA.
⁷ Department of Radiation Oncology, Emory University, Atlanta, GA, USA.
⁸ Department of Radiation Oncology, Boston Medical Center, Boston, MA, USA.
⁹ Department of Oncology, London Regional Cancer Program, London, ON, Canada.
¹⁰ Department of Radiation Oncology, University of Cincinnati, Cincinnati, OH, USA.
¹¹ Division of Hematology Oncology, University of Cincinnati, Cincinnati, OH, USA.
¹² Department of Radiation Oncology, University of Arizona College of Medicine, Tucson, AZ, USA.
¹³ Division of Hematology Oncology, University of Washington, Seattle, WA, USA.
¹⁴ Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, USA.
¹⁵ Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA.
¹⁶ Department of Radiation Oncology, University of Oklahoma, Oklahoma City, OK, USA.
¹⁷ Department of Radiation Oncology, Trinity Health Ann Arbor, Ann Arbor, MI, USA.
¹⁸ Department of Radiation Oncology, University of Alabama Birmingham, Birmingham, AL, USA.
¹⁹ Sanford USD Medical Center, Sioux Falls, SD, USA.
²⁰ Department of Radiation Oncology, University of Louisville, Louisville, KY, USA.
²¹ Division of Hematology Oncology, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
²² Department of Radiation Oncology, New York University Langone Medical Center, New York, NY, USA.
²³ Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, USA.
²⁴ Division of Hematology/Oncology, Department of Medicine, George Washington University and George Washington Cancer Center, Washington, DC, USA.
²⁵ NRG Oncology Statistics and Data Management Center, American College of Radiology, Philadelphia, PA, USA.
²⁶ Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA.

PMID: 39551064
PMCID: PMC11726348
DOI: 10.1016/S1470-2045(24)00507-2

Abstract

Background: Management of patients with locoregionally advanced head and neck squamous cell carcinoma (HNSCC) when cisplatin is contraindicated is controversial. We aimed to assess whether radiotherapy with concurrent and adjuvant durvalumab would improve outcomes compared with radiotherapy with cetuximab.

Methods: NRG-HN004 was designed as an open-label, multicentre, parallel-group, randomised, phase 2/3 trial with safety lead-in conducted at 89 academic and community medical centres in North America. Eligible patients were aged 18 years or older with American Joint Committee on Cancer 8th edition stage III-IVB p16-negative HNSCC or unfavourable stage I-III p16-positive oropharyngeal or unknown primary carcinoma, who had a contraindication to cisplatin (Eastern Cooperative Oncology Group [ECOG] performance status 2, renal or hearing impairment, peripheral neuropathy, aged at least 70 years with moderate or severe comorbidity, or aged younger than 70 years with severe comorbidity). Patients were randomly assigned (2:1) by permuted block randomisation (multiples of 6) to intravenous durvalumab 1500 mg starting 2 weeks before radiotherapy then every 4 weeks starting week 2 of radiotherapy (seven cycles) or intravenous cetuximab 400 mg/m² 1 week before radiotherapy then 250 mg/m² weekly beginning week 1 of radiotherapy (eight cycles), with intensity-modulated radiotherapy (70 Gy in 35 fractions over 7 weeks). Stratification factors were tumour and nodal stage, ECOG performance status and comorbidity, and primary site and p16 status. The phase 2 primary endpoint was progression-free survival in the intention-to-treat population. There was one prespecified interim futility analysis at 50% of progression-free survival information. If the observed hazard ratio was 1·0 or more, favouring cetuximab, early stopping would be considered. Extended follow-up analysis was post hoc. This trial is registered with ClinicalTrials.gov, NCT03258554, and is closed to enrolment.

Findings: Following a ten-patient safety lead-in, the phase 2 trial enrolled 190 patients from March 12, 2019, to July 30, 2021, 186 of whom were randomly assigned (123 to durvalumab and 63 to cetuximab). Median age was 72 years (IQR 64-77), 30 (16%) patients were women and 156 (84%) were men. Phase 2 accrual was suspended in July 30, 2021, following an interim futility analysis, and permanently closed in Sept 1, 2022. The phase 3 part of the trial was not conducted. At a median follow-up of 2·3 years (IQR 1·9-3·1) for the extended follow-up (data cutoff July 31, 2023; post-hoc analysis), 2-year progression-free survival was 50·6% (95% CI 41·5-59·8) in the durvalumab group versus 63·7% (51·3-76·1) in the cetuximab group (hazard ratio 1·33 [95% CI 0·84-2·12]; p=0·89). Adverse events were similar in both groups. The most common grade 3-4 adverse events were dysphagia (26 [22%] of 119 patients in the durvalumab group vs 18 [30%] of 61 patients in the cetuximab group), lymphopenia (33 [28%] vs 20 [33%]), and oral mucositis (13 [11%] vs 11 [18%]). Four (3%) patients in the durvalumab group and one (2%) in the cetuximab group died from treatment-related adverse events (death not otherwise specified, laryngeal oedema, lung infection, and respiratory failure in the durvalumab group and sudden death not otherwise specified in the cetuximab group).

Interpretation: Our findings suggest that durvalumab did not improve outcomes compared with cetuximab in patients with HNSCC with contraindications to cisplatin. Further trials are needed to define the standard of care for this population.

Funding: US National Cancer Institute and AstraZeneca.

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Conflict of interest statement

Declaration of interests MJA declares grants or contracts from the National Institutes of Health (NIH; R21 for phase 1 trial DEHART), receipt of equipment, materials, drugs, medical writing, gifts, or other services from Genentech for drug only support for NIH R21. JEB declares clinical trial grants from Aveo, Celldex, CUE, Genentech, and Moderna, and consulting fees from Bluedot Bio and Exelixis. ND declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca. CH declares participation on a medical advisory board for EMD Serono, and a leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid as co-chair of the Young Investigators Committee of the Head and Neck Cancer International Group. RCJ declares royalties or license from Elsevier for a textbook authorship. Q-TL declares a leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid as Radiation Therapy Oncology group chair for NRG Oncology. LKM declares grants or contracts from AstraZeneca and Merck to their institution, consulting fees from Pfizer, and payment for expert testimony from Arnold & Porter. HSP declares grants or contracts from RefleXion and Merck to their institution, consulting fees from AstraZeneca and RefleXion, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bristol Myers Squibb and G1 Therapeutics, and participation on a data safety monitoring board or advisory board at AstraZeneca and Galera. SP declares grants or contracts from Merck, Bristol Myers Squibb, Pfizer, Actuate, Vyriad, Nanobiotix, Seattle Genetics, AstraZeneca, Molecular Templates, and Sorrento to their institution, consulting fees from Bristol Myers Squibb to their institution, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Alkermes to their institution. CPR declares grants or contracts from AstraZeneca, Ayala, BMS, Cue Biopharma, Merck, Prelude, Sanofi Aventis, and Seagen to their institution, consulting fees from Vaccitech and Adaptimmune, and participation on a data safety monitoring board or advisory board at Pionyr Therapeutics. AGS declares grants or contracts from Merck, Bicara, AstraZeneca, Genentech/Roche, ALX Oncology, Regeneron, and Infinity Pharmaceuticals to their institution, consulting fees from Bicara, and payment or honoraria for lectures, presentations, speakers, bureaus, manuscript writing, or educational events from i3Health. VT declares grants or contracts from NIH and Veteran's Administration, support for attending meetings or travel from the American Society for Radiation Oncology and the American Board of Radiology, and receipt of equipment, materials, drugs, medical writing, gifts, or other services from Cardiff Oncology. PAT-S declares support for the current manuscript from NRG Oncology Statistics and Data Management Center grant from NCI. TW-D declares grants or contracts from Bristol Myers Squibb, Merck, Janssen, AstraZeneca/Medimmune, and Tesaro/GSK, and participation on a data safety monitoring board or advisory board at Merck. SSY declares grants or contracts from Bristol Myers Squibb and EMD Serono to their institution, honoraria for editorship from Elsevier, and leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid at ASTRO for editorship. All other authors declare no competing interests.

Figures

**Figure 1:. Trial profile**
*Discovery of liver metastasis likely to have been present before enrolment. †Missed doses could not be made up after radiotherapy per protocol. ‡One patient out of town, one physician decision, one persistent disease, and one likely metastasis before enrolment.

**Figure 2:. Kaplan–Meier estimates of progression-free survival in the post-hoc analysis**
Crosses denote censored patients.

**Figure 3:. Prespecified and post-hoc subgroup analysis of progression-free survival**
CCI=Charlson Comorbidity Index. CPS=combined positive score.

See this image and copyright information in PMC

References

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Radiotherapy with cetuximab or durvalumab for locoregionally advanced head and neck cancer in patients with a contraindication to cisplatin (NRG-HN004): an open-label, multicentre, parallel-group, randomised, phase 2/3 trial

Affiliations

Radiotherapy with cetuximab or durvalumab for locoregionally advanced head and neck cancer in patients with a contraindication to cisplatin (NRG-HN004): an open-label, multicentre, parallel-group, randomised, phase 2/3 trial

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