Concurrent Cetuximab and Nivolumab as a Second-Line or beyond Treatment of Patients with Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: Results of Phase I/II Study

Chung, Christine H.; Bonomi, Marcelo; Steuer, Conor E.; Li, Jiannong; Bhateja, Priyanka; Johnson, Matthew; Masannat, Jude; Song, Feifei; Hernández-Prera, Juan C.; Wenig, Bruce M.; Molina, Helen; Farinhas, Joaquim M.; McMullen, Caitlin; Wadsworth, J. Trad; Patel, Krupal; Kish, Julie A.; Kirtane, Kedar; Rocco, James W.; Schell, Michael J.; Saba, Nabil F.

doi:10.3390/cancers13051180

Cited by 36 publications

(32 citation statements)

References 31 publications

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“…On the other hand, for the nivolumab and cetuximab combination in platinum-refractory R/M HNC, the 1-year progression free survival (PFS) and overall survival (OS) rates were 19% and 44%, respectively. Although patients with no prior ICI showed improved PFS and OS compared to those with prior ICI, the difference was not significant ( 27 ).…”

Section: Targeted Agents Tested In Combination With Icis In Hncmentioning

confidence: 99%

Rational Combinations of Targeted Therapy and Immune Checkpoint Inhibitors in Head and Neck Cancers

2022

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Immunotherapy, especially the immune checkpoint inhibitors (ICIs) such as the pembrolizumab and nivolumab have contributed to significant improvements in treatment outcomes and survival of head and neck cancer (HNC) patients. Still, only a subset of patients benefits from ICIs and hence the race is on to identify combination therapies that could improve response rates. Increasingly, genetic alterations that occur within cancer cells have been shown to modulate the tumor microenvironment resulting in immune evasion, and these have led to the emergence of trials that rationalize a combination of targeted therapy with immunotherapy. In this review, we aim to provide an overview of the biological rationale and current strategies of combining targeted therapy with the approved ICIs in HNC. We summarize the ongoing combinatorial clinical trials and discuss emerging immunomodulatory targets. We also discuss the challenges and gaps that have yet to be addressed, as well as future perspectives in combining these different drug classes.

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Section: Targeted Agents Tested In Combination With Icis In Hncmentioning

confidence: 99%

Rational Combinations of Targeted Therapy and Immune Checkpoint Inhibitors in Head and Neck Cancers

2022

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“…Combination therapies of ICI with other, standard-of-care drugs may improve efficacy, for example in combination with cisplatin [ 198 , 199 ]. This may also apply for combining ICIs with different targets: Nivolumab is currently being tested in combination with Ipilimumab targeting CTLA4 [ 200 ].…”

Section: Targeting Oncogenic Pathways In Hnsccmentioning

confidence: 99%

“…Results of this trial are pending (NCT03700905 ClinicalTrials.gov, last accessed Nov. 17, 2021). Next, combination-therapy of Pembrolizumab with standard-of-care chemotherapy versus Cetuximab (targeting EGFR) was further tested in the KEYNOTE-048 and KEYNOTE-040 clinical trials [ 136 , 176 , 177 , 201 ] and also considered safe [ 202 ], but again showed significant survival benefits in only some patients [ 198 ]. The combination of Pembrolizumab with other therapies, such as chemoradiation, or as a maintenance therapy, was tested in the KEYNOTE-412 trial [ 165 , 203 ].…”

Section: Targeting Oncogenic Pathways In Hnsccmentioning

confidence: 99%

Shooting at Moving and Hidden Targets—Tumour Cell Plasticity and the Notch Signalling Pathway in Head and Neck Squamous Cell Carcinomas

Kałafut

Czerwonka

Anameriç

et al. 2021

Cancers

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Head and Neck Squamous Cell Carcinoma (HNSCC) is often aggressive, with poor response to current therapies in approximately 40–50% of the patients. Current therapies are restricted to operation and irradiation, often combined with a small number of standard-of-care chemotherapeutic drugs, preferentially for advanced tumour patients. Only very recently, newer targeted therapies have entered the clinics, including Cetuximab, which targets the EGF receptor (EGFR), and several immune checkpoint inhibitors targeting the immune receptor PD-1 and its ligand PD-L1. HNSCC tumour tissues are characterized by a high degree of intra-tumour heterogeneity (ITH), and non-genetic alterations that may affect both non-transformed cells, such as cancer-associated fibroblasts (CAFs), and transformed carcinoma cells. This very high degree of heterogeneity likely contributes to acquired drug resistance, tumour dormancy, relapse, and distant or lymph node metastasis. ITH, in turn, is likely promoted by pronounced tumour cell plasticity, which manifests in highly dynamic and reversible phenomena such as of partial or hybrid forms of epithelial-to-mesenchymal transition (EMT), and enhanced tumour stemness. Stemness and tumour cell plasticity are strongly promoted by Notch signalling, which remains poorly understood especially in HNSCC. Here, we aim to elucidate how Notch signal may act both as a tumour suppressor and proto-oncogenic, probably during different stages of tumour cell initiation and progression. Notch signalling also interacts with numerous other signalling pathways, that may also have a decisive impact on tumour cell plasticity, acquired radio/chemoresistance, and metastatic progression of HNSCC. We outline the current stage of research related to Notch signalling, and how this pathway may be intricately interconnected with other, druggable targets and signalling mechanisms in HNSCC.

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“…To assess these synergistic effects a phase I/II study evaluated the combination of cetuximab and nivolumab in RM SCCHN and found it was well-tolerated, but it did not improve OS at one year in this heavily pre-treated population. However, cetuximab and nivolumab combination therapy did have a more favorable PFS trends in patients without prior ICI therapy [ 95 ]. Currently, a study assessing pembrolizumab and cetuximab in RM SCCHN (NCT03082534) is actively recruiting patients [ 96 ].…”

Section: Dual Egfr Inhibition and Immunotherapymentioning

confidence: 99%

Current Aspects and Future Considerations of EGFR Inhibition in Locally Advanced and Recurrent Metastatic Squamous Cell Carcinoma of the Head and Neck

Patel

Saba

2021

Cancers

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Recurrent metastatic (RM) and locally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN) are devasting disease states with limited therapeutic options and poor overall survival. Targeting the epidermal growth factor receptor (EGFR) is one area that has helped improve outcomes in this disease. Anti-EGFR based therapies have been shown to improve overall survival and mitigate the significant toxicities incurred from standard radiation, chemotherapy, and/or surgical options. Cetuximab, the most well-studied anti-EGFR monoclonal antibody, has demonstrated a positive impact on outcomes for RM and LA SCCHN. However, the development of early resistance to cetuximab highlights the need for a wider arsenal of therapy for RM and LA diseases. The use of immune checkpoint inhibitors has recently transformed the treatment of recurrent SCCHN. Drugs such as pembrolizumab and nivolumab have demonstrated success in recent clinical trials and have been approved for the treatment of advanced disease. Given the positive results of both EGFR targeted agents and immune checkpoint inhibitors, ongoing trials are studying their synergistic effects.

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Concurrent Cetuximab and Nivolumab as a Second-Line or beyond Treatment of Patients with Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: Results of Phase I/II Study

Cited by 36 publications

References 31 publications

Rational Combinations of Targeted Therapy and Immune Checkpoint Inhibitors in Head and Neck Cancers

Rational Combinations of Targeted Therapy and Immune Checkpoint Inhibitors in Head and Neck Cancers

Shooting at Moving and Hidden Targets—Tumour Cell Plasticity and the Notch Signalling Pathway in Head and Neck Squamous Cell Carcinomas

Current Aspects and Future Considerations of EGFR Inhibition in Locally Advanced and Recurrent Metastatic Squamous Cell Carcinoma of the Head and Neck

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