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

AbstractSurgery 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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Effect of serpinE1 overexpression on the primary tumor and lymph node, and lung metastases in head and neck squamous cell carcinoma

Head & Neck ◽

10.1002/hed.25437 ◽

2018 ◽

Cited By ~ 2

Author(s):

Irene Arroyo‐Solera ◽

Miguel Ángel Pavón ◽

Xavier León ◽

Montserrat López ◽

Alberto Gallardo ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Lymph Node ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Primary Tumor ◽

Lung Metastases ◽

Neck Squamous Cell Carcinoma

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Phase Ib/II, open label, multicenter study of intratumoral SD-101 in combination with pembrolizumab in anti-PD-1 treatment naïve patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC)

Annals of Oncology ◽

10.1093/annonc/mdy287.006 ◽

2018 ◽

Vol 29 ◽

pp. viii375 ◽

Cited By ~ 2

Author(s):

E.E.W. Cohen ◽

A. Algazi ◽

D. Laux ◽

D.J. Wong ◽

A. Amin ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Multicenter Study ◽

Neck Squamous Cell Carcinoma ◽

Open Label ◽

Phase Ib ◽

Treatment Naïve

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Phase ib trial of dose-escalating AZD1775 in combination with concurrent radiation and cisplatin for intermediate and high risk head and neck squamous cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.15_suppl.tps6106 ◽

2016 ◽

Vol 34 (15_suppl) ◽

pp. TPS6106-TPS6106 ◽

Cited By ~ 5

Author(s):

Bhishamjit S. Chera ◽

Gaorav P. Gupta ◽

Jared Weiss ◽

Juneko E. Grilley-Olson ◽

Dominic T. Moore ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

High Risk ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Neck Squamous Cell Carcinoma ◽

Phase Ib ◽

Dose Escalating

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In Vivo Assessment of the Safety of Standard Fractionation Temporally Feathered Radiation Therapy (TFRT) for Head and Neck Squamous Cell Carcinoma: An R-IDEAL Stage 1/2a First-in-Humans/Feasibility Demonstration of New Technology Implementation

10.1101/2021.01.05.21249232 ◽

2021 ◽

Author(s):

Shireen Parsai ◽

Richard Lei J. Qiu ◽

Peng Qi ◽

Geoffrey Sedor ◽

Clifton D. Fuller ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Radiation Therapy ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Primary Endpoint ◽

Neck Squamous Cell Carcinoma ◽

Ct Simulation ◽

Grade 3 ◽

Stage 1

AbstractIntroductionPrior in silico simulations of studies of Temporally Feathered Radiation Therapy (TFRT) have demonstrated potential reduction in normal tissue toxicity. This R-IDEAL Stage 1/2A study seeks to demonstrate the first-in-human implementation of TFRT in treating patients with head and neck squamous cell carcinoma (HNSCC).Materials and MethodsPatients with HNSCC treated with definitive radiation therapy were eligible (70 Gy in 35 fractions) were eligible. The primary endpoint was feasibility of TFRT planning as defined by radiation start within 15 days of CT simulation. Secondary endpoints included estimates of acute grade 3-5 toxicity.ResultsThe study met its accrual goal of 5 patients. TFRT plans were generated in four of the five patients within 15 business days of CT simulation, therefore meeting the primary endpoint. One patient was not treated with TFRT at physician’s discretion, though the TFRT plan had been generated within sufficient time from the CT simulation. For patients who received TFRT, the median time from CT simulation to radiation start was 10 business days (range 8-15). The average time required for radiation planning was 6 days. In all patients receiving TFRT, each subplan and every daily fraction was delivered in the correct sequence without error. The OARs feathered included: oral cavity, each submandibular gland, each parotid gland, supraglottis, and posterior pharyngeal wall (OAR pharynx). Prescription dose PTV coverage (>95%) was ensured in each TFRT subplan and the composite TFRT plan. One of five patients developed an acute grade 3 toxicity.ConclusionsThis study demonstrates the first-in-human implementation of TFRT (R-IDEAL Stage 1), proving its feasibility in the modern clinical workflow. Additionally, assessments of acute toxicities and dosimetric comparisons to a standard radiotherapy plan were described (R-IDEAL Stage 2a).HighlightsThis prospective study is the first-in-human application for Temporally Feathered Radiation Therapy (TFRT).In theory, TFRT may reduce radiation-induced toxicities by optimizing the time through which radiation is delivered and consequently improve normal tissue recovery.In this study, patients with head and neck squamous cell carcinoma were treated with TFRT.The primary endpoint of technical feasibility was met when patients were successfully treated with TFRT techniques without introducing delays in radiation commencement.

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Safety and Efficacy of Pembrolizumab With Chemoradiotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma: A Phase IB Study

Journal of Clinical Oncology ◽

10.1200/jco.19.03156 ◽

2020 ◽

Vol 38 (21) ◽

pp. 2427-2437 ◽

Cited By ~ 7

Author(s):

Steven F. Powell ◽

Kathryn A. Gold ◽

Mark M. Gitau ◽

Christopher J. Sumey ◽

Michele M. Lohr ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Locally Advanced ◽

Neck Squamous Cell Carcinoma ◽

Safety And Efficacy ◽

Phase Ib ◽

Curative Radiotherapy ◽

Weekly Cisplatin

PURPOSE Pembrolizumab is a humanized monoclonal antibody that blocks interaction between programmed death receptor-1 (PD-1) and its ligands (PD-L1, PD-L2). Although pembrolizumab is approved for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), its role in the management of locally advanced (LA) disease is not defined. We report a phase IB study evaluating the safety and efficacy of adding pembrolizumab to cisplatin-based chemoradiotherapy in patients with LA HNSCC. PATIENTS AND METHODS Eligible patients included those with oral cavity (excluding lip), oropharyngeal, hypopharyngeal, or laryngeal stage III to IVB HNSCC (according to American Joint Committee on Cancer, 7th edition, staging system) eligible for cisplatin-based, standard-dose (70 Gy) chemoradiotherapy. Pembrolizumab was administered concurrently with and after chemoradiotherapy with weekly cisplatin. Safety was the primary end point and was determined by incidence of chemoradiotherapy adverse events (AEs) and immune-related AEs (irAEs). Efficacy was defined as complete response (CR) rate on end-of-treatment (EOT) imaging or with pathologic confirmation at 100 days postradiotherapy completion. Key secondary end points included overall (OS) and progression-free survival (PFS). RESULTS The study accrued 59 patients (human papillomavirus [HPV] positive, n = 34; HPV negative, n = 25) from November 2015 to October 2018. Five patients (8.8%) required discontinuation of pembrolizumab because of irAEs, all of which occurred during concurrent chemoradiotherapy; 98.3% of patients completed the full planned treatment dose (70 Gy) of radiotherapy without any delays ≥ 5 days; 88.1% of patients completed the goal cisplatin dose of ≥ 200 mg/m2. EOT CR rates were 85.3% and 78.3% for those with HPV-positive and -negative HNSCC, respectively. CONCLUSION Pembrolizumab in combination with weekly cisplatin-based chemoradiotherapy is safe and does not impair delivery of curative radiotherapy or chemotherapy in HNSCC. Early efficacy data support further investigation of this approach.

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Notch Intracellular Domain (NICD) Expression and Clinical Manifestations of Second Primary Tumor at Esophagus in Patients with Head and Neck Squamous Cell Carcinoma

OncoTargets and Therapy ◽

10.2147/ott.s227745 ◽

2019 ◽

Vol Volume 12 ◽

pp. 11175-11181

Author(s):

Tauangtham Anekpuritanang ◽

Warut Pongsapich ◽

Tanasarun Watcharadilokkul ◽

Premyot Ngaotepprutaram ◽

Paveena Pithuksurachai ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Primary Tumor ◽

Clinical Manifestations ◽

Neck Squamous Cell Carcinoma ◽

Second Primary ◽

Second Primary Tumor ◽

Notch Intracellular Domain

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Incidence of hypothyroidism in head and neck squamous cell carcinoma patients receiving radiotherapy with and without immune checkpoint inhibitors.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e18551 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e18551-e18551

Author(s):

Jennifer Leddon ◽

Martina Chirra ◽

Arushi Agrawal ◽

Logan Roof ◽

Danny Trotier ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Risk Factor ◽

Oral Cavity ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Primary Tumor ◽

Thyroid Dysfunction ◽

Neck Squamous Cell Carcinoma

e18551 Background: Treatment for locally advanced head and neck squamous cell carcinoma (HNSCC) involves a combination of surgery, chemotherapy, and radiotherapy (RT). RT for HNSCC is a known risk factor for the development of hypothyroidism. Recently, anti-PD1 therapies have been approved for recurrent and metastatic HNSCC and are moving to the forefront of HNSCC care. Similarly, thyroid dysfunction is a common immune-related adverse event following anti-PD1 therapy. Whether the addition of anti-PD1 to RT increases the likelihood of developing hypothyroidism remains unknown. Methods: The rate of hypothyroidism in HNSCC patients receiving RT (+/- chemotherapy and surgery) was compared to HNSCC patients receiving RT + anti-PD1 therapy either concurrently or after RT. Exclusion criteria were preexisting thyroid dysfunction, RT dose < 45 Gy and patients with incomplete treatment records. We defined clinical hypothyroidism as an elevation of TSH with low T3, T4 or elevation of TSH with symptoms requiring levothyroxine initiation. Hypothyroidism incidence was compared using Fisher’s exact test. Results: 153 patients were evaluated. In the RT group (N = 103), patients received RT +/- surgery or chemotherapy. 82/103 (80%) were male, median age was 57 and primary tumor groups included oropharynx 62/103 (60%), larynx 29/103 (28%), oral cavity 9/103 (9%) and other 3/103 (3%). In the RT + anti-PD1 group (N = 50), 36/50 (72%) were males, median age was 57 and primary tumor groups included oral cavity 19/50 (38%), oropharynx 17/50 (34%), larynx 8/50 (16%), and other 6/50 (12%). In the RT group, median follow up after RT was 801 days. In the RT+ anti-PD1 group, median follow up was 595 days from RT and 388 days from anti-PD1. The rate of hypothyroidism was significantly higher in the RT group 22.3% (23/103) versus 6% (3/50)after anti-PD1 therapy (p = 0.011). Multinomial logistical regression found no significant difference in hypothyroidism based on age, sex, or BMI. Larynx as primary tumor location was an independent risk factor for development of hypothyroidism (OR 4.74, p = 0.002). Conclusions: The addition of anti-PD1 therapy to standard HNSCC treatments does not significantly increase the risk of developing hypothyroidism. In fact, this study finds a lower incidence of hypothyroidism in HNSCC patient receiving RT + PD1 therapy which may be due to shorter duration of follow up and lower proportion of laryngeal cancer patients who are at relatively higher risk for surgical hypothyroidism.

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