Metastatic Squamous Cell Carcinoma Of The Head And Neck Research Articles

Phase 2 trial of retifanlimab (anti–PD-1) in combination with INCAGN02385 (anti–LAG-3) and INCAGN02390 (anti–TIM-3) as first-line treatment in patients with PD-L1–positive recurrent/metastatic squamous cell carcinoma of the head and neck.

TPS6104 Background: Anti–PD-(L)1 therapies have improved clinical outcomes in PD-L1+ squamous cell carcinoma of the head and neck (SCCHN). However, many patients either do not respond or develop resistance, partly due to additional immune checkpoint receptors including LAG-3 and TIM-3, which are frequently coexpressed with PD-1 on tumor-infiltrating lymphocytes. In preclinical studies, LAG-3 and TIM-3 blockade showed synergistic activity with PD-1 inhibition, and triple blockade improves T-cell reinvigoration and antitumor efficacy over single/double combinations. Emerging clinical evidence also supports blockade of PD-1, LAG-3, and TIM-3 as a promising combination approach in checkpoint inhibitor–naive patients. This study aims to assess the efficacy and safety of the anti–PD-1 antibody, retifanlimab, in combination with INCAGN02385 (anti–LAG-3) and INCAGN02390 (anti–TIM-3) antibodies as first-line treatment in PD-L1+ recurrent or metastatic SCCHN. Methods: This randomized, double-blind, multicenter, phase 2 study (NCT05287113) includes patients with previously untreated, recurrent or metastatic, PD-L1+ (combined positive score [CPS] ≥1%) SCCHN and ECOG status of 0 or 1. Approximately 162 patients will be randomized 1:1:1 to receive (1) intravenous (IV) retifanlimab 500 mg every 4 weeks (Q4W) plus placebo controls, (2) retifanlimab plus IV INCAGN02385 350 mg Q2W plus placebo, or (3) retifanlimab plus INCAGN02385 plus IV INCAGN02390 400 mg Q2W. Patients will be stratified at randomization by LAG-3 expression (tumor proportion score ≥5% vs < 5%), PD-L1 CPS (1%-19% vs ≥20%), and human papillomavirus p16 status (positive vs negative; oropharyngeal tumors only). Treatment will be administered in 4-week cycles for up to 2 years. The primary endpoint is progression-free survival (PFS; defined per Response Evaluation Criteria in Solid Tumors [RECIST] v1.1). Secondary endpoints are objective response rate per RECIST v1.1, duration of response, disease control, overall survival, and safety. Sample size calculation is based on a median PFS of 3 months, based on historical data for anti–PD-1 monotherapy in the first-line treatment setting for PD-(L)1+ advanced/metastatic SCCHN. PFS, overall survival, and duration of response data will be analyzed by the Kaplan-Meier method. Patient enrollment is ongoing. Clinical trial information: NCT05287113 .

Real-world Data of Palliative First-line Checkpoint Inhibitor Therapy for Head and Neck Cancer.

Pembrolizumab alone or combined with chemotherapy is now approved in PD-L1-positive patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Since real-world data are pending, our goal was to evaluate the efficacy and safety of immune checkpoint inhibitor (CPI) therapy in an unselected cohort of patients with SCCHN. We analyzed 78 patients with recurrent or metastatic SCCHN from three Austrian cancer centers that received CPI therapy alone or with chemotherapy as palliative first-line systemic treatment for this retrospective study. Patient characteristics, details on treatment, and survival were analyzed by a chart-based review. Of the 78 patients analyzed, 55 patients were treated with CPI alone (45 with Pembrolizumab, 10 with Nivolumab) and 23 patients received chemotherapy with a platinum and 5-FU in addition to CPI. With a median follow-up of twelve months, the median PFS of all patients was 4 months [95% confidence interval (CI)=2.2-5.8] and the median OS was 11 months (95% CI=7.1-14.9). The overall response and disease control rates were 20.5% and 46.1%, respectively. There was no statistically significant difference in clinical outcome between patient groups with a different combined positive score (CPS). The rate of reported immune related adverse events was comparable to existing data. Our findings confirm the results of the KEYNOTE-048 trial that CPI therapy alone or together with chemotherapy is an effective treatment for patients with recurrent or metastatic CPS-positive SCCHN.

A Phase 1 Study of TAK-676, a Novel STING Agonist, Plus Pembrolizumab Following Radiation Therapy in Patients with Advanced Non–Small-Cell Lung Cancer (NSCLC), Triple-Negative Breast Cancer (TNBC), or Squamous-Cell Carcinoma of the Head and Neck (SCCHN)

<h3>Purpose/Objective(s)</h3> Radiation therapy-induced cell death produces cytosolic DNA that activates the cyclic GMP-AMP synthase (cGAS)–STimulator of INterferon Genes (STING) pathway, crucial for the induction of Type I interferons (IFN-I). Checkpoint inhibitor (CPI) resistance mechanisms have been linked to impaired IFN signaling. Preclinical data have shown STING agonists to reverse CPI resistance in tumors with prior exposure, particularly when used with anti-PD-1/PD-L1 therapies. TAK-676 (a synthetic STING agonist) potently modulates the innate immune system, leading to cytokine release, adaptive immune activation, and antitumor responses in preclinical studies (Appleman et al., AACR 2022). TAK-676 is being investigated as a single agent, and in combination with pembrolizumab, for advanced solid tumors, in a first-in-human phase 1 study (NCT04420884). TAK-676 is optimally designed for intravenous (IV) delivery, with a prolonged half-life in serum and enhanced tissue permeability, allowing access to tumor sites and lymphatic tissue. Following radiation therapy, TAK-676 has the potential to stimulate T-cell mediated antitumor immunity via STING-mediated IFN-I release, particularly when used with anti-PD-1/PD-L1 therapies. Here, we present a second phase 1 study to investigate the safety and preliminary antitumor activity of TAK-676 in combination with pembrolizumab following radiation therapy, in patients with advanced or metastatic NSCLC, TNBC, or SCCHN who have progressed on CPIs (NCT04879849). <h3>Materials/Methods</h3> Patients aged ≥18 years who progressed on CPIs and have ≥2 lesions, of which one is targetable with radiation, are being enrolled. Patients receive 8 Gy x 3 followed by (after a minimum of 40 hours) escalating doses of IV TAK-676 on days 1, 8 and 15 of a 21-day cycle, and 200 mg of IV pembrolizumab on day 1 of each cycle until disease progression, intolerance, or withdrawal of consent. Dose escalation of TAK-676 will be guided by the Bayesian Optimal Interval design. At screening and between days 15–21 of cycle 1, patients with a safely accessible lesion outside of the radiation field will have paired biopsies collected once the pharmacologically active dose levels of TAK-676 have been observed. The primary objective is to determine the safety and tolerability of TAK-676 in combination with pembrolizumab following radiation therapy. Secondary objectives are to determine the recommended phase 2 dose of TAK-676 in combination with pembrolizumab following radiation therapy, and to assess the local (within the radiation field) and systemic (non-radiated lesions) preliminary antitumor activity. As of February 2022, ∼10% of the planned patients have been enrolled. <h3>Results</h3> TBD <h3>Conclusion</h3> TBD

705TiP Phase II trial of retifanlimab (anti–PD-1) in combination with INCAGN02385 (anti–LAG-3) and INCAGN02390 (anti-TIM-3) as first-line treatment in patients with PD-L1-positive recurrent/metastatic squamous cell carcinoma of the head and neck

Anti-PD-(L)1 therapies have improved clinical outcomes in PD-L1+ squamous cell carcinoma of the head and neck (SCCHN). However, many patients either do not respond or develop resistance, partly due to additional immune checkpoint receptors including LAG-3 and TIM-3, which are frequently coexpressed with PD-1 in tumor infiltrating lymphocytes. In preclinical studies, LAG-3 and TIM-3 blockade showed synergistic activity with PD-1 inhibition, and triple blockade improves T-cell reinvigoration and antitumor efficacy over single/double combinations. Emerging clinical evidence also supports blockade of PD-1, LAG-3, and TIM-3 as a promising combination approach in checkpoint inhibitor-naive patients. This study aims to assess the efficacy and safety of the anti–PD-1 antibody retifanlimab in combination with INCAGN02385 (anti–LAG3) and INCAGN02390 (anti–TIM-3) antibodies as first-line treatment in PD-L1+ recurrent or metastatic SCCHN. This randomized, double-blind, multicenter, phase 2 study (NCT05287113) includes patients with previously untreated, recurrent or metastatic, PD-L1+ (combined positive score (CPS) ≥1%) SCCHN and Eastern Cooperative Oncology Group (ECOG) status of 0 or 1. Approximately 162 patients will be randomized 1:1:1 to receive (1) intravenous (IV) retifanlimab 500 mg every 4 weeks (Q4W) plus placebo controls, (2) retifanlimab plus IV INCAGN02385 350 mg Q2W plus placebo, or (3) retifanlimab plus INCAGN02385 plus IV INCAGN02390 400 mg Q2W. Patients will be stratified at randomization by LAG-3 expression (tumor proportion score ≥5% vs <5%), PD-L1 CPS (1%–19% vs ≥20%), and human papillomavirus p16 status (positive vs negative; oropharyngeal tumors only). Treatment will be administered in 4-week cycles for up to 2 years. The primary endpoint is progression-free survival (defined per Response Evaluation Criteria in Solid Tumors [RECIST] v1.1). Secondary endpoints are objective response per RECIST v1.1, duration of response, disease control, overall survival and safety. NCT05287113. Writing assistance was provided by Cory Pfeiffenberger, PhD (ICON, Blue Bell, PA, USA). Incyte Corporation.

TAK-676 in combination with pembrolizumab after radiation therapy in patients (pts) with advanced non–small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), or squamous-cell carcinoma of the head and neck (SCCHN): Phase 1 study design.

TPS2698 Background: The cyclic GMP-AMP Synthase (cGAS)–STimulator of INterferon Genes (STING) pathway is an important modulator of the innate immune system via induction of type I interferon (IFN-I). Cytosolic DNA generated as a result of tumor cell death following radiation therapy has been demonstrated to activate the cGAS-STING signaling axis resulting in antitumor immunogenicity. TAK-676 is a novel, synthetic STING agonist and it has been shown in preclinical studies to potently modulate the innate immune system and subsequently activate the adaptive immune system to produce antitumor responses. TAK-676 is designed for prolonged half-life in serum and enhanced tissue permeability compared with other STING agonists designed for intratumoral injection, allowing for systemic IV delivery with access to tumor sites and lymphatic tissue. IFN signaling impairment has been linked to checkpoint inhibitor (CPI) resistance in tumors. Treatment with TAK-676 after radiation therapy has the potential to stimulate T cell-mediated antitumor immunity via STING-mediated IFN-I release, particularly when used with anti-PD-1/PD-L1 therapies. Preclinical data support the addition of STING agonists to reverse resistance in tumors with prior exposure to CPIs. TAK-676 is being investigated (+/- pembrolizumab) in an ongoing first-in-human phase 1 study (NCT04420884). Here, we describe another phase 1 trial to investigate the safety and preliminary antitumor activity of TAK-676 plus pembrolizumab following radiation therapy in pts with advanced or metastatic NSCLC, TNBC, or SCCHN (NCT04879849). Methods: Adult pts with progressive disease (PD) following CPI treatment and who have ≥2 lesions, 1 of which can be targeted with radiation, are being enrolled. Pts receive 8 Gy x 3 fractions of image-guided radiation followed (after ≥40 hours) by IV pembrolizumab 200 mg on day 1 plus escalating doses of IV TAK-676 on days 1, 8, and 15 of a 21-day cycle. TAK-676 dose escalation is guided by the Bayesian optimal interval design. Pts receive TAK-676 plus pembrolizumab until PD, intolerance to treatment, or withdrawal. Pts enrolled at TAK-676 dose levels shown to have pharmacodynamic activity, and who have a safely accessible lesion outside the radiation field, will have paired biopsies collected at screening and between days 15 and 21 of cycle 1. The primary objective is to determine the safety and tolerability of TAK-676 plus pembrolizumab following radiation therapy; secondary objectives are to establish the recommended phase 2 dose of TAK-676 plus pembrolizumab following radiation therapy, and to assess preliminary antitumor activity both locally (within the radiation field) and systemically (non-radiated lesions). As of February 2022, we have enrolled ̃10% of the planned pts. Clinical trial information: NCT04879849.

89Zr-DFO-Durvalumab PET/CT Before Durvalumab Treatment in Patients with Recurrent or Metastatic Head and Neck Cancer.

In this PD-L1 ImagiNg to prediCt durvalumab treatment response in SCCHN (PINCH) study, we performed 89Zr-DFO-durvalumab (anti-PD-L1 [programmed death ligand 1]) PET/CT in patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) before monotherapy durvalumab treatment. The primary aims were to assess safety and feasibility of 89Zr-DFO-durvalumab PET imaging and predict disease control rate during durvalumab treatment. Secondary aims were to correlate 89Zr-DFO-durvalumab uptake to tumor PD-L1 expression, 18F-FDG uptake, and treatment response of individual lesions. Methods: In this prospective multicenter phase I-II study (NCT03829007), patients with incurable R/M SCCHN underwent baseline 18F-FDG PET and CT or MRI. Subsequently, PD-L1 PET imaging was performed 5 d after administration of 37 MBq of 89Zr-DFO-durvalumab. To optimize imaging conditions, dose finding was performed in the first 14 patients. For all patients (n = 33), durvalumab treatment (1,500 mg/4 wk, intravenously) was started within 1 wk after PD-L1 PET imaging and continued until disease progression or unacceptable toxicity (maximum, 24 mo). CT evaluation was assessed according to RECIST 1.1 every 8 wk. PD-L1 expression was determined by combined positive score on (archival) tumor tissue. 89Zr-DFO-durvalumab uptake was measured in 18F-FDG-positive lesions, primary and secondary lymphoid organs, and blood pool. Results: In total, 33 patients with locoregional recurrent (n = 12) or metastatic SCCHN (n = 21) were enrolled. 89Zr-DFO-durvalumab injection was safe. A dose of 10 mg of durvalumab resulted in highest tumor-to-blood ratios. After a median follow-up of 12.6 mo, overall response rate was 26%. The disease control rate at 16 wk was 48%, with a mean duration of 7.8 mo (range, 1.7-21.1). On a patient level, 89Zr-DFO-durvalumab SUVpeak or tumor-to-blood ratio could not predict treatment response (hazard ratio, 1.5 [95% CI, 0.5-3.9; P = 0.45] and 1.3 [95% CI, 0.5-3.3; P = 0.60], respectively). Also, on a lesion level, 89Zr-DFO-durvalumab SUVpeak showed no substantial correlation to treatment response (Spearman ρ, 0.45; P = 0.051). Lesional 89Zr-DFO-durvalumab uptake did not correlate to PD-L1 combined positive score but did correlate to 18F-FDG SUVpeak (Spearman ρ, 0.391; P = 0.005). Conclusion: PINCH is the first, to our knowledge, PD-L1 PET/CT study in patients with R/M SCCHN and has shown the feasibility and safety of 89Zr-DFO-durvalumab PET/CT in a multicenter trial. 89Zr-DFO-durvalumab uptake did not correlate to durvalumab treatment response.

Efficacy and Safety of Tisotumab Vedotin in Patients with Head and Neck Squamous Cell Carcinoma: Results From a Phase II Cohort

<h3>Purpose/Objective(s)</h3> Tisotumab vedotin (TV) is an antibody-drug conjugate directed against tissue factor, which is highly prevalent in some solid tumors. In Sep 2021, the US FDA approved TV monotherapy for recurrent or metastatic cervical cancer (r/mCC) patients with disease progression on or after chemotherapy. Encouraging early data from investigational TV combinations with carboplatin and pembrolizumab in relapsed cervical cancer suggest that these combinations may have activity in other cancers (Vergote 2021). innovaTV 207 evaluated TV in solid tumors, including a cohort of squamous cell carcinoma of the head and neck (SCCHN). We report the clinical activity and safety of TV 2 mg/kg Q3W in this cohort. <h3>Materials/Methods</h3> In this global, open label, phase 2, multicenter study, SCCHN cohort patients received 2 mg/kg TV (max dose: 200 mg per infusion) IV on Day 1 of each 21-day cycle. Eligible patients had: 1) relapsed, locally advanced, or metastatic SCCHN, and experienced disease progression on or after their most recent systemic therapy, 2) received prior therapy with a platinum-based regimen and a checkpoint inhibitor (if eligible), 3) received anti-epithelial growth factor receptor therapy prior to study entry (if eligible), and 4) received no more than 3 systemic regimens in the recurrent/metastatic setting. The primary endpoint was investigator confirmed objective response rate (ORR) per RECIST v1.1. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and tolerability. <h3>Results</h3> Of 31 SCCHN patients enrolled, median age was 65.0 (range 47-78) years. As of 15 Oct 2020, median duration of ongoing TV therapy was 12.0 weeks (range 3-36). Confirmed ORR was 16% (95% CI: 5.5-33.7); 5 patients had a partial response. Confirmed DCR was 58.1% (95% CI: 39.1-75.5). Median PFS was 4.2 months (95% CI: 2.7–4.8), and median OS was 9.4 months (95% CI: 8.1-11.8). Twenty-two (71.0%) patients developed Grade ≥3 treatment-emergent adverse events (TEAEs); most commonly (≥10% of patients) anemia (16.1%), pneumonia (12.9%), and dyspnea (12.9%). Reported incidence for all grade TEAEs of special interest for ocular, bleeding, and peripheral neuropathy events was 54.8%, 51.6%, and 29.0%, respectively. Incidence of treatment-emergent serious adverse events (SAEs) was 51.6%, and treatment related SAEs was 6.5% (grade 3 hemoptysis [n=1] and grade 3 post procedural hemorrhage [n=1]). There were 2 adverse events leading to death (aspiration and pulmonary embolism); none were considered treatment related. <h3>Conclusion</h3> TV has a manageable safety profile and favorable preliminary antitumor activity in patients with SCCHN that have progressed after a platinum containing regimen and a checkpoint inhibitor. Continued evaluation of TV is warranted. This trial is ongoing and is registered with ClinicalTrials.gov (NCT03485209).

Quality of Life of Patients with Head and Neck Cancer Receiving Cetuximab, Fluorouracil, Cisplatin Comparing to Cetuximab, Fluorouracil, Cisplatin, and Docetaxel within the CEFCID Trial

Introduction: CeFCiD was a multicenter phase II study comparing the efficacy of cetuximab (C), 5-flourouracil, and cisplatin with the same regimen adding docetaxel (D) in recurrent/metastatic head and neck cancer. The primary analysis trial did not demonstrate survival benefit from therapy intensification in first-line recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). The current analysis of the trial assessed the impact of treatment on quality of life (QoL). Methods: The European Organization for Research and Treatment of Cancer Quality of life Questionnaire QLQ-C30 and the tumor-specific module for head and neck cancer (QLQ-H&N35) were used to assess QoL at baseline (visit 1), after 2 (visit 3), 4 (visit 5), and 6 (visit 7) cycles of chemotherapy. Results: Of 180 patients included in this study, 86 patients (47.8%) completed the questionnaires at baseline. Considering selected scores over treatment time, there was no difference in global QoL, dyspnea, swallowing, and speech between the treatment arms in the course. For fatigue, a significant increase from baseline to visit 3 (p = 0.02), visit 5 (p = 0.002), and to visit 7 (p = 0.003) was observed for patients receiving D, cisplatin or carboplatin (P), 5-fluorouracil (F), and C. At the end of chemotherapy, the manifestation of fatigue was similar compared in the 2 treatment arms. Discussion/Conclusion: Therapy intensification not adversely affects selected scores of QoL of patients with recurrent and/or metastatic SCCHN. Nevertheless, fatigue seems to be pronounced in patients treated with D.

Real-world study of the impact of recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) on quality of life and productivity in Europe

BackgroundAlthough current therapy for patients with early-stage squamous cell carcinoma of the head and neck (SCCHN) is potentially curative, the recurrence rate is high. Patients with recurrent or metastatic (R/M) SCCHN have a poor prognosis and substantial disease burden, including impaired health-related quality of life (HRQoL), productivity loss and indirect costs, such as need for caregiver support. The aim of this study was to characterize the impact of R/M SCCHN and its first-line treatment on patient and caregiver quality of life, daily activities and work productivity using real-world evidence from Europe.MethodsThis was a multicentre retrospective study of patients with R/M SCCHN in France, Germany, Italy, Spain and the United Kingdom incorporating patient and caregiver surveys, and a physician-reported medical chart review, conducted between January and May 2019. Patients aged 18 or over with a physician confirmed diagnosis R/M SCCHN completed four validated measures of disease activity and its impact on quality of life and work productivity, while caregivers also completed questionnaire to assess the burden of providing care. Physicians provided data for clinical characteristics, patient management, testing history and treatment patterns.ResultsA total of 195 medical/clinical oncologists provided data for 937, predominantly male (72%) patients, with almost half of patients aged over 65 years. The most frequently reported symptoms were fatigue (43%), weight loss (40%), pain (35%) and difficulty swallowing (32%). The EXTREME regimen was the most common first line therapy in over half of patients, who reported moderate or extreme pain/discomfort, and anxiety/depression, and problems with self-care resulting in a diminished health status compared with the general population. Only 14% were employed with high absenteeism or presenteeism, and over half of patients had a caregiver for whom the burden of care was substantial.ConclusionOur results provide real-world insight into the multi-faceted burden associated with R/M SCCHN. The combination of poor HRQoL and the impairment in daily activities, social life and employment illustrates the wider impact of R/M SCCHN on patients and their caregivers, and highlights a need for novel 1 L treatment regimens to improve the humanistic and productivity burdens of this cancer.

Circulating tumor cell analysis in locally advanced and metastatic squamous cell carcinoma of the head and neck.

BackgroundCirculating tumors cells (CTCs) are considered an early step towards metastasis and have been linked to poor prognosis in several types of cancer. CTCs in squamous cell carcinoma of the head and neck (SCCHN) have an unclear role.MethodsIn this prospective study, patients with locally advanced or metastatic SCCHN had CTC counts assessed before starting systemic treatment using the CellSearch System. Select cases also had sequential CTC evaluation. Presence of CTCs was correlated with patient characteristics and outcomes.ResultsForty‐eight patients enrolled, and 36 had evaluable clinical data and baseline CTC counts. Twenty‐five patients had locally advanced disease (LAD) and 11 had metastatic disease. ≥1 CTCs were detected in six patients with LAD (24%) and four with metastatic disease (36%). On univariate analysis, smoking was associated with CTCs.ConclusionCTCs are not associated with prognosis in patients with LAD and metastatic disease; however, they are present in this patient population, and ≥1 CTCs is associated with a history of smoking.Level of evidence1b; individual prospective cohort study.

Randomized Phase II Study with Cetuximab in Combination with 5-FU and Cisplatin or Carboplatin vs. Cetuximab in Combination with Paclitaxel and Carboplatin for Treatment of Patients with Relapsed or Metastatic Squamous Cell Carcinoma of the Head and Neck (CETMET Trial).

Simple SummaryThe purpose of the CET-MET trial was to find a new platinum- based chemotherapy regimen in combination with cetuximab for relapsed or metastatic squamous cell carcinoma of the head and neck (RM- SCCHN), that would achieve an equivalent PFS with standard cetuximab and 5-FU/platinum-based chemotherapy (EXTREME regimen), albeit with less toxicity. RM-SCCHN is a disease which affects patients with severe comorbidity and unhealthy life styles, rendering it difficult to treat with toxic regimens such as the EXTREME trial regimen. Immune checkpoint inhibition (ICI) with/or without the addition of chemotherapy has recently been introduced as a first- line treatment option for RM-SCCHN. However, these new treatment options will not be suitable for all patients. The experimental arm of this trial with Cetuximab and paclitaxel/carboplatin is easier to administer and perhaps more beneficial to combine with ICIs due to its favorable toxicity profile and the potential immunomodulatory effects of taxanes.Background: Platinum-based chemotherapy with cetuximab is the standard of care for relapsed or metastatic squamous cell carcinoma of the head and neck (SCCHN). The aim of this trial was to investigate whether cetuximab and paclitaxel/carboplatin can achieve similar progression-free survival (PFS) with standard cetuximab and 5-FU/platinum-based chemotherapy. Standard chemotherapy treatment for SCCHN is related to severe toxicity and new, less toxic regimens are needed. Methods: In this multicentre, randomized, controlled, phase 2 trial, 85 patients with relapsed or metastatic SCCHN were randomized in a 1:1 ratio to cetuximab and 5-FU/cisplatin or carboplatin (arm A) vs. cetuximab and paclitaxel/carboplatin (arm B). Eligibility criteria included age ≥18 years, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–1, and adequate organ functions. The primary endpoint was to investigate whether PFS in arm B is significantly worse than PFS in arm A. Results: Median PFS in arm A was 4.37 months (95% CI: 2.9–5.9 m) and 6.5 months (95% CI: 4.8–8.2 m) in arm B, (p = 0.064). Median overall survival (OS) was 8.4 months (95% CI: 5.3–11.5 m) in arm A and 10.2 months (95% CI: 5.4–15 m) in arm B, (HR = 0.71; 95% CI: 0.43–1.16). PFS HR for arm B was not significantly worse than arm A (HR = 0.65; 95% CI: 0.41–1.03). Adverse events ≥ grade 3 were more frequent in arm A than arm B (60% vs. 40%; p = 0.034). Conclusion: Cetuximab and paclitaxel/carboplatin was found to have similar efficacy and less toxicity compared to cetuximab and 5-FU/cisplatin or carboplatin. The experimental arm is easier to administer rendering it a favorable alternative to standard therapy.

Emerging role of immune checkpoint inhibitors and predictive biomarkers in head and neck cancers.

Head and neck cancers are a group of diverse and heterogeneous tumors, among which squamous cell carcinoma of the head and neck (SCCHN) is the most prevalent. Current treatment modalities have limited efficacy; therefore, new therapies are being actively developed and evaluated. The introduction of immune checkpoint inhibitors (ICIs) has led to a paradigm shift in the management of difficult-to-treat malignancies. In this review, we summarize recent advances in the development of immunotherapies, which are aimed at the functional restoration of the immune system to counteract immune-evasion strategies of cancer cells, and related biomarkers. Monotherapies with ICIs, which primarily target the programmed cell death-1 (PD-1) pathway, have shown promising results in clinical trials of patients with recurrent and metastatic SCCHN. Combinations of ICIs with conventional or virus therapies often have synergistic therapeutic effects, without increased toxicity. As only a small subset of patients respond to immunotherapy, biomarkers are essential for the prediction of treatment response and better selection of patients for ICIs. PD-1 ligand (PD-L1) expression is correlated with response but has several limitations as a predictive marker, as its expression is dynamic and heterogeneous, and the cut-off needs further confirmation. Therefore, tumor mutation burden, gene expression signatures, microsatellite instability, tumor-infiltrating lymphocytes, viral antigens, and the oral microbiota are being investigated as predictive biomarkers. Finally, we delineate other challenges and future prospects for improving patient outcomes, including the major challenge of identifying and validating predictive biomarkers that need to be addressed in future studies.

PD-1 Inhibitors: Safety of Use and Management of Immune-Mediated Adverse Reactions in Patients With Head and Neck Cancer.

Treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with programmed cell death protein 1 (PD-1) inhibitors has been associated with risk of developing immune-mediated adverse reactions (IMARs). This review provides nurses with an overview of the safety of PD-1 inhibitors approved by the U.S. Food and Drug Administration for recurrent or metastatic SCCHN following platinum chemotherapy, as well as recommendations for assisting with the diagnosis and management of IMARs. PubMed® searches were conducted to identify relevant articles to support this review. Algorithms from drug manufacturers for IMAR management were also reviewed. Before treatment with PD-1 inhibitors, nurses should map patients' baseline profiles, which play a key role in aiding the healthcare team in the timely diagnosis and treatment of IMARs. Nurses should educate patients and caregivers on identifying signs and symptoms of IMARs and their progression. Within the interprofessional healthcare team, nurses play an important role in ensuring efficient management of IMARs to minimize withholding or discontinuation of PD-1 immunotherapy.

Phase 1 Study Evaluating the Association of the Cyclin-Dependent Kinase 4/6 Inhibitor Ribociclib and Cetuximab in Recurrent/Metastatic p16-Negative Squamous Cell Carcinoma of the Head and Neck.

Background: The majority of human papillomavirus (HPV)-negative squamous cell carcinoma of the head and neck (SCCHN) present upregulation of the epidermal growth factor receptor (EGFR) and frequent alterations in the cyclin D1-cyclin dependent kinase (CDK) 4/6 (CDK 4/6)-retinoblastoma protein (pRb) pathway, resulting in cell cycle progression and tumor proliferation. This study investigated the combination of ribociclib, an orally highly selective inhibitor of CDK 4/6, and cetuximab in recurrent and/or metastatic (R/M) SCCHN.Methods: A phase I trial using a 3 + 3 design was performed to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of ribociclib with standard dose of weekly cetuximab in HPV-negative patients with R/M SCCHN. Ribociclib was administered orally (3 weeks on/1 week off) at dose level 1 of 400 mg daily and dose level 2 of 600 mg daily. The MTD of ribocilib was then further evaluated in an expansion cohort.Results: 10 patients were enrolled in the escalation trial. No DLTs were observed at dose level 1 (n = 3); at dose level 2, one patient was replaced due to rapid disease progression, and one patient out of six evaluable patients experienced a DLT (grade 4 thrombocytopenia >7 days). Ribociclib 600 mg daily was thus determined to be the MTD. Eleven additional patients were enrolled in the expansion cohort. Diarrhea (52%), rash (52%), fatigue (43%), nausea (33%), and mucositis (28%) were the most frequent grade 1–2 adverse events (AE). Neutropenia was the most frequent grade 3–4 AE (20%). Median progression-free survival (PFS) was 3.5 months (range 0.4–17.3 months) and median overall survival (OS) was 8.3 months (range 0.4–24.1 months). Among the 19 radiologically evaluable patients, two (10.5%) achieved a partial response and 11 (58%) had stable disease.Conclusions: The MTD of ribociclib is 600 mg daily when administered in combination with standard dose cetuximab for 3 weeks on and 1 week off. This combination was safe and showed efficacy. Further clinical trials should be conducted to evaluate the antitumor effects of this combination.Trial Information: ClinicalTrials.gov: NCT02429089; Eudract number 2014-005371-83.

Biweekly cetuximab in combination with platinum and 5-fluorouracil in metastatic head and neck carcinoma.

The combination of cetuximab with platinum and 5-fluorouracil (5-FU) chemotherapy prolongs survival in patients with metastatic or recurrent squamous-cell carcinoma of the head and neck (SCCHN). Biweekly (once in 2 weeks) administration of cetuximab requires fewer hospital visits and decreases treatment costs; therefore, it is more convenient both for the patients and for the healthcare providers. Here, we assessed the efficacy, safety, and tolerability of an alternative biweekly regimen of cetuximab in combination with platinum and 5-FU chemotherapy as a first-line treatment for these patients. Medical records of patients with metastatic or recurrent non-nasopharyngeal SCCHN who were treated with a biweekly regimen of cetuximab (500 mg/m2 on day 1), cisplatin (40 mg/m2 on day 1) or carboplatin (target area under the curve 3.5 mg/ml × min on day 1), folinic acid (400 mg/m2 on day 1), and 5-FU (400 mg/m2 bolus on day 1 followed by continuous infusion of 2,400 mg/m2 5-FU over 46 h) were retrospectively reviewed. Survival estimates were calculated with the Kaplan-Meier method. In total, 60 patients were included. The median age of the patients was 60.5. The objective response rate was 53.3% (95% confidence interval [CI] = 40.7-65.9). The median progression-free survival duration was 6.8 months (95% CI = 5.5-8.1) and the median overall survival duration was 13.3 months (95% CI = 8.4-18.2). The most common grade 3 or 4 adverse events were neutropenia (28.3%) and leucopenia (13.3%). Grade 3 or 4 rash was observed in 3.3% of the patients. Biweekly administration of cetuximab, cisplatin, and 5-FU is an effective regimen with a favorable toxicity profile for the first-line treatment of metastatic or recurrent SCCHN. These results warrant further evaluation of this regimen in prospective trials.

Efficacy and safety of nimotuzumab in unresectable, recurrent, and/or metastatic squamous cell carcinoma of the head and neck: A hospital-based retrospective evidence.

Context:Role of nimotuzumab in locally advanced head and neck cancer (HNC) is well established in India; however, no clinical evidence is available for its role in recurrent and/or metastatic HNC.Aims:The aim of this study is to evaluate the efficacy and safety of nimotuzumab when added to standard treatment in unresectable, recurrent, and metastatic squamous cell carcinoma of the head and neck (SCCHN).Settings and Design:Hospital records of 14 patients diagnosed with recurrent and/or metastatic HNC with histologically confirmed squamous cell carcinoma and being treated with nimotuzumab along with standard treatments from December 2010 to December 2016 were retrospectively evaluated.Subjects and Methods:The tumor response rate and overall survival (OS) were analyzed. Toxicity and adverse events (AEs) were assessed as per common terminology criteria for adverse events (CTCAE) v 4.Results:Oral cavity was most commonly involved region followed by hypopharynx and oropharynx. At 24 weeks after completion of treatment, overall response rate (complete response (CR) + partial response (PR)) was 75%. Survival rate at 1, 2, and 3 years was 77.80%, 64.81%, and 64.81%, respectively. At a median follow-up of 15.17 months, median OS was not reached. All AEs were either Grade I (66.7%) or Grade II (33.3%). No Grade III or Grade IV AEs were observed. No added toxicity was observed due to nimotuzumab.Conclusions:In the first of its kind study, the addition of nimotuzumab to standard treatment showed promising response rate as well as survival outcomes in recurrent and/or metastatic SCCHN patients without producing additional toxicity.

Treatment patterns and health care resource use in patients receiving multiple lines of therapy for metastatic squamous cell carcinoma of the head and neck in the United Kingdom.

This study evaluated the patterns of care and health care resource use (HCRU) in patients with metastatic squamous cell carcinoma of the head and neck (SCCHN) who received ≥3 lines of systemic therapy in the United Kingdom (UK). Oncologists (n = 40) abstracted medical records for patients with metastatic SCCHN who initiated third‐line systemic therapy during 1 January 2011–30 August 2014 (n = 220). Patient characteristics, treatment patterns and SCCHN‐related HCRU were summarised descriptively for the metastatic period; exploratory multivariable regression analyses were conducted on select HCRU outcomes. At metastatic diagnosis, most patients had an Eastern Cooperative Oncology Group performance status (PS) of 0/1 (95%). For patients with PS 0/1, the most common first‐line treatment was cisplatin+5‐fluorouracil (5‐FU); docetaxel was the most common second‐ and third‐line treatment. For patients with PS ≥ 2, the most common first‐, second‐, and third‐line treatments were carboplatin+5‐FU, cetuximab, and methotrexate, respectively. Most patients received supportive care during (85%) and after (89%) therapy. This study provides useful information, prior to the availability of immunotherapy, on patient characteristics, treatment patterns, HCRU, and survival in a real‐world UK population with metastatic SCCHN receiving ≥3 lines of systemic therapy. Patterns of care and HCRU varied among patients with metastatic SCCHN; specific systemic therapies varied by patient PS.

1109TiP - MEDINDUCTION: Phase I trial evaluating the safety of durvalumab in combination with Docetaxel, Cisplatin and 5-FU (DCF) in induction for locally advanced squamous cell carcinoma of the head and neck (SCCHN)

Background: SCCHN represents the sixth most common malignancy with 650 000 new cases and 350 000 SCCHN-related deaths reported annually worldwide. A majority of patients present with stage III or IV M0 disease, with a 5 year overall survival from 30% to 50%. Results of recent randomized trials evaluating induction chemotherapy by DCF are conflicting, and benefit on overall survival is uncertain. It is needed to improve efficacy of induction chemotherapy without increase toxicities. Tumours can actively evade destruction by the immune system by exploiting inhibitory checkpoint pathways that suppress antitumour T-cell responses. Antibody therapy to block immune checkpoints activated by the programmed cell death ligand-1 (PD-L1) has shown survival benefit in recurrent or metastatic SCCHN. Durvalumab is a selective, high affinity, engineered human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80. Durvalumab has shown encouraging antitumour activity in SCCHN with a manageable safety profile. The aim of this open-label, multi-center, Phase 1-b study is to characterize the safety profile of the combination of DCF with durvalumab. Trial design: Patients aged ≥ 18 yr with histologically confirmed SCC of the oral cavity, oropharynx, larynx or hypopharynx, previously untreated, with indication of induction chemotherapy will be eligible. The primary objective is to determine the recommended Phase 2 dose (RP2D). The secondary objectives are to document any antitumor activity (PFS, ORR, RECISTv1.1 criteria), to estimate the pharmacokinetic parameters of durvalumab, to explore the relationships between immune capacity, specificity, activation state and clinical outcome. The study will be conducted in 2 parts: a dose-deescalation part to determine the RP2D (6 pts), and an expansion part (30 pts). The durvalumab will be administered every 3 weeks for 3 injections at week 1, 4, 7. The durvalumab first dose level is 1120 mg and the dose level -1 is 750 mg Q3W. The chemotherapy will be administered every 3 weeks at week 1, 4, 7 at the following doses: Docetaxel 75mg/m2 on D2, Cisplatin 75mg/m2 on D2, 5 Fluorouracil 750mg/m2/day from D2 to D6. Clinical trial identification: NCT 02997332 Eudract number 2015-004146-25 Legal entity responsible for the study: Gustave Roussy Funding: INCA and ARC Aknowledgement to Astra Zeneca for providing the drug Disclosure: C. Even: Advisory board: AstraZeneca, Bristol-Myers Squibb, Innate Pharma, Merck Serrono, MSD. C. Le Tourneau: Consulting fees: AstraZeneca. J. Fayette: Honoraria: Bristol-Myers Squibb, AstraZeneca. All other authors have declared no conflicts of interest.

A randomized, open-label, Phase III clinical trial of nivolumab vs. therapy of investigator’s choice in recurrent squamous cell carcinoma of the head and neck: A subanalysis of Asian patients versus the global population in checkmate 141

ObjectivesTo assess efficacy and safety of nivolumab versus investigator’s choice of therapy (IC) in Asian patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Materials and methodsThirty-four patients from Japan, Taiwan, Hong Kong, and Korea received nivolumab 3mg/kg (n=23) every 2weeks or IC (n=11), as part of a global trial (n=361), until intolerable toxicity or disease progression. The primary endpoint was overall survival (OS). ResultsMedian OS was 9.5months (95% confidence interval [CI] 9.1–NR) with nivolumab and 6.2months (95% CI 2.6–NR) with IC. Seven (30.4%) patients receiving nivolumab and six (54.5%) receiving IC died. The hazard ratio (HR) for risk of death (nivolumab vs. IC) was 0.50 (95% CI 0.17–1.48). Median progression-free survival was 1.9months (95% CI 1.6–7.5) with nivolumab and 1.8months (95% CI 0.4–6.1) with IC (HR 0.57 [95% CI 0.25–1.33]). Objective response rates (complete+partial responses) were 26.1% (6/23 patients; 95% CI 10.2–48.4) for nivolumab and 0% (0/11 patients; 95% CI 0.0–28.5) for IC. Sixteen (69.6%) nivolumab-treated patients and 10 (90.9%) patients receiving IC had a treatment-related adverse event, most commonly decreased appetite (21.7%), pruritus, rash, and fatigue (17.4% each) with nivolumab, and nausea, stomatitis, and decreased appetite (27.3% each) with IC. ConclusionNivolumab demonstrated a survival advantage compared with conventional treatments in Asian patients with platinum-refractory recurrent or metastatic SCCHN, and was well tolerated.Clinical trial registration NCT02105636.

Prognostic score in patients with recurrent or metastatic carcinoma of the head and neck treated with cetuximab and chemotherapy.

Despite modern treatment approaches, survival of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) remains low and it is difficult to identify patients who derive optimal benefit from treatment. We therefore analyzed which commonly available laboratory and clinical parameters may help improve the prognostication in this patient group. This retrospective monocenter analysis includes 128 patients with recurrent or metastatic SCCHN treated with cetuximab alone or in combination with polychemotherapy as first line therapy. Factors with independent prognostic power in the multivariate analysis were used to build up a score separating patient groups with different survival. Patients had a median age of 61 years and 103 patients were treated with polychemotherapy plus cetuximab. An ECOG score above 1, high CRP and leukocyte levels, less intensive treatment and a time below 12 months from primary diagnosis to relapse remained as independent negative prognostic factors in multivariate analysis.Patients with 0 to 1 risk factors had a median OS of 13.6 months compared to a median OS of less than one month for patients 4 to 5 risk factors (p<0.001). This study identifies 5 clinical and serum values that influence survival of patients with recurrent or metastatic SCCHN treated with cetuximab. By combining these factors to create a score for OS, it is possible to distinguish a group of patients with significantly improved survival and define those most likely to have no benefit from cetuximab treatment.