Recurrent Head And Neck Squamous Cell Carcinoma Research Articles

Phase 1/2 study of pepinemab, an inhibitor of semaphorin 4D, in combination with pembrolizumab as first-line treatment of recurrent or metastatic head and neck cancer (KEYNOTE-B84).

e18033 Background: Immunosuppressive myeloid cells in the tumor microenvironment (TME) limit the efficacy of immune checkpoint inhibitors (ICIs) in head and neck squamous cell carcinoma (HNSCC). Preclinical and clinical studies demonstrated that antibody blockade of semaphorin 4D (SEMA4D) promotes tumor infiltration and activation of DCs and CD8+ T cells and reverses immunosuppression, including attenuation of MDSC recruitment and function, leading to enhanced efficacy of ICIs. Pepinemab, a SEMA4D blocking antibody, in combination (combo) with avelumab provided clinical benefit in some patients with ICI-resistant and PD-L1-low NSCLC. Pembrolizumab (pembro) is approved as monotherapy or in combo with chemo for the first-line treatment of recurrent or metastatic (R/M) HNSCC, representative of a class of tumors that express higher levels of SEMA4D and MDSC. The primary hypothesis of this proof-of-concept study is that pepinemab in combo with pembro will yield increased clinical benefit compared to the reported activity for pembro monotherapy in R/M HNSCC. Methods: KEYNOTE-B84 (NCT04815720) is a single-arm open-label study evaluating the safety, efficacy, and PK/PD of pepinemab in combo with pembro as first-line treatment of R/M HNSCC. Subjects with measurable disease per RECIST1.1, ECOG 0 or 1, are eligible; subjects who have received prior ICIs or other systemic treatment for R/M HNSCC are excluded. The study includes a safety run-in (n = 3) and dose-expansion phase (maximum n = 62). Pepinemab, previously found to be well-tolerated in combo with other ICIs, will be evaluated initially at the highest intended dose of 20 mg/kg, in combo with 200 mg pembro, both administered i.v. Q3W. The dose expansion phase plans to include nearly equal distribution of subjects who have tumor PD-L1 combined positive scores (CPS) of < 20 and ≥20. The primary efficacy endpoint is ORR, and the secondary endpoints are PFS, DoR, and OS, as well as exploratory biomarker analyses. Pre- and on-treatment biopsies will be collected for evaluation of immune contexture in TME. Results: The safety run-in phase (n = 3) is complete, and the combo appeared to be well-tolerated with no DLTs observed; SMC approved continuation to dose expansion. Strikingly, two of the three patients have been observed to experience a complete response (CR). Biomarker analysis revealed that tumors in both responders expressed low levels of PD-L1 (CPS < 20). The third patient progressed prior to first scan, suffering several unrelated SAEs attributed to a pre-existing co-morbidity. Conclusions: The ongoing KEYNOTE-B84 study completed the initial safety run-in phase, with two of three subjects achieving CR. Phase 2 will evaluate pepinemab, a SEMA4D inhibitor, as a novel strategy to potentially overcome resistance and enhance activity of pembro in R/M HNSCC. Clinical trial information: NCT04815720.

Immune checkpoint inhibitors in head and neck squamous cell carcinoma: A systematic review of phase-3 clinical trials.

BACKGROUNDThe outcomes of patients diagnosed with head and neck squamous cell carcinoma (HNSCC) who are not candidates for local salvage therapy and of those diagnosed with recurrent or metastatic disease are dismal. A relatively new systemic therapy option that emerged in recent years in the treatment of advanced HNSCC is immunotherapy using immune checkpoint inhibitors (ICIs). The safety profile and anti-tumor activity of these agents demonstrated in early phase clinical trials paved the way to the initiation of several promising phase-3 trials in the field.AIMTo evaluate the evidence on the effectiveness of ICIs in HNSCC, based on published phase-3 clinical trials.METHODSWe searched PubMed, Cochrane Library, Embase, and Scopus to identify published literature evaluating immunotherapy using ICIs in recurrent or metastatic HNSCC (R/M HNSCC) and locally advanced head and neck squamous cell carcinoma (LAHNSCC). We used a combination of standardized search terms and keywords including head and neck squamous cell carcinoma, recurrent, metastatic, locally advanced, immunotherapy, immune checkpoint inhibitors, monoclonal antibodies, programmed cell death protein-1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T- lymphocyte associated protein-4 (CTLA-4), and phase-3 clinical trial. A sensitive search filter was used to limit our results to randomized controlled trials.RESULTSFive phase-3 clinical trials have reported the data on the effectiveness of immunotherapy in HNSCC so far: Four in R/M HNSCC and one in LAHNSCC. In patients with R/M HNSCC, anti-PD-1 agents nivolumab and pembrolizumab demonstrated improved survival benefits in the second-line treatment setting compared to the standard of care (standard single-agent systemic therapy). While the net gain in overall survival (OS) with nivolumab was 2.4 mo [hazard ratio (HR) = 0.69, P = 0.01], that with pembrolizumab was 1.5 mo (HR = 0.80 nominal P = 0.0161). The anti-PD-L1 agent durvalumab with or without the anti-cytotoxic T- lymphocyte associated protein-4 agent tremelimumab did not result in any beneficial outcomes. In the first-line setting, in R/M HNSCC, pembrolizumab plus platinum-based chemotherapy resulted in significant improvement in survival with a net gain in OS of 2.3 mo (HR = 0.77, P = 0.0034) in the overall population and a net gain in OS of 4.2 mo in the PD-L1 positive (combined positive score > 20) population compared to standard of care (EXTREME regime). In patients with PD-L1 positive R/M HNSCC, monotherapy with pembrolizumab also demonstrated statistically significant improvement in survival compared to EXTREME. In LAHNSCC, immunotherapy using avelumab (an anti-PD-L1 agent) along with standard chemoradiation therapy did not result in improved outcomes compared to placebo plus chemoradiation therapy.CONCLUSIONAnti-PD-1 agents provide survival benefits in R/M HNSCC in the first and second-line settings, with acceptable toxicity profiles compared to standard therapy. There is no proven efficacy in the curative setting to date.

Dissecting Tissue Compartment-Specific Protein Signatures in Primary and Metastatic Oropharyngeal Squamous Cell Carcinomas.

Head and neck squamous cell carcinoma (HNSCC) often presents with locoregional or distant disease, despite multimodal therapeutic approaches, which include surgical resection, chemoradiotherapy, and more recently, immunotherapy for metastatic or recurrent HNSCC. Therapies often target the primary and nodal regional HNSCC sites, and their efficacy at controlling occult distant sites remains poor. While our understanding of the tumor microenvironment conducive to effective therapies is increasing, the biology underpinning locoregional sites remains unclear. Here, we applied targeted spatial proteomic approaches to primary and lymph node metastasis from an oropharyngeal SCC (OPSCC) cohort to understand the expression of proteins within tumors, and stromal compartments of the respective sites in samples of both matched and unmatched patients. In unmatched analyses of n = 43 primary and 11 nodal metastases, our data indicated that tumor cells in nodal metastases had higher levels of Ki-67, PARP, BAD, and cleaved caspase 9, suggesting a role for increased proliferation, DNA repair, and apoptosis within these metastatic cells. Conversely, in matched analyses (n = 7), pro-apoptotic markers BIM and BAD were enriched in the stroma of primary tumors. Univariate, overall survival (OS) analysis indicated CD25 in tumor regions of primary tumors to be associated with reduced survival (HR = 3.3, p = 0.003), while progesterone receptor (PR) was associated with an improved OS (HR = 0.33, p = 0.015). This study highlights the utility of spatial proteomics for delineating the tumor and stromal compartment composition, and utility toward understanding these properties in locoregional metastasis. These findings indicate unique biological properties of lymph node metastases that may elucidate further understanding of distant metastatic in OPSCC.

Tumor Histological Grade and Immunotherapy Response in Patients With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

Tumor histological factors that predict immunotherapy response in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) are not well defined. To investigate the association between tumor grade and immunotherapy response in patients with recurrent or metastatic mucosal HNSCC. In this retrospective cohort study, the medical records of 60 patients with recurrent or metastatic mucosal HNSCC treated with immune checkpoint inhibitors at Johns Hopkins Hospital between July 1, 2015, and January 22, 2020, were reviewed. High-grade tumors (HGTs) vs low-grade tumors (LGTs) in recurrent or metastatic HNSCC. Patients were divided into 2 groups: those with LGTs (well differentiated and moderately differentiated) and those with HGTs (poorly differentiated). The main outcome was a clinically beneficial immunotherapy response, defined as complete response or partial response. Univariable and multivariable logistic regressions were conducted to calculate odds ratios for each variable's association with immunotherapy response. Survival differences were evaluated using Kaplan-Meier survival curves with multivariable Cox proportional hazards regression models. The 60 patients (35 with HGTs and 25 with LGTs) had a mean (SD) age of 64.6 (8.88) years; 51 were male (85%); and 38 were current or former smokers (63%). The oropharynx was the most common primary tumor site both in patients with HGTs (22 of 35; 63%) and those with LGTs (12 of 25; 48%). Bivariate analysis showed the proportion of patients having a beneficial response to immunotherapy was greater for patients with HGTs (12 of 35; 34.3%) than those with LGTs (2 of 25, 8.0%) (difference, 26.3%; 95% CI, 7.3%-45.3%). Upon multivariable analysis, patients with HGTs had 5.35-fold increased odds (95% CI, 1.04-27.37) of having a clinically beneficial response to immunotherapy. Among patients with available tumor genomic profiling data, the mean tumor mutational burden was greater for patients with HGTs (mean [SD], 8.6 [5.4] mut/Mb; n = 8) than patients with LGTs (mean [SD], 3.6 [1.1] mut/Mb; n = 4) (difference = 5.0 mut/Mb; 95% CI -1.4 to 11.4 mut/Mb; Cohen d = 1.2). In this cohort study, tumor grade was independently associated with immunotherapy response in patients with recurrent or metastatic mucosal HNSCC. These findings highlight the potential role of tumor grade in predicting immunotherapy response in mucosal HNSCC.

Pembrolizumab with or without chemotherapy versus cetuximab plus chemotherapy to treat recurrent or metastatic head and neck squamous cell carcinoma: An updated KEYNOTE-048 based cost-effectiveness analysis

ObjectivesRecently, updated data from KEYNOTE-048 revealed that pembrolizumab with or without chemotherapy could improve progression-free survival (PFS)2 compared with cetuximab plus chemotherapy in recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Materials and methodsA Markov structure was conducted to evaluate the cost and effectiveness of pembrolizumab monotherapy or pembrolizumab plus chemotherapy vs. cetuximab plus chemotherapy in the first-line treatment of recurrent or metastatic HNSCC from the United States payer’s perspective. Total cost, health outcomes, and incremental cost-effective ratios (ICERs) were estimated. Additional analyses were conducted in the total population and in two different programmed cell death 1 ligand 1 (PD-L1) combined positive scores (CPSs) (≥1 and ≥ 20) population. Sensitivity analysis were used to test the stability of the model. ResultsWhen compared with cetuximab plus chemotherapy, the pembrolizumab monotherapy strategy was dominated by lower cost and better efficacy in all three populations. The incremental costs and quality adjusted life years (QALYs) yielded by pembrolizumab plus chemotherapy compared with cetuximab plus chemotherapy were $16016.88 and 0.11 in the total population, and $24467.47 and 0.18 and $30448.46 and 0.20 in the populations with a PD-L1 CPS ≥ 1 and CPS ≥ 20, respectively, leading to ICERs of $147876.14, $134237.84, and $153660.78 per QALY, respectively. ConclusionFirst-line treatment with pembrolizumab or pembrolizumab plus chemotherapy are cost-effective strategies compared with cetuximab plus chemotherapy when the value of willingness-to-pay (WTP) was $150000 per QALY for the total and PD-L1 CPS ≥ 1 populations with recurrent or metastatic HNSCC.

Quality of Life in Patients With Recurrent and Second Primary Head and Neck Cancer.

In the setting of similar outcomes, quality of life (QOL) measures can be utilized to compare treatment modalities in head and neck squamous cell carcinoma (HNSCC). We evaluate QOL and symptoms in patients treated for primary, second primary, and recurrent HNSCC. Retrospective cohort study. Head and neck cancer survivorship clinic. We identified patients seen between 2016 and 2019. QOL and symptoms were assessed with the University of Washington Quality of Life (UW-QOL) questionnaire, 10-item Eating Assessment Tool, 8-item Patient Health Questionnaire, 7-item Generalized Anxiety Disorder, and Neck Disability Index. Regression analysis was utilized to explore associations and compare QOL outcomes. Our cohort comprised 662 patients: 546 with primary HNSCC, 34 with second primary HNSCC, and 82 with recurrent HNSCC. Multimodality therapy was associated with lower UW-QOL Physical Subscale (UW-QOL-PS) vs single modality: chemoradiation therapy (-12.17 [95% CI, -16.57 to -7.78]) and surgery + postadjuvant treatment (-12.11 [-16.06 to -8.16]). Multimodality therapy was also associated with lower UW-QOL Social-Emotional Subscale (UW-QOL-SS): chemoradiation therapy (-6.70 [-11.41 to -1.99]) and surgery + postadjuvant treatment (-7.41 [-11.63 to -3.19]). Recurrence (-14.42 [-18.80 to -10.04]) and second primary (-11.15 [-17.71 to -4.59]) demonstrated lower UW-QOL-PS vs primary. Radiation for recurrence or second primary had worse UW-QOL-PS (-10.43 [-19.27 to -1.59]) and UW-QOL-SS (-10.58 [-18.76 to -1.54]) and higher Eating Assessment Tool (6.08 [1.39-10.77]) than surgery alone. Surgery + postadjuvant treatment showed worse UW-QOL-PS (-12.65 [-23.76 to -1.54]) and UW-QOL-SS (-12.20 [-22.38 to -2.03]). Multimodality therapy, particularly with recurrent and second primary HNSCC, is more likely to contribute to diminished QOL and symptoms. This important consideration should play a role in framing informed discussions with patients regarding treatment.

An Update on the Immunotherapy for Oropharyngeal Squamous Cell Carcinoma.

Oropharyngeal squamous cell carcinoma (OPSCC) is an uncommon malignancy worldwide. Remarkably, the rising incidence of OPSCC has been observed in many developed countries over the past few decades. On top of tobacco smoking and alcohol consumption, human papillomavirus (HPV) infection has become a major etiologic factor for OPSCC. The radiotherapy-based or surgery-based systemic therapies are recommended equally as first-line treatment, while chemotherapy-based strategy is applied to advanced diseases. Immunotherapy in head and neck squamous cell carcinoma (HNSCC) is currently under the spotlight, especially for patients with advanced diseases. Numerous researches on programmed death-1/programmed death-ligand 1 checkpoint inhibitors have proven beneficial to patients with metastatic HNSCC. In 2016, nivolumab and pembrolizumab were approved as the second-line treatment for advanced metastatic HNSCC by the USA Food and Drug Administration. Soon after, in 2019, the USA Food and Drug Administration approved pembrolizumab as the first-line treatment for patients with unresectable, recurrent, and metastatic HNSCC. It has been reported that HPV-positive HNSCC patients were associated with increased programmed death-ligand 1 expression; however, whether HPV status indicates different treatment outcomes among HNSCC patients treated with immunotherapy has contradicted. Notably, HPV-positive OPSCC exhibits a significantly better clinical response to primary treatment (i.e., radiotherapy, surgery, and chemotherapy) and a more desirable prognosis compared to the HPV-negative OPSCC. This review summarizes the current publications on immunotherapy in HNSCC/OPSCC patients and discusses the impact of HPV infection in immunotherapeutic efficacy, providing an update on the immune landscape and future perspectives in OPSCC.

Targeting PI3Kα/δ and the ErbB Family of Protein-Tyrosine Kinases in Cisplatin-Resistant Head and Neck Squamous Cell Carcinomas

<h3>Purpose/Objective(s)</h3> The mortality rate for advanced head and neck squamous cell carcinoma (HNSCC) remains very high due to cancer recurrence and metastasis. Cisplatin is a commonly used anti-cancer drug for treatment of recurrent and metastatic HNSCC, but the majority of patients will eventually develop resistance. Therefore, there is an urgent, yet still unmet, need for improved therapies for cisplatin-resistant HNSCC. Increasing evidence has demonstrated that ErbB family kinase and PI3K/Akt are the most important regulators and targets in HNSCC. Our goal is to find new therapeutics to treat cisplatin resistant HNSCC without use of cisplatin. Here, we determined the efficacy of a combination of the PI3Kinase inhibitor, Copanlisib with the ErbB inhibitor, Afatinib, on suppressing cisplatin resistant HNSCC <i>in vitro</i> and <i>in vivo</i>. <h3>Materials/Methods</h3> Both cisplatin sensitive (Cal27 and FaDu) and resistant (Cal27CP and FaDu-CP) HNSCC cells were treated with copanlisib, afatinib, or a combination of copanlisib and afatinib. The effects on cell signaling pathways were tested by Western blot assay and RT-PCR. Cell proliferation was determined by MTT assay. Apoptosis was assayed by Annexin V. Migration and invasion was monitored via the xCELLigence real-time cell system tic cells. Xenograft tumor formation was observed in nude mice. <h3>Results</h3> We found that the combination of Copanlisib and Afatinib completely blocked PI3K/Akt/mTOR pathways and ErbB kinase family and significantly suppressed cell proliferation, survival, migration, and invasion <i>in vitro</i>, as well as xenograft tumor formation in animals. <h3>Conclusion</h3> We found that the combination of Copanlisib and Afatinib completely blocked PI3K/Akt/mTOR pathways and ErbB kinase family and significantly suppressed cell proliferation, survival, migration, and invasion <i>in vitro</i>, as well as xenograft tumor formation in animals.

Phase 1/2 Study of Pepinemab in Combination with Pembrolizumab as First-Line Treatment of Advanced, Recurrent or Metastatic Head and Neck Cancer (KEYNOTE B84)

<h3>Purpose/Objective(s)</h3> Immunosuppressive myeloid cells in the tumor microenvironment (TME) limit the efficacy of immune checkpoint inhibitors (ICIs) in head and neck squamous cell carcinoma (HNSCC). Preclinical and clinical studies demonstrated that antibody blockade of semaphorin 4D (SEMA4D) promotes tumor infiltration and activation of DCs and CD8+ T cells and reverses immunosuppression, including attenuation of MDSC recruitment and function, leading to enhanced efficacy of ICIs. Pepinemab, a humanized SEMA4D blocking antibody, in combination with avelumab provided clinical benefit in some patients with difficult to treat ICI-resistant and PD-L1-low NSCLC. Pembrolizumab is approved as monotherapy or in combination with chemotherapy for the first-line treatment of recurrent or metastatic (R/M) HNSCC. More effective treatments are, however, needed to increase the frequency and duration of responses. The primary hypothesis of this proof-of-concept study is that pepinemab in combination with pembrolizumab will yield increased clinical benefit compared to the reported activity for pembrolizumab monotherapy in R/M HNSCC. <h3>Materials/Methods</h3> KEYNOTE B84 (NCT04815720) is a multicenter, single-arm open-label study to evaluate the safety, efficacy, and PK/PD of pepinemab in combination with pembrolizumab as first-line treatment of R/M HNSCC. Subjects with measurable disease per RECIST1.1, and an ECOG PS of 0 or 1, are eligible; subjects who have received prior ICIs or other systemic treatment for R/M HNSCC are excluded. The study will include a safety run-in phase (n=3-6) and dose-expansion phase (maximum n=62). Pepinemab, previously found to be well-tolerated in combination with other ICIs, will be evaluated initially at the highest intended dose of 20 mg/kg, in combination with 200 mg pembrolizumab, both administered i.v. Q3W. The dose expansion phase will include an equal distribution of subjects who have tumor PD-L1 combined positive scores (CPS) of <20 and ≥20. The primary efficacy endpoint is ORR, and the secondary endpoints include PFS, DoR, and OS, as well as exploratory biomarker analyses. Pre- and on-treatment biopsies will be collected for evaluation of immune contexture in TME. <h3>Results</h3> Enrollment has been initiated at several of 18 participating sites. Preliminary data from the safety run-in phase will be evaluated at a safety monitoring review meeting planned for December 2021. In addition, multiplex immunohistochemistry panels have been established to immunophenotype cells in the TME, including CD8+ T cells, DCs, MDSCs, Tregs, monocytes, and macrophages. <h3>Conclusion</h3> There remains a clear unmet need for more effective treatment options to overcome immunosuppressive factors in the TME. The KEYNOTE B84 study will evaluate pepinemab, a SEMA4D inhibitor, as a novel strategy to potentially overcome resistance and enhance activity of pembrolizumab in R/M HNSCC.

Therapy-Related Transcriptional Subtypes in Matched Primary and Recurrent Head and Neck Cancer.

The genetic relatedness between primary and recurrent head and neck squamous cell carcinomas (HNSCC) reflects the extent of heterogeneity and therapy-driven selection of tumor subpopulations. Yet, current treatment of recurrent HNSCC ignores the molecular characteristics of therapy-resistant tumor populations. From 150 tumors, 74 primary HNSCCs were RNA sequenced and 38 matched primary/recurrent tumor pairs were both whole-exome and RNA sequenced. Transcriptome analysis determined the predominant classical (CL), basal (BA), and inflamed-mesenchymal (IMS) transcriptional subtypes according to an established classification. Genomic alterations and clonal compositions of tumors were evaluated from whole-exome data. Although CL and IMS subtypes were more common in primary HNSCC with low recurrence rates, the BA subtype was more prevalent and stable in recurrent tumors. The BA subtype was associated with a transcriptional signature of partial epithelial-to-mesenchymal transition (p-EMT) and early recurrence. In 44% of matched cases, the dominant subtype changed from primary to recurrent tumors, preferably from IMS to BA or CL. Expression analysis of prognostic gene sets identified upregulation of hypoxia, p-emt, and radiotherapy resistance signatures and downregulation of tumor inflammation in recurrences compared with index tumors. A relevant subset of primary/recurrent tumor pairs presented no evidence for a common clonal origin. Our study showed a high degree of genetic and transcriptional heterogeneity between primary/recurrent tumors, suggesting therapy-related selection of a transcriptional subtype with characteristics unfavorable for therapy. We conclude that therapy decisions should be based on genetic and transcriptional characteristics of recurrences rather than primary tumors to enable optimally tailored treatment strategies.

Pharmacologic inhibition of ataxia telangiectasia and Rad3-related (ATR) in the treatment of head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) poses significant treatment challenges, with high recurrence rates for locally advanced disease despite aggressive therapy typically involving a combination of surgery, radiation therapy, and/or chemotherapy. HNSCCs commonly exhibit reduced or absent TP53 function due to genomic alterations or human papillomavirus (HPV) infection, leading to dependence on the S- and G2/M checkpoints for cell cycle regulation. Both of these checkpoints are activated by Ataxia Telangiectasia and Rad3-related (ATR), which tends to be overexpressed in HNSCC relative to adjacent normal tissues and represents a potentially promising therapeutic target, particularly in combination with other treatments. ATR is a DNA damage signaling kinase that is activated in response to replication stress and single-stranded DNA breaks, such as those induced by radiation therapy and certain chemotherapies. ATR kinase inhibitors are currently being investigated in several clinical trials as part of the management of locally advanced, recurrent, or metastatic HNSCC, along with other malignancies. In this review article, we summarize the rationale and preclinical data supporting incorporation of ATR inhibition into therapeutic regimens for HNSCC.

What&amp;apos;s New in Molecular Targeted Therapies for Head and Neck Cancer?

Head and neck cancer is the 6&lt;sup&gt;th&lt;/sup&gt; most frequently diagnosed solid tumor in the world. Alcohol consumption, smoking, and HPV infection are associated with the incidence of head and neck squamous cell carcinoma (HNSCC). Although a multidisciplinary approach is a key strategy for the treatment of locally advanced HNSCC, systemic therapy is the mainstream of recurrent or metastatic HNSCC treatment. Stage IV HNSCC has a relatively poor prognosis with median overall survival of around one year. There have been many clinical trials to investigate the efficacy of target agents in the treatment of HNSCC. In the HPV-negative HNSCC, TP53 and CDKN2A are the most commonly mutated genes. In the HPV-positive HNSCC, the PI3K pathway is frequently altered. EGFR, PI3K, cell cycle pathway, MET, HRAS, and IL6/JAK/STAT pathway are explored targets in HNSCC. In this study, we review the target pathways and agents under research. We also introduce here umbrella trials of recurrent or metastatic HNSCC conducted by the Korea Cancer Study Group. The combination of target agents with immune checkpoint inhibitors or cytotoxic chemotherapies would be a future step in the precision medicine of HNSCC treatment.

Multi-Institutional Study Validates Safety of Intraoperative Cesium-131 Brachytherapy for Treatment of Recurrent Head and Neck Cancer.

IntroductionSurgery is the primary treatment for resectable, non-metastatic recurrent head and neck squamous cell carcinoma (HNSCC). We explore the safety and oncologic benefit of intraoperative Cesium-131 (Cs-131) brachytherapy combined with salvage local and/or regional surgical resection.Methods and MaterialsFindings were reported from a single arm multi-institutional prospective phase 1/2 trial involving surgery plus Cs-131 (surgery + Cs-131) treatment. The results of two retrospective cohorts—surgery alone and surgery plus intensity modulated radiation therapy (surgery + ReIMRT)—were also described. Included patients had recurrent HNSCC and radiation history. Safety, tumor re-occurrence, and survival were evaluated.ResultsForty-nine patients were enrolled in the surgery + Cs-131 prospective study. Grade 1 to 3 adverse events (AEs) occurred in 18 patients (37%), and grade 4 AEs occurred in 2 patients. Postoperative percutaneous endoscopic gastrostomy (PEG) tubes were needed in 10 surgery + Cs-131 patients (20%), and wound and vascular complications were observed in 12 patients (24%). No cases of osteoradionecrosis were reported in the surgery + Cs-131 cohort. We found a 49% 2-year disease-free survival at the site of treatment with a substantial number of patients (31%) developing metastatic disease, which led to a 31% overall survival at 5 years.ConclusionsAmong patients with local/regional recurrent HNSCC status-post radiation, surgery + Cs-131 demonstrated acceptable safety with compelling oncologic outcomes, as compared to historic control cohorts.Clinical Trial Registration ClinicalTrials.gov, identifiers NCT02794675 and NCT02467738.

Recent Research on Combination of Radiotherapy with Targeted Therapy or Immunotherapy in Head and Neck Squamous Cell Carcinoma: A Review for Radiation Oncologists.

Simple SummaryRadiotherapy (RT) is an effective treatment for head and neck squamous cell carcinoma (HNSCC). Concurrent RT with high dose cisplatin (100 mg/m2, days 1, 22, and 42) is the standard of care (SOC) for non-operative HNSCC in curative settings, however, it is associated with both significant toxicities. In this review, we discussed the evidence of combination of anti-epidermal growth factor receptor, cetuximab, or immune checkpoint inhibitors (ICIs) with RT to compare with SOC. Cetuximab has been shown to be a less effective agent than cisplatin multiple recent trials, but it remains a reasonable alternative for those who are not fit for cisplatin. ICIs are active agents in recurrent and metastatic HNSCC. The role of ICIs with RT in the curative setting is yet to be defined. Multiple clinical trials are currently recruiting. Combining ICIs with stereotactic body radiotherapy (SBRT) is an attractive treatment in patients with oligometastatic or oligoprogressive HNSCC to boost the anti-tumor immune response.Radiotherapy plays an important role of managing head and neck squamous cell carcinoma (HNSCC). Concurrent radiotherapy with radiosensitizing cisplastin chemotherapy is the standard of care (SOC) for non-operable locally advanced HNSCC. Cetuximab, a monoclonal antibody of epidermal growth factor receptor, was the most extensively studied targeted therapy as a chemo-sparing agent that was used concurrently with radiotherapy. Immunotherapy is used in the treatment of metastatic HNSCC. There is evidence to support the synergistic effect when combining radiotherapy with immunotherapy to potentiate anti-tumor immune response. There has been increasing interest to incorporate immune checkpoint inhibitor (ICI) with radiotherapy in the curative setting for HNSCC. In this review, we discuss the latest evidence that supports concurrent radiotherapy with cisplatin which remains the SOC for locally advanced HNSCC (LA-HNSCC). Cetuximab is suitable for patients who are not fit for cisplatin. We then summarize the clinical trials that incorporate ICI with radiotherapy for LA-HNSCC in concurrent, neoadjuvant, and adjuvant settings. We also discuss the potential of combining immunotherapy with radiotherapy as a treatment de-escalating strategy in HPV-associated oropharyngeal carcinoma. Finally, the pre-clinical and clinical evidence of the abscopal effect when combining stereotactic body radiotherapy with ICIs is presented.

Salvage surgery for recurrent squamous cell carcinoma of the head and neck: Systematic review and meta-analysis.

The present study aims to estimate a pooled hazard ratio (HR) comparing overall survival (OS) for salvage surgery compared to nonsurgical management of recurrent head and neck squamous cell carcinoma (HNSCC). PubMed/MEDLINE and Embase-Ovid were searched on March 5, 2020, for English-language articles reporting survival for salvage surgery and nonsurgical management of recurrent HNSCC. Meta-analysis of HR estimates using random effects model was performed. Fifteen studies reported survival for salvage surgery and nonsurgical management of recurrence. Five-year OS ranged from 26% to 67% for the salvage surgery groups, compared to 0% to 32% for the nonsurgical management groups. Six studies reported HRs comparing salvage surgery to nonsurgical management; the pooled HR was 0.25 (95% CI[0.16, 0.38]; p< 0.0001). Selection for salvage surgery was associated with one quarter of the mortality rate associated with nonsurgical management in light of confounding factors including subsite and treatment intent.

Genetic Alterations as Predictors of Radiation-Induced Toxicity in Head and Neck Squamous Cell Carcinoma

Optimizing the therapeutic ratio for radiation therapy (RT) in head and neck squamous cell carcinoma (HNSCC) is uniquely challenging owing to high rates of early and late toxicity involving nearby organs at risk (OAR). These toxicities have a profound impact on treatment compliance and quality of life. Emerging evidence suggests that RT dose alone cannot fully account for the variable severity of RT-related adverse events (rtAEs) observed in HNSCC patients. Next-generation sequencing has become an increasingly valuable tool with widespread use in the oncologic setting and offers a potentially powerful predictive tool for rtAEs beyond dosimetric data.Next-generation sequencing data was collected from HNSCC patients who received RT for primary or locally recurrent HNSCC. Early and late toxicity data including mucositis, dysphagia and xerostomia were collected and reported based on common terminology criteria for adverse events (CTCAE) Version 5.0. Dosimetric parameters were collected for pertinent structures including the pharyngeal constrictor muscles (PCM), cricopharyngeus and submandibular glands. Based on dosimetric and toxicity outcomes, two patient subsets were defined as RT supersensitive or RT insensitive.A total of 37 patients met inclusion criteria. Genetic alterations in BRCA2, ERBB3, NOTCH1 and CCND1 were all associated with higher mean grade of toxicity with BRCA2 alteration implicated in all toxicity parameters evaluated including mucositis (32%), early dysphagia (45%), xerostomia (37%) and late dysphagia (5%). Further, patients who exhibited alterations in both BRCA2 and ERBB3 experienced a 2-fold or greater increase in early dysphagia, early xerostomia and late dysphagia compared to ERBB3 alteration alone. Interestingly, several alterations including ATR, ESR1 and FAT1 were associated with improved toxicity outcomes compared to their wild-type counterparts. Within the RT insensitive subset (n = 7), alterations were found in TNFAIP3, HNF1A, SPTA1 and CASP8, all of which were found in no patients in the RT supersensitive subset (n = 6). Conversely, more than 17 genetic alterations were found in the RT supersensitive group that were found in no patients in the RT insensitive group.Despite consistent RT dosimetric parameters, patients with HNSCC experience heterogeneous patterns of rtAEs. Identifying additional factors associated with toxicity outcomes offers a new avenue for personalized therapy and prophylactic management. Here, next-generation sequencing in a population of HNSCC patients correlates several genetic alterations including BRCA2, ERBB3, ATR and TNFAIP3 with severity of rtAEs. Further analysis is urgently needed in order to identify both somatic and germline genetic patterns associated with rtAEs so that we may optimize therapeutic regimens and reduce harmful outcomes in this challenging population.

Head and Neck Stereotactic Body Radiation Therapy Re-Irradiation for Patients With Carotid or Skin Involvement Ineligible for RTOG 3507

Patients with recurrent head and neck squamous cell carcinoma (HNSCC) who present with carotid encasement (CE) > 180˚, skin involvement and/or require bolus are not eligible for SBRT per RTOG 3507. The objective of this study was to characterize our institutional experience of SBRT for patients ineligible for RTOG 3507.Patients with recurrent HNSCC treated with SBRT from 2010-2020 with a history of prior radiation were extracted from an IRB approved database. Patients were evaluated based on CE > 180˚ or ≤180˚ and if there was skin involvement and/or use of bolus. The primary outcome was incidence of treatment related carotid bleeding event (CBE) and skin toxicity after SBRT in the absence of disease.Thirty-one patients were treated with SBRT to 37 sites with a median follow up of 8 months (mo) (range 2-47). The median time from prior radiation to SBRT was 13 mo (range 2-257). SBRT fractionation included 35 Gy (13%), 40 Gy (57%), and 45 Gy (30%) in 5 fractions. SBRT was delivered every other day (76%) or 2 fractions (24%) per week. Concurrent immunotherapy was given in 11% and cetuximab in 8%. A total of 30% (N = 11) of sites treated exhibited CE > 180˚ and 70% (N = 26) ≤180˚. There were no CBE related to SBRT, however 18% (N = 2) of patients with CE > 180˚ experienced fatal CBE related to progressive disease at 2.3 mo and 7.6 mo from SBRT. The risk of CBE was potentially related to CE > 180˚ (P = 0.08). Skin involvement and/or use of bolus was present in 43% (N = 16) of sites treated and absent in 57% (N = 21). The rate of treatment related skin toxicity was 19% (N = 3) and only occurred in those with pre-SBRT skin involvement and/or use of bolus. The cumulative incidence of treatment related skin toxicity at 3 mo and 6 mo was 13% (95% CI 1.9-33.6) and 27% (95% CI 4.0-58.8), respectively. Of the 3 treatment related skin toxicities there was one each of grade 2, 3, and 5. Grade 5 toxicity was related to untreated SBRT wound infection as the patient transitioned to hospice. The risk of treatment related skin toxicity was possibly related to pre-SBRT skin involvement and/or use of bolus (P = 0.007). Of the 13 sites with pre-SBRT skin involvement, 31% (N = 4) completely resolved, 54% (N = 7) had residual ulceration attributed to disease, and 15% (N = 2) had ulceration related to SBRT toxicity. The cumulative incidence of local failure at site of SBRT at 3 mo and 6 mo was 13% (95% CI 4-27.3) and 38% (95% CI 20.5-55.9), respectively. The median time of local and regional recurrence free survival were 7 and 5.5 mo, respectively. Median OS was 8 mo and the estimated 1-year OS was 25% (95% CI 9.9-40.9).The risk of toxicity following SBRT for patients with > 180˚ CE, skin involvement and/or use of bolus appears to be largely related to persistent or recurrent disease. There were no CBE related to SBRT in the absence of disease and 31% of patients with pre-SBRT skin involvement exhibited complete healing after SBRT. Consideration of SBRT may still be beneficial for such patients with appropriate counselling.

Immunotherapy for Head and Neck Cancer: A Paradigm Shift From Induction Chemotherapy to Neoadjuvant Immunotherapy.

Neoadjuvant immunotherapy has the potential to enhance clinical outcomes by increasing anti-tumor immune responses in the presence of abundant tumor-derived antigen in an immune microenvironment that has not been exposed to previous therapy. The current mainstay of advanced head and neck squamous cell carcinoma (HNSCC) treatment remains surgery and radiotherapy with/without conventional chemotherapy. Despite this multi-modality treatment, advanced human papillomavirus (HPV)-negative HNSCC shows poor prognosis. Treatment intensification with neoadjuvant (induction) chemotherapies with platinum drugs are insufficient to significantly prolong overall survival. Although only 15-20% of patients benefit, immunotherapies have been approved and widely used for recurrent and metastatic HNSCC. These successes have led to checkpoint blockade therapies being testing in earlier treatment settings. Recent clinical trials of neoadjuvant immunotherapy show promising results and this methodology has the potential to change the treatment algorithm of HNSCC. This overview examines the treatment history of neoadjuvant approaches for HNSCC, and especially focuses on the recent topics of neoadjuvant immunotherapy for HNSCC.

867P A phase I trial of nab-paclitaxel-based induction followed by nab-paclitaxel-based concurrent chemotherapy and re-irradiation in previously treated head and neck squamous cell carcinoma

Recurrent head and neck squamous cell carcinoma (HNSCC) is generally treated palliatively with immunotherapy-based treatment, yet survival remains poor. Re-irradiation is an aggressive but potentially curative salvage approach in this setting. This study evaluated nab-paclitaxel based re-induction and re-irradiation with concurrent nab-paclitaxel-based chemotherapy in recurrent HNSCC. We report the primary analysis and outcomes.

860MO Preoperative durvalumab (D) with or without tremelimumab (T) for resectable head and neck squamous cell carcinoma (HNSCC)

Although antibodies that block PD-1/PD-L1 axis improve survival in patients with recurrent and/or metastatic HNSCC, safety and efficacy of neoadjuvant immunotherapy with PD-L1 with or without CTLA-4 blockade has not been explored. Here, we evaluate the safety and efficacy of a single dose of preoperative D with or without T (D+/-T) in patients with resectable HNSCC. Patients with locally advanced but resectable HNSCC were eligible. Enrolled patients were randomized into D or D+T, stratified by primary site and human papilloma (HPV) infection status. A single dose of preoperative D (1500mg) or D+T (1500mg+75mg) was administered, with surgery planned 2 to 8 weeks later for curative resection. Postoperative (chemo) radiation was prescribed based on standard guidelines, followed by maintenance with D every 4 weeks for 1 year. The primary objective was to determine the local recurrence rate. Secondary endpoints included pathologic response, safety, tolerability, survival outcome, and exploration of immune dynamics. As of May 14, 2021 for interim analysis, a total of 44 patients were enrolled and received surgical resection with available data for pathologic response (D: 20 patients, D+T: 24 patients). Oropharyngeal cancer was most common (n=22), followed by hypopharyngeal (n=9), oral cavity (n=8), and laryngeal cancer (n=5). Human papilloma virus-mediated cancer was observed in 20 patients (45.4%). Neaoadjuvant D+/-T had an acceptable safety profiles and was not associated with delays in surgery or unexpected adverse events. Tumor shrinkage was observed in 31 patients (70.5%), with 16.0% of average tumor shrinkage (95% CI; 4.7% to 27.3%) in the overall population. Major pathologic response (no more than 10% of viable tumor cells) was achieved in 3 patients (6.8%), including 2 cases with pathologic complete response (4.5%). During median follow-up duration of 176 days after surgery, local recurrence was documented in 2 patients (4.5%). These early data suggested that preoperative D+/-T was safe and feasible and had the potential to provide clinical benefits for patients with resectable HNSCC. The trial is ongoing and the updated outcomes with immune correlates will be presented with ESMO.