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BACKGROUND: MET signaling is a well described mechanism of resistance to anti-EGFR therapy, and MET overexpression is common in head and neck squamous cell carcinomas (HNSCCs). In the current trial, the authors compared the oral MET inhibitor tivantinib (ARQ197) in combination with cetuximab (the TC arm) versus a control arm that received cetuximab monotherapy (C) in patients with recurrent/metastatic HNSCC. METHODS: In total, 78 evaluable patients with cetuximab-naive, platinum-refractory HNSCC were enrolled, including 40 on the TC arm and 38 on the C arm (stratified by human papillomavirus [HPV] status). Patients received oral tivantinib 360 mg twice daily and intravenous cetuximab 500 mg/m2 once every 2 weeks. The primary outcome was the response rate (according to Response Evaluation Criteria in Solid Tumors, version 1.1), and secondary outcomes included progression-free and overall survival. After patients progressed on the C arm, tivantinib monotherapy was optional. RESULTS: The response rate was 7.5% in the TC arm (N = 3; 1 complete response) and 7.9% in the C arm (N = 3; not significantly different [NS]). The median progression-free survival in both arms was 4 months (NS), and the median overall survival was 8 months (NS). Both treatments were well tolerated, with a trend toward increased hematologic toxicities in the TC arm (12.5% had grade 3 leukopenia). The response rate in 31 HPV-positive/p16-positive patients was 0% in both arms, whereas the response rate in HPV-negative patients was 12.7% (12.5% in the TC arm and 13% in the C arm). Fifteen patients received tivantinib monotherapy, and no responses were observed. CONCLUSIONS: Combined tivantinib plus cetuximab does not significantly improve the response rate or survival compared with cetuximab alone but does increase toxicity in an unselected HNSCC population. Cetuximab responses appear to be limited to patients who have HPV-negative HNSCC. MET-aberration-focused trials for HNSCC and the use of higher potency, selective MET inhibitors remain of interest.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Cetuximab/administración & dosificación , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Pirrolidinonas/administración & dosificación , Quinolinas/administración & dosificación , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Administración Intravenosa , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cetuximab/efectos adversos , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Pirrolidinonas/efectos adversos , Quinolinas/efectos adversos , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: The authors hypothesized that unilateral intensity-modulated radiotherapy (IMRT) would decrease toxicity compared with bilateral IMRT for patients with lateralized palatine tonsillar cancer and a neck classification of N0 to N2b, with similar oncological outcomes. METHODS: A total of 154 patients were treated with postoperative IMRT from 1997 through 2013. Data were collected prospectively from 2005 to 2013 and retrospectively collected before 2005. Of those patients with lateralized primary and N0 to N2b disease, 48 received unilateral IMRT (group 1) and 59 received bilateral IMRT (group 2); a total of 47 patients had nonlateralized primary or N2c to N3 disease and received bilateral IMRT (group 3). RESULTS: The median follow-up was 5.5 years. The 5-year locoregional control rates were similar in group 1, group 2, and group 3 (100%, 96%, and 94%, respectively; pooled comparison: P = .39 and group 1 vs group 2 comparison: P = .19). The 5-year overall survival rates were similar in group 1, group 2, and group 3 (85%, 79%, and 76%, respectively; pooled comparison: P = .60 and group 1 vs group 2 comparison: P = .25). There were no contralateral neck recurrences noted among unilaterally treated patients. Unilateral IMRT reduced acute toxicity and improved patient-reported quality of life compared with bilateral IMRT. CONCLUSIONS: Unilateral IMRT appears to reduce acute toxicity and achieves oncological outcomes similar to those of bilateral IMRT in selected patients with lateralized palatine tonsillar cancer with a neck classification of N0 to N2b. Cancer 2017;123:4594-4607. © 2017 American Cancer Society.
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Carcinoma de Células Escamosas/radioterapia , Recurrencia Local de Neoplasia/radioterapia , Tonsila Palatina/efectos de la radiación , Calidad de Vida , Radioterapia de Intensidad Modulada/métodos , Neoplasias Tonsilares/radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/secundario , Carcinoma de Células Escamosas/cirugía , Femenino , Estudios de Seguimiento , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/cirugía , Tonsila Palatina/patología , Tonsila Palatina/cirugía , Pronóstico , Estudios Prospectivos , Dosificación Radioterapéutica , Radioterapia Adyuvante , Estudios Retrospectivos , Tasa de Supervivencia , Neoplasias Tonsilares/patología , Neoplasias Tonsilares/cirugíaRESUMEN
The NCCN Guidelines for Bone Cancer provide interdisciplinary recommendations for treating chordoma, chondrosarcoma, giant cell tumor of bone, Ewing sarcoma, and osteosarcoma. These NCCN Guidelines Insights summarize the NCCN Bone Cancer Panel's guideline recommendations for treating Ewing sarcoma. The data underlying these treatment recommendations are also discussed.
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Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Óseas/terapia , Recurrencia Local de Neoplasia/terapia , Sarcoma de Ewing/terapia , Amputación Quirúrgica , Biopsia , Neoplasias Óseas/epidemiología , Neoplasias Óseas/patología , Quimioradioterapia Adyuvante/normas , Quimioterapia Adyuvante/normas , Ensayos Clínicos como Asunto , Resistencia a Antineoplásicos , Humanos , Incidencia , Imagen por Resonancia Magnética , Oncología Médica/normas , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Tomografía Computarizada por Tomografía de Emisión de Positrones , Guías de Práctica Clínica como Asunto , Pronóstico , Sarcoma de Ewing/epidemiología , Sarcoma de Ewing/patología , Tasa de SupervivenciaRESUMEN
BACKGROUND: Radiation treatment volumes in head and neck squamous cell carcinoma (HNSCC) are controversial. The authors report the outcomes, patterns of failure, and quality of life (QOL) of patients who received treatment for HNSCC using intensity-modulated radiation therapy (IMRT) that eliminated the treatment of contralateral retropharyngeal lymph nodes (RPLNs) in the clinically uninvolved neck. METHODS: A prospective institutional database was used to identify patients who had primary oral cavity, oropharyngeal, hypopharyngeal, laryngeal, and unknown primary HNSCC for which they received IMRT. There were 3 temporal groups (generations 1-3). Generation 1 received comprehensive neck IMRT with parotid sparing, generation 2 eliminated the contralateral high level II (HLII) lymph nodes, and generation 3 further eliminated the contralateral RPLNs in the clinically uninvolved neck. Patterns of failure and survival analyses were completed, and QOL data measured using the MD Anderson Dysphagia Inventory were compared in a subset of patients from generations 1 and 3. RESULTS: In total, 748 patients were identified. Of the 488 patients who received treatment in generation 2 or 3, 406 had a clinically uninvolved contralateral neck. There were no failures in the spared RPLNs (95% confidence interval, 0%-1.3%) or in the high contralateral neck (95% confidence interval, 0%-0.7%). QOL data were compared between 44 patients in generation 1 and 51 patients in generation 3. QOL improved both globally and in all domains assessed for generation 3, in which reduced radiotherapy volumes were used (P < .007). CONCLUSIONS: For patients with locally advanced HNSCC, eliminating coverage to the contralateral HLII lymph nodes and contralateral RPLNs in the clinically uninvolved side of the neck is associated with minimal risk of failure in these regions and significantly improved patient-reported QOL.
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Carcinoma de Células Escamosas/radioterapia , Neoplasias de Cabeza y Cuello/radioterapia , Irradiación Linfática/efectos adversos , Calidad de Vida , Planificación de la Radioterapia Asistida por Computador/métodos , Radioterapia de Intensidad Modulada/efectos adversos , Privación de Tratamiento , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Femenino , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/patología , Humanos , Ganglios Linfáticos/patología , Ganglios Linfáticos/efectos de la radiación , Irradiación Linfática/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Cuello , Faringe , Dosificación Radioterapéutica , Radioterapia de Intensidad Modulada/métodos , Estudios Retrospectivos , Carcinoma de Células Escamosas de Cabeza y Cuello , Carga Tumoral , Adulto JovenRESUMEN
PURPOSE: This study aims to characterize patterns in ototoxicity monitoring and identify potential barriers to audiologic follow-up. METHODS: We performed a single-institution retrospective cohort study on adult (≥ 18 years old) cancer patients treated with cisplatin from January 2014 to September 2021. Our primary outcomes were rates of baseline and post-treatment audiograms at the following time points: 3, 6, 12, and greater than 12 months. Time-to-event analyses were performed to describe additional insights to ototoxicity monitoring patterns. RESULTS: Nine hundred fifty-five patients with cancer were included for analysis. The most common primary cancer sites were head and neck (64%), followed by cervical (24%). Three hundred seventy-three patients (39%) underwent baseline audiometric assessment, 38 patients (4%) received audiologic evaluation during chemotherapy, and 346 patients (36%) obtained at least one post-treatment audiogram. Audiologic follow-up was greatest within 3 months of completing chemotherapy (26%), but this tapered dramatically to less than 10% at every other post-treatment time point. Patients with head and neck cancer achieved higher rates of audiologic follow-up at every time point than patients with non-head and neck cancer except for during treatment. CONCLUSIONS: Ototoxicity monitoring is an inconsistent practice, particularly during chemotherapy and for long-term surveillance of hearing loss. Patients with non-head and neck cancer may be at increased risk for loss of audiologic follow-up. IMPLICATIONS FOR CANCER SURVIVORS: Cisplatin ototoxicity is a common occurrence that can be effectively managed with auditory rehabilitation. Therefore, referrals to audiology and counseling on treatment-related ototoxicity are recommended throughout chemotherapy and cancer survivorship.
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Primary bone cancers are extremely rare neoplasms, accounting for fewer than 0.2% of all cancers. The evaluation and treatment of patients with bone cancers requires a multidisciplinary team of physicians, including musculoskeletal, medical, and radiation oncologists, and surgeons and radiologists with demonstrated expertise in the management of these tumors. Long-term surveillance and follow-up are necessary for the management of treatment late effects related to surgery, radiation therapy, and chemotherapy. These guidelines discuss the management of chordoma, giant cell tumor of the bone, and osteosarcoma.
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Neoplasias Óseas/diagnóstico , Neoplasias Óseas/terapia , Humanos , Estadificación de NeoplasiasRESUMEN
OBJECTIVE: Chemoradiation for patients with laryngeal squamous cell carcinoma (SCC) may achieve organ preservation, but appropriate patient selection remains unknown. This study investigates pre-treatment risk factors associated with functional and survival outcomes after radiation-based therapy in patients with advanced laryngeal SCC. METHODS: A retrospective cohort study was performed on 75 adult patients with stage III or IV laryngeal SCC receiving definitive radiation-based therapy from 1997 to 2016 at a tertiary care center. Tracheostomy and gastrostomy dependence were the primary functional outcomes. Multivariable logistic regressions were performed to evaluate relationships between pre-treatment factors and tracheostomy and gastrostomy dependence. Time-to-event analyses were performed to determine risk factors associated with overall survival. RESULTS: Among 75 patients included in the analysis, 30 (40%) patients were tracheostomy dependent and 31 (41%) were gastrostomy tube dependent. The median length of follow-up was 31 months (range = 1 to 142 months). Pre-treatment tracheostomy was a significant predictor of post-treatment tracheostomy (aOR = 13.9, 95% CI = 3.35 to 57.5) and moderate-severe comorbidity was a significant predictor of post-treatment gastrostomy dependence (aOR = 2.96, 95% CI = 1.04 to 8.43). The five-year overall survival was 51% (95% CI = 38 to 64%). Pre-treatment gastrostomy tube dependence was associated with an increased risk of death (aHR = 2.45, 95% CI = 1.09 to 5.53). CONCLUSIONS: Baseline laryngeal functional status and overall health in advanced laryngeal SCC are associated with poor functional outcomes after radiation-based therapy, highlighting the importance of patient selection when deciding between surgical and non-surgical treatment plans. Laryngoscope, 133:594-600, 2023.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias Laríngeas , Adulto , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello , Estudios Retrospectivos , Carcinoma de Células Escamosas/patología , Factores de Riesgo , Neoplasias Laríngeas/patología , Resultado del TratamientoRESUMEN
OBJECTIVE: To explore whether deintensification of adjuvant therapy reduces ototoxicity among patients with human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC). STUDY DESIGN: Retrospective cohort study. SETTING: Single academic center. METHODS: The ototoxicity rate among adult patients with HPV-related OPSCC enrolled in the Minimalist Trial (MINT), a prospective phase 2 trial of surgery followed by risk-adjusted deintensified adjuvant therapy (42 Gy radiation given alone or with a single 100 mg/m2 dose of cisplatin), was compared to that among a historical cohort treated with standard adjuvant therapy (60-66 Gy radiation with up to three 100 mg/m2 doses of cisplatin). Ototoxicity was defined as Common Terminology Criteria for Adverse Events v5.0 ≥ Grade 2. Mixed model analysis was performed to investigate the association between deintensified adjuvant therapy and treatment-related hearing loss. RESULTS: A total of 29 patients (58 ears) were analyzed in the MINT cohort, and 27 patients (54 ears) in the historical cohort. The ototoxicity rate was 5% (n = 3/58 ears) in the MINT cohort and 46% (n = 25/54 ears) in the historical cohort (difference, 41%; 95% confidence interval [CI] = 27%-56%). Patients in the MINT cohort demonstrated a 95% decrease in risk of ototoxicity compared to those in the historical cohort (adjusted odds ratio: 0.05, 95% CI = 0.01-0.31). Differences in estimated marginal mean threshold shifts were statistically and clinically significant at frequencies ≥ 3 kHz. CONCLUSION: The deintensified adjuvant therapy given in MINT led to less ototoxicity than standard adjuvant therapy among patients with HPV-related OPSCC.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias Orofaríngeas , Ototoxicidad , Infecciones por Papillomavirus , Adulto , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/terapia , Carcinoma de Células Escamosas/patología , Virus del Papiloma Humano , Neoplasias Orofaríngeas/patología , Cisplatino/efectos adversos , Estudios Retrospectivos , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/terapia , Infecciones por Papillomavirus/patología , Estudios Prospectivos , AudiciónRESUMEN
OBJECTIVES: Evaluate factors associated with adherence to ototoxicity monitoring among patients with head and neck cancer treated with cisplatin and radiation therapy at a tertiary care center. METHODS: We performed a single-institution retrospective cohort study on adults with head and neck cancer treated with cisplatin and radiation therapy who participated in an ototoxicity monitoring program. The primary outcomes were rates of post-treatment audiograms at the following time points: one, three, six, 12, and greater than 12 months. Multivariable logistic regression was performed to identify risk factors associated with complete loss of follow-up after pre-treatment evaluation. RESULTS: Two hundred ninety-four head and neck cancer patients were analyzed. Overall, 220 (74.8%) patients had at least one post-treatment audiogram; 58 (20.0%) patients had more than one audiogram. The time point with the highest follow-up rate was at 3 months (n = 170, 57.8%); rates at the remaining times ranged from 7.1% to 14.3%. When controlling for covariates, patients without insurance and those with stage IV cancers were associated with complete loss of audiologic follow-up (aOR = 7.18, 95% CI = 2.75-19.90; aOR = 1.96, 95% CI = 1.02-3.77, respectively). Among 156 patients recommended for a hearing aid, only 39 (24.8%) patients received one. CONCLUSIONS: Head and neck cancer patients enrolled in an ototoxicity monitoring program demonstrate moderately high follow-up rates for at least one post-treatment audiogram. However, follow-up tapers dramatically after 6 months, and overall hearing aid utilization is low. Further research is needed to understand barriers to long-term audiologic follow-up and hearing aid utilization to decrease untreated hearing loss in cancer survivorship. LEVEL OF EVIDENCE: Level 3 Laryngoscope, 133:3161-3168, 2023.
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Antineoplásicos , Neoplasias de Cabeza y Cuello , Ototoxicidad , Adulto , Humanos , Cisplatino/efectos adversos , Antineoplásicos/efectos adversos , Estudios de Seguimiento , Estudios Retrospectivos , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/radioterapiaRESUMEN
Outcomes for patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) are poor, with median overall survival (OS) ranging from 6 to 18 months. For those who progress on standard-of-care (chemo)immunotherapy, treatment options are limited, necessitating the development of rational therapeutic strategies. Toward this end, we targeted the key HNSCC drivers PI3K-mTOR and HRAS via the combination of tipifarnib, a farnesyltransferase (FTase) inhibitor, and alpelisib, a PI3Kα inhibitor, in multiple molecularly defined subsets of HNSCC. Tipifarnib synergized with alpelisib at the level of mTOR in PI3Kα- or HRAS-dependent HNSCCs, leading to marked cytotoxicity in vitro and tumor regression in vivo. On the basis of these findings, the KURRENT-HN trial was launched to evaluate the effectiveness of this combination in PIK3CA-mutant/amplified and/or HRAS-overexpressing R/M HNSCC. Preliminary evidence supports the clinical activity of this molecular biomarker-driven combination therapy. Combined alpelisib and tipifarnib has potential to benefit >45% of patients with R/M HNSCC. By blocking feedback reactivation of mTORC1, tipifarnib may prevent adaptive resistance to additional targeted therapies, enhancing their clinical utility. SIGNIFICANCE: The mechanistically designed, biomarker-matched strategy of combining alpelisib and tipifarnib is efficacious in PIK3CA- and HRAS-dysregulated head and neck squamous carcinoma and could improve outcomes for many patients with recurrent, metastatic disease. See related commentary by Lee et al., p. 3162.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Serina-Treonina Quinasas TOR/metabolismo , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/genética , Fosfatidilinositol 3-Quinasa Clase I/genética , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Biomarcadores , Proteínas Proto-Oncogénicas p21(ras)/genéticaRESUMEN
PURPOSE: Head and neck squamous cell carcinoma (HNSCC) is an aggressive tumor with low response rates to frontline PD-1 blockade. Natural killer (NK) cells are a promising cellular therapy for T cell therapy-refractory cancers, but are frequently dysfunctional in patients with HNSCC. Strategies are needed to enhance NK cell responses against HNSCC. We hypothesized that memory-like (ML) NK cell differentiation, tumor targeting with cetuximab, and engineering with an anti-EphA2 (Erythropoietin-producing hepatocellular receptor A2) chimeric antigen receptor (CAR) enhance NK cell responses against HNSCC. EXPERIMENTAL DESIGN: We generated ML NK and conventional (c)NK cells from healthy donors, then evaluated their ability to produce IFNγ, TNF, degranulate, and kill HNSCC cell lines and primary HNSCC cells, alone or in combination with cetuximab, in vitro and in vivo using xenograft models. ML and cNK cells were engineered to express anti-EphA2 CAR-CD8A-41BB-CD3z, and functional responses were assessed in vitro against HNSCC cell lines and primary HNSCC tumor cells. RESULTS: Human ML NK cells displayed enhanced IFNγ and TNF production and both short- and long-term killing of HNSCC cell lines and primary targets, compared with cNK cells. These enhanced responses were further improved by cetuximab. Compared with controls, ML NK cells expressing anti-EphA2 CAR had increased IFNγ and cytotoxicity in response to EphA2+ cell lines and primary HNSCC targets. CONCLUSIONS: These preclinical findings demonstrate that ML differentiation alone or coupled with either cetuximab-directed targeting or EphA2 CAR engineering were effective against HNSCCs and provide the rationale for investigating these combination approaches in early phase clinical trials for patients with HNSCC.
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Neoplasias de Cabeza y Cuello , Receptores Quiméricos de Antígenos , Humanos , Cetuximab/farmacología , Cetuximab/uso terapéutico , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Línea Celular Tumoral , Células Asesinas Naturales , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Anticuerpos Monoclonales/metabolismo , Diferenciación CelularRESUMEN
About 50% of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) experience recurrences after definitive therapy. The presurgical administration of anti-programmed cell death protein 1 (PD-1) immunotherapy results in substantial pathologic tumor responses (pTR) within the tumor microenvironment (TME). However, the mechanisms underlying the dynamics of antitumor T cells upon neoadjuvant PD-1 blockade remain unresolved, and approaches to increase pathologic responses are lacking. In a phase 2 trial (NCT02296684), we observed that 45% of patients treated with two doses of neoadjuvant pembrolizumab experienced marked pTRs (≥50%). Single-cell analysis of 17,158 CD8+ T cells from 14 tumor biopsies, including 6 matched pre-post neoadjuvant treatment, revealed that responding tumors had clonally expanded putative tumor-specific exhausted CD8+ tumor-infiltrating lymphocytes (TILs) with a tissue-resident memory program, characterized by high cytotoxic potential (CTX+) and ZNF683 expression, within the baseline TME. Pathologic responses after 5 weeks of PD-1 blockade were consistent with activation of preexisting CTX+ZNF683+CD8+ TILs, paralleling loss of viable tumor and associated tumor antigens. Response was associated with high numbers of CD103+PD-1+CD8+ T cells infiltrating pretreatment lesions, whereas revival of nonexhausted persisting clones and clonal replacement were modest. By contrast, nonresponder baseline TME exhibited a relative absence of ZNF683+CTX+ TILs and subsequent accumulation of highly exhausted clones. In HNSCC, revival of preexisting ZNF683+CTX+ TILs is a major mechanism of response in the immediate postneoadjuvant setting.
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Antineoplásicos , Neoplasias de Cabeza y Cuello , Humanos , Terapia Neoadyuvante , Linfocitos T CD8-positivos , Carcinoma de Células Escamosas de Cabeza y Cuello , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Microambiente TumoralRESUMEN
PURPOSE: Anti-PD-1 therapy provides clinical benefit in 40-50% of patients with relapsed and/or metastatic head and neck squamous cell carcinoma (RM-HNSCC). Selection of anti- PD-1 therapy is typically based on patient PD-L1 immunohistochemistry (IHC) which has low specificity for predicting disease control. Therefore, there is a critical need for a clinical biomarker that will predict clinical benefit to anti-PD-1 treatment with high specificity. METHODS: Clinical treatment and outcomes data for 103 RM-HNSCC patients were paired with RNA-sequencing data from formalin-fixed patient samples. Using logistic regression methods, we developed a novel biomarker classifier based on expression patterns in the tumor immune microenvironment to predict disease control with monotherapy PD-1 inhibitors (pembrolizumab and nivolumab). The performance of the biomarker was internally validated using out-of-bag methods. RESULTS: The biomarker significantly predicted disease control (65% in predicted non-progressors vs. 17% in predicted progressors, p < 0.001) and was significantly correlated with overall survival (OS; p = 0.004). In addition, the biomarker outperformed PD-L1 IHC across numerous metrics including sensitivity (0.79 vs 0.64, respectively; p = 0.005) and specificity (0.70 vs 0.61, respectively; p = 0.009). CONCLUSION: This novel assay uses tumor immune microenvironment expression data to predict disease control and OS with high sensitivity and specificity in patients with RM-HNSCC treated with anti-PD-1 monotherapy.
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IMPORTANCE: Anti-programmed cell death receptor-1 (PD-1) therapy is standard of care for incurable recurrent or metastatic non-nasopharyngeal head and neck cancer. In contrast, there are no regulatory agency-approved anti-PD-1 agents indicated for the treatment of recurrent or metastatic nasopharyngeal carcinomas (RM-NPC) in the Western hemisphere, and no standard treatment option exists beyond first-line chemotherapy for RM-NPC. The pace of development of novel systemic therapy regimens for RM-NPC has been slow compared to many other advanced tumor types, leaving an unmet clinical need for these patients with a poor prognosis. OBSERVATIONS: Recent clinical trials have documented the clinical activity of anti-PD-1 therapy in RM-NPC. In particular, randomized clinical trials in the first-line setting have demonstrated significant improvements in progression-free survival (PFS) with the addition of anti-PD-1 therapy to standard chemotherapy. Whether the observed PFS benefits require combination chemoimmunotherapy or can be achieved with chemotherapy followed by crossover to immunotherapy upon progression remains unknown. Ongoing clinical trials are exploring novel anti-PD-1 therapy-based combinations, which may further solidify a role for these agents in RM-NPC. CONCLUSIONS AND RELEVANCE: Among patients with RM-NPC, anti-PD-1 therapy added to first-line standard-of-care gemcitabine plus cisplatin provides significantly better efficacy outcomes compared to chemotherapy alone, and anti-PD-1 monotherapy appears to have comparable clinical activity and better tolerability than chemotherapy in previously treated disease. Thus, anti-PD-1 therapy is poised to advance standard of care for the treatment of RM-NPC.
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Neoplasias de Cabeza y Cuello , Neoplasias Nasofaríngeas , Antígeno B7-H1 , Cisplatino , Humanos , Carcinoma Nasofaríngeo/tratamiento farmacológico , Neoplasias Nasofaríngeas/tratamiento farmacológico , Neoplasias Nasofaríngeas/patología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patologíaRESUMEN
In phase I development, CDX-3379, an anti-ErbB3 monoclonal antibody, showed promising molecular and antitumor activity in head and neck squamous cell carcinoma (HNSCC), alone or in combination with cetuximab. Preliminary biomarker data raised the hypothesis of enhanced response in tumors harboring FAT1 mutations. This phase II, multicenter trial used a Simon 2-stage design to investigate the efficacy of CDX-3379 and cetuximab in 30 patients with recurrent/metastatic, HPV-negative, cetuximab-resistant HNSCC. The primary endpoint was objective response rate (ORR). Secondary endpoints included ORR in patients with somatic FAT1 mutations, progression-free survival (PFS), overall survival (OS), and safety. Thirty patients were enrolled from March 2018 to September 2020. The ORR in genomically unselected patients was 2/30 (6.7%; 95% confidence interval [CI], 0.8-22.1). Median PFS and OS were 2.2 (95% CI: 1.3-3.6) and 6.6 months (95% CI: 2.7-7.5), respectively. Tissue was available in 27 patients including one of two responders. ORR was 1/10 (complete response; 10%; 95% CI 0.30-44.5) in the FAT1-mutated versus 0/17 (0%; 95% CI: 0-19.5) in the FAT1-wildtype cohorts. Sixteen patients (53%) experienced treatment-related adverse events (AEs) ≥ grade 3. The most common AEs were diarrhea (83%) and acneiform dermatitis (53%). Dose modification was required in 21 patients (70%). The modest ORR coupled with excessive, dose-limiting toxicity of this combination precludes further clinical development. Dual ErbB3-EGFR inhibition remains of scientific interest in HPV-negative HNSCC. Should more tolerable combinations be identified, development in an earlier line of therapy and prospective evaluation of the FAT1 hypothesis warrant consideration.
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Historically, administration of dacarbazine to sarcoma patients was limited by frequent treat-ment-related nausea/vomiting and neutropenia. These toxicities are now largely preventable with contemporary antiemetics and growth factor support. In this single-arm, phase II study, dacarbazine 850 mg/m2 was given on day 1 of each 3-week cycle until disease progression or intolerance with prophylactic serotonin-3 receptor, neurokinin-1 antagonists, corticosteroids, and pegfilgrastim. Coprimary endpoints included clinical benefit rate (CBR), and any grade of nausea/vomiting and/or grade 3-4 neutropenia. With a sample size of 80 patients, >24 patients with clinical benefit would indicate that the CBR exceeds the historical (<20%) [Power 0.80; alpha 0.05]. In addition, we hypothesized that the rates of nausea/vomiting would be 27% and grade 3-4 neutropenia would be 1% (historical: 90% and 36%, respectively) [power 0.95; alpha 0.05]. The CBR was 30% (24 patients: PR-2 and stable-22). The rate of nausea/vomiting was 37.5% (31 patients) and grades 3-4 neutropenia was 10% (8 patients). Median time-to-progression was 8.1 weeks (95% CI 8-9.7) and median overall survival was 35.8 weeks (95% CI 26.2-55.4). PET scans demonstrated no association with response. Modern prophylactic anti-emetics and pegfilgrastim given with dacarbazine reduced the rates of treatment related nausea/vomiting and serious neutropenia.
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OBJECTIVES: This study examined whether palbociclib and cetuximab prolonged overall survival (OS) versus placebo and cetuximab. MATERIALS AND METHODS: In this double-blind, randomized, phase 2 trial (PALATINUS), patients with platinum-resistant, cetuximab-naïve, human papillomavirus-unrelated recurrent/metastatic head and neck squamous-cell carcinoma received cetuximab and either palbociclib (arm A) or placebo (arm B). The primary endpoint was OS; 120 patients were required to have ≥80% power to detect a hazard ratio (HR) of 0.6 (median OS of 10 months in arm A and 6 months in arm B) using a one-sided, log-rank test (P = 0.10). RESULTS: 125 patients were randomized (arm A: 65, arm B: 60). Median follow-up was 15.9 months (IQR, 11.3-22.7). Median OS was 9.7 months in arm A and 7.8 months in arm B (HR, 0.82; 95% CI, 0.54-1.25; P = 0.18). Median progression-free survival was 3.9 months in arm A and 4.6 months in arm B (HR, 1.00; 95% CI, 0.67-1.5; P = 0.50). The most common treatment-related adverse events in arm A were rash (39 patients, 60.9%) and neutropenia (26, 40.6%; three febrile) and in arm B was rash (32, 53.3%). CONCLUSION: There was no significant difference in median OS with palbociclib and cetuximab versus placebo and cetuximab. FUNDING: Pfizer Inc (NCT02499120).
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Cetuximab/uso terapéutico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Piperazinas/uso terapéutico , Piridinas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carcinoma de Células Escamosas/patología , Cetuximab/farmacología , Método Doble Ciego , Femenino , Neoplasias de Cabeza y Cuello/patología , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia , Piperazinas/farmacología , Piridinas/farmacología , Resultado del TratamientoRESUMEN
PURPOSE: In a head and neck squamous cell carcinoma (HNSCC) "window of opportunity" clinical trial, we reported that trametinib reduced MEK-Erk1/2 activation and resulted in tumor responses in a subset of patients. Here, we investigated resistance to trametinib and molecular correlates in HNSCC cell lines and patient samples. EXPERIMENTAL DESIGN: HNSCC cell lines were treated with trametinib to generate resistant lines. Candidate bypass pathways were assessed using immunoblotting, CRISPR knockout, and survival assays. Effectiveness of combined trametinib and verteporfin targeting was evaluated. Patient-derived xenografts (PDXs) from responder patients were treated with trametinib and resistant tumors were analyzed. Window trial clinical samples were subjected to whole-exome and RNA sequencing. RESULTS: HNSCC cell lines developed resistance (CAL27-TR and HSC3-TR) after prolonged trametinib exposure. Downstream effectors of the Hippo pathway were activated in CAL27-TR and HSC3-TR, and combined trametinib and verteporfin treatment resulted in synergistic treatment response. We defined the Hippo pathway effector Yap1 as an induced survival pathway promoting resistance to trametinib in HSC3-TR. Yap1 was necessary for HSC3-TR trametinib resistance, and constitutively active Yap1 was sufficient to confer resistance in parental HSC3. Analysis of trametinib neoadjuvant trial patient tumors indicated canonical MEK-Erk1/2 pathway activating mutations were infrequent, and Yap1 activity increased following trametinib treatment. Trametinib treatment of a PDX from a responder patient resulted in evolution of resistance with increased Yap1 expression and activity. CONCLUSIONS: These studies identify a Yap1-dependent resistance to trametinib therapy in HNSCCs. Combined Yap1 and MEK targeting may represent a strategy to enhance HNSCC response.
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Resistencia a Antineoplásicos/genética , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Piridonas/farmacología , Pirimidinonas/farmacología , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Proteínas Señalizadoras YAP/metabolismo , Animales , Biopsia , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Técnicas de Inactivación de Genes , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/patología , Vía de Señalización Hippo/genética , Humanos , Sistema de Señalización de MAP Quinasas/genética , Ratones , Piridonas/uso terapéutico , Pirimidinonas/uso terapéutico , RNA-Seq , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Secuenciación del Exoma , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas Señalizadoras YAP/genéticaRESUMEN
INTRODUCTION: Delays in radiation are multifactorial, frequent, and associated with poor outcomes. This study investigates the effect of both primary and adjuvant radiation therapy duration and their interaction with other measures of treatment delay on survival in head and neck squamous cell carcinoma (HNSCC). METHODS: We built a retrospective cohort using the National Cancer Database, consisting of primary oral cavity, hypopharynx, larynx and oropharynx squamous cell carcinoma without distant metastasis and with at least six weeks of radiation. The primary exposure was the duration of radiation therapy (DRT), and the primary outcome was death. We estimated the association between DRT and 5-year overall survival (OS) using Kaplan-Meier curves and hazard ratios (HRs) with Cox proportional hazard regression. RESULTS: In both primary (definitive) and adjuvant (post-surgical) radiation settings, increased DRT results in decreased survival. In the primary radiation cohort, 5-year OS was 59.7% [59.1%-60.3%] among those with 47-53 days DRT, which decreased significantly with each subsequent week to completion (81+ days: 38.4% [36.2%-40.7%]). In the surgical cohort, survival decreased 16.5% when DRT extended beyond 75 days (40-46 days: 68.2% [67.3%-69.1%] vs. 75+ days: 53.3% [50.1%-56.7%]). Multivariate analyses showed increased hazard of death with increased DRT (primary radiation: 81+ days HR: 1.69 [1.58-1.81]); surgical: 75+ days HR: 1.61 [1.37-1.88]), with effects intensifying when restricting to those receiving full-dose radiation. CONCLUSION: A prolonged DRT was associated with worse OS in head and neck cancer. Radiation treatment delays of even a week lead to a significant survival disadvantage. DRT had a stronger association with survival than time to initiation of postoperative adjuvant radiotherapy.
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Neoplasias de Cabeza y Cuello/radioterapia , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Neoplasias de Cabeza y Cuello/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Análisis de Supervivencia , Factores de TiempoRESUMEN
Introduction: Multikinase inhibitors have clinical activity in radioactive iodine refractory (RAIR) differentiated thyroid cancers (DTCs) but are not curative; optimal management and salvage therapies remain unclear. This study assessed clinical effects of pazopanib therapy in RAIR-DTC patients with progressive disease, examining in parallel biomarker that might forecast/precede therapeutic response. Methods: Assessment of responses and toxicities and of any association between thyroglobulin (Tg) changes cycle 1 and RECIST (response evaluation criteria in solid tumors) response to pazopanib therapy were prospectively undertaken in Tg antibody negative RAIR-DTC patients. RECIST progressive metastatic disease <6 months preceding enrollment was required. With a sample size of 68 (assuming 23 attaining partial response [PR]), there would be 90% chance of detecting a difference of >30% when the proportion of patients attaining PR whose Tg values decrease by >50% is >50% cycle 1 (one-sided α = 0.10, two sample test of proportions). Mean corpuscular volume (MCV) change or mutational status or pretreatment were also explored as early correlates of eventual RECIST response. Results: From 2009 to 2011, 60 individuals were treated and evaluated; (one additional patient withdrew; another was found ineligible before therapy initiation); 91.7% had previous systemic therapy beyond RAI. Adverse events included one death (thromboembolic) deemed possibly pazopanib associated. Twenty-two confirmed RECIST PRs resulted (36.7%, confidence interval; CI [24.6-50.1]); mean administered 4-week cycles was 10. Among 44 fully accessible patients, the Tg nadir was greater among the 20 attaining PR (median: -86.8%; interquartile range [IQR]: -90.7% to -70.9%) compared with the 28 who did not (median: -69.0%; IQR: -78.1% to -27.7%, Wilcoxon rank-sum test: p = 0.002). However, the difference in the proportion of PRs among those whose Tg fell ≥50% after cycle 1 versus those that did not were not significantly correlated (-23.5% [CI: -55.3 to 8.3]; Fisher's exact test p-value = 0.27). RECIST response was also not correlated with/predicted by early MCV change, receipt of prior therapy, or tumor mutational status. Conclusions: This trial prospectively confirmed pazopanib to have clinical activity and manageable toxicities in patients with progressive RAIR-DTC. Response to pazopanib, however, was not robustly forecast by early associated changes in Tg or MCV, by prior therapy, or by tumor mutational status. ClinicalTrials.gov NCT00625846.