A Phase II Trial of Alisertib (MLN8237) in Salvage Malignant Mesothelioma.

LESSONS LEARNED: Treatment with the Aurora kinase A inhibitor yields often durable disease control, but limited tumor regression, in heavily pretreated patients with unresectable malignant pleural or peritoneal mesothelioma. In a limited sample size, MYC copy-number gain or gene amplification, a candidate predictive biomarker for alisertib, did not correlate with improved response numbers or patient outcomes. BACKGROUND: Malignant mesothelioma is an aggressive disease for which few effective therapies are available. The Aurora family kinases are critical for mitotic fidelity and highly expressed in mesothelioma, wherein their inhibition leads to growth arrest in vitro. We evaluated the efficacy of alisertib, an Aurora A kinase inhibitor, in relapsed malignant mesothelioma. METHODS: Twenty-six patients with previously treated, unresectable pleural or peritoneal mesothelioma were enrolled on a single-arm, single-institution phase II trial of alisertib at a dosage of 50 mg twice daily for 7 of every 21 days. The primary endpoint was 4-month disease control rate. Secondary endpoints included overall response rate, progression free survival, overall survival, safety/toxicity, and correlation of endpoints with MYC copy number. RESULTS: Of the 25 evaluable patients treated on study, 8 (32%) experienced 4-month disease control, surpassing the futility endpoint. There were no confirmed partial or complete responses. Median progression-free and overall survival were 2.8 months and 6.3 months, respectively. No associations between MYC copy number and outcomes were observed. CONCLUSION: Alisertib has modest activity in this unselected malignant mesothelioma population. Several patients achieved durable disease control. Although the study did meet its prespecified futility endpoint, the sponsor elected to close the trial at the interim analysis.

Erlotinib in the treatment of recurrent or metastatic cutaneous squamous cell carcinoma: A single-arm phase 2 clinical trial.

BACKGROUND: Cutaneous squamous cell carcinoma (CSCC) is a very common malignancy in which most patients present with localized disease. Recurrent and metastatic disease is rare, and there is no standard therapy. These tumors frequently overexpress the epidermal growth factor receptor (EGFR). We conducted a phase 2 trial to determine the response rate to therapy with erlotinib, an EGFR tyrosine kinase inhibitor, in patients with locoregionally recurrent or metastatic CSCC that was not amenable to curative treatment (NCT01198028). METHODS: Eligible patients had CSCC not amenable to curative intent therapy. Patients who had previously received anti-EGFR targeted therapy were excluded. All patients received oral therapy with erlotinib 150 mg daily. Response was assessed every 8 weeks, and treatment continued until progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was overall response rate according to RECIST 1.1 criteria. RESULTS: A total of 39 patients received treatment during the trial; 29 of these patients were evaluable for response. The overall response rate was 10% (3/29); all responses were partial responses. The disease control rate (partial response + stable disease) was 72% (21/29). The median progression-free survival was 4.7 months (95% confidence interval, 3.5-6.2 months); the median overall survival was 13 months (95% confidence interval, 8.4-20.5 months). No unexpected toxicities were seen. CONCLUSION: Erlotinib therapy was feasible for most patients with incurable CSCC and was associated with expected toxicities. However, only a modest response rate of 10% was observed. Further study of EGFR tyrosine kinase inhibitors in this patient population is not warranted. Cancer 2018;124:2169-73. © 2018 American Cancer Society.

Frequent PTEN loss and differential HER2/PI3K signaling pathway alterations in salivary duct carcinoma: Implications for targeted therapy.

BACKGROUND: Patients with advanced primary and recurrent salivary duct carcinoma (SDC), a rare and lethal malignancy, have limited therapeutic options. Novel small-molecule agents aimed at targeting critical signaling associated with SDC tumorigenesis may lead to new therapeutic options for patients with these tumors. The human epidermal growth factor receptor 2 (HER2)/phosphoinositide 3-kinase (PI3K) axis, an important oncogenic pathway, has been targeted for therapy in several solid tumors. Currently, little is known about the role and clinical implications of alterations of the HER2/PI3K pathway in patients with SDC. METHODS: The authors investigated the clinicopathologic features, genetic alterations, and expression of key members of the HER2/PI3K pathway in 43 primary tumors and conducted in vitro functional and targeted drug-response analyses on cell lines derived from salivary epithelial carcinomas. RESULTS: In primary tumors, loss of phosphatase and tensin homolog (PTEN) expression was identified in 22 of 43 tumors (51%), overexpression of HER2 was observed in 12 of 43 tumors (28%), and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations were identified in 12 of 43 tumors (28%). Phosphorylated protein kinase B (p-AKT) was highly expressed in most tumors. Most tumors (70%) displayed mutually exclusive alterations of PI3K members, whereas 8 tumors (19%) had 2 or more concurrent abnormalities. In vitro studies demonstrated a direct association between PTEN loss and PI3K pathway activation and evidence of response to combined PI3Kα and PI3Kß and/or pan-PI3K inhibitors. CONCLUSIONS: The current analyses reveal frequent PTEN loss and mutually exclusive alterations of key PI3K pathway members in SDC and demonstrate in vitro evidence of a response to pan-PI3K inhibitors. These results provide a framework for a biomarker-based substratification of patients with SDC in future targeted therapy. Cancer 2018;124:3523-32. © 2018 American Cancer Society.

Single Arm, Phase II Study of Cisplatin, Docetaxel, and Erlotinib in Patients with Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinomas.

LESSONS LEARNED: The combination of cisplatin, docetaxel, and erlotinib as frontline treatment for recurrent and/or metastatic head and neck squamous cell carcinomas led to a response rate of 62%.This result exceeded the prespecified target response rate of 50% and represented an improvement compared with historical controls.This regimen warrants further investigation. BACKGROUND: The epidermal growth factor receptor (EGFR) plays a key role in the carcinogenesis of head and neck squamous cell carcinomas (HNSCC). We conducted this clinical study to test the hypothesis that the addition of erlotinib to first-line cisplatin and docetaxel for patients with recurrent and/or metastatic HNSCC would yield a response rate of at least 50%, representing an improvement from historical controls. METHODS: Patients with recurrent and/or metastatic HNSCC, with at least one measurable lesion, no prior chemotherapy for recurrent and/or metastatic disease, prior combined modality therapy completed >6 months before enrollment, and performance status ≤2 were treated with cisplatin, docetaxel, and erlotinib for up to six cycles, followed by maintenance erlotinib until disease progression. The primary endpoint was response rate. RESULTS: Fifty patients were enrolled (42 male, 12 never smokers, 19 with oropharynx cancer). The median number of cycles was five; 31 patients initiated maintenance erlotinib; 14 patients required erlotinib dose reductions. The objective response rate was 62%, and the median progression-free and overall survival were 6.1 and 11.0 months, respectively. Toxicity profiles were consistent with the known side effects of the study drugs. CONCLUSION: The study met its primary endpoint and improved response rates compared with historical controls. The findings support further evaluation of the regimen for recurrent and/or metastatic HNSCCs.

Gefitinib for patients with incurable cutaneous squamous cell carcinoma: A single-arm phase II clinical trial.

BACKGROUND: Preclinical data demonstrate a key role for the epidermal growth factor receptor (EGFR) in the carcinogenesis of cutaneous squamous cell carcinomas (CSCCs). There are, however, limited data on the efficacy of EGFR inhibitors in incurable, recurrent, and/or metastatic CSCC. OBJECTIVE: To determine the response rate to gefitinib in patients with CSCC not amenable to curative therapy including surgery or radiation. METHODS: This was a single-arm phase II study. A total of 40 patients were treated with gefitinib, 250 mg orally daily, until disease progression or intolerable toxicities. The prespecified target response rate of interest was 20%. RESULTS: The overall response rate was 16% (95% confidence interval, 0.06-0.32; 6 partial responses in 37 evaluable patients). An additional 13 patients (35%) had stable disease at 8 weeks. The median durations of response and progression-free survival were 31.4 months (95% confidence interval, 3.91-not applicable) and 3.8 months (95% confidence interval, 2.2-5.7), respectively. The side effect profile was consistent with the previous experience with gefitinib in other tumor types. LIMITATIONS: This was a single-institution, single-arm study. The prespecified target response rate was not met. CONCLUSION: Gefitinib demonstrated modest activity in incurable CSCC, with a favorable adverse event profile.

Prognostic value of pretherapy platelet elevation in oropharyngeal cancer patients treated with chemoradiation.

The purpose of this study is to evaluate potential associations between increased platelets and oncologic outcomes in oropharyngeal cancer patients receiving concurrent chemoradiation. A total of 433 oropharyngeal cancer patients (OPC) treated with intensity-modulated radiation therapy (IMRT) with concurrent chemotherapy between 2002 and 2012 were included under an approved IRB protocol. Complete blood count (CBC) data were extracted. Platelet and hemoglobin from the last phlebotomy (PLTpre-chemoRT, Hgbpre-chemoRT ) before start of treatment were identified. Patients were risk-stratified using Dahlstrom-Sturgis criteria and were tested for association with survival and disease-control outcomes. Locoregional control (LRC), freedom from distant metastasis (FDM) and overall survival (OS) were decreased (p < 0.03, p < 0.04 and p < 0.0001, respectively) for patients with PLTpre-chemoRT value of ≥350 × 10(9) /L. Actuarial 5-year locoregional control (LRC) and FDM were 83 and 85% for non-thrombocythemic patients while patient with high platelets had 5-year LRC and FDM of 73 and 74%, respectively. Likewise, 5-year OS was better for patients with normal platelet counts by comparison (76 vs. 57%; p < 0.0001). Comparison of univariate parametric models demonstrated that PLTpre-chemoRT was better among tested models. Multivariate assessment demonstrated improved performance of models which included pretherapy platelet indices. On Bayesian information criteria analysis, the optimal prognostic model was then used to develop nomograms predicting 3-, 5- and 10-year OS. In conclusion, pretreatment platelet elevation is a promising predictor of prognosis, and further work should be done to elucidate the utility of antiplatelets in modifying risk in OPC patients.

Radiation therapy (with or without neck surgery) for phenotypic human papillomavirus-associated oropharyngeal cancer.

BACKGROUND: Favorable outcomes for human papillomavirus-associated oropharyngeal cancer have led to interest in identifying a subgroup of patients with the lowest risk of disease recurrence after therapy. De-intensification of therapy for this group may result in survival outcomes that are similar to those associated with current therapy but with less toxicity. To advance this effort, this study analyzed the outcomes of oropharyngeal cancer patients treated with or without systemic therapy. METHODS: This was a retrospective study of patients with oropharyngeal cancer treated between 1985 and 2012. The criteria for inclusion were ≤10 pack-years of cigarette smoking and stage III/IVA cancer limited to T1-3, N1-N2b, and T3N0 disease. A survival analysis was performed with the primary endpoint of progression-free survival (PFS). RESULTS: The cohort included 857 patients. Systemic therapy was given to 439 patients (51%). The median survival was 80 months. The 2-year PFS rate was 91%. When the analysis was limited to 324 patients irradiated without systemic therapy, the 2- and 5-year PFS rates were 90% and 85%, respectively. Furthermore, for these 324 patients, the 5-year PFS rates for T1, T2, and T3 disease were 90%, 83%, and 70%, respectively. The 5-year PFS rate for patients treated with systemic therapy for T3 disease was 77% (P = .07). CONCLUSIONS: According to the low-risk definition currently established in cooperative trials, the patients had a 2-year PFS rate approximating 90%. When patients who were treated with radiation alone were evaluated, no compromise was observed in this high rate of PFS, which is higher than the 2-year PFS thresholds used in current cooperative trials. Cancer 2016;122:1702-7. © 2016 American Cancer Society.

Depression and Oropharynx Cancer Outcome.

BACKGROUND: Studies have shown a modest relationship between depression and mortality in patients with cancer. Our study addressed methodological weaknesses in the literature by restricting the sample to patients with one cancer type, adjusting for factors known to affect outcome, and following up patients for a sufficient period. METHODS: We prospectively followed patients newly diagnosed with squamous cell oropharyngeal cancer from the start of radiation therapy until death or until date of last clinical visit. All patients were optimally treated with radiation and sometimes chemotherapy. After adjusting for tumor stage, treatment, comorbidities, smoking, excessive alcohol use, and demographic factors, we assessed the effects of baseline self-reported depression on overall survival and recurrence. RESULTS: One hundred thirty participants were followed for a median of 5 years. The average age was 56 years, and 83% were male. Eighteen participants died during the study and 15 experienced disease recurrence. Self-reported depression was associated with decreased overall survival duration (hazard ratio = 3.6, 95% confidence interval = 1.2-10.8) and disease recurrence (hazard ratio = 3.8, 95% confidence interval = 1.2-12.2) in multivariate analysis. In addition, smoking was associated with disease recurrence. CONCLUSIONS: Patients with oropharyngeal cancer may benefit from depression screening and evidence-based treatments, if appropriate. Future studies are needed to determine whether depression is an independent prognostic factor of outcome and to elucidate biobehavioral mechanisms involved in patients with oropharyngeal cancer.

Head and Neck Cancers, Version 1.2015.

These NCCN Guidelines Insights focus on recent updates to the 2015 NCCN Guidelines for Head and Neck (H&N) Cancers. These Insights describe the different types of particle therapy that may be used to treat H&N cancers, in contrast to traditional radiation therapy (RT) with photons (x-ray). Research is ongoing regarding the different types of particle therapy, including protons and carbon ions, with the goals of reducing the long-term side effects from RT and improving the therapeutic index. For the 2015 update, the NCCN H&N Cancers Panel agreed to delete recommendations for neutron therapy for salivary gland cancers, because of its limited availability, which has decreased over the past 2 decades; the small number of patients in the United States who currently receive this treatment; and concerns that the toxicity of neutron therapy may offset potential disease control advantages.

Detailed genome-wide SNP analysis of major salivary carcinomas localizes subtype-specific chromosome sites and oncogenes of potential clinical significance.

The molecular genetic alterations underlying the development and diversity of salivary gland carcinomas are largely unknown. To characterize these events, comparative genomic hybridization analysis was performed, using a single-nucleotide polymorphism microarray platform, of 60 fresh-frozen specimens that represent the main salivary carcinoma types: mucoepidermoid carcinoma (MEC), adenoid cystic carcinoma (ACC), and salivary duct carcinoma (SDC). The results were correlated with the clinicopathologic features and translocation statuses to characterize the genetic alterations. The most commonly shared copy number abnormalities (CNAs) in all types were losses at chromosomes 6q23-26 and the 9p21 region. Subtype-specific CNAs included a loss at 12q11-12 in ACC and a gain at 17q11-12 in SDC. Focal copy number losses included 1p36.33-p36-22 in ACC, 9p13.2 in MEC, and 3p12.3-q11-2, 6q21-22.1, 12q14.1, and 12q15 in SDC. Tumor-specific amplicons were identified at 11q23.3 (PVRL1) in ACC, 11q13.3 (NUMA1) in MEC, and 6p21.1 (CCND3), 9p13.2 (PAX5), 12q15 (CNOT2/RAB3IP), 12q21.1 (GLIPR1L1), and 17q12 (ERBB2/CCL4) in SDC. A comparative CNA analysis of fusion-positive and fusion-negative ACCs and MECs revealed relatively lower CNAs in fusion-positive tumors than in fusion-negative tumors in both tumor types. An association between CNAs and high grade and advanced stage was observed in MECs only. These findings support the pathogenetic segregation of these entities and define novel chromosomal sites for future identification of biomarkers and therapeutic targets.

Phase I clinical trial of lenalidomide in combination with sorafenib in patients with advanced cancer.

BACKGROUND: Preclinical data have shown that lenalidomide and sorafenib target endothelial cells, inhibiting growth of ocular melanoma cells in a xenograft model. We conducted a Phase I study of lenalidomide and sorafenib in patients with advanced cancer. METHODS: During the escalation phase, lenalidomide (days 1-21) and sorafenib (days 1-28) were given orally once daily at the following respective doses: level 1 (10 mg, 200 mg); level 2 (10 mg, 400 mg); level 3 (20 mg, 400 mg); and level 4 (25 mg, 400 mg) (1 cycle = 28 days). A "3 + 3" study design was used. RESULTS: Forty-one patients were treated (median age: 50 years). The most common diagnoses were adenoid cystic carcinoma (N = 9), ovarian adenocarcinoma (N = 7), and melanoma (N = 6); 142 cycles (median: 3) were administered. No dose-limiting toxicities were noted. The maximum tested dose (dose level 4) was used in the expansion phase. Grade 3-4 treatment-related toxicities were neutropenia, thrombocytopenia, skin rash, and thromboembolism. Of 38 patients who were evaluable for response, stable disease (SD) was noted in 53 % of patients (SD ≥6 months: 16 %). Tumor types with SD ≥ 6 months were as follows: ocular melanoma, 2/2 (100 %); other melanoma, 1/4 (25 %); adenoid cystic carcinoma, 2/9 (22 %); and ovarian cancer, 1/6 (17 %). The median progression-free survival duration was 3.5 months (95 % CI, 1.9-5.0), and the median overall survival duration was 12.3 months (95 % CI, 10.1-14.5). CONCLUSIONS: Lenalidomide and sorafenib was well tolerated and associated with disease stabilization for ≥6 months in patients with melanoma, adenoid cystic carcinoma, and ovarian adenocarcinoma.

Head and neck cancers, Version 2.2014. Clinical practice guidelines in oncology.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers focuses on glottic laryngeal cancer, which is the most common type of laryngeal cancer and has an excellent cure rate. The lymphatic drainage of the glottis is sparse, and early stage primaries rarely spread to regional nodes. Because hoarseness is an early symptom, most glottic laryngeal cancer is early stage at diagnosis. Updates to these guidelines for 2014 include revisions to "Principles of Radiation Therapy" for each site and "Principles of Surgery," and the addition of a new section on "Principles of Dental Evaluation and Management."

Phase I clinical trial of lenalidomide in combination with temsirolimus in patients with advanced cancer.

BACKGROUND: Lenalidomide, an immunomodulatory and anti-angiogenic drug, and temsirolimus, an mTOR inhibitor, have synergistic anti-cancer effects in preclinical models. We conducted a phase I study of the combination in patients with advanced cancers. PATIENTS AND METHODS: A "3 + 3" study design was used. During the escalation phase, lenalidomide (orally, days 1-21) and temsirolimus (intravenously, once a week) were given at the following respective doses: level 1 (10 mg, 15 mg); level 2 (10 mg, 20 mg); level 3 (20 mg, 20 mg); and level 4 (20 mg, 25 mg) (1 cycle = 28 days). The maximum tolerated dose, dose-limiting toxicity, and response were assessed. RESULTS: Forty-three patients were treated (median age: 58 years (range, 21-80); male/female: 26/17). The most common diagnoses were colorectal cancer (N = 5), sarcoma (N = 5), neuroendocrine carcinoma (N = 4) and adenoid cystic carcinoma (N = 4). Overall, 121 cycles (median: 2) were administered. No dose-limiting toxicities were observed. The maximum tested dose (dose level 4) was used in the expansion phase. Grade 3-4 treatment-related hematologic toxicities (all reversible) were seen in 19 (72%) patients and included neutropenia (N = 12), thrombocytopenia (N = 6), and infection (N = 1). Grade 3 hyperglycemia and Grade 3 hypertriglyceridemia were noted in 21% and 20% of patients, respectively. Of 43 patients, 30 (70%) received prophylactic anticoagulation. There were no thrombotic events. Response was evaluable in 40 patients: one (2.5%) patient had a partial response and 19 (48%) had stable disease (SD), with SD ≥ 6 months in 6 (15%) patients. Tumor types with SD ≥ 6 months were soft tissue sarcoma (2/5; 40%), adenoid cystic carcinoma (1/4; 25%), parotid adenocarcinoma (1/2; 50%), adrenocortical carcinoma (1/3; 33%), and neuroendocrine carcinoma (1/4; 25%). The median progression-free survival duration was 2.2 months (95% CI, 1.5-2.9), and the median overall survival duration was 7.8 months (95% CI, 5.1-10.6). CONCLUSIONS: Lenalidomide and temsirolimus combination therapy was well tolerated and associated with clinical benefit in patients with soft tissue sarcoma, adenoid cystic carcinoma, neuroendocrine carcinoma, parotid carcinoma, and adrenocortical carcinoma.

Head and neck cancers, version 2.2013. Featured updates to the NCCN guidelines.

These NCCN Guidelines Insights focus on nutrition and supportive care for patients with head and neck cancers. This topic was a recent addition to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers. The NCCN Guidelines Insights focus on major updates to the NCCN Guidelines and discuss the new updates in greater detail. The complete version of the NCCN Guidelines for Head and Neck Cancers is available on the NCCN Web site (NCCN.org).

Prognostic factors in mucoepidermoid carcinoma of the salivary glands.

BACKGROUND: Mucoepidermoid carcinoma (MEC) is the most common malignancy of the major salivary glands. Prior reports noted histological grade and tumor stage as consistently important prognostic factors. This study reviewed the experience of patients with MEC at the University of Texas MD Anderson Cancer Center to determine the impact of clinical and pathologic findings on disease outcomes. METHODS: A retrospective clinical review was performed of patients with salivary gland MEC treated at a tertiary cancer center from 1990 to 2007. RESULTS: A total of 125 patients were included. The 5-year overall survival and disease-free survival of all patients were 79.3% and 76.5%, respectively. Patients with low- and intermediate-grade disease had significantly better overall survival and disease-free survival than patients with high-grade disease, but no difference in survival rates was found between low- and intermediate-grade disease. Pathologic results of positive lymph nodes, extracapsular lymph node spread, and perineural invasion were all found to be poor prognostic indicators. On multivariate analysis, advanced disease stage and perineural invasion were found to be the most significant prognostic factors. CONCLUSIONS: Patients with either low- or intermediate-grade tumors uniformly have favorable local control and survival. High histological grade, advanced stage, perineural invasion, positive surgical margins, and submandibular location all portend for poor outcomes in MEC. Further advances in therapy are needed to improve outcomes for high-grade and advanced-stage disease.

Induction chemotherapy with or without erlotinib in patients with head and neck squamous cell carcinoma amenable for surgical resection.

PURPOSE: Neoadjuvant chemotherapy prior to definitive surgery has been utilized widely for locally advanced oral squamous cell carcinoma (OSCC). We evaluated neoadjuvant erlotinib with platinum-docetaxel vs. placebo with platinum-docetaxel in stage III-IVB OSCC patients. EXPERIMENTAL DESIGN: Patients with newly diagnosed stage III, IVA, IVB (AJCC 7th) OSCC amenable to surgical resection were included. Patients were randomized to receive up to 3 cycles of chemotherapy with concurrent erlotinib or placebo, followed by surgery. The primary endpoint was major pathologic response (MPR) rate, secondary endpoints included safety, overall (OS) and progression-free survival (PFS). RESULTS: Fifty-two patients received at least one cycle of treatment and 47 were evaluable with surgical resection. MPR rate was not different between erlotinib (30%, 7/23) and placebo arms (41.7%, 10/24) (p=0.55). At median follow up of 26.5 months, there was no difference on OS or PFS between groups. Patients who received erlotinib with chemotherapy and achieved MPR (n=7) had no recurrence. The treatment-related adverse event rates were not different between the two groups (96% vs. 96%). However, rash, mostly low grade, was more common in the erlotinib arm (79% vs. 50%). Transcriptomic analysis in the pre-treatment samples indicated that genes in protein glycosylation and Wnt signaling pathways were associated with benefit in those treated with erlotinib plus chemotherapy. CONCLUSIONS: The addition of erlotinib to platinum-taxane chemotherapy was well-tolerated but did not induce higher rates of MPR or PFS or OS survival benefit. Patients who received chemotherapy with erlotinib and achieved major pathological responses had excellent clinical outcome.

Evolutionary Action Score of TP53 Analysis in Pathologically High-Risk Human Papillomavirus-Negative Head and Neck Cancer From a Phase 2 Clinical Trial: NRG Oncology Radiation Therapy Oncology Group 0234.

Purpose: An evolutionary action scoring algorithm (EAp53) based on phylogenetic sequence variations stratifies patients with head and neck squamous cell carcinoma (HNSCC) bearing TP53 missense mutations as high-risk, associated with poor outcomes, or low-risk, with similar outcomes as TP53 wild-type, and has been validated as a reliable prognostic marker. We performed this study to further validate prior findings demonstrating that EAp53 is a prognostic marker for patients with locally advanced HNSCC and explored its predictive value for treatment outcomes to adjuvant bio-chemoradiotherapy. Methods and Materials: Eighty-one resection samples from patients treated surgically for stage III or IV human papillomavirus-negative HNSCC with high-risk pathologic features, who received either radiation therapy + cetuximab + cisplatin (cisplatin) or radiation therapy + cetuximab + docetaxel (docetaxel) as adjuvant treatment in a phase 2 study were subjected to TP53 targeted sequencing and EAp53 scoring to correlate with clinical outcomes. Due to the limited sample size, patients were combined into 2 EAp53 groups: (1) wild-type or low-risk; and (2) high-risk or other. Results: At a median follow-up of 9.8 years, there was a significant interaction between EAp53 group and treatment for overall survival (P = .008), disease-free survival (P = .05), and distant metastasis (DM; P = .004). In wild-type or low-risk group, the docetaxel arm showed significantly better overall survival (hazard ratio [HR] 0.11, [0.03-0.36]), disease-free survival (HR 0.24, [0.09-0.61]), and less DM (HR 0.04, [0.01-0.31]) than the cisplatin arm. In high-risk or other group, differences between treatments were not statistically significant. Conclusions: The docetaxel arm was associated with better survival than the cisplatin arm for patients with wild-type or low-risk EAp53. These benefits appear to be largely driven by a reduction in DM.

Precision medicine: preliminary results from the Initiative for Molecular Profiling and Advanced Cancer Therapy 2 (IMPACT2) study.

Precision medicine is associated with favorable outcomes in selected patients with cancer. Herein, we report an interim analysis of IMPACT2, an ongoing randomized study evaluating genomic profiling and targeted agents in metastatic cancer. Patients with metastatic cancer underwent tumor genomic profiling (ClinialTrials.gov: NCT02152254), and 69 patients met the criteria for randomization. Tumor board and multidisciplinary review of molecular alterations optimized treatment selection. From 5/2014 to 4/2017, 320 patients (median age, 63 years; men, 47%) had tumor molecular aberrations, and 213 (66.56%) received anticancer therapy. The most frequently mutated genes were TP53 (42%), KRAS (16%), PIK3CA (12%), and CDKN2A (11%). The median OS was 10.9 months (95% CI, 8.8-12.9). OS was shorter in patients with higher tumor mutational burden. Independent factors associated with shorter OS were age ≥60 years, liver metastases, low albumin levels, high LDH levels, and KRAS and TP53 mutations. Outcomes for randomized patients will be reported after completion of the study.

Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck.

BACKGROUND: We conducted a multinational, randomized study to compare radiotherapy alone with radiotherapy plus cetuximab, a monoclonal antibody against the epidermal growth factor receptor, in the treatment of locoregionally advanced squamous-cell carcinoma of the head and neck. METHODS: Patients with locoregionally advanced head and neck cancer were randomly assigned to treatment with high-dose radiotherapy alone (213 patients) or high-dose radiotherapy plus weekly cetuximab (211 patients) at an initial dose of 400 mg per square meter of body-surface area, followed by 250 mg per square meter weekly for the duration of radiotherapy. The primary end point was the duration of control of locoregional disease; secondary end points were overall survival, progression-free survival, the response rate, and safety. RESULTS: The median duration of locoregional control was 24.4 months among patients treated with cetuximab plus radiotherapy and 14.9 months among those given radiotherapy alone (hazard ratio for locoregional progression or death, 0.68; P=0.005). With a median follow-up of 54.0 months, the median duration of overall survival was 49.0 months among patients treated with combined therapy and 29.3 months among those treated with radiotherapy alone (hazard ratio for death, 0.74; P=0.03). Radiotherapy plus cetuximab significantly prolonged progression-free survival (hazard ratio for disease progression or death, 0.70; P=0.006). With the exception of acneiform rash and infusion reactions, the incidence of grade 3 or greater toxic effects, including mucositis, did not differ significantly between the two groups. CONCLUSIONS: Treatment of locoregionally advanced head and neck cancer with concomitant high-dose radiotherapy plus cetuximab improves locoregional control and reduces mortality without increasing the common toxic effects associated with radiotherapy to the head and neck. (ClinicalTrials.gov number, NCT00004227.)