ABSTRACT
Salivary gland cancers are a rare, histologically diverse group of tumors. They range from indolent to aggressive and can cause significant morbidity and mortality. Surgical resection remains the mainstay of treatment, but radiation and systemic therapy are also critical parts of the care paradigm. Given the rarity and heterogeneity of these cancers, they are best managed in a multidisciplinary program. In this review, the authors highlight standards of care as well as exciting new research for salivary gland cancers that will strive for better patient outcomes.
Subject(s)
Salivary Gland Neoplasms , Humans , Salivary Gland Neoplasms/diagnosis , Salivary Gland Neoplasms/therapyABSTRACT
Immunotherapy has dramatically changed the treatment landscape for patients with cancer. Programmed death-ligand 1/programmed death-1 checkpoint inhibitors have been in the forefront of this clinical revolution. Currently, there are 6 US Food and Drug Administration-approved checkpoint inhibitors for approximately 18 different histologic types of cancer. Lung cancer and head and neck squamous cell carcinoma (HNSCC) are 2 diseases that have led the way in the development of immunotherapy. Atezolizumab, durvalumab, nivolumab, and pembrolizumab are all currently used as part of standard-of-care treatment for different stages of lung cancer. Similarly, nivolumab and pembrolizumab have US regulatory approval as treatment for advanced metastatic HNSCC. This is significant because lung cancer represents the most common and most fatal cancer globally, and HNSCC is the sixth most common. Currently, most of the approvals for the use of immunotherapy agents are for patients diagnosed in the metastatic setting. However, research is ongoing to evaluate these drugs in earlier stage disease. There is plausible biological rationale to expect that pharmacologic activation of the immune system will be effective for early-stage and smaller tumors. In addition, selecting patients who are more likely to respond to immunotherapy and understanding why resistance develops are crucial areas of ongoing research. The objective of this review was to provide an overview of the current immune landscape and future directions in lung cancer and HNSCC.
Subject(s)
Head and Neck Neoplasms/immunology , Head and Neck Neoplasms/therapy , Immune Checkpoint Inhibitors/therapeutic use , Lung Neoplasms/immunology , Lung Neoplasms/therapy , Squamous Cell Carcinoma of Head and Neck/immunology , Squamous Cell Carcinoma of Head and Neck/therapy , Biomarkers, Tumor , Carcinoma, Non-Small-Cell Lung/immunology , Carcinoma, Non-Small-Cell Lung/therapy , Humans , Small Cell Lung Carcinoma/immunology , Small Cell Lung Carcinoma/therapyABSTRACT
Transparent and precise endpoint definitions are a crucial aspect of clinical trial conduct and reporting, and are used to communicate the benefit of an intervention. Previous studies have identified inconsistencies in endpoint definitions across oncological clinical trials. Here, the Head and Neck Cancer International Group assessed endpoint definitions from phase 3 trials or trials considered practice-changing for patients with recurrent or metastatic mucosal head and neck squamous cell carcinoma, published between 2008 and 2021. We identify considerable and global heterogeneity in endpoint definitions, which undermines the interpretation of results and development of future studies. We show how fundamental components of even incontrovertible endpoints such as overall survival vary widely, highlighting an urgent need for increased rigour in reporting and harmonisation of endpoints.
Subject(s)
Consensus , Endpoint Determination , Head and Neck Neoplasms , Neoplasm Recurrence, Local , Squamous Cell Carcinoma of Head and Neck , Humans , Squamous Cell Carcinoma of Head and Neck/pathology , Squamous Cell Carcinoma of Head and Neck/mortality , Squamous Cell Carcinoma of Head and Neck/secondary , Squamous Cell Carcinoma of Head and Neck/therapy , Neoplasm Recurrence, Local/pathology , Head and Neck Neoplasms/pathology , Head and Neck Neoplasms/mortality , Head and Neck Neoplasms/therapy , Endpoint Determination/standards , Clinical Trials, Phase III as Topic , Neoplasm MetastasisABSTRACT
Answer questions and earn CME/CNE Laryngeal cancer remains one of the most common tumors of the respiratory tract. Fortunately, significant advancements have been made over the past decade in the treatment of laryngeal cancer. Although surgery has been the historical mainstay for localized disease and still is an integral part of treatment, nonsurgical options like radiation and systemic therapy have emerged as viable options. In addition, in the metastatic setting, novel agents are showing promise for this patient population. The care for patients with laryngeal cancer continues to evolve and truly requires a multidisciplinary team-based approach. Unique morbidities, such as loss of natural voice, respiration, and airway protection during swallowing, are observed with this disease and require special consideration. CA Cancer J Clin 2017;67:31-50. © 2016 American Cancer Society.
Subject(s)
Laryngeal Neoplasms/diagnosis , Laryngeal Neoplasms/therapy , Female , Humans , Incidence , Laryngeal Neoplasms/epidemiology , Male , Patient Care Team , Racial Groups/statistics & numerical data , Risk Factors , Sex Distribution , Survival Rate , United States/epidemiologyABSTRACT
BACKGROUND: The PACIFIC trial established consolidative durvalumab after concurrent chemoradiation as standard-of-care in patients with stage III or unresectable non-small cell lung cancer (NSCLC). Black patients, however, comprised just 2% (n = 14) of randomized patients in this trial, warranting real-world evaluation of the PACIFIC regimen in these patients. METHODS: This single-institution, multi-site study included 105 patients with unresectable stage II/III NSCLC treated with concurrent chemoradiation followed by durvalumab between 2017 and 2021. Overall survival (OS), progression-free survival (PFS), and grade ≥3 pneumonitis-free survival (PNFS) were compared between Black and non-Black patients using Kaplan-Meier and Cox regression analyses. RESULTS: A total of 105 patients with a median follow-up of 22.8 months (interquartile range, 11.3-37.3 months) were identified for analysis, including 57 Black (54.3%) and 48 (45.7%) non-Black patients. The mean radiation prescription dose was higher among Black patients (61.5 ± 2.9 Gy vs. 60.5 ± 1.9 Gy; p = .031), but other treatment characteristics were balanced between groups. The median OS (not-reached vs. 39.7 months; p = .379) and PFS (31.6 months vs. 19.3 months; p = .332) were not statistically different between groups. Eight (14.0%) Black patients discontinued durvalumab due to toxicity compared to 13 (27.1%) non-Black patients (p = .096). The grade ≥3 pneumonitis rate was similar between Black and non-Black patients (12.3% vs. 12.5%; p = .973), and there was no significant difference in time to grade ≥3 PNFS (p = .904). Three (5.3%) Black patients and one (2.1%) non-Black patient developed grade 5 pneumonitis. CONCLUSIONS: The efficacy and tolerability of consolidative durvalumab after chemoradiation appears to be comparable between Black and non-Black patients.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Pneumonia , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/radiotherapy , Lung Neoplasms/drug therapy , Lung Neoplasms/radiotherapy , Chemoradiotherapy/adverse effectsABSTRACT
OBJECTIVES: The aim of the study was to investigate the association of surgical margin conditions, including positive specimen margins revised to negative relative to local recurrence, disease-free survival, and overall survival (OS) within a cohort of HPV-mediated oropharyngeal squamous cell carcinoma (OPSCC) who underwent en bloc resection via transoral robotic surgery (TORS). MATERIALS AND METHODS: Retrospective cohort of patients with untreated HPV-mediated OPSCC cT1 or T2 undergoing TORS resection between October 2014 and March 2020. The methodologic description of our interdisciplinary institutional approach, number of cut-through margins (CTMs) during intraoperative consultation, percentage of final positive margin cases, and disease-free survival and OS stratified by margin status and margin tumor-free distance is identified. RESULTS: 135 patients with primary cT1/T2 HPV-mediated OPSCC met inclusion criteria. Twenty-eight of 135 (20.7%) specimens revealed CTM and were revised during the same operative setting. Three of 135 (2.2%) surgical cases had positive final margin status. Local control rate was 97%. On univariate analysis, margin distance did not impact OS. CTM and final positive margins had lower OS than initially negative margins (p = 0.044). Pathologic N-stage significantly impacted OS (p < 0.001). CONCLUSIONS: High local control rate and low final positive margin status confound the study of specimen margin-based techniques in HPV-mediated OPSCC resected en bloc with TORS. Pathologic N-stage may impact OS more than margin status. Larger numbers are needed to confirm differences.
Subject(s)
Carcinoma, Squamous Cell , Head and Neck Neoplasms , Oropharyngeal Neoplasms , Papillomavirus Infections , Robotic Surgical Procedures , Humans , Squamous Cell Carcinoma of Head and Neck/surgery , Margins of Excision , Carcinoma, Squamous Cell/surgery , Carcinoma, Squamous Cell/pathology , Oropharyngeal Neoplasms/surgery , Oropharyngeal Neoplasms/pathology , Robotic Surgical Procedures/methods , Retrospective Studies , Papillomavirus Infections/complications , Papillomavirus Infections/surgeryABSTRACT
Recent evidence confirmed the significant clinical benefit from using immune check point inhibitors, namely PD-1 inhibitors, in patients with advanced cutaneous squamous cell carcinomas. The activity of these different agents seems to be strikingly equivalent. This phase 2 trial confirms a similar clinical benefit to single agent nivolumab in treating this disease. The replication of these findings raises the question of whether substitution of these immunotherapeutic agents can be justified based on smaller confirmatory trials.
Subject(s)
Carcinoma, Squamous Cell , Skin Neoplasms , Humans , Carcinoma, Squamous Cell/drug therapy , Skin Neoplasms/drug therapy , Skin Neoplasms/pathology , Nivolumab/therapeutic useABSTRACT
OPINION STATEMENT: Patients with HPV-associated oropharyngeal squamous cell carcinoma have improved prognosis relatively to those with tumors not driven by HPV. Both definitive radiotherapy (typically with concurrent chemotherapy) and transoral robotic surgery (with adjuvant therapies based on pathologic risk factors) are both acceptable treatment options for patients. The decision on which treatment is optimal depends on individual patient factors and should be made in a multi-disciplinary setting with input from a radiation oncologist, head and neck surgeon, and medical oncologist. Where appropriate, patients in this setting should be considered for enrollment on clinical studies evaluating de-escalation of treatment intensity given the very favorable outcomes and high toxicity profile associated with conventional therapies. However, caution is needed given negative data for de-escalation in the definitive chemotherapy and radiation setting. It remains unclear what the prognostic significance of HPV status is in patients with squamous cell carcinomas of the head and neck outside of the oropharynx.
Subject(s)
Carcinoma, Squamous Cell , Head and Neck Neoplasms , Oropharyngeal Neoplasms , Papillomavirus Infections , Carcinoma, Squamous Cell/etiology , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/therapy , Head and Neck Neoplasms/diagnosis , Head and Neck Neoplasms/etiology , Head and Neck Neoplasms/therapy , Humans , Oropharyngeal Neoplasms/diagnosis , Oropharyngeal Neoplasms/pathology , Oropharyngeal Neoplasms/therapy , Squamous Cell Carcinoma of Head and Neck/therapyABSTRACT
LESSONS LEARNED: Inhibition of glycoprotein fucosylation, as monotherapy and in combination with immune checkpoint blockade, is a promising therapeutic strategy for treating a broad range of cancers. In this first-in-human, first-in-class, phase I study in advanced solid tumors, SGN-2FF demonstrated dose-proportional pharmacokinetics, evidence of pharmacodynamic target inhibition of glycoprotein fucosylation, and preliminary antitumor activity. SGN-2FF was associated with thromboembolic events that led to study termination. BACKGROUND: We conducted a first-in-human, first-in-class, phase I study of SGN-2FF, a potent small-molecule inhibitor of glycoprotein fucosylation, in patients with advanced solid tumors. METHODS: The study consisted of four parts: SGN-2FF monotherapy dose-escalation (part A) and expansion (part B), and SGN-2FF + pembrolizumab dose-escalation (part C) and expansion (part D). The objectives were to evaluate safety and tolerability, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of SGN-2FF monotherapy and SGN-2FF + pembrolizumab. RESULTS: Forty-six patients were enrolled (part A, n = 33; part B, n = 6; part C, n = 7; part D did not enroll any patients). During part A (n = 32) exploring 1-15 g once daily (QD) and 2-5 g twice daily (b.i.d.), grade 3 dose-limiting toxicities were diarrhea (2 g and 15 g QD) and increased lipase (2 g QD). The MTD was 10 g daily. In part A, common toxicities were grades 1-2 diarrhea, fatigue, and nausea (each 47%); thromboembolic events (grades 2-5) occurred in 5 of 32 patients (16%). Safety measures included concurrent prophylactic anticoagulation with low-molecular weight heparin (LMWH). In part C, despite the safety measures implemented, a thromboembolic event occurred in one of seven patients (14%) during the SGN-2FF lead-in period. Of 28 evaluable patients in part A, 1 patient with advanced head and neck squamous cell carcinoma achieved Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 complete response (CR) and 10 (36%) had RECIST v1.1 stable disease, including 1 patient with advanced triple-negative breast cancer with 51% tumor burden reduction. SGN-2FF administration led to dose-proportional increases in exposure and PD reduction in protein fucosylation. CONCLUSION: SGN-2FF demonstrated proof-of-mechanism and preliminary antitumor activity but was associated with thromboembolic events leading to study termination.
Subject(s)
Head and Neck Neoplasms , Lymphoma, Follicular , Heparin, Low-Molecular-Weight , Humans , Maximum Tolerated Dose , Response Evaluation Criteria in Solid TumorsABSTRACT
BACKGROUND: Body mass index (BMI) is used to define obesity, but it is an imperfect measure of body composition. In the current study, the authors explored the association between types of fat and survival in patients treated with immunotherapy. METHODS: A retrospective analysis of 90 patients who were treated with immunotherapy on phase 1 clinical trials at the Winship Cancer Institute in Atlanta, Georgia, from 2009 through 2017 was performed. Overall survival (OS) and progression-free survival (PFS) were used to measure clinical outcomes. Baseline BMI and radiographic images at the middle of the third lumbar vertebrae were obtained. Fat densities were calculated and converted to indices (subcutaneous fat index [SFI], intermuscular fat index [IFI], and visceral fat index [VFI]) after dividing by height in meters squared. Risk groups were created using recursive partitioning and the regression trees method for SFI and IFI, which were selected by stepwise variable selection among all fat-related variables. The Cox proportional hazards model and Kaplan-Meier method were used for the association with OS and PFS. RESULTS: The majority of patients (59%) were male and diagnosed with melanoma (33%) or gastrointestinal cancers (22%). The median BMI was 27.4 kg/m2 , the median SFI was 62.78, the median IFI was 4.06, and the median VFI was 40.53. Low-risk patients (those with an SFI ≥73) had a significantly longer OS (hazard ratio, 0.20; 95% CI, 0.09-0.46 [P < .001]) and PFS (hazard ratio, 0.38; 95% CI, 0.20-0.72 [P = .003]) compared with patients at intermediate risk (those with an SFI <73 and IFI <3.4) and poor risk (those with an SFI <73 and IFI ≥3.4). The Uno concordance statistics were found to be higher for fat risk groups than BMI in predicting OS (0.603 vs 0.574; P = .581) and PFS (0.602 vs 0.586; P = .71). CONCLUSIONS: Increased BMI, increased SFI, and decreased IFI may be associated with prolonged survival in patients with cancer who are treated with immunotherapy. Further studies are needed to elucidate the effect of adiposity on the host immune response to immunotherapy.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Immunotherapy/statistics & numerical data , Neoplasms/therapy , Obesity/therapy , Adiposity , Adult , Aged , Body Mass Index , Female , Georgia/epidemiology , Humans , Male , Middle Aged , Neoplasm Staging , Neoplasms/complications , Neoplasms/immunology , Neoplasms/pathology , Obesity/complications , Obesity/immunology , Obesity/pathology , Progression-Free Survival , Proportional Hazards Models , Risk FactorsABSTRACT
BACKGROUND: Purpose: The combination of a mammalian target of rapamycin inhibitor and lenalidomide showed enhanced preclinical cytotoxicity. We conducted a phase 1 study in advanced solid tumour patients to assess safety, efficacy and pharmacodynamic (PD) outcomes. METHODS: We employed a 3+3 dose escalation design to establish the safety and recommended phase 2 doses (RP2D) of daily everolimus and lenalidomide in patients with advanced solid tumours. The starting doses were 5 and 10 mg, respectively, with planned escalation to maximum single-agent doses of 10 and 25 mg in the absence of dose-limiting toxicity. PD endpoints of lymphocyte subsets and immune cytokines were assessed in peripheral blood using multiparameter flow cytometry and LUMINEX assay. Efficacy was evaluated by cross-sectional imaging after every two cycles of treatment. RESULTS: The study enrolled 44 patients, median age of 58 years and 28 males (63.6%). The RP2D was established as 10 and 25 mg daily continuously for everolimus and lenalidomide. Common (>5%) grade ≥3 adverse events included rash (19%), neutropenia (19%), hypokalaemia (11%) and fatigue (9%). Best efficacy outcomes in 36 evaluable patients were partial response in 5 (13.8%), stable disease in 24 (55.8%) and progressive disease in 7 (19.4%) patients. PD assessment revealed significant association of cytokine levels (interleukin-2 (IL2), IL21 and IL17), baseline activated and total CD8+ lymphocytes and change in B cell lymphocytes and activated NK cells with clinical benefit. CONCLUSIONS: The study demonstrated the safety of everolimus and lenalidomide with promising efficacy signal in thyroid and adenoid cystic cancers. CLINICAL TRIAL REGISTRATION: NCT01218555.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Adenoid Cystic/drug therapy , Everolimus/administration & dosage , Lenalidomide/administration & dosage , Neoplasms/drug therapy , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Adenoid Cystic/immunology , Cytokines/blood , Everolimus/adverse effects , Everolimus/pharmacology , Female , Humans , Lenalidomide/adverse effects , Lenalidomide/pharmacology , Male , Maximum Tolerated Dose , Middle Aged , Neoplasms/immunologyABSTRACT
BACKGROUND: Significant controversy remains regarding the care of patients with clinical stage III (N2-positive) NSCLC. Although multimodality therapy is effective, the roles of surgery, chemotherapy, and radiotherapy are not fully defined and the optimal treatment approach is not firmly established. We analyzed outcomes and predictors associated with trimodality therapy (TT) in the National Cancer Database. MATERIALS AND METHODS: The NCDB was queried from 2004 to 2014 for patients with NSCLC diagnosed with stage III (N2) disease and treated with chemotherapy and radiation (CRT). Three cohorts of patients were studied: CRT only/no surgery (NS), CRT plus lobectomy (LT), and CRT plus pneumonectomy (PT). The univariate and multivariable analyses (MVA) were conducted using Cox proportional hazards model and log-rank tests. RESULTS: A total of 29,754 patients were included in this analysis: NS 90.1%, LT 8.4%, and PT 1.5%. Patient characteristics: median age 66 years; male 56% and white 85%. Patients treated at academic centers were more likely to receive TT compared with those treated at community centers (odds ratio: 1.85 [1.53-2.23]; p < .001). On MVA, patients that received TT were associated with better survival than those that received only CRT (hazard ratio: 0.59 [0.55-0.62]; p < .001). The LT group was associated with significantly better survival than the PT and NS groups (median survival: 62.8 months vs. 51.8 months vs. 34.2 months, respectively). In patients with more than two nodes involved, PT was associated with worse survival than LT and NS (median survival: 51.4 months in LT and 39 months in NS vs. 37 months in PT). The 30-day and 90-day mortality rates were found to be significantly higher in PT patients than in LT. CONCLUSION: TT was used in less than 10% of patients with stage III N2 disease, suggesting high degree of patient selection. In this selected group, TT was associated with favorable outcomes relative to CRT alone. IMPLICATIONS FOR PRACTICE: This analysis demonstrates that trimodality therapy could benefit a selected subset of patients with stage III (N2) disease. This plan should be considered as a treatment option following patient evaluation in a multidisciplinary setting in experienced medical centers with the needed expertise.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Aged , Carcinoma, Non-Small-Cell Lung/pathology , Combined Modality Therapy , Humans , Lung Neoplasms/pathology , Male , Neoplasm Staging , Pneumonectomy , Retrospective Studies , Treatment OutcomeABSTRACT
BACKGROUND: Sarcopenia and inflammation have been associated with poor survival in patients with cancer. We explored the combined effects of these variables on survival in patients with cancer treated with immunotherapy. METHODS: We performed a retrospective review of 90 patients enrolled on immunotherapy-based phase I clinical trials at Emory University from 2009 to 2017. Baseline neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, and platelet-to-lymphocyte ratio (PLR) were used as surrogates of inflammation. The skeletal muscle index (SMI) was derived from the skeletal muscle density calculated from baseline abdominal computed tomography images. Optimal cutoffs for continuous inflammation biomarkers and SMI were determined by bias-adjusted log-rank test. A four-level risk stratification was used to create low-risk (PLR <242 and nonsarcopenic), intermediate-risk (PLR <242 and sarcopenic), high-risk (PLR ≥242 and nonsarcopenic), and very-high-risk (PLR ≥242 and sarcopenic) groups with subsequent association with survival. RESULTS: Most patients (59%) were male, and the most common cancers were melanoma (33%) and gastrointestinal (22%). Very high-risk, high-risk, and intermediate-risk patients had significantly shorter overall survival (hazard ratio [HR], 8.46; 95% confidence interval [CI], 2.65-27.01; p < .001; HR, 5.32; CI, 1.96-14.43; p = .001; and HR, 4.01; CI, 1.66-9.68; p = .002, respectively) and progression-free survival (HR, 12.29; CI, 5.15-29.32; p < .001; HR, 3.51; CI, 1.37-9.02; p = .009; and HR, 2.14; CI, 1.12-4.10; p = .022, respectively) compared with low-risk patients. CONCLUSION: Baseline sarcopenia and elevated inflammatory biomarkers may have a combined effect on decreasing survival in immunotherapy-treated patients in phase I trials. These data may be immediately applicable for medical oncologists for the risk stratification of patients beginning immunotherapeutic agents. IMPLICATIONS FOR PRACTICE: Sarcopenia and inflammation have been associated with poor survival in patients with cancer, but it is unclear how to apply this information to patient care. The authors created a risk-stratification system that combined sarcopenia and platelet-to-lymphocyte ratio as a marker of systemic inflammation. The presence of sarcopenia and systemic inflammation decreased progression-free survival and overall survival in our cohort of 90 patients who received immunotherapy in phase I clinical trials. The data presented in this study may be immediately applicable for medical oncologists as a way to risk-stratify patients who are beginning treatment with immunotherapy.
Subject(s)
Neoplasms , Sarcopenia , Female , Humans , Immunotherapy , Inflammation , Lymphocyte Count , Male , Neoplasms/complications , Neoplasms/drug therapy , Prognosis , Retrospective StudiesABSTRACT
BACKGROUND: Most head and neck squamous-cell carcinomas (HNSCCs) are driven by p16INK4A inactivation and cyclin D1 overexpression that results in hyperactivation of cyclin-dependent kinase 4 and 6 (CDK4/6), rather than by the human papillomavirus (HPV). Deregulated cyclin D1 expression also causes resistance to EGFR inhibitors. We previously reported that palbociclib (a selective CDK4/6 inhibitor) given with cetuximab (an EGFR inhibitor) was safe. The aim of this study was to establish the proportion of patients achieving an objective response with palbociclib and cetuximab in recurrent or metastatic HNSCC. METHODS: We did a multicentre, multigroup, phase 2 trial to evaluate the activity of palbociclib and cetuximab in platinum-resistant (group 1) and cetuximab-resistant (group 2) HPV-unrelated HNSCC. The study was done across eight university sites in the USA. Eligibility required measurable disease (according to Response Evaluation Criteria in Solid Tumors, version 1·1 [RECIST 1·1]), Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, age of 18 years or older, and disease progression on platinum but cetuximab-naive (group 1) or disease progression on cetuximab (group 2). All patients received palbociclib orally (125 mg/day, on days 1-21) and intravenous cetuximab (400 mg/m2 on cycle one, day 1, then 250 mg/m2 once per week) in 28-day cycles. The primary endpoint was objective response (complete responses and partial responses per RECIST 1·1). Analyses were done per protocol. This trial was registered with ClinicalTrials.gov, NCT02101034, and is ongoing, but both groups are closed to accrual. FINDINGS: Between Oct 19, 2015, and Nov 7, 2018, 62 patients were enrolled onto the trial: 30 patients were enrolled in group 1 and 32 in group 2. Median follow-up was 5·4 months (IQR 4·4-12·1) for group 1 and 5·5 months (4·3-8·3) for group 2. In group 1, of 28 evaluable patients, an objective response was achieved by 11 (39%; 95% CI 22-59). In group 2, of 27 evaluable patients, an objective response was achieved by five (19%; 6-38) in group 2. The most common grade 3-4 palbociclib-related adverse event was neutropenia (in 21 [34%] of 62 patients). No treatment-related deaths occurred. INTERPRETATION: In patients with platinum-resistant or cetuximab-resistant HPV-unrelated HNSCC, palbociclib and cetuximab results in promising activity outcomes. Further studies of CDK4/6 inhibitors are warranted in HPV-unrelated HNSCC. FUNDING: Pfizer.
Subject(s)
Cetuximab/administration & dosage , Cyclin-Dependent Kinase 4/genetics , Cyclin-Dependent Kinase 6/genetics , Piperazines/administration & dosage , Pyridines/administration & dosage , Squamous Cell Carcinoma of Head and Neck/drug therapy , Aged , Cetuximab/adverse effects , Cyclin D1/genetics , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Cyclin-Dependent Kinase Inhibitor p16/genetics , Disease-Free Survival , Drug Resistance, Neoplasm/drug effects , Female , Humans , Male , Middle Aged , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Papillomaviridae/pathogenicity , Piperazines/adverse effects , Platinum/administration & dosage , Platinum/adverse effects , Pyridines/adverse effects , Squamous Cell Carcinoma of Head and Neck/genetics , Squamous Cell Carcinoma of Head and Neck/pathology , Squamous Cell Carcinoma of Head and Neck/virology , Treatment OutcomeABSTRACT
BACKGROUND: With an expectation of excellent locoregional control, ongoing efforts to de-intensify therapy for patients with human papillomavirus-associated squamous cell oropharyngeal cancer necessitate a better understanding of the metastatic risk for patients with this disease. The objective of this study was to determine what factors affect the risk of metastases in patients with squamous cell cancers of the oropharynx. METHODS: Under a shared use agreement, 547 patients from Radiation Therapy Oncology Group 0129 and 0522 with nonmetastatic oropharyngeal squamous cell cancers who had a known p16 status and smoking status were analyzed to assess the association of clinical features with the development of distant metastases. The analyzed factors included the p16 status, sex, T stage, N stage, age, and smoking history. RESULTS: A multivariate analysis of 547 patients with a median follow-up of 4.8 years revealed that an age ≥ 50 years (hazard ratio [HR], 3.28; P = .003), smoking for more than 0 pack-years (HR, 3.09; P < .001), N3 disease (HR, 2.64; P < .001), T4 disease (HR, 1.63; P = .030), and a negative p16 status (HR, 1.60; P = .044) were all factors associated with an increased risk of distant disease. CONCLUSIONS: Age, smoking, N3 disease, T4 disease, and a negative p16 status were associated with the development of distant metastases in patients with squamous cell cancers of the oropharynx treated definitively with concurrent chemoradiation.
Subject(s)
Carcinoma, Squamous Cell/pathology , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Oropharyngeal Neoplasms/pathology , Papillomavirus Infections/complications , Tobacco Smoking/epidemiology , Adult , Age Factors , Aged , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/virology , Female , Humans , Male , Middle Aged , Neoplasm Metastasis , Neoplasm Staging , Oropharyngeal Neoplasms/metabolism , Oropharyngeal Neoplasms/virology , Papillomavirus Infections/pathology , Prospective Studies , Risk AssessmentABSTRACT
BACKGROUND: Optimal prognostic and predictive biomarkers for patients with advanced-stage cancer patients who received immunotherapy (IO) are lacking. Inflammatory markers, such as the neutrophil-to-lymphocyte ratio (NLR), the monocyte-to-lymphocyte ratio (MLR), and the platelet-to-lymphocyte ratio (PLR), are readily available. The authors investigated the association between these markers and clinical outcomes of patients with advanced-stage cancer who received IO. METHODS: A retrospective review was conducted of 90 patients with advanced cancer who received treatment on phase 1 clinical trials of IO-based treatment regimens. NLR, MLR, and PLR values were log-transformed and treated as continuous variables for each patient. Overall survival (OS), progression-free survival (PFS), and clinical benefit were used to measure clinical outcomes. For univariate associations and multivariable analyses, Cox proportional-hazards models or logistic regression models were used. RESULTS: The median patient age was 63 years, and most were men (59%). The most common histologies were melanoma (33%) and gastrointestinal cancers (22%). High baseline NLR, MLR, and PLR values were associated significantly with worse OS and PFS (P < .05) and a lower chance of benefit (NLR and PLR; P < .05). Increased NLR, MLR, and PLR values 6 weeks after baseline were associated with shorter OS and PFS (P ≤ .052). CONCLUSIONS: Baseline and early changes in NLR, MLR, and PLR values were strongly associated with clinical outcomes in patients who received IO-based treatment regimens on phase 1 trials. Confirmation in a homogenous patient population treated on late-stage trials or outside of trial settings is warranted. These values may warrant consideration for inclusion when risk stratifying patients enrolled onto phase 1 clinical trials of IO agents.
Subject(s)
Biomarkers, Tumor/immunology , Immunotherapy/methods , Neoplasms/drug therapy , Neoplasms/pathology , Clinical Trials, Phase I as Topic , Female , Humans , Leukocyte Count , Logistic Models , Lymphocyte Count , Male , Middle Aged , Neoplasm Staging , Neoplasms/blood , Neoplasms/immunology , Platelet Count , Prognosis , Retrospective Studies , Survival Analysis , Treatment OutcomeABSTRACT
Lung cancer is the leading cause of cancer death in the United States and many other parts of the world. Non-small cell lung cancer (NSCLC) comprises 85-90% of lung cancers. Historically, the expected survival of patients with advanced disease has been estimated in months. In recent years, however, lung cancer has come to be seen as a treatable disease with multiple therapeutic options. Enormous advances in the understanding of its pathways and mechanisms have enabled personalized therapy in NSCLC. The evolving approach to therapy focuses on genomic profiling of the tumors to find molecular targets and develop specific agents for individualized therapy. In addition, maintenance therapy has emerged as a valid approach, and the choice of chemotherapy now varies by histology. Most recently, immunotherapy with checkpoint inhibitors has shown promising results, with impressive durations of response and a tolerable toxicity profile. Together, these discoveries have improved overall survival substantially in patient populations that have access to these advancements. We review the clinical data surrounding these impressive improvements.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Anaplastic Lymphoma Kinase , Angiogenesis Inhibitors/administration & dosage , Antineoplastic Agents, Immunological/therapeutic use , Carcinoma, Non-Small-Cell Lung/secondary , Genes, erbB-1/genetics , Humans , Lung Neoplasms/pathology , Maintenance Chemotherapy , Molecular Targeted Therapy , Mutation , Platinum Compounds/administration & dosage , Receptor Protein-Tyrosine Kinases/geneticsABSTRACT
Background Given the increasing number of available immunotherapeutic agents, more patients are presenting after failing immunotherapy in need of new treatment options. In this study, we investigated the clinical outcomes of patients treated with sequential immunotherapy. Methods We performed a retrospective review of 90 advanced stage cancer patients treated on immunotherapy-based phase 1 clinical trials at Winship Cancer Institute from 2009 to 2017. We included 49 patients with an immune checkpoint inhibitor (ICI)-indicated histology. Patients were analyzed based on whether they had received prior ICI. Clinical outcomes were overall survival (OS), progression-free survival (PFS), and clinical benefit (best response of complete response, partial response, or stable disease). Univariate analysis (UVA) and multivariate analysis (MVA) were performed using Cox proportional hazard or logistic regression model. Covariates included age, liver metastases, number of prior lines of therapy, histology, and Royal Marsden Hospital (RMH) risk group. Results The most common histologies were melanoma (61%) and lung/head and neck cancers (37%). More than half of patients (n = 27, 55%) received at least one ICI prior to trial enrollment: ten received anti-PD-1, two received anti-CTLA-4, five received anti-PD-1/CTLA-4 combination, and ten received multiple ICI. In MVA, ICI-naïve patients had significantly longer OS (HR: 0.22, CI: 0.07-0.70, p = 0.010) and trended towards higher chance of CB (HR: 2.52, CI: 0.49-12.97, p = 0.268). Patients who received prior ICI had substantially shorter median OS (10.9 vs 24.3 months, p = 0.046) and PFS (2.8 vs. 5.1 months, p = 0.380) than ICI-naïve patients per Kaplan-Meier estimation. Within the ICI-naïve group, 78% (7 of 9) of patients who received prior interleukin (IL-2) or interferon gamma (IFNγ) experienced disease control for at least 6 months, compared to a disease control rate of 15% (2 of 13) in patients who had received chemotherapy, targeted therapy, or no prior treatment. Conclusions ICI-naïve patients may experience improved clinical outcomes on immunotherapy-based phase 1 clinical trials than patients who have received prior ICI. This may be particularly true for patients who received prior IL-2 or IFNγ. Further development of immunotherapy combination therapies is needed to improve clinical outcomes of these patients. These results should be validated in a larger study.
Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Immunotherapy , Interferon-gamma/therapeutic use , Interleukin-2/therapeutic use , Neoplasms/drug therapy , Aged , Female , Humans , Male , Neoplasms/mortality , Survival Analysis , Treatment OutcomeABSTRACT
BACKGROUND: Selecting the appropriate patients to receive immunotherapy (IO) remains a challenge due to the lack of optimal biomarkers. The presence of liver metastases has been implicated as a poor prognostic factor in patients with metastatic cancer. We investigated the association between sites of metastatic disease and clinical outcomes in patients receiving IO. METHODS: We conducted a retrospective review of 90 patients treated on IO-based phase 1 clinical trials at Winship Cancer Institute of Emory University between 2009 and 2017. Overall survival (OS) and progression-free survival (PFS) were measured from the first dose of IO to date of death or hospice referral and clinical or radiographic progression, respectively. Clinical benefit (CB) was defined as a best response of complete response (CR), partial response (PR), or stable disease (SD). Univariate analysis (UVA) and Multivariate analysis (MVA) were carried out using Cox proportional hazard model or logistic regression model. Covariates included age, whether IO is indicated for the patient's histology, ECOG performance status, Royal Marsden Hospital (RMH) risk group, number of metastatic sites, and histology. RESULTS: The median age was 63 years and 53% of patients were men. The most common histologies were melanoma (33%) and gastrointestinal cancers (22%). Most patients (73.3%) had more than one site of distant metastasis. Sites of metastasis collected were lymph node (n = 58), liver (n = 40), lung (n = 37), bone (n = 24), and brain (n = 8). Most patients (80.7%) were RMH good risk. Most patients (n = 62) had received 2+ prior lines of systemic treatment before receiving IO on trial; 27 patients (30.0%) received prior ICB. Liver metastases were associated with significantly shorter OS (HR: 0.38, CI: 0.17-0.84, p = 0.017). Patients with liver metastasis also trended towards having shorter PFS (HR: 0.70, CI: 0.41-1.19, p = 0.188). The median OS was substantially longer for patients without liver metastases (21.9 vs. 8.1 months, p = 0.0048). CONCLUSIONS: Liver metastases may be a poor prognostic factor in patients receiving IO on phase 1 clinical trials. The presence of liver metastases may warrant consideration in updated prognostic models if these findings are validated in a larger prospective cohort.
Subject(s)
Immunotherapy/methods , Liver Neoplasms/secondary , Neoplasms/therapy , Aged , Clinical Trials, Phase I as Topic , Female , Humans , Liver Neoplasms/therapy , Male , Middle Aged , Neoplasm Staging , Neoplasms/pathology , Retrospective Studies , Risk Factors , Survival Analysis , Treatment OutcomeABSTRACT
BACKGROUND: Treatment for advanced lung adenocarcinoma (AC) has become increasingly personalized based on molecular results. However, for patients with AC brain metastases (BMs), intracranial outcomes based on molecular subtype and the frequency of molecular aberrations are less well defined. This study sought to report targeted next-generation sequencing results and investigate molecularly based outcomes for patients with AC-BMs treated with radiotherapy. METHODS: The records of 132 patients with AC-BMs treated at Emory University from September 2008 to August 2016 with successful next-generation sequencing were reviewed. Rates of local disease recurrence, distant brain failure (DBF), and salvage whole-brain radiotherapy (WBRT) were estimated using cumulative incidence with competing risk analysis. Univariate and multivariate analyses were performed. RESULTS: The most common aberrations included tumor protein 53 (TP53) (60%), KRAS (29%), epidermal growth factor receptor (EGFR) (20.5%), phosphatase and tensin homolog (PTEN) loss (15.5%), and MET amplification (13%). The majority of patients (62%) were treated with stereotactic radiosurgery alone. In these patients, KRAS mutation, anaplastic lymphoma kinase (ALK) rearrangement, and having ≥ 6 BMs were associated with an increased risk of salvage WBRT (P < .05). KRAS mutation remained significant for an increased risk of salvage WBRT when compared with EGFR/ALK/KRAS-negative patients (hazard ratio, 5.17; P < .05), despite a similar risk of DBF. PTEN loss was associated with increased risk of DBF (P < .05), whereas EGFR and ALK aberrations were associated with a decreased risk of local disease recurrence (P < .05). CONCLUSIONS: The results of the current study quantified the frequency of genetic aberrations in patients with AC-BMs and demonstrated their association with intracranial outcomes. In particular, a cohort of patients with KRAS mutations and ≥6 BMs were identified to be at high risk of requiring salvage WBRT after undergoing upfront stereotactic radiosurgery.