The 50 most-cited articles in Journal of Clinical Oncology, 2018

Purpose To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events in patients treated with immune checkpoint inhibitor (ICPi) therapy. Methods A multidisciplinary, multi-organizational panel of experts in medical oncology, dermatology, gastroenterology, rheumatology, pulmonology, endocrinology, urology, neurology, hematology, emergency medicine, nursing, trialist, and advocacy was convened to develop the clinical practice guideline. Guideline development involved a systematic review of the literature and an informal consensus process. The systematic review focused on guidelines, systematic reviews and meta-analyses, randomized controlled trials, and case series published from 2000 through 2017. Results The systematic review identified 204 eligible publications. Much of the evidence consisted of systematic reviews of observational data, consensus guidelines, case series, and case reports. Due to the paucity of high-quality evidence on management of immune-related adverse events, recommendations are based on expert…

Purpose To update key recommendations of the American Society of Clinical Oncology/College of American Pathologists human epidermal growth factor receptor 2 (HER2) testing in breast cancer guideline. Methods Based on the signals approach, an Expert Panel reviewed published literature and research survey results on the observed frequency of less common in situ hybridization (ISH) patterns to update the recommendations. Recommendations Two recommendations addressed via correspondence in 2015 are included. First, immunohistochemistry (IHC) 2+ is defined as invasive breast cancer with weak to moderate complete membrane staining observed in > 10% of tumor cells. Second, if the initial HER2 test result in a core needle biopsy specimen of a primary breast cancer is negative, a new HER2 test may (not "must") be ordered on the excision specimen based on specific clinical criteria. The HER2 testing algorithm for breast cancer is updated to address the recommended work-up for less common clinical scenarios (approximately 5% of cases) observed when using a dual-probe ISH assay. These scenarios…

Purpose Nivolumab provides clinical benefit (objective response rate [ORR], 31%; 95% CI, 20.8 to 42.9; disease control rate, 69%; 12-month overall survival [OS], 73%) in previously treated patients with DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC); nivolumab plus ipilimumab may improve these outcomes. Efficacy and safety results for the nivolumab plus ipilimumab cohort of CheckMate-142, the largest single-study report of an immunotherapy combination in dMMR/MSI-H mCRC, are reported. Patients and Methods Patients received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg once every 2 weeks. Primary end point was investigator-assessed ORR. Results Of 119 patients, 76% had received ≥ two prior systemic therapies. At median follow-up of 13.4 months, investigator-assessed ORR was 55% (95% CI, 45.2 to 63.8), and disease control rate for ≥ 12 weeks was 80%. Median duration of response was not reached; most responses (94%) were ongoing at data cutoff. Progression-free…

Purpose To provide current recommendations about fertility preservation for adults and children with cancer. Methods A systematic review of the literature published from January 2013 to March 2017 was completed using PubMed and the Cochrane Library. An Update Panel reviewed the identified publications. Results There were 61 publications identified and reviewed. None of these publications prompted a significant change in the 2013 recommendations. Recommendations Health care providers should initiate the discussion on the possibility of infertility with patients with cancer treated during their reproductive years or with parents/guardians of children as early as possible. Providers should be prepared to discuss fertility preservation options and/or to refer all potential patients to appropriate reproductive specialists. Although patients may be focused initially on their cancer diagnosis, providers should advise patients regarding potential threats to fertility as early as possible in the treatment process so as to allow for the widest array of options for fertility preservation. The…

Purpose To provide guidance regarding the practical assessment and management of vulnerabilities in older patients undergoing chemotherapy. Methods An Expert Panel was convened to develop clinical practice guideline recommendations based on a systematic review of the medical literature. Results A total of 68 studies met eligibility criteria and form the evidentiary basis for the recommendations. Recommendations In patients ≥ 65 years receiving chemotherapy, geriatric assessment (GA) should be used to identify vulnerabilities that are not routinely captured in oncology assessments. Evidence supports, at a minimum, assessment of function, comorbidity, falls, depression, cognition, and nutrition. The Panel recommends instrumental activities of daily living to assess for function, a thorough history or validated tool to assess comorbidity, a single question for falls, the Geriatric Depression Scale to screen for depression, the Mini-Cog or the Blessed Orientation-Memory-Concentration test to screen for cognitive impairment, and an assessment of unintentional weight loss to evaluate…

Purpose Treatment of advanced non-small-cell lung cancer with immune checkpoint inhibitors (ICIs) is characterized by durable responses and improved survival in a subset of patients. Clinically available tools to optimize use of ICIs and understand the molecular determinants of response are needed. Targeted next-generation sequencing (NGS) is increasingly routine, but its role in identifying predictors of response to ICIs is not known. Methods Detailed clinical annotation and response data were collected for patients with advanced non-small-cell lung cancer treated with anti-programmed death-1 or anti-programmed death-ligand 1 [anti-programmed cell death (PD)-1] therapy and profiled by targeted NGS (MSK-IMPACT; n = 240). Efficacy was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and durable clinical benefit (DCB) was defined as partial response/stable disease that lasted > 6 months. Tumor mutation burden (TMB), fraction of copy number-altered genome, and gene alterations were compared among patients with DCB and no durable benefit (NDB). Whole-exome…

Purpose Venous thromboembolism (VTE) is common in patients with cancer. Long-term daily subcutaneous low molecular weight heparin has been standard treatment for such patients. The purpose of this study was to assess if an oral factor Xa inhibitor, rivaroxaban, would offer an alternative treatment for VTE in patients with cancer. Patient and Methods In this multicenter, randomized, open-label, pilot trial in the United Kingdom, patients with active cancer who had symptomatic pulmonary embolism (PE), incidental PE, or symptomatic lower-extremity proximal deep vein thrombosis (DVT) were recruited. Allocation was to dalteparin (200 IU/kg daily during month 1, then 150 IU/kg daily for months 2-6) or rivaroxaban (15 mg twice daily for 3 weeks, then 20 mg once daily for a total of 6 months). The primary outcome was VTE recurrence over 6 months. Safety was assessed by major bleeding and clinically relevant nonmajor bleeding (CRNMB). A sample size of 400 patients would provide estimates of VTE recurrence to within ± 4.5%, assuming a VTE recurrence rate at 6 months of 10%. Results A total of…

Purpose This phase III study evaluated ribociclib plus fulvestrant in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer who were treatment naïve or had received up to one line of prior endocrine therapy in the advanced setting. Patients and Methods Patients were randomly assigned at a two-to-one ratio to ribociclib plus fulvestrant or placebo plus fulvestrant. The primary end point was locally assessed progression-free survival. Secondary end points included overall survival, overall response rate, and safety. Results A total of 484 postmenopausal women were randomly assigned to ribociclib plus fulvestrant, and 242 were assigned to placebo plus fulvestrant. Median progression-free survival was significantly improved with ribociclib plus fulvestrant versus placebo plus fulvestrant: 20.5 months (95% CI, 18.5 to 23.5 months) versus 12.8 months (95% CI, 10.9 to 16.3 months), respectively (hazard ratio, 0.593; 95% CI, 0.480 to 0.732; P < .001). Consistent treatment effects were observed in patients who were treatment naïve in…

Purpose Docetaxel added to androgen-deprivation therapy (ADT) significantly increases the longevity of some patients with metastatic hormone-sensitive prostate cancer. Herein, we present the outcomes of the CHAARTED (Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) trial with more mature follow-up and focus on tumor volume. Patients and Methods In this phase III study, 790 patients with metastatic hormone-sensitive prostate cancer were equally randomly assigned to receive either ADT in combination with docetaxel 75 mg/m 2 for up to six cycles or ADT alone. The primary end point of the study was overall survival (OS). Additional analyses of the prospectively defined low- and high-volume disease subgroups were performed. High-volume disease was defined as presence of visceral metastases and/or ≥ four bone metastases with at least one outside of the vertebral column and pelvis. Results At a median follow-up of 53.7 months, the median OS was 57.6 months for the chemohormonal therapy arm versus 47.2 months for ADT alone (hazard…

PURPOSE: Treatment with programmed cell death-1 or programmed death ligand 1 (PD-(L)1) inhibitors is now standard therapy for patients with lung cancer. The immunosuppressive effect of corticosteroids may reduce efficacy of PD-(L)1 blockade. On-treatment corticosteroids for treatment of immune-related adverse events do not seem to affect efficacy, but the potential impact of baseline corticosteroids at the time of treatment initiation is unknown. Clinical trials typically excluded patients who received baseline corticosteroids, which led us to use real-world data to examine the effect of corticosteroids at treatment initiation. METHODS: We identified patients who were PD-(L)1-naïve with advanced non-small-cell lung cancer from two institutions-Memorial Sloan Kettering Cancer Center and Gustave Roussy Cancer Center-who were treated with single-agent PD-(L)1 blockade. Clinical and pharmacy records were reviewed to identify corticosteroid use at the time of beginning anti-PD-(L)1 therapy. We performed multivariable analyses using Cox proportional hazards regression model and logistic…

Purpose CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin that delivers a synergistic 5:1 drug ratio into leukemia cells to a greater extent than normal bone marrow cells. Prior clinical studies demonstrated a sustained drug ratio and exposure in vivo and prolonged survival versus standard-of-care cytarabine plus daunorubicin chemotherapy (7+3 regimen) in older patients with newly diagnosed secondary acute myeloid leukemia (sAML). Patients and Methods In this open-label, randomized, phase III trial, 309 patients age 60 to 75 years with newly diagnosed high-risk/sAML received one to two induction cycles of CPX-351 or 7+3 followed by consolidation therapy with a similar regimen. The primary end point was overall survival. Results CPX-351 significantly improved median overall survival versus 7+3 (9.56 v 5.95 months; hazard ratio, 0.69; 95% CI, 0.52 to 0.90; one-sided P = .003). Overall remission rate was also significantly higher with CPX-351 versus 7+3 (47.7% v 33.3%; two-sided P = .016). Improved outcomes were observed across age-groups and AML subtypes.…

Purpose The efficacy of neoadjuvant chemoradiotherapy (NCRT) plus surgery for locally advanced esophageal squamous cell carcinoma (ESCC) remains controversial. In this trial, we compared the survival and safety of NCRT plus surgery with surgery alone in patients with locally advanced ESCC. Patients and Methods From June 2007 to December 2014, 451 patients with potentially resectable thoracic ESCC, clinically staged as T1-4N1M0/T4N0M0, were randomly allocated to NCRT plus surgery (group CRT; n = 224) and surgery alone (group S; n = 227). In group CRT, patients received vinorelbine 25 mg/m 2 intravenously (IV) on days 1 and 8 and cisplatin 75 mg/m 2 IV day 1, or 25 mg/m 2 IV on days 1 to 4 every 3 weeks for two cycles, with a total concurrent radiation dose of 40.0 Gy administered in 20 fractions of 2.0 Gy on 5 days per week. In both groups, patients underwent McKeown or Ivor Lewis esophagectomy. The primary end point was overall survival. Results The pathologic complete response rate was 43.2% in group CRT. Compared with group S, group CRT had a higher R0 resection rate (98.4% v…

PURPOSE: Biomarkers that can predict response to anti-programmed cell death 1 (PD-1) therapy across multiple tumor types include a T-cell-inflamed gene-expression profile (GEP), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (TMB). Associations between these biomarkers and the clinical efficacy of pembrolizumab were evaluated in a clinical trial that encompassed 20 cohorts of patients with advanced solid tumors. METHODS: KEYNOTE-028 ( ClinicalTrials.gov identifier: NCT02054806) is a nonrandomized, phase Ib trial that enrolled 475 patients with PD-L1-positive advanced solid tumors who were treated with pembrolizumab 10 mg/kg every 2 weeks for 2 years or until confirmed disease progression or unacceptable toxicity occurred. The primary end point was objective response rate (ORR; by RECIST v1.1, investigator review). Secondary end points included safety, progression-free survival (PFS), and overall survival (OS). Relationships between T-cell-inflamed GEP, PD-L1 expression, and TMB and antitumor activity were exploratory end points. RESULTS: ORRs (with 95%…

Purpose Clinical use of analytical tests to assess genomic variants in circulating tumor DNA (ctDNA) is increasing. This joint review from ASCO and the College of American Pathologists summarizes current information about clinical ctDNA assays and provides a framework for future research. Methods An Expert Panel conducted a literature review on the use of ctDNA assays for solid tumors, including pre-analytical variables, analytical validity, interpretation and reporting, and clinical validity and utility. Results The literature search identified 1,338 references. Of those, 390, plus 31 references supplied by the Expert Panel, were selected for full-text review. There were 77 articles selected for inclusion. Conclusion The evidence indicates that testing for ctDNA is optimally performed on plasma collected in cell stabilization or EDTA tubes, with EDTA tubes processed within 6 hours of collection. Some ctDNA assays have demonstrated clinical validity and utility with certain types of advanced cancer; however, there is insufficient evidence of clinical validity and utility for the…

Purpose We report CNS efficacy of osimertinib versus standard epidermal growth factor receptor ( EGFR) tyrosine kinase inhibitors (TKIs) in patients with untreated EGFR-mutated advanced non-small-cell lung cancer from the phase III FLAURA study. Patients and Methods Patients (N = 556) were randomly assigned to osimertinib or standard EGFR-TKIs (gefitinib or erlotinib); brain scans were not mandated unless clinically indicated. Patients with asymptomatic or stable CNS metastases were included. In patients with symptomatic CNS metastases, neurologic status was required to be stable for ≥ 2 weeks after completion of definitive therapy and corticosteroids. A preplanned subgroup analysis with CNS progression-free survival as primary objective was conducted in patients with measurable and/or nonmeasurable CNS lesions on baseline brain scan by blinded independent central neuroradiologic review. The CNS evaluable-for-response set included patients with ≥ one measurable CNS lesion. Results Of 200 patients with available brain scans at baseline, 128 (osimertinib, n = 61; standard EGFR-TKIs, n…

Purpose The prevalence and features of treatment-emergent small-cell neuroendocrine prostate cancer (t-SCNC) are not well characterized in the era of modern androgen receptor (AR)-targeting therapy. We sought to characterize the clinical and genomic features of t-SCNC in a multi-institutional prospective study. Methods Patients with progressive, metastatic castration-resistant prostate cancer (mCRPC) underwent metastatic tumor biopsy and were followed for survival. Metastatic biopsy specimens underwent independent, blinded pathology review along with RNA/DNA sequencing. Results A total of 202 consecutive patients were enrolled. One hundred forty-eight (73%) had prior disease progression on abiraterone and/or enzalutamide. The biopsy evaluable rate was 79%. The overall incidence of t-SCNC detection was 17%. AR amplification and protein expression were present in 67% and 75%, respectively, of t-SCNC biopsy specimens. t-SCNC was detected at similar proportions in bone, node, and visceral organ biopsy specimens. Genomic alterations in the DNA repair pathway were nearly mutually…

Purpose Therapies with novel mechanisms of action are needed for multiple myeloma (MM). T cells can be genetically modified to express chimeric antigen receptors (CARs), which are artificial proteins that target T cells to antigens. B-cell maturation antigen (BCMA) is expressed by normal and malignant plasma cells but not normal essential cells. We conducted the first-in-humans clinical trial, to our knowledge, of T cells expressing a CAR targeting BCMA (CAR-BCMA). Patients and Methods Sixteen patients received 9 × 10 6 CAR-BCMA T cells/kg at the highest dose level of the trial; we are reporting results of these 16 patients. The patients had a median of 9.5 prior lines of MM therapy. Sixty-three percent of patients had MM refractory to the last treatment regimen before protocol enrollment. T cells were transduced with a γ-retroviral vector encoding CAR-BCMA. Patients received CAR-BCMA T cells after a conditioning chemotherapy regimen of cyclophosphamide and fludarabine. Results The overall response rate was 81%, with 63% very good partial response or complete response. Median…

Purpose Genetic alterations causing overexpression of programmed death-1 ligands are near universal in classic Hodgkin lymphoma (cHL). Nivolumab, a programmed death-1 checkpoint inhibitor, demonstrated efficacy in relapsed/refractory cHL after autologous hematopoietic cell transplantation (auto-HCT) in initial analyses of one of three cohorts from the CheckMate 205 study of nivolumab for cHL. Here, we assess safety and efficacy after extended follow-up of all three cohorts. Methods This multicenter, single-arm, phase II study enrolled patients with relapsed/refractory cHL after auto-HCT treatment failure into cohorts by treatment history: brentuximab vedotin (BV)-naïve (cohort A), BV received after auto-HCT (cohort B), and BV received before and/or after auto-HCT (cohort C). All patients received nivolumab 3 mg/kg every 2 weeks until disease progression/unacceptable toxicity. The primary end point was objective response rate per independent radiology review committee. Results Overall, 243 patients were treated; 63 in cohort A, 80 in cohort B, and 100 in cohort C. After a median…

Purpose In two phase III studies, nivolumab, a programmed death-1 (PD-1) inhibitor antibody, improved overall survival (OS) versus docetaxel in pretreated advanced non-small-cell lung cancer (NSCLC). We report 5-year follow-up results from an early phase I study of nivolumab in this patient population and describe characteristics of 5-year survivors. Patients and Methods Patients with pretreated, advanced NSCLC received nivolumab 1, 3, or 10 mg/kg every 2 weeks in 8-week cycles for up to 96 weeks. OS from the time of first dose was estimated by the Kaplan-Meier method. Results The estimated 5-year OS rate was 16% for all treated patients (N = 129); 5-year OS rates were similar for squamous (16%) and nonsquamous (15%) NSCLC. Of 16 5-year survivors, most (88%) were known current or former smokers. Of 10 5-year survivors with quantifiable PD-1 ligand 1 expression, 70% had ≥ 1% PD-1 ligand 1 expression at baseline. Twelve 5-year survivors (75%) achieved a partial response to nivolumab per Response Evaluation Criteria in Solid Tumors, version 1.0, and two each (12%) had stable disease…

PURPOSE: To determine the activity of pembrolizumab as neoadjuvant immunotherapy before radical cystectomy (RC) for muscle-invasive bladder carcinoma (MIBC) for which standard cisplatin-based chemotherapy is poorly used. PATIENTS AND METHODS: In the PURE-01 study, patients had a predominant urothelial carcinoma histology and clinical (c)T≤3bN0 stage tumor. They received three cycles of pembrolizumab 200 mg every 3 weeks before RC. The primary end point in the intention-to-treat population was pathologic complete response (pT0). Biomarker analyses included programmed death-ligand 1 (PD-L1) expression using the combined positive score (CPS; Dako 22C3 pharmDx assay), genomic sequencing (FoundationONE assay), and an immune gene expression assay. RESULTS: Fifty patients were enrolled from February 2017 to March 2018. Twenty-seven patients (54%) had cT3 tumor, 21 (42%) cT2 tumor, and two (4%) cT2-3N1 tumor. One patient (2%) experienced a grade 3 transaminase increase and discontinued pembrolizumab. All patients underwent RC; there were 21 patients with pT0 (42%; 95% CI, 28.2% to 56.8%).…

Purpose DNX-2401 (Delta-24-RGD; tasadenoturev) is a tumor-selective, replication-competent oncolytic adenovirus. Preclinical studies demonstrated antiglioma efficacy, but the effects and mechanisms of action have not been evaluated in patients. Methods A phase I, dose-escalation, biologic-end-point clinical trial of DNX-2401 was conducted in 37 patients with recurrent malignant glioma. Patients received a single intratumoral injection of DNX-2401 into biopsy-confirmed recurrent tumor to evaluate safety and response across eight dose levels (group A). To investigate the mechanism of action, a second group of patients (group B) underwent intratumoral injection through a permanently implanted catheter, followed 14 days later by en bloc resection to acquire post-treatment specimens. Results In group A (n = 25), 20% of patients survived > 3 years from treatment, and three patients had a ≥ 95% reduction in the enhancing tumor (12%), with all three of these dramatic responses resulting in > 3 years of progression-free survival from the time of treatment. Analyses of post-treatment surgical…

Purpose Selective internal radiation therapy or radioembolization (RE) shows efficacy in unresectable hepatocellular carcinoma (HCC) limited to the liver. This study compared the safety and efficacy of RE and sorafenib in patients with locally advanced HCC. Patients and Methods SIRveNIB (selective internal radiation therapy v sorafenib), an open-label, investigator-initiated, phase III trial, compared yttrium-90 ( 90 Y) resin microspheres RE with sorafenib 800 mg/d in patients with locally advanced HCC in a two-tailed study designed for superiority/detriment. Patients were randomly assigned 1:1 and stratified by center and presence of portal vein thrombosis. Primary end point was overall survival (OS). Efficacy analyses were performed in the intention-to-treat population and safety analyses in the treated population. Results A total of 360 patients were randomly assigned (RE, 182; sorafenib, 178) from 11 countries in the Asia-Pacific region. In the RE and sorafenib groups, 28.6% and 9.0%, respectively, failed to receive assigned therapy without significant cross-over to either…

PURPOSE: To update the ASCO clinical practice guideline on adjuvant endocrine therapy based on emerging data about the optimal duration of aromatase inhibitor (AI) treatment. METHODS: ASCO conducted a systematic review of randomized clinical trials from 2012 to 2018. Guideline recommendations were based on the Panel's review of the evidence from six trials. RESULTS: The six included studies of AI treatment beyond 5 years of therapy demonstrated that extension of AI treatment was not associated with an overall survival advantage but was significantly associated with lower risks of breast cancer recurrence and contralateral breast cancer compared with placebo. Bone-related toxic effects were more common with extended AI treatment. RECOMMENDATIONS: The Panel recommends that women with node-positive breast cancer receive extended therapy, including an AI, for up to a total of 10 years of adjuvant endocrine treatment. Many women with node-negative breast cancer should consider extended therapy for up to a total of 10 years of adjuvant endocrine treatment based on considerations of…

PURPOSE: Metastatic esophagogastric cancer treatments after failure of second-line chemotherapy are limited. Nivolumab demonstrated superior overall survival (OS) versus placebo in Asian patients with advanced gastric or gastroesophageal junction cancers. We assessed the safety and efficacy of nivolumab and nivolumab plus ipilimumab in Western patients with chemotherapy-refractory esophagogastric cancers. PATIENTS AND METHODS: Patients with locally advanced or metastatic chemotherapy-refractory gastric, esophageal, or gastroesophageal junction cancer from centers in the United States and Europe received nivolumab or nivolumab plus ipilimumab. The primary end point was objective response rate. The association of tumor programmed death-ligand 1 status with response and survival was also evaluated. RESULTS: Of 160 treated patients (59 with nivolumab 3 mg/kg, 49 with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, 52 with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg), 79% had received two or more prior therapies. At the data cutoff, investigator-assessed objective response rates were 12% (95%…

PURPOSE: Microsatellite instability (MSI) and/or mismatch repair deficiency (MMR-D) testing has traditionally been performed in patients with colorectal (CRC) and endometrial cancer (EC) to screen for Lynch syndrome (LS)-associated cancer predisposition. The recent success of immunotherapy in high-frequency MSI (MSI-H) and/or MMR-D tumors now supports testing for MSI in all advanced solid tumors. The extent to which LS accounts for MSI-H across heterogeneous tumor types is unknown. Here, we establish the prevalence of LS across solid tumors according to MSI status. METHODS: MSI status was determined using targeted next-generation sequencing, with tumors classified as MSI-H, MSI-indeterminate, or microsatellite-stable. Matched germline DNA was analyzed for mutations in LS-associated mismatch repair genes ( MLH1, MSH2, MSH6, PMS2, EPCAM). In patients with LS with MSI-H/I tumors, immunohistochemical staining for MMR-D was assessed. RESULTS: Among 15,045 unique patients (more than 50 cancer types), LS was identified in 16.3% (53 of 326), 1.9% (13 of 699), and 0.3% (37 of 14,020) of…

Purpose To provide an updated joint ASCO/Infectious Diseases Society of America (IDSA) guideline on antimicrobial prophylaxis for adult patients with immunosuppression associated with cancer and its treatment. Methods ASCO and IDSA convened an update Expert Panel and conducted a systematic review of relevant studies from May 2011 to November 2016. The guideline recommendations were based on the review of evidence by the Expert Panel. Results Six new or updated meta-analyses and six new primary studies were added to the updated systematic review. Recommendations Antibacterial and antifungal prophylaxis is recommended for patients who are at high risk of infection, including patients who are expected to have profound, protracted neutropenia, which is defined as < 100 neutrophils/µL for > 7 days or other risk factors. Herpes simplex virus–seropositive patients undergoing allogeneic hematopoietic stem-cell transplantation or leukemia induction therapy should receive nucleoside analog-based antiviral prophylaxis, such as acyclovir. Pneumocystis jirovecii prophylaxis is recommended for…

Purpose Stereotactic body radiotherapy (SBRT) may stimulate innate and adaptive immunity to augment immunotherapy response. Multisite SBRT is an emerging paradigm for treating metastatic disease. Anti-PD-1-treatment outcomes may be improved with lower disease burden. In this context, we conducted a phase I study to evaluate the safety of pembrolizumab with multisite SBRT in patients with metastatic solid tumors. Patients and Methods Patients progressing on standard treatment received SBRT to two to four metastases. Not all metastases were targeted, and metastases > 65 mL were partially irradiated. SBRT dosing varied by site and ranged from 30 to 50 Gy in three to five fractions with predefined dose de-escalation if excess dose-limiting toxicities were observed. Pembrolizumab was initiated within 7 days after completion of SBRT. Pre- and post-SBRT biopsy specimens were analyzed in a subset of patients to quantify interferon-γ-induced gene expression. Results A total of 79 patients were enrolled; three patients did not receive any treatment and three patients only received SBRT.…

Purpose Human epidermal growth factor receptor 2 ( HER2, ERBB2)-activating mutations occur in 2% of lung cancers. We assessed the activity of ado-trastuzumab emtansine, a HER2-targeted antibody-drug conjugate, in a cohort of patients with HER2-mutant lung cancers as part of a phase II basket trial. Patients and Methods Patients received ado-trastuzumab emtansine at 3.6 mg/kg intravenously every 3 weeks until progression. The primary end point was overall response rate using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. A Simon two-stage optimal design was used. Other end points included progression-free survival and toxicity. HER2 testing was performed on tumor tissue by next generation sequencing, fluorescence in situ hybridization, immunohistochemistry, and protein mass spectrometry. Results We treated 18 patients with advanced HER2-mutant lung adenocarcinomas. The median number of prior systemic therapies was two (range, zero to four prior therapies). The partial response rate was 44% (95% CI, 22% to 69%), meeting the primary end point. Responses were seen in…

Purpose Alterations in DNA damage response and repair (DDR) genes are associated with increased mutation load and improved clinical outcomes in platinum-treated metastatic urothelial carcinoma. We examined the relationship between DDR alterations and response to PD-1/PD-L1 blockade. Methods Detailed demographic, treatment response, and long-term outcome data were collected on patients with metastatic urothelial carcinoma treated with atezolizumab or nivolumab who had targeted exon sequencing performed on pre-immunotherapy tumor specimens. Presence of DDR alterations was correlated with best objective response per Response Evaluation Criteria in Solid Tumors (RECIST) and progression-free and overall survival. Results Sixty patients with urothelial cancer enrolled in prospective trials of anti-PD-1/PD-L1 antibodies met inclusion criteria. Any DDR and known or likely deleterious DDR mutations were identified in 28 (47%) and 15 (25%) patients, respectively. The presence of any DDR alteration was associated with a higher response rate (67.9% v 18.8%; P < .001). A higher response rate was…

Purpose Studies suggest that a subset of patients with triple-negative breast cancer (TNBC) have tumors that express the androgen receptor (AR) and may benefit from an AR inhibitor. This phase II study evaluated the antitumor activity and safety of enzalutamide in patients with locally advanced or metastatic AR-positive TNBC. Patients and Methods Tumors were tested for AR with an immunohistochemistry assay optimized for breast cancer; nuclear AR staining > 0% was considered positive. Patients received enzalutamide 160 mg once per day until disease progression. The primary end point was clinical benefit rate (CBR) at 16 weeks. Secondary end points included CBR at 24 weeks, progression-free survival, and safety. End points were analyzed in all enrolled patients (the intent-to-treat [ITT] population) and in patients with one or more postbaseline assessment whose tumor expressed ≥ 10% nuclear AR (the evaluable subgroup). Results Of 118 patients enrolled, 78 were evaluable. CBR at 16 weeks was 25% (95% CI, 17% to 33%) in the ITT population and 33% (95% CI, 23% to 45%) in the evaluable…

Purpose Uterine serous carcinoma is a rare, aggressive variant of endometrial cancer. Trastuzumab is a humanized monoclonal antibody that targets human epidermal growth factor receptor 2 (HER2)/neu, a receptor overexpressed in 30% of uterine serous carcinoma. This multicenter, randomized phase II trial compared carboplatin-paclitaxel with and without trastuzumab in patients with advanced or recurrent uterine serous carcinoma who overexpress HER2/neu. Methods Eligible patients had primary stage III or IV or recurrent HER2/neu-positive disease. Participants were randomly assigned to receive carboplatin-paclitaxel (control arm) for six cycles with or without intravenous trastuzumab (experimental arm) until progression or unacceptable toxicity. The primary end point was progression-free survival, which was assessed for differences between treatment arms via one-sided log-rank tests. Results From August 2011 to March 2017, 61 patients were randomly assigned. Forty progression-free survival-related events occurred among 58 evaluable participants. Among all patients, median…

Purpose In patients with epidermal growth factor receptor ( EGFR) mutation-positive advanced non-small-cell lung cancer (NSCLC), there is an unmet need for EGFR-tyrosine kinase inhibitors with improved CNS penetration and activity against CNS metastases, either at initial diagnosis or time of progression. We report the first comparative evidence of osimertinib CNS efficacy versus platinum-pemetrexed from a phase III study (AURA3; ClinicalTrials.gov identifier: NCT02151981) in patients with EGFR T790M-positive advanced NSCLC who experience disease progression with prior EGFR-tyrosine kinase inhibitor treatment. Methods Patients with asymptomatic, stable CNS metastases were eligible for enrollment and were randomly assigned 2:1 to osimertinib 80 mg once daily or platinum-pemetrexed. A preplanned subgroup analysis was conducted in patients with measurable and/or nonmeasurable CNS lesions on baseline brain scan by blinded independent central neuroradiological review. The CNS evaluable for response set included only patients with one or more measurable CNS lesions. The primary objective…

Purpose Detection of specific molecular alterations in tumors guides the selection of effective targeted treatment of patients with several types of cancer. These molecular alterations may occur in other tumor types for which the efficacy of targeted therapy remains unclear. The MyPathway study evaluates the efficacy and safety of selected targeted therapies in tumor types that harbor relevant genetic alterations but are outside of current labeling for these treatments. Methods MyPathway ( ClinicalTrials.gov identifier: NCT02091141) is a multicenter, nonrandomized, phase IIa multiple basket study. Patients with advanced refractory solid tumors harboring molecular alterations in human epidermal growth factor receptor-2, epidermal growth factor receptor, v-raf murine sarcoma viral oncogene homolog B1, or the Hedgehog pathway are treated with pertuzumab plus trastuzumab, erlotinib, vemurafenib, or vismodegib, respectively. The primary end point is investigator-assessed objective response rate within each tumor-pathway cohort. Results Between April 1, 2014 and November 1, 2016, 251…

PURPOSE: Approximately 3% to 10% of EGFR (epidermal growth factor receptor) -mutant non-small cell lung cancers (NSCLCs) undergo transformation to small-cell lung cancer (SCLC), but their clinical course is poorly characterized. METHODS: We retrospectively identified patients with EGFR-mutant SCLC and other high-grade neuroendocrine carcinomas seen at our eight institutions. Demographics, disease features, and outcomes were analyzed. RESULTS: We included 67 patients-38 women and 29 men; EGFR mutations included exon 19 deletion (69%), L858R (25%), and other (6%). At the initial lung cancer diagnosis, 58 patients had NSCLC and nine had de novo SCLC or mixed histology. All but these nine patients received one or more EGFR tyrosine kinase inhibitor before SCLC transformation. Median time to transformation was 17.8 months (95% CI, 14.3 to 26.2 months). After transformation, both platinum-etoposide and taxanes yielded high response rates, but none of 17 patients who received immunotherapy experienced a response. Median overall survival since diagnosis was 31.5 months (95% CI, 24.8 to 41.3…

PURPOSE: Outcomes for patients with diffuse large B-cell lymphoma remain heterogeneous, with existing methods failing to consistently predict treatment failure. We examined the additional prognostic value of circulating tumor DNA (ctDNA) before and during therapy for predicting patient outcomes. PATIENTS AND METHODS: We studied the dynamics of ctDNA from 217 patients treated at six centers, using a training and validation framework. We densely characterized early ctDNA dynamics during therapy using cancer personalized profiling by deep sequencing to define response-associated thresholds within a discovery set. These thresholds were assessed in two independent validation sets. Finally, we assessed the prognostic value of ctDNA in the context of established risk factors, including the International Prognostic Index and interim positron emission tomography/computed tomography scans. RESULTS: Before therapy, ctDNA was detectable in 98% of patients; pretreatment levels were prognostic in both front-line and salvage settings. In the discovery set, ctDNA levels changed rapidly, with a…

PURPOSE: Improvements in magnetic resonance imaging (MRI), total mesorectal excision (TME) surgery, and the use of (chemo)radiotherapy ([C]RT) have improved local control of rectal cancer; however, we have been unable to eradicate local recurrence (LR). Even in the face of TME and negative resection margins (R0), a significant proportion of patients with enlarged lateral lymph nodes (LLNs) suffer from lateral LR (LLR). Japanese studies suggest that the addition of an LLN dissection (LLND) could reduce LLR. This multicenter pooled analysis aims to ascertain whether LLNs actually pose a problem and whether LLND results in fewer LLRs. PATIENTS AND METHODS: Data from 1,216 consecutive patients with cT3/T4 rectal cancers up to 8 cm from the anal verge who underwent surgery in a 5-year period were collected. LLND was performed in 142 patients (12%). MRIs were re-evaluated with a standardized protocol to assess LLN features. RESULTS: On pretreatment MRI, 703 patients (58%) had visible LLN, and 192 (16%) had a short axis of at least 7 mm. One hundred eight patients developed LR (5-year LR…

Purpose In response to advances in the field, the College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) recently updated their recommendations for molecular testing for the selection of patients with lung cancer for treatment with targeted tyrosine kinase inhibitors. ASCO has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations. Methods The molecular testing guideline was reviewed for developmental rigor by methodologists. Then an ASCO Expert Panel reviewed the content and the recommendations. Results The ASCO Expert Panel determined that the recommendations from the CAP/IASLC/AMP molecular testing guideline are clear, thorough, and based upon the most relevant scientific evidence. ASCO endorsed the guideline with minor modifications. Recommendations This update clarifies that any sample with adequate cellularity and preservation may be tested and that analytical methods must be able to detect…

Purpose We compared the efficacy and toxicity of neoadjuvant chemotherapy followed by radical surgery versus standard cisplatin-based chemoradiation in patients with locally advanced squamous cervical cancer. Patients and Methods This was a single-center, phase III, randomized controlled trial ( ClinicalTrials.gov identifier: NCT00193739). Eligible patients were between 18 and 65 years old and had stage IB2, IIA, or IIB squamous cervical cancer. They were randomly assigned, after stratification by stage, to receive either three cycles of neoadjuvant chemotherapy using paclitaxel and carboplatin once every 3 weeks followed by radical hysterectomy or standard radiotherapy with concomitant cisplatin once every week for 5 weeks. Patients in the neoadjuvant group received postoperative adjuvant radiation or concomitant chemotherapy and radiotherapy, if indicated. The primary end point was disease-free survival (DFS), defined as survival without relapse or death related to cancer, and secondary end points included overall survival and toxicity. Results Between September 2003 and February…

Purpose This multinational study evaluated the antitumor activity of nivolumab in nasopharyngeal carcinoma (NPC). Tumor and plasma-based biomarkers were investigated in an exploratory analysis. Patients and Methods Patients with multiply pretreated recurrent or metastatic NPC were treated with nivolumab until disease progression. The primary end point was objective response rate (ORR) and secondary end points included survival and toxicity. The expression of programmed death-ligand 1 (PD-L1) and human leukocyte antigens A and B in archived tumors and plasma clearance of Epstein-Barr virus DNA were correlated with ORR and survival. Results A total of 44 patients were evaluated and the overall ORR was 20.5% (complete response, n = 1; partial response, n = 8). Nine patients received nivolumab for > 12 months (20%). The 1-year overall survival rate was 59% (95% CI, 44.3% to 78.5%) and 1-year progression-free survival (PFS) rate was 19.3% (95% CI, 10.1% to 37.2%). There was no statistical correlation between ORR and the biomarkers; however, a descriptive analysis showed that the…

Purpose ARCHER 1050, a randomized, open-label, phase III study of dacomitinib versus gefitinib in treatment-naïve patients with advanced non-small-cell lung cancer (NSCLC) and activating mutations in EGFR, reported significant improvement in progression-free survival with dacomitinib. The mature overall survival (OS) analysis for the intention-to-treat population is presented here. Patients and Methods In this multinational, multicenter study, patients age 18 years or older (≥ 20 years in Japan and Korea) who had an Eastern Cooperative Oncology Group performance status of 0 or 1 and newly diagnosed NSCLC with activating mutations in EGFR (exon 19 deletion or exon 21 L858R) were enrolled and randomly assigned in a 1:1 manner to dacomitinib (n = 227) or gefitinib (n = 225). Random assignment was stratified by race (Japanese, Chinese, other East Asian, or non-Asian) and EGFR mutation type. The final OS analysis was conducted with a data cutoff date of February 17, 2017; at that time 220 deaths (48.7%) were observed. Results During a median follow-up time of 31.3 months, 103 (45.4%) and…

Purpose We report the first-in-human phase Ia study to our knowledge ( ClinicalTrials.gov identifier: NCT01219699) identifying the maximum tolerated dose and assessing safety and preliminary efficacy of single-agent alpelisib (BYL719), an oral phosphatidylinositol 3-kinase α (PI3Kα)-selective inhibitor. Patients and Methods In the dose-escalation phase, patients with PIK3CA-altered advanced solid tumors received once-daily or twice-daily oral alpelisib on a continuous schedule. In the dose-expansion phase, patients with PIK3CA-altered solid tumors and PIK3CA-wild-type, estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast cancer received alpelisib 400 mg once daily. Results One hundred thirty-four patients received treatment. Alpelisib maximum tolerated doses were established as 400 mg once daily and 150 mg twice daily. Nine patients (13.2%) in the dose-escalation phase had dose-limiting toxicities of hyperglycemia (n = 6), nausea (n = 2), and both hyperglycemia and hypophosphatemia (n = 1). Frequent all-grade, treatment-related adverse events included…

Purpose To provide an updated joint ASCO/Infectious Diseases Society of American (IDSA) guideline on outpatient management of fever and neutropenia in patients with cancer. Methods ASCO and IDSA convened an Update Expert Panel and conducted a systematic review of relevant studies. The guideline recommendations were based on the review of evidence by the Expert Panel. Results Six new or updated meta-analyses and six new primary studies were added to the updated systematic review. Recommendation Clinical judgment is recommended when determining which patients are candidates for outpatient management, using clinical criteria or a validated tool such as the Multinational Association of Support Care in Cancer risk index. In addition, psychosocial and logistic considerations are outlined within the guideline. The panel continued to endorse consensus recommendations from the previous version of this guideline that patients with febrile neutropenia receive initial doses of empirical antibacterial therapy within 1 hour of triage and be monitored for ≥ 4 hours before discharge. An oral…

Purpose Diffuse intrinsic pontine glioma (DIPG) is a brainstem malignancy with a median survival of < 1 year. The International and European Society for Pediatric Oncology DIPG Registries collaborated to compare clinical, radiologic, and histomolecular characteristics between short-term survivors (STSs) and long-term survivors (LTSs). Materials and Methods Data abstracted from registry databases included patients from North America, Australia, Germany, Austria, Switzerland, the Netherlands, Italy, France, the United Kingdom, and Croatia. Results Among 1,130 pediatric and young adults with radiographically confirmed DIPG, 122 (11%) were excluded. Of the 1,008 remaining patients, 101 (10%) were LTSs (survival ≥ 2 years). Median survival time was 11 months (interquartile range, 7.5 to 16 months), and 1-, 2-, 3-, 4-, and 5-year survival rates were 42.3% (95% CI, 38.1% to 44.1%), 9.6% (95% CI, 7.8% to 11.3%), 4.3% (95% CI, 3.2% to 5.8%), 3.2% (95% CI, 2.4% to 4.6%), and 2.2% (95% CI, 1.4% to 3.4%), respectively. LTSs, compared with STSs, more commonly presented at age < 3 or > 10 years…

Purpose The Society for Integrative Oncology (SIO) produced an evidence-based guideline on use of integrative therapies during and after breast cancer treatment that was determined to be relevant to the American Society of Clinical Oncology (ASCO) membership. ASCO considered the guideline for endorsement. Methods The SIO guideline addressed the use of integrative therapies for the management of symptoms and adverse effects, such as anxiety and stress, mood disorders, fatigue, quality of life, chemotherapy-induced nausea and vomiting, lymphedema, chemotherapy-induced peripheral neuropathy, pain, and sleep disturbance. Interventions of interest included mind and body practices, natural products, and lifestyle modifications. SIO systematic reviews focused on randomized controlled trials that were published from 1990 through 2015. The SIO guideline was reviewed by ASCO content experts for clinical accuracy and by ASCO methodologists for developmental rigor. On favorable review, an ASCO Expert Panel was convened to review the guideline contents and recommendations. Results The ASCO…

Purpose To provide evidence-based recommendations to practicing physicians and others on the management of malignant pleural mesothelioma. Methods ASCO convened an Expert Panel of medical oncology, thoracic surgery, radiation oncology, pulmonary, pathology, imaging, and advocacy experts to conduct a literature search, which included systematic reviews, meta-analyses, randomized controlled trials, and prospective and retrospective comparative observational studies published from 1990 through 2017. Outcomes of interest included survival, disease-free or recurrence-free survival, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. Results The literature search identified 222 relevant studies to inform the evidence base for this guideline. Recommendations Evidence-based recommendations were developed for diagnosis, staging, chemotherapy, surgical cytoreduction, radiation therapy, and multimodality therapy in patients with malignant pleural mesothelioma. Additional information is available at…

PURPOSE: High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) has a poor outcome after standard chemoimmunotherapy. We sought to understand the biologic underpinnings of HGBL-DH/TH with BCL2 rearrangements (HGBL-DH/TH- BCL2) and diffuse large B-cell lymphoma (DLBCL) morphology through examination of gene expression. PATIENTS AND METHODS: We analyzed RNA sequencing data from 157 de novo germinal center B-cell-like (GCB)-DLBCLs, including 25 with HGBL-DH/TH- BCL2, to define a gene expression signature that distinguishes HGBL-DH/TH- BCL2 from other GCB-DLBCLs. To assess the genetic, molecular, and phenotypic features associated with this signature, we analyzed targeted resequencing, whole-exome sequencing, RNA sequencing, and immunohistochemistry data. RESULTS: We developed a 104-gene double-hit signature (DHITsig) that assigned 27% of GCB-DLBCLs to the DHITsig-positive group, with only one half harboring MYC and BCL2 rearrangements (HGBL-DH/TH- BCL2). DHITsig-positive patients had inferior outcomes after rituximab plus cyclophosphamide, doxorubicin,…

Purpose The phase III PROFILE 1014 trial compared crizotinib with chemotherapy as first-line treatment in patients with anaplastic lymphoma kinase (ALK) –positive advanced nonsquamous non–small-cell lung cancer. Here, we report the final overall survival (OS) results. Patients and Methods Patients were randomly assigned to receive oral crizotinib 250 mg twice daily (n = 172) or intravenous pemetrexed 500 mg/m 2 plus cisplatin 75 mg/m 2 or carboplatin (area under the concentration–time curve of 5 to 6 mg·mL/min) every 3 weeks for a maximum of six cycles (n = 171). Crossover to crizotinib was permitted after disease progression. OS was analyzed using a stratified log-rank test and a prespecified rank-preserving structural failure time model to account for crossover. Results Median follow-up duration for OS was approximately 46 months for both arms. In the chemotherapy arm, 144 patients (84.2%) received crizotinib in subsequent lines. Hazard ratio for OS was 0.760 (95% CI, 0.548 to 1.053; two-sided P = .0978). Median OS was not reached (NR) with crizotinib (95% CI, 45.8 months to NR)…

we have identified U2AF1Q157 as an additional HMR mutation3 and also defined new sex- and severity-adjusted hemoglobin thresholds that were prognostically more discriminative than hemoglobin < 10 g/dL; the new hemoglobin thresholds included severe anemia, defined by hemoglobin levels of < 8 g/dL in women and < 9 g/dL in men, and moderate anemia, defined by hemoglobin levels of 8 to 9.9 g/dL in women and 9 to 10.9 g/dL in men.4 We conducted a study to consider these new developments and revise MIPSS70+ into MIPSS70+ version 2.0.

Purpose Both temozolomide (TMZ) and poly (ADP-ribose) polymerase (PARP) inhibitors are active in small-cell lung cancer (SCLC). This phase II, randomized, double-blind study evaluated whether addition of the PARP inhibitor veliparib to TMZ improves 4-month progression-free survival (PFS). Patients and Methods A total of 104 patients with recurrent SCLC were randomly assigned 1:1 to oral veliparib or placebo 40 mg twice daily, days 1 to 7, and oral TMZ 150 to 200 mg/m2/day, days 1 to 5, of a 28-day cycle until disease progression, unacceptable toxicity, or withdrawal of consent. Response was determined by imaging at weeks 4 and 8, and every 8 weeks thereafter. Improvement in PFS at 4 months was the primary end point. Secondary objectives included overall response rate (ORR), overall survival (OS), and safety and tolerability of veliparib with TMZ. Exploratory objectives included PARP-1 and SLFN11 immunohistochemical expression, MGMT promoter methylation, and circulating tumor cell quantification. Results No significant difference in 4-month PFS was noted between TMZ/veliparib (36%)…

Purpose The role of temporary ovarian suppression with gonadotropin-releasing hormone agonists (GnRHa) during chemotherapy as a strategy to preserve ovarian function and fertility in premenopausal women remains controversial. This systematic review and meta-analysis using individual patient-level data was conducted to better assess the efficacy and safety of this strategy in patients with early breast cancer. Methods The trials in which premenopausal women with early breast cancer were randomly assigned to receive (neo)adjuvant chemotherapy alone or with concurrent GnRHa were eligible for inclusion. Primary end points were premature ovarian insufficiency (POI) rate and post-treatment pregnancy rate. Disease-free survival and overall survival were secondary end points. Because each study represents a cluster, statistical analyses were performed using a random effects model. Results A total of 873 patients from five trials were included. POI rate was 14.1% in the GnRHa group and 30.9% in the control group (adjusted odds ratio, 0.38; 95% CI, 0.26 to 0.57; P < .001). A total of 37…