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This report describes the management of small cell lung cancer (SCLC) transformation in a patient with untreated ALK-mutated advanced disease and a minimal smoking history, and a separate case of a de novo SCLC in a lifelong nonsmoker found to have a potentially targetable ERBB2 alteration. In the first case, chemotherapy followed by a targeted inhibitor was chosen due to the presence of the ALK rearrangement, as well as a somewhat discordant response to induction chemotherapy, suggesting possible progression of the ALK inhibitor–sensitive component. Molecular testing for the identification of driver mutations should be considered in patients with SCLC who have light/never smoking histories in order to help understand the incidence and ultimate optimal management strategies.

Living guidelines are developed for selected topic areas with rapidly evolving evidence that drives frequent change in recommended clinical practice. Living guidelines are updated on a regular schedule by a standing expert panel that systematically reviews the health literature on a continuous basis, as described in the ASCO Guidelines Methodology Manual . ASCO Living Guidelines follow the ASCO Conflict of Interest Policy Implementation for Clinical Practice Guidelines . Living Guidelines and updates are not intended to substitute for independent professional judgment of the treating provider and do not account for individual variation among patients. See Appendix 1 (online only) for disclaimers and other important information. Updates are published regularly and can be found at https://ascopubs.org/nsclc-da-living-guideline .

Purpose:To investigate the relationship of pembrolizumab pharmacokinetics (PK) and overall survival (OS) in patients with advanced melanoma and non–small cell lung cancer (NSCLC).Patients and Methods:PK dependencies in OS were evaluated across three pembrolizumab studies of either 200 mg or 2 to 10 mg/kg every 3 weeks (Q3W). Kaplan–Meier plots of OS, stratified by dose, exposure, and baseline clearance (CL0), were assessed per indication and study. A Cox proportional hazards model was implemented to explore imbalances of typical prognostic factors in high/low NSCLC CL0 subgroups.Results:A total of 1,453 subjects were included: 340 with pembrolizumab-treated melanoma, 804 with pembrolizumab-treated NSCLC, and 309 with docetaxel-treated NSCLC. OS was dose independent from 2 to 10 mg/kg for pembrolizumab-treated melanoma [HR = 0.98; 95% confidence interval (CI), 0.94–1.02] and NSCLC (HR = 0.98; 95% CI, 0.95–1.01); however, a strong CL0–OS association was identified for both cancer types (unadjusted melanoma HR = 2.56; 95% CI, 1.72–3.80 and NSCLC HR = 2.64; 95% CI, 1.94–3.57). Decreased OS in subjects with higher pembrolizumab CL0 paralleled disease severity markers associated with end-stage cancer anorexia-cachexia syndrome. Correction for baseline prognostic factors did not fully attenuate the CL0–OS association (multivariate-adjusted CL0 HR = 1.64; 95% CI, 1.06–2.52 for melanoma and HR = 1.88; 95% CI, 1.22–2.89 for NSCLC).Conclusions:These data support the lack of dose or exposure dependency in pembrolizumab OS for melanoma and NSCLC between 2 and 10 mg/kg. An association of pembrolizumab CL0 with OS potentially reflects catabolic activity as a marker of disease severity versus a direct PK-related impact of pembrolizumab on efficacy. Similar data from other trials suggest such patterns of exposure–response confounding may be a broader phenomenon generalizable to antineoplastic mAbs.See related commentary by Coss et al., p. 5787

Fig S1. Kaplan-Meier plots of overall survival, stratified by pembrolizumab dose, demonstrate similarity of efficacy across a 5-fold dose range (2 to 10 mg/kg Q3W) in A) advanced ipilimumab-refractory melanoma, KEYNOTE-002 (Cox HR 0.98; 95% CI 0.94-1.02) and B) advanced, previously-treated PD-L1 positive NSCLC, KEYNOTE-010 (Cox HR 0.98; 95%CI 0.95-1.01). Subjects with at least one available PK measurement were included. Fig S2. Overall pooled exposure-response patterns demonstrate trends incongruent with similarity in dose-response patterns across 2 to 10 mg/kg in A) advanced ipilimumab-refractory melanoma, KEYNOTE-002 and B) advanced, previously-treated PD-L1 positive NSCLC, KEYNOTE-010. Fig S3. Similarity in OS between respective within-dose exposure quartiles at 2 and 10 mg/kg shows E-R patterns from pooled data (Fig S2 above) to be misleading in A-B) advanced ipilimumab-refractory melanoma, KEYNOTE-002 and C-D) advanced, previously-treated PD-L1 positive NSCLC, KEYNOTE-010. Fig S4. Kaplan-Meier plots of OS by all CL0 quartiles in KEYNOTE-002 (melanoma; left) and KEYNOTE-010 (previously-treated NSCLC; right) using the complete case datasets. Fig S5. Kaplan-Meier plots of OS by baseline clearance (CL0) quartiles in advanced, previously-untreated NSCLC with PD-L1 expression at least 50 percent. Pembrolizumab administered at 200 mg Q3W (KEYNOTE-024; n=152). Subjects with at least one available PK measurement were included. Fig S6. Forest plot of Docetaxel-treated NSCLC Cox proportional hazards model-estimated overall survival hazard ratios (n=249). Complete case dataset was used. Supplementary Table S1. Source Profile of PK - Overall Survival Analysis Datasets (KEYNOTE-002 and -010) Used in Multivariate Cox Models. Supplementary Table S2. Demographics and Baseline Characteristics for Subjects with {greater than or equal to} 1 Pembrolizumab PK Measurement (KEYNOTE-010/-024 and -002). Supplementary Table S3. Comparison of Univariate HR Results using Baseline Clearance from Time-dependent PK Model Versus a Steady-state Clearance from a Static PK Model Shows the Choice of Exposure Interval is Not Expected to Impact Rank Order of Exposure Estimates and that a Modest, Time-dependent Change in Pembrolizumab Clearance Does Not Meaningfully Alter Interpretations Described in this Study. Supplementary Table S4. Protocol-specified Pharmacokinetic Sampling Strategy.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. We report 5-year efficacy and safety outcomes from the phase III KEYNOTE-407 study (ClinicalTrials.gov identifier: NCT02775435 ). Eligible patients with previously untreated, metastatic squamous non–small-cell lung cancer (NSCLC) were randomly assigned 1:1 to pembrolizumab 200 mg or placebo plus carboplatin and paclitaxel/nab-paclitaxel once every 3 weeks for four cycles, followed by pembrolizumab or placebo for up to 35 cycles. Primary end points were overall survival (OS) and progression-free survival (PFS) per RECIST version 1.1 by blinded independent central review (BICR). Five hundred fifty-nine patients were randomly assigned in the intention-to-treat population (pembrolizumab plus chemotherapy, n = 278; placebo plus chemotherapy, n = 281). The median time from random assignment to data cutoff was 56.9 (range, 49.9-66.2) months. OS and PFS were improved with pembrolizumab plus chemotherapy versus placebo plus chemotherapy (hazard ratio [95% CI], 0.71 [0.59 to 0.85] and 0.62 [0.52 to 0.74]), with 5-year OS rates of 18.4% versus 9.7%, respectively. Toxicity was manageable. Among 55 patients who completed 35 cycles of pembrolizumab, the objective response rate was 90.9% and the 3-year OS rate after completion of 35 cycles (approximately 5 years after random assignment) was 69.5%. Pembrolizumab plus chemotherapy maintained an OS and PFS benefit versus placebo plus chemotherapy in previously untreated, metastatic squamous NSCLC and is a standard-of-care first-line treatment option for metastatic squamous NSCLC regardless of programmed death ligand 1 expression.

Objective To define the impact of first-line dual therapy involving immune checkpoint inhibitors (ICI) on survival outcomes in patients with advanced renal cell carcinoma (aRCC) of International Metastatic RCC Database Consortium favourable-risk. Materials and Methods Systematic review of Medline, EMBASE, and Cochrane Central Register of Controlled trials were conducted to select all phase II/III randomized clinical trials involving first-line, palliative-intent dual therapy in aRCC patients of favourable-risk. Inverse-variance with random-effects model was used for meta-analysis. Sensitivity analysis with exclusion of immune checkpoint inhibitors (ICI)-ICI combination was conducted. Study outcomes were overall survival (OS) and progression free survival (PFS). Results Seven phase II/III randomized controlled trials (N = 1214) were included in the meta-analysis. There were no significant OS differences detected in the favourable-risk group on dual therapy in comparison to sunitinib monotherapy (HR 0.96, 95%CI 0.73-1.26, P = .79). Sensitivity analysis also did not show significant OS benefit when excluding ICI-ICI regimen (HR 0.99, 95%CI 0.69-1.43, P = .96). PFS was not shown to have significant benefit for dual therapy in the favourable-risk group (HR 0.75, 95%CI 0.50-1.13, P = .17), but it met statistical significance when ICI-ICI regimen was excluded from the analysis (HR 0.63, 95%CI 0.50-0.79, P Conclusion There was no OS benefit when comparing dual therapy vs sunitinib monotherapy in aRCC favourable-risk group. Longer follow-up would be required to definitively detect potential OS benefit, if any. Careful patient-clinician discussion of alternative management options are required prior to initiating dual-therapy in all aRCC favourable-risk group.

For patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after an androgen receptor axis-targeted therapy and docetaxel, poly (ADP-ribose) polymerase (PARP) inhibitors and chemotherapy with cabazitaxel have shown promise. We address the trials for the two approaches and consider possible sequencing of these drugs. We suggest that only patients with a BRCA2 mutation should receive a PARP inhibitor, and docetaxel or cabazitaxel should be favored in the absence of BRCA2 alterations, provided the patient is naïve to these drugs.

PURPOSE We report the first 5-year follow-up of any first-line phase III immunotherapy trial for non–small-cell lung cancer (NSCLC). KEYNOTE-024 (ClinicalTrials.gov identifier: NCT02142738 ) is an open-label, randomized controlled trial of pembrolizumab compared with platinum-based chemotherapy in patients with previously untreated NSCLC with a programmed death ligand-1 (PD-L1) tumor proportion score of at least 50% and no sensitizing EGFR or ALK alterations. Previous analyses showed pembrolizumab significantly improved progression-free survival and overall survival (OS). METHODS Eligible patients were randomly assigned (1:1) to pembrolizumab (200 mg once every 3 weeks for up to 35 cycles) or platinum-based chemotherapy. Patients in the chemotherapy group with progressive disease could cross over to pembrolizumab. The primary end point was progression-free survival; OS was a secondary end point. RESULTS Three hundred five patients were randomly assigned: 154 to pembrolizumab and 151 to chemotherapy. Median (range) time from randomization to data cutoff (June 1, 2020) was 59.9 (55.1-68.4) months. Among patients initially assigned to chemotherapy, 99 received subsequent anti–PD-1 or PD-L1 therapy, representing a 66.0% effective crossover rate. Median OS was 26.3 months (95% CI, 18.3 to 40.4) for pembrolizumab and 13.4 months (9.4-18.3) for chemotherapy (hazard ratio, 0.62; 95% CI, 0.48 to 0.81). Kaplan-Meier estimates of the 5-year OS rate were 31.9% for the pembrolizumab group and 16.3% for the chemotherapy group. Thirty-nine patients received 35 cycles (ie, approximately 2 years) of pembrolizumab, 82.1% of whom were still alive at data cutoff (approximately 5 years). Toxicity did not increase with longer treatment exposure. CONCLUSION Pembrolizumab provides a durable, clinically meaningful long-term OS benefit versus chemotherapy as first-line therapy for metastatic NSCLC with PD-L1 tumor proportion score of at least 50%.

Living guidelines are routinely updated guidelines that are developed for selected topic areas with rapidly evolving evidence that drives frequent change in clinical practice. These guidelines are updated on a regular schedule, based on the work of a standing panel that reviews the literature on a continuous basis. Updates will be made regularly and can be found at https://ascopubs.org/nsclc-da-living-guideline . PURPOSE To provide evidence-based recommendations updating the 2021 ASCO and Ontario Health (Cancer Care Ontario) guideline on systemic therapy for patients with stage IV non–small-cell lung cancer (NSCLC) with driver alterations. METHODS ASCO updated recommendations on the basis of an ongoing systematic review of randomized control trials from 2020 to 2021. RESULTS This guideline update reflects changes in evidence since the previous update. Two studies provide the evidence base. Outcomes of interest include efficacy and safety. RECOMMENDATIONS For patients with an anaplastic lymphoma kinase rearrangement, a performance status (PS) of 0-2, and previously untreated NSCLC, clinicians should offer alectinib or brigatinib or lorlatinib. For patients with an anaplastic lymphoma kinase rearrangement, a PS of 0-2, and previously untreated NSCLC, if alectinib, brigatinib, or lorlatinib are not available, clinicians should offer ceritinib or crizotinib. For patients with a RET rearrangement, a PS of 0-2, and previously untreated NSCLC, clinicians may offer selpercatinib or pralsetinib. In second line, for patients with a RET rearrangement who have not received RET-targeted therapy, clinicians may offer selpercatinib or pralsetinib. Additional information is available at www.asco.org/thoracic-cancer-guidelines .

PURPOSE Testicular cancer survivors may experience mental illness as a consequence of their cancer diagnosis and treatment. METHODS All incident cases of testicular cancer treated with orchiectomy in Ontario, Canada (2000-2010), were identified using the Ontario Cancer Registry. Cases were matched to controls in a 1:5 ratio on age and geography. Population-level databases were used to identify mental health service use episodes; outpatient use included visits to a general practitioner for a mental health concern or any visit to a psychiatrist. Negative binomial regression modeling was used to estimate the rate of mental health service use in the pretreatment (2 years prior until 1 month before orchiectomy), peritreatment (1 month before until 1 month after orchiectomy), and post-treatment periods (1 month after orchiectomy until end of follow-up). Rate ratios (RR) comparing cases with controls in the peri- and post-treatment periods were adjusted for baseline mental health service use. RESULTS Two thousand six hundred nineteen cases of testicular cancer were matched to 13,095 controls. There was no baseline difference in the rate of mental health service use. Cases were significantly more likely than controls to have an outpatient visit for a mental health concern in the peritreatment (adjusted RR [aRR], 2.45; 95% CI, 2.06 to 2.92) and post-treatment periods (aRR, 1.30; 95% CI, 1.12 to 1.52). The difference in mental health service use persisted over a median follow-up of 12 years. In the postorchiectomy period, cases with baseline mental health service use were those most likely to use mental health services (aRR, 5.64; 95% CI, 4.64 to 6.85). CONCLUSION Testicular cancer survivors use mental health services more often than healthy controls. Survivorship care plans that address the long-term mental healthcare needs of this population are needed.

Background Fibroblast growth factor receptor 3 (FGFR3) mutations have been implicated in urothelial tumorigenesis. FGFR3 inhibitors are being explored in clinical trials. Objective We aimed to study the association between FGFR3 mutations and survival in urothelial carcinoma. Design, setting, and participants We performed a systematic literature search of PubMed, Cochrane, Ovid, and Web of Science from January 1985 to October 2018. The search terms were as follows: targeted therapies, FGFR and its subtypes, urothelial, bladder, and cancer. We included case-control or cohort studies of FGFR3 mutations in urothelial carcinoma. We included studies reporting hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes comparing FGFR3 mutations with FGFR3 wild type. Two reviewers performed article selection. Outcome measurements and statistical analysis We assessed heterogeneity among study-specific HRs using I2 statistic. We used a random effect model to obtain HR and 95% CI for event-free survival (EFS), composed of recurrence-free and progression-free survival. Statistical tests were two sided. Results and limitations Eleven studies (seven retrospective and four prospective) comprising 2162 patients were included. Analysis was performed for two groups. The first group included 1651 patients with non–muscle-invasive (NMI) urothelial carcinomas (886 [53.6%] had FGFR3 mutations). Compared with FGFR3 wild type, FGFR3 mutation did not influence EFS (HR = 0.99, CI = 0.77–1.28, p = 0.96). There was no significant heterogeneity (I2 = 25%). The second group included 511 patients with NMI and muscle-invasive (MI) urothelial carcinomas (151 [30%] had FGFR3 mutations). FGFR3 mutation was not prognostic (HR = 1.54, CI = 0.41–5.81, p = 0.52). There was heterogeneity (I2 = 91%). Conclusions There is no association between FGFR3 mutation and EFS in NMI urothelial carcinoma, and in NMI and MI urothelial carcinoma groups. Patient summary Fibroblast growth factor receptor 3 (FGFR3) mutation is not associated with a worse survival outcome in urothelial carcinoma. This is important as FGFR inhibitors are emerging as a new treatment option., Take Home Message Fibroblast growth factor receptor 3 (FGFR3) mutation is not associated with a worse survival outcome in urothelial carcinoma. This is relevant as clinical trials are being conducted to assess the response of FGFR inhibitors in urothelial carcinoma.

Introduction While no direct comparative data exist for crizotinib in ROS1+ non-small cell lung cancer (NSCLC), studies have suggested clinical benefit with this targeted agent. The objective of this study was to assess the cost-effectiveness of crizotinib compared to standard platinum-doublet chemotherapy for first-line treatment of ROS1+ advanced NSCLC. Methods A Markov model was developed with a 10-year time horizon from the perspective of the Canadian publicly-funded health care system. Health states included progression-free survival (PFS), up to two further lines of therapy post-progression, palliation and death. Given a lack of comparative data and small study samples, crizotinib or chemotherapy studies with advanced ROS1+ NSCLC patients were identified and time-to-event data from digitized Kaplan-Meier curves were collected to pool PFS data. Costs of drugs, treatment administration, monitoring, adverse events and palliative care were included in 2018 Canadian dollars, with 1.5% discounting. An incremental cost-effectiveness ratio (ICER) was estimated probabilistically using 5000 simulations. Results In the base-case probabilistic analysis, crizotinib produced additional 0.885 life-years and 0.772 quality-adjusted life-years (QALYs) at an incremental cost of $238,077, producing an ICER of $273,286/QALY gained. No simulations were found to be cost-effective at a willingness-to-pay threshold of $100,000/QALY gained. A scenario analysis assuming efficacy equivalent to the ALK+ NSCLC population showed a slightly more favorable cost-effectiveness profile for crizotinib. Conclusions Available data appear to support superior activity of crizotinib compared to chemotherapy in ROS1+ advanced NSCLC. At the list price, crizotinib was not cost-effective at commonly accepted willingness-to-pay thresholds across a wide range of sensitivity analyses.

PURPOSE The National Cancer Grid (NCG) of India has recently published clinical practice guidelines that are relevant in the Indian context. We evaluated the extent to which breast cancer care at a teaching hospital in South India was concordant with NCG guidelines. METHODS All patients who had surgery for breast cancer at a single center from January 2014 to December 2015 were included. Demographic, pathologic, and treatment characteristics were extracted from the electronic medical record. Patients were classified as being concordant with six elements selected from the NCG guideline. The indicators related to appropriate use of sentinel lymph node (SLN) biopsy, lymph node harvest, adjuvant radiotherapy, adjuvant chemotherapy, human epidermal growth factor receptor 2 (HER2) testing, and delivery of adjuvant trastuzumab. RESULTS A total of 401 women underwent surgery for breast cancer; mean age (standard deviation) was 57 (12) years. Lymph node involvement was present in 47% (188 of 401) of the cohort; 23% (94 of 401) had T1 disease. Ninety-two percent (368 of 401) underwent radical modified mastectomy. SLN biopsy was performed in 75% (167 of 222) of eligible patients. Eighty percent (208 of 261) of patients with a positive SLN biopsy or no SLN biopsy had a lymph node harvest of more than 10. Adjuvant chemotherapy with an anthracycline and a taxane was delivered to 67% of patients (118 of 177) with node-positive disease. Adjuvant radiotherapy was delivered to 84% (180 of 213) of patients with breast-conserving surgery, T4 tumors, or 3+ positive lymph nodes. Fluorescent in situ hybridization testing was performed in 59% of patients (43 of 73) with 2+ HER2-positive lymph nodes on immunohistochemistry. Among patients with HER2 overexpression, 40% (36 of 91) received adjuvant trastuzumab. CONCLUSION Concordance with NCG guidelines for breast cancer care ranged from 40% to 84%. Guideline concordance was lowest for those elements of care associated with the highest direct costs to patients.

Chemoradiation with curative intent is considered the standard of care in patients with locally advanced, stage iii non-small-cell lung cancer (nsclc). However, some patients with stage iii (N2 or N3, excluding T4) nsclc might be eligible for surgery. The objective of the present systematic review was to investigate the efficacy of surgery after chemoradiotherapy compared with chemoradiotherapy alone in patients with potentially resectable locally advanced nsclc. A search of the medline, embase, and PubMed databases sought randomized controlled trials (rcts) comparing surgery after chemoradiotherapy with chemoradiotherapy alone in patients with stage iii (N2 or N3, excluding T4) nsclc. Three included rcts consistently found no statistically significant difference in overall survival between patients with locally advanced nsclc who received surgery and chemoradiotherapy or chemoradiotherapy alone. Only one rct found that progression-free survival was significantly longer in patients treated with chemoradiation and surgery (hazard ratio: 0.77, 95% confidence interval: 0.62 to 0.96). In a post hoc analysis of the same trial, the overall survival rate was higher in the surgical group than in matched patients in a chemoradiation-only group if a lobectomy was performed (p = 0.002), but not if a pneumonectomy was performed. Furthermore, fewer treatment-related deaths occurred in patients who underwent lobectomy than in those who underwent pneumonectomy. For patients with locally advanced nsclc, the benefits of surgery after chemoradiation are uncertain. Surgery after chemoradiation for patients who do not require a pneumonectomy might be an option.

Introduction: Imaging is an integral component of active surveillance following orchiectomy for stage 1 non-seminoma (NSGCT) and seminoma germ cell tumors. In this population-based study, we describe use of imaging among patients with early-stage testicular cancer and evaluate whether they are concordant with guideline recommendations. Methods: This is a population-based, retrospective cohort study to describe utilization of imaging among all patients with early-stage testicular cancer treated with active surveillance in the Canadian province of Ontario. The Ontario Cancer Registry was linked to electronic records of treatment to identify use of chest and abdomen/pelvis imaging. Data from 2000–-2010 were included with followup for up to five years for patients with non-seminoma and 10 years for patients with seminoma. The key outcome of interest was the frequency of imaging at temporal milestones following orchiectomy. Compared to the most contemporaneous guidelines in Ontario, any discordant frequency of imaging was defined as underutilization or overutilization. Substantial under- or overutilization was defined as >1 imaging test less/more than what was recommended during a 12-month period. Results: The study population included 569 patients with NSGCT (median age 28) and 1107 with seminoma (median age 37). Among patients with NSGCT, adherence with body imaging was low in years 1–3 of surveillance (range 26–37%, predominantly underuse) and higher in years 4–5 (63–67%, predominantly overuse). Adherence with chest imaging was even lower (range 11–34% during years 1–5). Among patients with seminoma, adherence with abdominal and chest imaging was relatively stable and comparable throughout the 10-year followup period (range 23–47% abdomen and 28–47% chest). Multivariable analysis confirmed that underutilization of imaging was more common in recent years. NSGCT histology was associated with underutilization in years 1–2 but overutilization in years 3–5. Conclusions: In routine clinical practice, patients with testicular cancer commonly receive imaging discordant to the protocol for active surveillance, with a substantial proportion receiving both under- and overutilization at various times during surveillance followup.

PURPOSE To provide evidence-based recommendations updating the 2017 ASCO guideline on systemic therapy for patients with stage IV non–small-cell lung cancer (NSCLC) with driver alterations. A guideline update for systemic therapy for patients with stage IV NSCLC without driver alterations was published separately. METHODS The American Society of Clinical Oncology and Ontario Health (Cancer Care Ontario) NSCLC Expert Panel updated recommendations based on a systematic review of randomized controlled trials (RCTs) from December 2015 to January 2020 and meeting abstracts from ASCO 2020. RESULTS This guideline update reflects changes in evidence since the previous update. Twenty-seven RCTs, 26 observational studies, and one meta-analysis provide the evidence base (total 54). Outcomes of interest included efficacy and safety. Additional literature suggested by the Expert Panel is discussed. RECOMMENDATIONS All patients with nonsquamous NSCLC should have the results of testing for potentially targetable mutations (alterations) before implementing therapy for advanced lung cancer, regardless of smoking status recommendations, when possible, following other existing high-quality testing guidelines. Most patients should receive targeted therapy for these alterations: Targeted therapies against ROS-1 fusions, BRAF V600e mutations, RET fusions, MET exon 14 skipping mutations, and NTRK fusions should be offered to patients, either as initial or second-line therapy when not given in the first-line setting. New or revised recommendations include the following: Osimertinib is the optimal first-line treatment for patients with activating epidermal growth factor receptor mutations (exon 19 deletion, exon 21 L858R, and exon 20 T790M); alectinib or brigatinib is the optimal first-line treatment for patients with anaplastic lymphoma kinase fusions. For the first time, to our knowledge, the guideline includes recommendations regarding RET, MET, and NTRK alterations. Chemotherapy is still an option at most stages. Additional information is available at www.asco.org/thoracic-cancer-guidelines .

Purpose Despite triple antiemetic therapy use for breast cancer patients receiving emetogenic chemotherapy, nausea remains a clinical challenge. We evaluated adding olanzapine (5 mg) to triple therapy on nausea control in patients at high personal risk of chemotherapy-induced nausea and vomiting (CINV). Methods This multi-centre, placebo-controlled, double-blind trial randomized breast cancer patients scheduled to receive neo/adjuvant chemotherapy with anthracycline-cyclophosphamide or platinum-based chemotherapy to olanzapine (5 mg, days 1–4) or placebo. Primary endpoint was frequency of self-reported significant nausea, repeated for all cycles of chemotherapy. Secondary endpoints included: duration of nausea, overall total control of CINV, Health Related Quality of Life (HRQoL) using FLIE questionnaire, use of rescue mediation and treatment-related adverse events. Results 218 eligible patients were randomised to placebo (105) or olanzapine (113). From days 0–5 following each cycle of chemotherapy, 41.3% (95%CI: 36.1–46.7%) of patients in the placebo group reported significant nausea compared to 27.7% (95%CI: 23.2–32.4%) in the olanzapine group (p = 0.001). Across all cycles of chemotherapy, patients receiving olanzapine experienced a statistically significant improvement in HRQoL (p, Highlights • Double-blind trial evaluated the addition of olanzapine to triple therapy in patients at high personal risk of CINV. • Adding 5 mg olanzapine was associated with significantly improved nausea control with no unexpected toxicities. • Olanzapine plus triple therapy should be considered standard of care for breast cancer patients at high risk of CINV.

Early published data on COVID-19 in patients with cancer are being referenced in clinical guidelines, despite methodological flaws that limit the quality of much of this evidence. In the next phase of research in this area, we argue that the quality of observational evidence should be prioritized over speed of publication.

Introduction In the randomized KEYNOTE-407 study ( ClinicalTrials.gov , NCT02775435 ), pembrolizumab plus carboplatin and paclitaxel/nab-paclitaxel (chemotherapy) significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo plus chemotherapy in patients with previously untreated metastatic squamous NSCLC. We report updated efficacy outcomes from the protocol-specified final analysis and, for the first time, progression on next line of treatment. Methods Eligible patients were randomized to chemotherapy plus either pembrolizumab (n = 278) or placebo (n = 281). After positive results from the second interim analysis, patients still receiving placebo could cross over to pembrolizumab monotherapy at the time of confirmed progressive disease. The primary end points were OS and PFS. PFS-2 (time from randomization to progression on next-line treatment/death, whichever occurred first) was an exploratory end point. Results After median (range) follow-up of 14.3 (0.1–31.3) months, pembrolizumab plus chemotherapy continued to exhibit a clinically meaningful improvement over placebo plus chemotherapy in OS (median, 17.1 mo [95% confidence interval (CI): 14.4‒19.9] versus 11.6 mo [95% CI: 10.1‒13.7]; hazard ratio [HR], 0.71 [95% CI: 0.58‒0.88]) and PFS (median, 8.0 mo [95% CI: 6.3‒8.4] versus 5.1 mo [95% CI: 4.3‒6.0]; HR, 0.57 [95% CI: 0.47‒0.69]). PFS-2 was longer for patients randomized to first-line pembrolizumab plus chemotherapy (HR, 0.59 [95% CI: 0.49‒0.72]). Grade 3 to 5 adverse events occurred in 74.1% and 69.6% of patients receiving pembrolizumab plus chemotherapy and placebo plus chemotherapy, respectively. Conclusions Pembrolizumab plus chemotherapy continued to exhibit substantially improved OS and PFS in patients with metastatic squamous NSCLC. The PFS-2 outcomes support pembrolizumab plus chemotherapy as a standard first-line treatment in patients with metastatic squamous NSCLC.

PURPOSE The aim of this work is to provide evidence-based recommendations updating the 2017 ASCO guideline on systemic therapy for patients with stage IV non–small-cell lung cancer (NSCLC) without driver alterations. A guideline update for patients with stage IV NSCLC with driver alterations will be published separately. METHODS The American Society of Clinical Oncology and Ontario Health (Cancer Care Ontario) NSCLC Expert Panel made updated recommendations based on a systematic review of randomized controlled trials from December 2015 to 2019. RESULTS This guideline update reflects changes in evidence since the previous guideline update. Five randomized controlled trials provide the evidence base. Additional literature suggested by the Expert Panel is discussed. RECOMMENDATIONS Recommendations apply to patients without driver alterations in epidermal growth factor receptor or ALK. For patients with high programmed death ligand 1 (PD-L1) expression (tumor proportion score [TPS] ≥ 50%) and non–squamous cell carcinoma (non-SCC), the Expert Panel recommends single-agent pembrolizumab. Additional treatment options include pembrolizumab/carboplatin/pemetrexed, atezolizumab/carboplatin/paclitaxel/bevacizumab, or atezolizumab/carboplatin/nab-paclitaxel. For most patients with non-SCC and either negative (0%) or low positive (1% to 49%) PD-L1, the Expert Panel recommends pembrolizumab/carboplatin/pemetrexed. Additional options are atezolizumab/carboplatin/nab-paclitaxel, atezolizumab/carboplatin/paclitaxel/bevacizumab, platinum-based two-drug combination chemotherapy, or non–platinum-based two-drug therapy. Single-agent pembrolizumab is an option for low positive PD-L1. For patients with high PD-L1 expression (TPS ≥ 50%) and SCC, the Expert Panel recommends single-agent pembrolizumab. An additional treatment option is pembrolizumab/carboplatin/(paclitaxel or nab-paclitaxel). For most patients with SCC and either negative (0%) or low positive PD-L1 (TPS 1% to 49%), the Expert Panel recommends pembrolizumab/carboplatin/(paclitaxel or nab-paclitaxel) or chemotherapy. Single-agent pembrolizumab is an option in select cases of low positive PD-L1. Recommendations are conditional on the basis of histology, PD-L1 status, and/or the presence or absence of contraindications. Additional information is available at www.asco.org/lung-cancer-guidelines .

Purpose: To investigate the relationship of pembrolizumab pharmacokinetics (PK) and overall survival (OS) in patients with advanced melanoma and non–small cell lung cancer (NSCLC). Patients and Methods: PK dependencies in OS were evaluated across three pembrolizumab studies of either 200 mg or 2 to 10 mg/kg every 3 weeks (Q3W). Kaplan–Meier plots of OS, stratified by dose, exposure, and baseline clearance (CL0), were assessed per indication and study. A Cox proportional hazards model was implemented to explore imbalances of typical prognostic factors in high/low NSCLC CL0 subgroups. Results: A total of 1,453 subjects were included: 340 with pembrolizumab-treated melanoma, 804 with pembrolizumab-treated NSCLC, and 309 with docetaxel-treated NSCLC. OS was dose independent from 2 to 10 mg/kg for pembrolizumab-treated melanoma [HR = 0.98; 95% confidence interval (CI), 0.94–1.02] and NSCLC (HR = 0.98; 95% CI, 0.95–1.01); however, a strong CL0–OS association was identified for both cancer types (unadjusted melanoma HR = 2.56; 95% CI, 1.72–3.80 and NSCLC HR = 2.64; 95% CI, 1.94–3.57). Decreased OS in subjects with higher pembrolizumab CL0 paralleled disease severity markers associated with end-stage cancer anorexia-cachexia syndrome. Correction for baseline prognostic factors did not fully attenuate the CL0–OS association (multivariate-adjusted CL0 HR = 1.64; 95% CI, 1.06–2.52 for melanoma and HR = 1.88; 95% CI, 1.22–2.89 for NSCLC). Conclusions: These data support the lack of dose or exposure dependency in pembrolizumab OS for melanoma and NSCLC between 2 and 10 mg/kg. An association of pembrolizumab CL0 with OS potentially reflects catabolic activity as a marker of disease severity versus a direct PK-related impact of pembrolizumab on efficacy. Similar data from other trials suggest such patterns of exposure–response confounding may be a broader phenomenon generalizable to antineoplastic mAbs. See related commentary by Coss et al., p. 5787

OBJECTIVES Surgical resection for locally advanced rectal adenocarcinoma commonly occurs 6 to 10 weeks after completion of neoadjuvant chemoradiation (nCRT). We sought to determine the optimal timing of surgery related to the pathologic complete response rate and survival endpoints. METHODS The study is a retrospective analysis of 92 patients treated with nCRT followed by surgery from 2004 to 2011 at our institution. Univariate and multivariate analyses were performed to assess the impact of timing of surgery on locoregional control, distant failure (DF), disease-free survival, and overall survival (OS). RESULTS Time-to-surgery was ≤8 weeks (group A) in 72% (median 6.1 wk) and >8 weeks (group B) in 28% (median 8.9 wk) of patients. No significant differences in patient characteristics, locoregional control, or pathologic complete response rates were noted between the groups. Univariate analysis revealed that group B had significantly shorter time to DF (group B, median 33 mo; group A, median not reached, P=0.047) and shorter OS compared with group A (group B, median 52 mo; group A, median not reached, P=0.03). Multivariate analysis revealed that increased time-to-surgery showed a significant increase in DF (HR=2.96, P=0.02) and trends toward worse OS (HR=2.81, P=0.108) and disease-free survival (HR=2.08, P=0.098). CONCLUSIONS We found that delaying surgical resection longer than 8 weeks after nCRT was associated with an increased risk of DF. This study, in combination with a recent larger study, questions the recent trend in promoting surgical delay beyond the traditional 6 to 10 weeks. Larger, prospective databases or randomized studies may better clarify surgical timing following nCRT in rectal adenocarcinoma.

ObjectiveTo evaluate the effectiveness of remote proactive management of toxicities during chemotherapy for early stage breast cancer.DesignPragmatic, cluster randomised trial.Setting20 cancer centres in Ontario, Canada, allocated by covariate constrained randomisation to remote management of toxicities or routine care.ParticipantsAll patients starting adjuvant or neoadjuvant chemotherapy for early stage breast cancer at each centre. 25 patients from each centre completed patient reported outcome questionnaires.InterventionsProactive, standardised, nurse led telephone management of common toxicities at two time points after each chemotherapy cycle.Main outcome measuresThe primary outcome, cluster level mean number of visits to the emergency department or admissions to hospital per patient during the whole course of chemotherapy treatment, was evaluated with routinely available administrative healthcare data. Secondary patient reported outcomes included toxicity, self-efficacy, and quality of life.ResultsBaseline characteristics of participants were similar in the intervention (n=944) and control arms (n=1214); 22% were older than 65 years. Penetration (that is, the percentage of patients who received the intervention at each centre) was 50-86%. Mean number of visits to the emergency department or admissions to hospital per patient was 0.91 (standard deviation 0.28) in the intervention arm and 0.94 (0.40) in the control arm (P=0.94); 47% (1014 of 2158 patients) had at least one visit to the emergency department or a hospital admission during chemotherapy. Among 580 participants who completed the patient reported outcome questionnaires, at least one grade 3 toxicity was reported by 48% (134 of 278 patients) in the intervention arm and by 58% (163 of 283) in the control arm. No differences in self-efficacy, anxiety, or depression were found. Compared with baseline, the functional assessment of cancer therapy trial outcome index decreased by 6.1 and 9.0 points in the intervention and control participants, respectively.ConclusionsProactive, telephone based management of toxicities during chemotherapy did not result in fewer visits to the emergency department or hospital admissions. With the rapid rise in remote care because of the covid-19 pandemic, identifying scalable strategies for remote management of patients during cancer treatment is particularly relevant.Trial registrationClinicalTrials.govNCT02485678.

Background Progression-free survival (PFS) is often used as a clinical trials outcome for evaluating new therapies for solid tumors. While PFS is a validated surrogate for overall survival (OS) or quality of life (QOL) in some settings, it is increasingly used in contexts where surrogacy is not established. PFS is a composite endpoint of survival, symptomatic progression, and imaging-only progression. The intrinsic value of asymptomatic (imaging-only) progression from the patient perspective is not known. Methods Patients with advanced metastatic cancer (lung, colorectal, or ovarian) participated in a discrete choice experiment, with a structured treatment choice trade-off exercise. The interview guide and visual aids were developed by a multidisciplinary team including patient representatives. Participants were provided with a hypothetical clinical scenario and treatment options resulting in the same OS duration. A sliding scale was used for duration of delay in imaging progression to determine each patient’s willingness to trade longer time for a given level of toxicity. Results 20 (11 M, 9 F) patients participated. 85 % (n = 17) of patients chose treatment with less toxicity and shorter duration even if associated with a shorter time to worsening imaging. Two patients chose a trade-off for a more toxic treatment with an increase in imaging PFS by 18 months and 24 months respectively. One patient chose to always opt for most aggressive treatment irrespective of PFS benefit and toxicity. Conclusions Most patients with metastatic cancer currently being treated with palliative chemotherapy considered delayed imaging progression in the absence of OS gain to be of low value. Policy statement PFS should not be assumed to have intrinsic value to patients in the absence of surrogacy for OS or QOL when making drug treatment and policy decisions.

Introduction We retrospectively evaluated outcomes in patients with programmed death-ligand 1 (PD-L1)–positive non–small-cell lung cancer (NSCLC) to determine whether baseline (i.e., at study enrollment) brain metastases were associated with the efficacy of pembrolizumab versus chemotherapy. Methods We pooled data for patients with previously treated or untreated PD-L1‒positive (tumor proportion score [TPS], ≥1%) advanced or metastatic NSCLC in KEYNOTE-001 (NCT01295827), KEYNOTE-010 (NCT01905657), KEYNOTE-024 (NCT02142738), and KEYNOTE-042 (NCT02220894). Patients received pembrolizumab (2 mg/kg, 10 mg/kg, or 200 mg every 3 wk or 10 mg/kg every 2 wk); chemotherapy was a comparator in all studies except KEYNOTE-001. All studies included patients with previously treated, stable brain metastases. Results A total of 3170 patients were included, 293 (9.2%) with and 2877 (90.8%) without baseline brain metastases; median (range) follow-up at data cutoff was 12.9 (0.1‒43.7) months. Pembrolizumab improved overall survival versus chemotherapy in patients with or without baseline brain metastases: benefit was seen in patients with PD-L1 TPS ≥50% (0.67 [95% confidence intervals (CI): 0.44‒1.02] and 0.66 [95% CI: 0.58‒0.76], respectively) and PD-L1 TPS ≥1% (0.83 [95% CI: 0.62‒1.10] and 0.78 [95% CI: 0.71‒0.85], respectively). Progression-free survival was improved, objective response rates were higher, and duration of response was longer with pembrolizumab versus chemotherapy regardless of brain metastasis status. The incidence of treatment-related adverse events with pembrolizumab versus chemotherapy was 66.3% versus 84.4% in patients with brain metastases and 67.2% versus 88.3% in those without. Conclusions Pembrolizumab monotherapy improved outcomes and was associated with fewer adverse events than chemotherapy in patients with treatment-naive and previously treated PD-L1‒positive advanced/metastatic NSCLC regardless of the presence of baseline treated, stable brain metastases.

The benefit of adjuvant chemotherapy in patients with locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiotherapy (nCRT) and surgery is controversial. We examined the association of perineural invasion (PNI) with outcomes to determine whether PNI could be used to risk-stratify patients. We performed a retrospective study of 110 patients treated with nCRT and surgery for LARC at our institution from 2004 to 2011. Eighty-seven patients were identified in our final analysis. We evaluated the association of PNI with locoregional control, distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival, using log-rank and Cox proportional hazard modeling. Fourteen patients (16%) were PNI+ and 73 patients (84%) were PNI−. The median follow-up was 27 months (range, 0.9 to 84 mo). The median DMFS was 13.5 months for PNI+ and median not reached (>40 mo) for PNI− (P

Summary Background In the phase 3 KEYNOTE-024 trial, treatment with pembrolizumab conferred longer progression-free survival than did platinum-based therapy in patients with treatment-naive, advanced non-small-cell lung cancer (NSCLC) with a programmed cell death-ligand 1 (PD-L1) tumour proportion score of 50% or greater (PD-L1-positive). Here we report the prespecified exploratory endpoint of pembrolizumab versus chemotherapy on patient-reported outcomes (PROs). Methods In this multicentre, international, randomised, open-label, phase 3 trial, we recruited patients with treatment-naive, stage IV NSCLC in 102 sites in 16 countries. Eligible patients had measurable disease (per RECIST version 1.1) and an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Patients were randomly assigned (1:1) via an interactive voice response system and integrated web response system to receive either pembrolizumab 200 mg every 3 weeks (35 cycles) or investigator-choice platinum-doublet chemotherapy (4–6 cycles or until documented disease progression or unacceptable toxicity). Randomisation was stratified according to geography, ECOG performance status, and histology. PROs were assessed at day 1 of cycles 1–3, every 9 weeks thereafter, at the treatment discontinuation visit, and at the 30-day safety assessment visit using the European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 items (QLQ-C30), the EORTC Quality of Life Questionnaire Lung Cancer 13 items (QLQ-LC13), and the European Quality of Life 5 Dimensions-3 Level (EQ-5D-3L) questionnaire. The key exploratory PRO endpoints (analysed for all patients who received at least one dose of study treatment and completed at least one PRO instrument at at least one timepoint) were baseline-to-week-15 change in the QLQ-C30 global health status (GHS)/quality-of-life (QOL) score and time to deterioration of the composite of cough, chest pain, and dyspnoea in the QLQ-LC13. This study is registered with ClinicalTrials.gov, number NCT02142738, and is ongoing but no longer enrolling patients. Findings Between Sept 19, 2014, and Oct 29, 2015, 305 patients were randomly assigned to pembrolizumab (n=154) or chemotherapy (n=151). Three patients in each group did not complete any PRO instruments at any timepoints, and so 299 patients were included in the full analysis set. Of these patients, one in each group did not complete any PRO instruments before week 15, and so were not included in analyses of change from baseline to week 15. PRO compliance was greater than 90% at baseline and approximately 80% at week 15 for both groups. Least-squares mean baseline-to-week-15 change in QLQ-C30 GHS/QOL score was 6·9 (95% CI 3·3 to 10·6) for pembrolizumab and −0·9 (−4·8 to 3·0) for chemotherapy, for a difference of 7·8 (2·9 to 12·8; two-sided nominal p=0·0020). Fewer pembrolizumab-treated patients had deterioration in the QLQ-LC13 composite endpoint than did chemotherapy-treated patients (46 [31%] of 151 patients vs 58 [39%] of 148 patients). Time to deterioration was longer with pembrolizumab than with chemotherapy (median not reached [95% CI 8·5 to not reached] vs 5·0 months [3·6 to not reached]; hazard ratio 0·66, 95% CI 0·44–0·97; two-sided nominal p=0·029). Interpretation Pembrolizumab improves or maintains health-related QOL compared with that for chemotherapy, and might represent a new first-line standard of care for PD-L1-expressing, advanced NSCLC. Funding Merck & Co.

Palliative chemotherapy for advanced bladder cancer is recommended in clinical practice guidelines because of the results achieved in clinical trials. However, real-world treatment and outcomes have not been well described. We report the treatment delivery and survival associated with palliative chemotherapy in routine clinical practice.The population-based Ontario Cancer Registry was linked to electronic records of treatment to identify all patients with bladder cancer treated with palliative chemotherapy in Ontario during 1994 to 2008. Treatment regimens were identified for those cases treated at regional cancer centers. Overall survival (OS) and cancer-specific survival (CSS) were determined from the start of palliative chemotherapy. A Cox proportional hazards model was used to identify the factors associated with OS and CSS.The palliative chemotherapy regimen was identified for 710 patients with bladder cancer in Ontario during 1994 to 2008. Gemcitabine-cisplatin (Gem-Cis) was delivered to 37% (261 of 710), gemcitabine-carboplatin (Gem-Carbo) to 14% (96 of 710), and MVAC (methotrexate, vinblastine, Adriamycin, and cisplatin) to 8% (56 of 710). Other regimens were delivered to 42% of cases. The proportion of cases treated with Gem-Cis increased during the study period: 3% in 1994 to 1999, 32% in 2000 to 2003, and 52% in 2004 to 2008 (P .001). The median survival and 5-year OS by regimen was 10 months and 16% for Gem-Cis, 7 months and 6% for Gem-Carbo, and 10 months and 13% for MVAC, respectively. Multivariate analysis controlling for age and comorbidity demonstrated improved survival for Gem-Cis and MVAC compared with Gem-Carbo (hazard ratio, 1.53; 95% confidence interval, 1.19-1.98).The median survival associated with palliative chemotherapy for bladder cancer in routine practice is slightly inferior to the outcomes reported in clinical trials. However, consistent with the clinical trial results, a proportion of patients treated with palliative chemotherapy will achieve long-term survival. Gem-Carbo is associated with inferior survival compared with Gem-Cis and MVAC in routine practice.

Aims Venous thromboembolism (VTE) is a potential complication among germ cell tumour patients. We evaluated the incidence rate, timing and factors associated with VTE among patients with germ cell cancer in routine practice. Materials and methods The Ontario Cancer Registry was linked to electronic records of treatment to identify all cases of testicular cancer treated in Ontario during 2000–2010. Administrative databases were used to identify VTE in the 3 months before and 5 years after orchiectomy. We explored patient-, disease- and treatment-related factors associated with VTE among all patients as well as those with detailed chemotherapy records available. Results During 2000–2010, 2650 patients underwent orchiectomy for testicular cancer; among this cohort, 920 (33%) received chemotherapy. The VTE rate was 8% (69/920) among patients treated with chemotherapy and 0.6% (11/1730) among those without chemotherapy. Among the patients treated with chemotherapy who had VTE, 13% (9/69) occurred in the month before starting chemotherapy, 62% (42/69) in the first 3 months after starting and 25% thereafter. For patients who received three and four cycles, VTE rates were 8% (21/258) and 16% (19/121), respectively. In adjusted analyses, the only factor independently associated with VTE was increasing number of cycles (odds ratio 3.91 for four cycles, odds ratio 1.63 for three cycles (P = 0.022) compared with one to two cycles). Conclusion This population-based study confirms findings from institutional case series regarding the high rate of VTE among patients with germ cell tumours treated with chemotherapy. Future studies should evaluate the extent to which VTE prophylactic strategies might mitigate this risk.

Cancer is a genetic disease resulting from germline or somatic genetic aberrations. Rapid progress in the field of genomics in recent years is allowing for increased characterization and understanding of the various forms of the disease. The Ontario-wide Cancer Targeted Nucleic Acid Evaluation (octane) clinical trial, open at cancer centres across Ontario, aims to increase access to genomic sequencing of tumours and to facilitate the collection of clinical data related to enrolled patients and their clinical outcomes. The study is designed to assess the clinical utility of next-generation sequencing (ngs) in cancer patient care, including enhancement of treatment options available to patients. A core aim of the study is to encourage collaboration between cancer hospitals within Ontario while also increasing international collaboration in terms of sharing the newly generated data. The single-payer provincial health care system in Ontario provides a unique opportunity to develop a province-wide registry of ngs testing and a repository of genomically characterized, clinically annotated samples. It also provides an important opportunity to use province-wide real-world data to evaluate outcomes and the cost of ngs for patients with advanced cancer. The octane study is attempting to translate knowledge to help deliver precision oncology in a Canadian environment. In this article, we discuss the background to the study and its implementation, current status, and future directions.

Purpose In the randomized, open-label, phase III KEYNOTE-024 study, pembrolizumab significantly improved progression-free survival and overall survival (OS) compared with platinum-based chemotherapy in patients with previously untreated advanced non–small-cell lung cancer (NSCLC) with a programmed death ligand 1 tumor proportion score of 50% or greater and without EGFR/ALK aberrations. We report an updated OS and tolerability analysis, including analyses adjusting for potential bias introduced by crossover from chemotherapy to pembrolizumab. Patients and Methods Patients were randomly assigned to pembrolizumab 200 mg every 3 weeks (for up to 2 years) or investigator’s choice of platinum-based chemotherapy (four to six cycles). Patients assigned to chemotherapy could cross over to pembrolizumab upon meeting eligibility criteria. The primary end point was progression-free survival; OS was an important key secondary end point. Crossover adjustment analysis was done using the following three methods: simplified two-stage method, rank-preserving structural failure time, and inverse probability of censoring weighting. Results Three hundred five patients were randomly assigned (pembrolizumab, n = 154; chemotherapy, n = 151). At data cutoff (July 10, 2017; median follow-up, 25.2 months), 73 patients in the pembrolizumab arm and 96 in the chemotherapy arm had died. Median OS was 30.0 months (95% CI, 18.3 months to not reached) with pembrolizumab and 14.2 months (95% CI, 9.8 to 19.0 months) with chemotherapy (hazard ratio, 0.63; 95% CI, 0.47 to 0.86). Eighty-two patients assigned to chemotherapy crossed over on study to receive pembrolizumab. When adjusted for crossover using the two-stage method, the hazard ratio for OS for pembrolizumab versus chemotherapy was 0.49 (95% CI, 0.34 to 0.69); results using rank-preserving structural failure time and inverse probability of censoring weighting were similar. Treatment-related grade 3 to 5 adverse events were less frequent with pembrolizumab compared with chemotherapy (31.2% v 53.3%, respectively). Conclusion With prolonged follow-up, first-line pembrolizumab monotherapy continues to demonstrate an OS benefit over chemotherapy in patients with previously untreated, advanced NSCLC without EGFR/ALK aberrations, despite crossover from the control arm to pembrolizumab as subsequent therapy.

BackgroundPembrolizumab is a humanized monoclonal antibody against programmed death 1 (PD-1) that has antitumor activity in advanced non–small-cell lung cancer (NSCLC), with increased activity in tumors that express programmed death ligand 1 (PD-L1). MethodsIn this open-label, phase 3 trial, we randomly assigned 305 patients who had previously untreated advanced NSCLC with PD-L1 expression on at least 50% of tumor cells and no sensitizing mutation of the epidermal growth factor receptor gene or translocation of the anaplastic lymphoma kinase gene to receive either pembrolizumab (at a fixed dose of 200 mg every 3 weeks) or the investigator’s choice of platinum-based chemotherapy. Crossover from the chemotherapy group to the pembrolizumab group was permitted in the event of disease progression. The primary end point, progression-free survival, was assessed by means of blinded, independent, central radiologic review. Secondary end points were overall survival, objective response rate, and safety. ResultsMedi...

Background Palliative chemotherapy for advanced bladder cancer is recommended in clinical practice guidelines. Patterns of care in routine clinical practice have not been well described. This article describes use rates of chemotherapy and referral rates to medical oncology in the last year of life among patients who have died of bladder cancer. Methods A population-based cohort of patients with bladder cancer was identified from the Ontario Cancer Registry; the study population included patients who died of bladder cancer between 1995 and 2009. Electronic records of treatment and physician billing records were used to identify treatment patterns and referral to medical oncology. Log-binomial and modified Poisson regression were used to examine factors associated with chemotherapy use and medical oncology consultation. Results A total of 8,005 patients died of bladder cancer, 25% (n=1,964) of whom received chemotherapy in the last year of life. Use was independently associated with patient age, comorbidities, socioeconomic status, sex, time period, and treatment region. A total of 68% (n=5,426) of patients were seen by a medical oncologist. Referral to medical oncology was associated with age, comorbidities, year of death. Geographic variation was seen with chemotherapy use-from 18% to 30%-that persisted on adjusted analysis. Conclusions The efficacy of palliative chemotherapy demonstrated in clinical trials and recommended in guidelines has not translated into widespread use in practice. Understanding the extent to which patient preferences and health system factors influence use is needed. Access to acceptable palliative systemic treatments remains an unmet need for most patients dying of bladder cancer.

The development of a continuous process for the thermal Overman rearrangement of O-[(2R,3S)-2-(tert-butyldimethylsilyloxymethyl)-3,6-dihydro-2H-pyran-3-yl]-trichloro-ethanecarboximidate 3 to the corresponding trichloroacetamide 4 is described. Trichloroacetimidate 4 is an intermediate for an active pharmaceutical intermediate (API) under development at Actelion Pharmaceuticals Ltd. The instability of compounds 3 and 4 at temperatures above 100 °C prevented scale-up of the original batch mode procedure to the required multikilogram scale. This problem was solved by developing a flow chemistry process used for the successful production of 95 kg of 4.

Background: Anti-PD-(L)1-directed therapy following radiotherapy or following concurrent chemoradiation is associated with significantly longer PFS and OS in patients with advanced or metastatic NSCLC, including those with locally advanced inoperable tumors. KEYNOTE-867 (NCT03924869) evaluates the efficacy and safety of SBRT with or without pembrolizumab in patients with inoperable stage I/IIA NSCLC. Trial Design: In this phase 3, randomized, placebo-controlled study, approximately 530 adult patients with previously untreated, medically inoperable, histologically/cytologically confirmed stage I/IIA NSCLC are randomized 1:1 to receive thoracic SBRT to primary tumors for ≤2 wk (Table) and either pembrolizumab 200 mg or placebo every 3 wk for 17 cycles (approximately 1 year) or until disease recurrence, development of unacceptable AEs, SBRT not started for any reason, or study withdrawal. Randomization is stratified by disease stage (I/IIA), ECOG PS (0-1/2), and geographic region (East Asia/other). Imaging assessment by blinded independent central review (BICR) occurs at 12 wk (≥10 wk after SBRT completion), followed by every 16 wk for 3 y, and then every 6 mo. Primary endpoints are event-free survival (EFS) by BICR and OS. Secondary endpoints include time to death or distant metastases and safety; exploratory endpoints are time to subsequent treatment, disease-specific survival, and time to recurrence/progression on subsequent line of therapy. AEs are monitored throughout the trial until 30 d after last dose (90 for serious AEs) and graded according to NCI CTCAE version 4.0. EFS and OS are analyzed by the nonparametric Kaplan-Meier method, treatment differences by stratified log-rank test, and hazard ratios by stratified Cox proportional hazard model with Efron's method of tie handling. Enrollment started on June 17, 2019, at 131 sites. Table.Stereotactic Body Radiotherapy RegimenUnit Dose Strength(s)Peripheral tumors3×15 Gy or 3×18 Gy fractions (preferred regimens); 4×12 Gy or 5×10 Gy fractions (acceptable regimens)Tumors abutting the chest wall4×12 Gy fractions or 5×10 Gy fractionsCentral tumors5×10 Gy fractions Citation Format: Salma K. Jabbour, Baerin Houghton, Andrew G. Robinson, Xavier Quantin, Thomas Wehler, Dariusz Kowalski, Myung-Ju Ahn, Mustafa Erman, Giuseppe Giaccone, Hossein Borghaei, Jessica McLean, Jin Zhang, Fabricio Souza, Roy Decker. Phase 3, randomized, placebo-controlled study of stereotactic body radiotherapy (SBRT) with or without pembrolizumab in patients with inoperable stage I/IIA non-small-cell lung cancer (NSCLC): KEYNOTE-867 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT288.

Introduction Maintenance of chemotherapy dose intensity is a cornerstone of management in testicular germ cell tumors. We describe chemotherapy delivery and outcomes of patients in routine practice. Methods The Ontario Cancer Registry was linked to electronic records of treatment to identify patients diagnosed with testicular cancer treated with orchiectomy and chemotherapy from 2005 to 2010. We describe chemotherapy delivery and dose intensity. Overall survival was measured from the start of chemotherapy. Results During the study period, 552 new cases of testicular cancer were treated with orchiectomy and chemotherapy; drug/regimen details were available for 475 (86%) cases. The study population included 324 patients with nonseminoma and 151 with seminoma. The majority of patients were treated with bleomycin, etoposide, and cisplatin (BEP) (83%, 394/475) or etoposide and cisplatin (EP) (6%, 30/475); 89% (379/424) received 3 to 4 cycles of treatment. Thirty two percent of all BEP patients (125/394) had at least 1 dose omission of bleomycin; this rate increased to 51% of patients treated with BEP × 4. Eight percent (33/397) of evaluable BEP/EP patients had a dose reduction/omission of cisplatin and 21% (82/397) had a dose delay of >6 days. Among the BEP/EP cases, 44% (174/397) had reduced chemotherapy dose intensity. Five-year overall survival for all cases was 95%. Conclusions Almost half of patients treated with BEP/EP chemotherapy in routine practice have some form of reduced chemotherapy delivery. Despite this, long-term survival in the general population is very high. Further studies are required to understand the extent to which dose delivery might influence outcomes.

Background In the randomized KEYNOTE-407 study (NCT02775435), pembro + carboplatin and paclitaxel/nab-paclitaxel (chemo) significantly improved OS, PFS, and ORR compared with placebo + chemo in patients (pts) with previously untreated metastatic squamous NSCLC. Benefit was observed irrespective of PD-L1 TPS. We report updated OS from the protocol-specified final analysis and, for the first time, PFS2. Methods Eligible pts were randomized 1:1 to pembro (n=278) or placebo (n=281) + 4 cycles of carboplatin and paclitaxel/nab-paclitaxel. Randomization was stratified by PD-L1 TPS (≥1%/ Results With median follow-up of 14.3mo (range, 0.1–31.3) and 365 total deaths, pembro + chemo continued to improve OS (median [95% CI], 17.1 [14.4–19.9] vs 11.6 [10.1–13.7] mo), PFS (median [95% CI], 8.0 [6.3–8.4] vs 5.1 [4.3–6.0]; Table) and ORR (62.6% vs 38.4%). 2L+ therapy was received by 32.0% in the pembro + chemo arm and 59.4% (49.1% 2L+ antiPD[L]1) in the placebo + chemo arm. PFS2 was longer for 1L pembro + chemo (median [95% CI], 13.8 [12.2–15.9] mo vs 9.1 [8.2–10.2] mo), with no difference by PD-L1 TPS.TableLBA82TableAll Patients N=559PD-L1 TPS ≥50% N=146PD-L1 TPS 1–49% N=207PD-L1 TPS Conclusions Pembro + chemo continued to demonstrate improved outcomes, including OS, PFS, ORR and PFS2, compared with placebo + chemo for previously untreated metastatic squamous NSCLC, with a manageable safety profile. These results support first-line pembro + chemo in pts with metastatic squamous NSCLC. Clinical trial identification NCT02775435. Editorial acknowledgement Writing support was provided by Sheri Arndt, PharmD, of C4 MedSolutions, LLC (Yardley, PA, USA), a CHC Group company, funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Legal entity responsible for the study Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA Funding Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure L. Paz-Ares: Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Roche; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Lilly; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Boehringer Ingelheim; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: AstraZeneca; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Novartis; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Pfizer; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Amgen; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: BMS; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: MSD; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Merck; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Sanofi; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: PharmaMar; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Servier; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Sysmex; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Incyte; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Ipsen; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Adacap; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Bayer; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Blueprint Medicines; Honoraria (self), Spouse / Financial dependant, honoraria to self/spouse for scientific advice or as a speaker: Celgene; Honoraria to self/spouse for scientific advice or as a speaker for Roche, Lilly, Boehringer Ingelheim, AstraZeneca, Novartis, Pfizer, Amgen, BMS, MSD, Merck, Sanofi, PharmaMar, Servier, Sysmex, Incyte, Ipsen, Adacap, Bayer, Blueprint Medicines, and Celgene; board member for Genomica; grants to institution from MSD, BMS, AstraZeneca, and Pfizer. D. Vicente: Honoraria (self), Self/spouse for scientific advice or as a speaker: Boehringer Ingelheim, AstraZeneca, Pfizer, BMS, and MSD . A. Robinson: Research grant / Funding (institution), funding for clinical trials: Merck, AstraZeneca, Roche, and Pfizer; Advisory / Consultancy: Merck. H. Soto Parra: Advisory / Consultancy: AstraZeneca, MSD, BMS, Roche, and Eli Lilly. J. Mazieres: Honoraria (institution): Roche, AstraZeneca, Boehringer Ingelheim, Pfizer, BMS, MSD, Merck, Pierre Fabre, PharmaMar, Bayer, and Blueprint; Research grant / Funding (institution): Roche, MSD, BMS, and AstraZeneca. B. Hermes: Travel / Accommodation / Expenses: PharmaMar and Eli Lilly; Honoraria (institution), honoraria for lectures: BMS and Pfizer; Research grant / Funding (institution): MSD, Novartis, BMS, Bayer, Roche, Eli Lilly, and PharmaMar. I. Cicin: Advisory / Consultancy: AstraZeneca, Boehringer Ingelheim, Eli Lilly, MSD, F. Hoffmann-La Roche, and Pfizer; Research grant / Funding (self), personal fees for lectures: Eli Lilly, MSD, Novartis, Pfizer, Quintiles, and Roche; Research grant / Funding (institution), funding to the institution to support trial conduct: Astellas, AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, MSD, Parexel, Pfizer, Quintiles, Taiho, and Merck Serono. J. Rodriguez Cid: Research grant / Funding (institution), funding to the institution during conduct of this trial: MSD; Research grant / Funding (institution), funding to the institution to support trial conduct: Bayer, BMS, Celgene, Eli Lilly, MSD, Novartis, and Roche. I. Okamoto: Research grant / Funding (self), grants and personal fees: AstraZeneca, Taiho Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, MSD Oncology, Eli Lilly, BMS, Chugai Pharma; Research grant / Funding (self), personal fees : Pfizer; Research grant / Funding (institution), grants: Astellas Pharma, Novartis, and AbbVie. R. Ramlau: Honoraria (self), honoraria to self/spouse for scientific advice or as a speaker: Roche, Eli Lilly, Boehringer Ingelheim, AstraZeneca, Novartis, Pfizer, Amgen, BMS, MSD, Merck, and Sanofi; Officer / Board of Directors, board member: Boehringer Ingelheim, Pfizer, MSD, BMS, Novartis, Takeda, AbbVie, AstraZeneca, Eli Lilly, and Roche. X. Deng: Full / Part-time employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.. T. Bas: Full / Part-time employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.. B. Piperdi: Full / Part-time employment: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.. B. Halmos: Research grant / Funding (institution): Merck, BMS, Boehringer Ingelheim, Eli Lilly, Novartis, GSK, Pfizer, AbbVie, AstraZeneca, Mirati, Takeda, and Guardant Health; Advisory / Consultancy, consultant : Merck, Novartis, Boehringer Ingelheim, AstraZeneca, Novartis, Pfizer, Guardant Health, Spectrum, BMS, and Genentech. All other authors have declared no conflicts of interest.

While clinical trials have led to many advances in the treatment of bladder cancer, important gaps in knowledge persist. Population-based studies have made important contributions to what is known about bladder cancer and can contribute unique insights to practice and policy. In addition to evaluating effectiveness of interventions in routine practice, population-based studies can identify gaps between evidence and practice, and generate knowledge that cannot be gained from clinical trials. In this review we will highlight how population-based research has informed practice, policy, and the research agenda for bladder cancer.

Background In this phase Ib multicenter study, we sought to characterize the PK, safety and tolerability of durvalumab (D), an anti-PD-L1 antibody, ± tremelimumab (T), an anti-CTLA-4 antibody, in combination with one of four standard platinum-doublet chemotherapy regimens. We will present the PK, and update overall survival data. Methods Regardless of tumour PD-L1 status, patients were enrolled into one of four cohorts: pemetrexed, gemcitabine, etoposide (each with cisplatin or carboplatin) or nab-paclitaxel (with carboplatin), each of which were evaluated in one of six dose levels [Table]. Dose escalation followed a Rolling Six type design. Concurrent enrollment of cohorts was allowed. Limited PK was collected ≤1 hour pre-dose and ≤10 minutes post-dose on day 1 of cycles 1-3 as well as week 6 or 8 post chemotherapy. Results One hundred and thirty-six patients (median age=62 (range 30-83); males:females=67:69; ECOG PS 0/1=32%/68%). The majority of patients had non-small cell (53.7%) or small cell (13.2%) lung cancer. Immune-related adverse events (irAEs) that were considered related to D or T were mainly Table . 474P Dose Level Durvalumab Q3W Tremelimumab (with chemotherapy) Tremelimumab (after chemotherapy) 0 15mg/kg - - 1 15mg/kg 1 mg/kg X 1 1-2 doses 2a 15mg/kg 1 mg/kg X 3 Q6w 1-2 doses 2b 15mg/kg 3 mg/kg X 1 1-2 doses Q6w 3 1125mg 56 mg X 4 Q3w 56 mg X 2 Q3w 4 1500mg 75 mg X 4 Q3w 75 mg X 1 Conclusions Standard platinum-doublet chemotherapy regimens did not alter the PK of D+T or D compared with historical monotherapy therapy data. Toxicities were manageable and were not associated with PK. Clinical trial identification NCT02537418. Legal entity responsible for the study Canadian Cancer Trials Group (CCTG). Funding AstraZeneca provided drug and partial funding to support of this Canadian Cancer Trials Group (CCTG) study. Disclosure D. Hao: Honoraria (self), Advisory Board: Roche; Honoraria (self), Advisory Board; funding for clinical trial: BMS; Honoraria (self), Research grant / Funding (institution), Advisory Board; funding for clinical trial: AstraZeneca; Honoraria (self), Research grant / Funding (institution), Advisory Board; funding for clinical trial: Merck; Honoraria (self), Advisory Board: BI. P.M. Ellis: Honoraria (self), Advisory / Consultancy, Advisory Board: AstraZeneca; Advisory / Consultancy, Advisory Board: Takeda; Honoraria (self), Advisory / Consultancy, Advisory Board: Abbvie; Honoraria (self): Pfizer; Honoraria (self): BMS. R.A. Juergens: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Pfizer. P.A. Bradbury: Honoraria (self), Advisory / Consultancy: Abbvie; Honoraria (self): Pfizer; Honoraria (self): Lilly; Advisory / Consultancy: BI. M. Tsao: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Merck. M. Tehfe: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: Celegen; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck; Advisory / Consultancy: Taiho; Advisory / Consultancy: Takeda. C.K. Kollmannsberger: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Eisai; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: Roche; Travel / Accommodation / Expenses: Sanofi. J.R. Goffin: Honoraria (self), Speaker Bureau / Expert testimony, 2014, 2018: Amgen; Honoraria (self), 2015: Boehringer Ingelheim; Honoraria (self), 2015: Bristol-Myers Squibb; Honoraria (self), 2018: Merck; Travel / Accommodation / Expenses, 2017: AstraZeneca. P. Wheatley-Price: Advisory / Consultancy: Takeda; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Merck; Advisory / Consultancy: Abbvie; Advisory / Consultancy: Roche. J. Hilton: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Puma; Advisory / Consultancy: Eli Lilly. L.K. Seymour: Research grant / Funding (institution), Shareholder / Stockholder / Stock options, Received funding on behalf of CCTG from AstraZeneca to support the study: AstraZeneca. All other authors have declared no conflicts of interest.