Erdafitinib treatment in metastatic urothelial carcinoma: a real-world analysis.

Background: Erdafitinib, a fibroblast growth factor receptor (FGFR) inhibitor is a standard post chemotherapy advanced treatment line for metastatic urothelial carcinoma harboring FGFR2/3 genomic alterations. It was approved based on a phase 2 clinical trial, revealing a 40% response rate, and 13.8 months overall survival. These FGFR genomic alterations are uncommon. Thus, real-world data on erdafitinb use is scant. We herein describe erdafitinib treatment outcome in a real world patient cohort. Methods: We retrospectively reviewed the data of patients treated with erdafitinib from 9 Israeli medical centers. Results: Twenty-five patients with metastatic urothelial carcinoma (median age 73, 64% male, 80% with visceral metastases) were treated with erdafitinib between January 2020 to October 2022. A clinical benefit (complete response 12%, partial response 32%, stable disease 12%) was seen in 56%. Median progression-free survival was 2.7 months, and median overall survival 6.73 months. Treatment related toxicity ≥ grade 3 occurred in 52%, and 32% discontinued therapy due to adverse events. Conclusions: Erdafitinib therapy is associated with a clinical benefit in the real world setting, and associated with similar toxicity as reported in prospective clinical trials.

Implantable Cardioverter Defibrillator for the Primary Prevention of Sudden Cardiac Death among Patients With Cancer.

Data are limited regarding the characteristics and outcomes of patients with cancer who are found eligible for primary defibrillator therapy. We performed a single-center retrospective analysis of patients with preexisting cancer diagnoses who become eligible for a primary prevention implantable cardioverter defibrillator (ICD) or cardiac resynchronization therapy (CRT) defibrillator. Multicenter Automatic Defibrillator Implantation Trial-ICD (MADIT-ICD) benefit scores were calculated. The study included 75 cancer patients at a median age of 73 (interquartile range 64, 81) years at heart failure diagnosis. Active cancer was present in 51%. Overall, 55% of the cohort had coronary artery disease and 37% were CRT eligible. We found that 48%, 49%, and 3% of cohorts had low, intermediate, and high MADIT-ICD Benefit scores, respectively. Only 27% of patients underwent primary defibrillator implantation. Using multivariate analysis, indication for CRT and intermediate/high MADIT-ICD Benefit categories were found as independent predictors for implantation (odds ratio 8.42 p <0.001 and odds ratio 3.74 p = 0.040, respectively). During a median follow-up of 5.3 (interquartile range 4.5, 7.2) years, one patient (5%) with a defibrillator had appropriate shock therapy and 2 patients (10%) had bacteremia. Of 13 patients with CRT defibrillator-implants, one patient was admitted for heart failure exacerbation (8%). Using a time-varying covariate model, we did not observe statistically significant differences in the survival of patients with cancer implanted versus those not implanted with primary defibrillators (hazard ratio 0.521, p = 0.127). In conclusion, although primary defibrillator therapy is underutilized in patients with cancer, its relative benefit is limited because of competing risk of nonarrhythmic mortality. These findings highlight the need for personalized cardiologic and oncologic coevaluation.

Searching for the emotional roots of breast cancer: A cross-disciplinary analysis integrating psychology, Chinese medicine, and oncology biomarkers.

OBJECTIVE: We employed a multidisciplinary approach incorporating theoretical ideas, clinical experience, psychology, physiology, traditional Chinese medicine (CM), modern practice of CM, and oncology to explore the effect of patients' repression of negative emotions and traumatic events on breast cancer (BC) pathogenesis. METHODS: BC female patients, older than 18 years of age, with available pathology reports who were treated at Rabin Medical Center were recruited. All participants completed questionnaires regarding medical history, behavioral tendencies, negative emotions, trauma, symptoms, and pathology (from a CM perspective). Data on tumor characteristics were collected from the pathology reports. The associations were examined using hierarchical binary logistic regressions. RESULTS: A total of 155 BC patients were enrolled. The median age was 52 years, with a range of 26-79; 95% were mothers; 28% had estrogen receptor (ER)-negative BC, 52% had progesterone receptor (PR)-negative BC, 48% had human epidermal growth factor receptor 2-negative BC, and antigen Ki-67 ≥ 20% was reported for 52% of tumors. Statistically significant associations were found between the emotional markers (sense of motherhood failure, and lack of self-fulfillment), avoidance behavior, and physical symptoms that are related to emotional repression based on CM. Significant associations were also found between variables associated with physical symptoms of emotional repression, which involves the production and accumulation of non-substantial phlegm (i.e., "high-lipid Qi-like microscopic phlegm"), avoidance behavior which unconsciously uses "high-lipid Qi-like microscopic phlegm" in order to achieve emotional repression, and tumor parameters including tumor grade, PR status, and Ki-67. Patients with higher levels of "high-lipid Qi-like microscopic phlegm" were more likely to have tumors with worse prognosis (PR-negative, higher grade, and higher Ki-67). CONCLUSION: We demonstrated a relationship between emotional parameters, behavioral tendencies, CM parameters, and oncologic parameters in BC. Additional research is warranted to explore these associations and their relevance to clinical practice.

Taxane versus vinorelbine in combination with trastuzumab and pertuzumab for first-line treatment of metastatic HER2-positive breast cancer: a retrospective two-center study.

BACKGROUND: The combination of a taxane with trastuzumab and pertuzumab is standard of care for first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. The combination of vinorelbine with trastuzumab and pertuzumab showed anti-tumor activity in a phase 2 trial. PATIENTS AND METHODS: The databases of two tertiary medical centers were retrospectively searched for patients with HER2-positive metastatic breast cancer who underwent first-line treatment in 2013-2019 with a taxane or vinorelbine in combination with trastuzumab and pertuzumab. Groups were compared for progression-free survival (PFS), overall survival (OS), and toxicity profile. RESULTS: The study included 87 patients in the taxane group and 65 in the vinorelbine group. Overall median PFS was significantly longer in the taxane group [HR 0.56 (0.36-0.88), P = 0.01], but on multivariate analysis the difference was not statistically significant [HR 0.68 (0.4-1.1, P = 0.11)]. PFS was comparable in both groups of patients with recurrent disease [HR 0.94 (0.5-1.79), P = 0.85]. However, in patients with de novo metastatic disease, the difference in favor of the taxane group was pronounced [HR 0.4 (0.2-0.78), P = 0.007] and maintained significance on multivariate analysis [HR 0.46 (0.2-0.97, P = 0.04)]. There was no statistical significant difference in OS in the whole cohort [HR 0.69 (0.39-1.23)] or the subgroups. CONCLUSIONS: Patients with HER2-positive metastatic breast cancer had similar survival with first-line treatment of taxane or vinorelbine combined with trastuzumab and pertuzumab. When the analysis was adjusted for prognostic factors, there was no PFS benefit for taxanes except in the subgroup with de novo disease.

Association between multitarget tyrosine kinase inhibitors and changes in CT appearance of submucosal fat in the gastrointestinal tract.

INTRODUCTION: Submucosal fat deposition (SMF) in the gastrointestinal tract can be seen in patients treated with vascular endothelial growth factor receptor multitarget tyrosine kinase inhibitors (mtTKIs). We aimed to assess the association between mtTKIs treatment and appearance of SMF on computed tomography (CT). METHODS: We performed retrospective evaluation of patients who started mtTKI treatment between 2016 and 2018, with a comparison patient cohort treated with single-target tyrosine kinase inhibitors (stTKIs). SMF amount for each gastrointestinal tract segment (stomach, duodenum, jejunum, ileum, terminal ileum, right colon, left colon) was scored as follows: 0 = none; 1 = low amount (<2 mm thick); 2 = high amount (>2 mm layer). For each CT, segment scores were aggregated to create an SMF index (SMFI). Maximal increase in SMFI between pretreatment and posttreatment CTs was documented. SMF ⩾3 was defined as positive. RESULTS: Forty patients treated with mtTKIs and 23 patients receiving stTKIs were included. Maximal increase in SMFI during treatment was 0-1 in 56/63 patients (89%) and 3-6 in 7/63 patients (11%). All patients with positive SMFI received mtTKIs compared to 0 patients treated with stTKIs (17.5% vs. 0%; p = 0.04). mtTKI treatment was associated with higher incidence of nausea/vomiting (4/7) and diarrhea (4/7) when positive SMF was noted, as compared to patients with negative SMF (6/33 patients each; p = 0.048). CONCLUSION: Gastrointestinal tract SMF deposition occurs in a considerable proportion of patients treated with mtTKIs with association to abdominal symptoms. This may be unique to mtTKIs and was not found in patients receiving stTKIs.

Central nervous system metastases in breast cancer: the impact of age on patterns of development and outcome.

PURPOSE: The purpose of this study is to explore differences in the pattern and outcome of central nervous system (CNS) involvement in breast cancer by age at diagnosis. METHODS: A retrospective database of a tertiary cancer center yielded 174 consecutive patients with breast cancer who were diagnosed with CNS metastases in 2006-2019. Data on histopathology, characteristics of CNS involvement, treatments, and survival (at three time points during the disease course) were compared between patients aged ≤ 45 and > 45 years. Pearson Chi-square or Fisher exact test and Kaplan-Meier survival curves with log-rank test were used for statistical analyses. RESULTS: Study population was divided according to age at diagnosis of breast cancer. 65 patients were ≤ 45 years old and 109 patients > 45 years old. The younger group was characterized by longer median overall survival (117.1 months vs 88 months, p = 0.017) and longer interval between breast cancer diagnosis to development of CNS metastases (97.4 months vs 75.9 months, p = 0.026). Median survival after development of CNS disease was not significantly different (18.7 months vs 11.1 months, p = 0.341), although it was significantly longer in younger patients within the subgroup of patients with triple-negative disease (22.5 vs 7.9 months, p = 0.033). There were no between-group differences in number, location, and clinical presentation of CNS metastases or in systemic and CNS-directed treatment approaches. CONCLUSION: While the presentation of CNS involvement was similar between the different age groups, younger patients had significantly longer CNS-free interval and longer overall survival, and for the subgroups of triple-negative patients, younger age at breast cancer diagnosis was associated with longer survival after diagnosis of CNS disease.

Survival outcomes and independent response assessment with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma: 42-month follow-up of a randomized phase 3 clinical trial.

BACKGROUND: The extent to which response and survival benefits with immunotherapy-based regimens persist informs optimal first-line treatment options. We provide long-term follow-up in patients with advanced renal cell carcinoma (aRCC) receiving first-line nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib (SUN) in the phase 3 CheckMate 214 trial. Survival, response, and safety outcomes with NIVO+IPI versus SUN were assessed after a minimum of 42 months of follow-up. METHODS: Patients with aRCC were enrolled from October 16, 2014, through February 23, 2016. Patients stratified by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk and region were randomized to nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every 3 weeks for four doses, followed by nivolumab (3 mg/kg) every 2 weeks; or SUN (50 mg) once per day for 4 weeks (6-week cycle). Primary endpoints: overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) per independent radiology review committee in IMDC intermediate-risk/poor-risk patients. Secondary endpoints: OS, PFS, and ORR in the intention-to-treat (ITT) population and safety. Favorable-risk patient outcomes were exploratory. RESULTS: Among ITT patients, 550 were randomized to NIVO+IPI (425 intermediate/poor risk; 125 favorable risk) and 546 to SUN (422 intermediate/poor risk; 124 favorable risk). Among intermediate-risk/poor-risk patients, OS (HR, 0.66; 95% CI, 0.55-0.80) and PFS (HR, 0.75; 95% CI, 0.62-0.90) benefits were observed, and ORR was higher (42.1% vs 26.3%) with NIVO+IPI versus SUN. In ITT patients, both OS benefits (HR, 0.72; 95% CI, 0.61-0.86) and higher ORR (39.1% vs 32.6%) were observed with NIVO+IPI versus SUN. In favorable-risk patients, HR for death was 1.19 (95% CI, 0.77-1.85) and ORR was 28.8% with NIVO+IPI versus 54.0% with SUN. Duration of response was longer (HR, 0.46-0.54), and more patients achieved complete response (10.1%-12.8% vs 1.4%-5.6%) with NIVO+IPI versus SUN regardless of risk group. The incidence of treatment-related adverse events was consistent with previous reports. CONCLUSIONS: NIVO+IPI led to improved efficacy outcomes versus SUN in both intermediate-risk/poor-risk and ITT patients that were maintained through 42 months' minimum follow-up. A complete response rate >10% was achieved with NIVO+IPI regardless of risk category, with no new safety signals detected in either arm. These results support NIVO+IPI as a first-line treatment option with the potential for durable response. TRIAL REGISTRATION NUMBER: NCT02231749.

Prospective Long-Term Follow-Up of Pulmonary Diffusion Capacity Reduction Caused by Dose-Dense Chemotherapy in Patients with Breast Cancer.

BACKGROUND: Our previous study of pulmonary function in 34 patients with early breast cancer without preexisting lung disease showed that anthracycline- and taxane-based adjuvant dose-dense chemotherapy (DDC) caused a significant 16.4% mean reduction in carbon monoxide diffusing capacity (DLCO). The present study reports the pulmonary and oncological outcomes of these patients on long-term follow-up. PATIENTS AND METHODS: The primary endpoint was DLCO measured by the pulmonary function test (PFT) performed at a median of 27 months after DDC (range, 8-97) in 25 patients without disease recurrence. DLCO values were recorded as a percentage of predicted values according to age, height, and hemoglobin level and analyzed relative to baseline pre-DDC DLCO values. The secondary endpoints were symptoms, additional therapies, and cancer outcomes during a median of 11 years' follow-up (range, 4.4-11.4). RESULTS: A longitudinal general linear model showed significant effects of time on DLCO and its trend (F(1, 87) = 14.68, p < 0.001 and F(1, 87) = 10.26, p=0.002, respectively). Complementary descriptive analysis showed a significant recovery on the follow-up PFT (75.6% vs. 81.9%, p=0.002), but it was still significantly lower than the baseline DLCO (81.9% vs. 92.0%, p=0.003). Five patients (20%) still showed a >20% relative DLCO reduction from baseline. Patients with dyspnea or fatigue at later clinical follow-up had a significantly lower DLCO value on the follow-up PFT than nonsymptomatic patients (80.5% vs. 92.1%, p=0.02). DLCO recovery was inversely correlated with age (R = -0.39, p=0.05), but no significant correlation was found with the length of time until the follow-up PFT or additional therapies. There was no association of DDC-related DLCO reduction with cancer outcomes. CONCLUSIONS: The significant reduction in DLCO seen after DDC in patients with potentially curable breast cancer is evident years afterwards, especially in older patients. While most patients partly recover, some will have a lasting symptomatic DLCO impairment.

Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial.

BACKGROUND: In the ongoing phase 3 CheckMate 214 trial, nivolumab plus ipilimumab showed superior efficacy over sunitinib in patients with previously untreated intermediate-risk or poor-risk advanced renal cell carcinoma, with a manageable safety profile. In this study, we aimed to assess efficacy and safety after extended follow-up to inform the long-term clinical benefit of nivolumab plus ipilimumab versus sunitinib in this setting. METHODS: In the phase 3, randomised, controlled CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by International Metastatic Renal Cell Carcinoma Database Consortium risk status into favourable-risk, intermediate-risk, and poor-risk subgroups and randomly assigned (1:1) to open-label nivolumab (3 mg/kg intravenously) plus ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, followed by nivolumab (3 mg/kg intravenously) every 2 weeks; or sunitinib (50 mg orally) once daily for 4 weeks (6-week cycle). Randomisation was done through an interactive voice response system, with a block size of four and stratified by risk status and geographical region. The co-primary endpoints for the trial were overall survival, progression-free survival per independent radiology review committee (IRRC), and objective responses per IRRC in intermediate-risk or poor-risk patients. Secondary endpoints were overall survival, progression-free survival per IRRC, and objective responses per IRRC in the intention-to-treat population, and adverse events in all treated patients. In this Article, we report overall survival, investigator-assessed progression-free survival, investigator-assessed objective response, characterisation of response, and safety after extended follow-up. Efficacy outcomes were assessed in all randomly assigned patients; safety was assessed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but now closed to recruitment. FINDINGS: Between Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) eligible patients were randomly assigned to nivolumab plus ipilimumab or sunitinib (550 vs 546 in the intention-to-treat population; 425 vs 422 intermediate-risk or poor-risk patients, and 125 vs 124 favourable-risk patients). With extended follow-up (median follow-up 32·4 months [IQR 13·4-36·3]), in intermediate-risk or poor-risk patients, results for the three co-primary efficacy endpoints showed that nivolumab plus ipilimumab continued to be superior to sunitinib in terms of overall survival (median not reached [95% CI 35·6-not estimable] vs 26·6 months [22·1-33·4]; hazard ratio [HR] 0·66 [95% CI 0·54-0·80], p<0·0001), progression-free survival (median 8·2 months [95% CI 6·9-10·0] vs 8·3 months [7·0-8·8]; HR 0·77 [95% CI 0·65-0·90], p=0·0014), and the proportion of patients achieving an objective response (178 [42%] of 425 vs 124 [29%] of 422; p=0·0001). Similarly, in intention-to-treat patients, nivolumab and ipilimumab showed improved efficacy compared with sunitinib in terms of overall survival (median not reached [95% CI not estimable] vs 37·9 months [32·2-not estimable]; HR 0·71 [95% CI 0·59-0·86], p=0·0003), progression-free survival (median 9·7 months [95% CI 8·1-11·1] vs 9·7 months [8·3-11·1]; HR 0·85 [95% CI 0·73-0·98], p=0·027), and the proportion of patients achieving an objective response (227 [41%] of 550 vs 186 [34%] of 546 p=0·015). In all treated patients, the most common grade 3-4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 [10%] of 547), increased amylase (31 [6%]), and increased alanine aminotransferase (28 [5%]), whereas in the sunitinib group they were hypertension (90 [17%] of 535), fatigue (51 [10%]), and palmar-plantar erythrodysaesthesia (49 [9%]). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related. INTERPRETATION: The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories. FUNDING: Bristol-Myers Squibb and ONO Pharmaceutical.

The Financial Impact of Hypofractionated Radiation for Localized Prostate Cancer in the United States.

BACKGROUND: Until recently, dose intensified radiotherapy was the standard radiation method for localized prostate cancer. Multiple studies have demonstrated similar efficacy and tolerability with moderate hypofractionation. In recent years there has been an increasing focus placed on understanding the cost and value of cancer care. In this study we aimed to assess the economic impact of moderate hypofractionation for payers in the United States. METHODS: We performed a population-based analysis of the total cost of external beam radiotherapy (EBRT) for localized prostate cancer in the US annually. The national annual target population of patients treated with definitive EBRT was calculated using the Surveillance, Epidemiology, and End Results (SEER) database. Treatment costs for various fractionation schemes were based on billing codes and 2018 pricing by the Centers for Medicare and Medicaid Services (CMS). RESULTS: We estimate that 27,146 patients with localized prostate cancer are treated with EBRT annually in the US. The cost of standard fractionation in 45 or 39 fractions is US$ 26,782 and 23,625 per patient, respectively. With moderate hypofractionation in 28 or 20 fractions, the cost is US$ 17,793 and 13,402 per patient, respectively. The use of moderate hypofractionation would lead to 25-50% annual savings US$158,315,472-US$363,213,480 in the US. CONCLUSIONS: Moderate hypofractionation may have the potential to save approximately US$0.16-0.36 billion annually, likely without impacting survival or tolerability. This may lead to lower personal financial toxicity. It would be reasonable for public and private payers to consider which type of radiation is most suited to reimbursement.

A Cost-Effectiveness Analysis of Nivolumab and Ipilimumab Versus Sunitinib in First-Line Intermediate- to Poor-Risk Advanced Renal Cell Carcinoma.

BACKGROUND: The treatment paradigm of advanced renal cell carcinoma (RCC) has changed rapidly in recent years. In first-line treatment of intermediate- to poor-risk patients, the CheckMate 214 study demonstrated a significant survival advantage for nivolumab and ipilimumab versus sunitinib. The high cost of combined immune-modulating agents warrants an understanding of the combination's value by considering both efficacy and cost. The objective of this study was to estimate the cost-effectiveness of nivolumab and ipilimumab compared with sunitinib for first-line treatment of intermediate- to poor-risk advanced RCC from the U.S. payer perspective. MATERIALS AND METHODS: A Markov model was developed to compare the costs and effectiveness of nivolumab and ipilimumab with those of sunitinib in the first-line treatment of intermediate- to poor-risk advanced RCC. Health outcomes were measured in life-years and quality-adjusted life-years (QALYs). Drug costs were based on Medicare reimbursement rates in 2017. We extrapolated survival beyond the trial closure using Weibull distribution. Model robustness was addressed in univariable and probabilistic sensitivity analyses. RESULTS: The total mean cost per-patient of nivolumab and ipilimumab versus sunitinib was $292,308 and $169,287, respectfully. Nivolumab and ipilimumab generated a gain of 0.978 QALYs over sunitinib. The incremental cost-effectiveness ratio (ICER) for nivolumab and ipilimumab was $125,739/QALY versus sunitinib. CONCLUSION: Our analysis established that the base case ICER in the model for nivolumab and ipilimumab versus sunitinib is below what some would consider the upper limit of the theoretical willingness-to-pay threshold in the U.S. ($150,000/QALY) and is thus estimated to be cost-effective. IMPLICATIONS FOR PRACTICE: This article assessed the cost-effectiveness of nivolumab and ipilimumab versus sunitinib for treatment of patients with intermediate- to poor-risk metastatic kidney cancer, from the U.S. payer perspective. It would cost $125,739 to gain 1 quality-adjusted life-year with nivolumab and ipilimumab versus sunitinib in these patients.

Cost-effectiveness of Pembrolizumab in Second-line Advanced Bladder Cancer.

BACKGROUND: Immune-modulating drugs have recently been introduced to the second-line setting of advanced bladder cancer. Pembrolizumab increases overall survival and is associated with less toxicity compared with chemotherapy in this setting based on the Keynote 045 study. The high cost of immunotherapy necessitates an assessment of its value by considering both efficacy and cost. OBJECTIVE: To estimate the cost-effectiveness of pembrolizumab for the second-line treatment of advanced bladder cancer from the perspective of payers in multiple countries. DESIGN, SETTING, AND PARTICIPANTS: We developed a Markov model to compare the cost and effectiveness of pembrolizumab with those of chemotherapy in the second-line treatment of advanced bladder cancer based on the Keynote 045 study. Drug costs were acquired for the United States (US), United Kingdom (UK), Canada, and Australia. All costs were converted from local currency to US dollars at the exchange rates in September 2017. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Health outcomes were measured in quality-adjusted life-years (QALYs). RESULTS AND LIMITATIONS: Pembrolizumab generated a gain of 0.36-0.37 QALYs compared with chemotherapy. Our analysis established the following incremental cost-effectiveness ratios (ICERs) for pembrolizumab versus chemotherapy in second-line advanced bladder cancer treatment: US $122 557/QALY; UK $91 995/QALY; Canada $90 099/QALY; and Australia $99 966/QALY. The willingness-to-pay (WTP) thresholds per QALY are considered to be around 100 000-150 000 US dollars for the US, 20 000-50 000 pounds for the UK (US$25 000-65 000), 20 000-100 000 CAD for Canada (US$16 000-80 000), and 40 000-75 000 AUD for Australia (US$32 000-60 000). CONCLUSIONS: Cost-effectiveness and WTP thresholds vary between countries. Compared with the other countries examined, US drug prices were found to be the highest, leading to the highest ICER. With standard WTP thresholds, pembrolizumab may be considered cost-effective in the US but not in the other countries examined. PATIENT SUMMARY: This article assessed the cost-effectiveness of pembrolizumab for the treatment of patients with metastatic bladder cancer who had previously failed one treatment regimen. It would cost $122 557 in the United States, $91 995 in the United Kingdom, $90 099 in Canada, and $99 966 in Australia to gain one quality-adjusted life-year with pembrolizumab versus chemotherapy in these patients, which may be considered cost-effective only in the United States because of the differences in willingness-to-pay thresholds.

Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma.

BACKGROUND: Nivolumab plus ipilimumab produced objective responses in patients with advanced renal-cell carcinoma in a pilot study. This phase 3 trial compared nivolumab plus ipilimumab with sunitinib for previously untreated clear-cell advanced renal-cell carcinoma. METHODS: We randomly assigned adults in a 1:1 ratio to receive either nivolumab (3 mg per kilogram of body weight) plus ipilimumab (1 mg per kilogram) intravenously every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks, or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The coprimary end points were overall survival (alpha level, 0.04), objective response rate (alpha level, 0.001), and progression-free survival (alpha level, 0.009) among patients with intermediate or poor prognostic risk. RESULTS: A total of 1096 patients were assigned to receive nivolumab plus ipilimumab (550 patients) or sunitinib (546 patients); 425 and 422, respectively, had intermediate or poor risk. At a median follow-up of 25.2 months in intermediate- and poor-risk patients, the 18-month overall survival rate was 75% (95% confidence interval [CI], 70 to 78) with nivolumab plus ipilimumab and 60% (95% CI, 55 to 65) with sunitinib; the median overall survival was not reached with nivolumab plus ipilimumab versus 26.0 months with sunitinib (hazard ratio for death, 0.63; P<0.001). The objective response rate was 42% versus 27% (P<0.001), and the complete response rate was 9% versus 1%. The median progression-free survival was 11.6 months and 8.4 months, respectively (hazard ratio for disease progression or death, 0.82; P=0.03, not significant per the prespecified 0.009 threshold). Treatment-related adverse events occurred in 509 of 547 patients (93%) in the nivolumab-plus-ipilimumab group and 521 of 535 patients (97%) in the sunitinib group; grade 3 or 4 events occurred in 250 patients (46%) and 335 patients (63%), respectively. Treatment-related adverse events leading to discontinuation occurred in 22% and 12% of the patients in the respective groups. CONCLUSIONS: Overall survival and objective response rates were significantly higher with nivolumab plus ipilimumab than with sunitinib among intermediate- and poor-risk patients with previously untreated advanced renal-cell carcinoma. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 214 ClinicalTrials.gov number, NCT02231749 .).

Cost Effectiveness of Nivolumab in Advanced Renal Cell Carcinoma.

BACKGROUND: In recent years, new drugs have been introduced for second-line treatment of advanced renal cell carcinoma (RCC). Nivolumab increases overall survival and is associated with less toxicity compared to everolimus in this setting according to the CheckMate 025 study. However, because of the high cost of nivolumab, there is a need to define its value by considering both efficacy and cost. OBJECTIVE: To estimate the cost effectiveness of nivolumab for second-line treatment of advanced RCC from the US payer perspective. DESIGN, SETTING, AND PARTICIPANTS: A Markov model was developed to compare the costs and effectiveness of nivolumab with those of everolimus and placebo in second-line treatment of advanced RCC. Health outcomes were measured in life-years (LYs) and quality-adjusted LYs (QALYs). Drug costs were based on 2016 Medicare reimbursement rates. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Model robustness was assessed in univariable and probabilistic sensitivity analyses. We addressed the issue of the extensive duration of immunotherapy treatment among long-term survivors, which may or may not be approved by payers. RESULTS AND LIMITATIONS: The total mean cost per patient was $101 070 for nivolumab and $50 935 for everolimus. Nivolumab generated a gain of 0.24 LYs (0.34 QALYs) compared to everolimus. The incremental cost-effectiveness ratio (ICER) for nivolumab was $146 532/QALY versus everolimus and $226 197/QALY versus placebo. Limiting the maximal treatment duration of nivolumab to 2 yr reduced the ICER to $121 788/QALY versus everolimus. The analysis is limited by data availability and our assumptions. CONCLUSIONS: Our analysis established that with a willingness-to-pay threshold of $100 000 to $150 000 per QALY, nivolumab is estimated to be cost-effective versus everolimus, but not cost-effective versus placebo. PATIENT SUMMARY: We assessed the cost effectiveness of nivolumab in previously treated metastatic kidney cancer. In the USA, it would cost $146 532 to gain one quality-adjusted life-year with nivolumab versus everolimus, or $226 197 versus placebo. Nivolumab is considered cost-effective versus everolimus, but not versus placebo.

The association between smoking and breast cancer characteristics and outcome.

BACKGROUND: Smoking is associated with an increased incidence of hormone receptor positive breast cancer. Data regarding worse breast cancer outcome in smokers are accumulating. Current literature regarding the impact of smoking on breast cancer characteristics is limited. We evaluated the impact of smoking on breast cancer characteristics and outcome. METHODS: This was a retrospective single center study. All women diagnosed from 4/2005 through 3/2012 and treated in our institute for early, estrogen receptor positive, human epidermal growth factor receptor 2 (HER2) negative breast cancer, whose tumors were sent for Oncotype DX analysis were included. Medical records were reviewed for demographics, clinico-pathological parameters, treatment and outcome. Data regarding smoking were retrieved according to patients' history at the first visit in the oncology clinic. Patients were grouped and compared according to smoking history (ever smokers vs. never smokers), smoking status (current vs. former and never smokers) and smoking intensity (pack years ≥30 vs. the rest of the cohort). Outcomes were adjusted in multivariate analyses and included age, menopausal status, ethnicity, tumor size, nodal status and grade. RESULTS: A total of 662 women were included. 28.2% had a history of smoking, 16.6% were current smokers and 11.3% were heavy smokers. Smoking had no impact on tumor size, nodal involvement and Oncotype DX recurrence score. Angiolymphatic and perineural invasion rates were higher in current smokers than in the rest of the cohort (10.4% vs. 5.1%, p = 0.045, 8.3% vs. 3.5%, p = 0.031, respectively). Smoking had no other impact on histological characteristics. Five-year disease free survival and overall survival rates were 95.7% and 98.5%, respectively. Smoking had no impact on outcomes. Adjusted disease free survival and overall survival did not influence the results. CONCLUSIONS: Smoking had no clinically significant influence on tumor characteristics and outcome among women with estrogen receptor positive, HER2 negative, early breast cancer. As the study was limited to a specific subgroup of the breast cancer population in this heterogeneous disease and since smoking is a modifiable risk factor for the disease, further research is required to clarify the possible impact of smoking on breast cancer.