Safety of Extended Pirtobrutinib Exposure in Relapsed and/or Refractory B-Cell Malignancies.

INTRODUCTION: Pirtobrutinib, a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor, has demonstrated promising efficacy in B-cell malignancies and is associated with low rates of discontinuation and dose reduction. Pirtobrutinib is administered until disease progression or toxicity, necessitating an understanding of the safety profile in patients with extended treatment. METHODS: Here we report the safety of pirtobrutinib in patients with relapsed/refractory B-cell malignancies with extended (≥12 months) drug exposure from the BRUIN trial. Assessments included median time-to-first-occurrence of adverse events (AEs), dose reductions, and discontinuations due to treatment-emergent AEs (TEAEs) and select AEs of interest (AESIs). RESULTS: Of 773 patients enrolled, 326 (42%) received treatment for ≥12 months. In the extended exposure cohort, the median time-on-treatment was 19 months. The most common all-cause TEAEs were fatigue (32%) and diarrhea (31%). TEAEs leading to dose reduction occurred in 23 (7%) and discontinuations in 11 (3%) extended exposure patients. One patient had a fatal treatment-related AE (COVID-19 pneumonia). Infections (73.0%) were the most common AESI with a median time-to-first-occurrence of 7.4 months. Majority of TEAEs and AESIs occurred during the first year of therapy. CONCLUSIONS: Pirtobrutinib therapy continues to demonstrate an excellent safety profile amenable to long-term administration without evidence of new or worsening toxicity signals.

Real-world maintenance therapy and survival outcomes for pembrolizumab plus pemetrexed and platinum for non-small-cell lung cancer in USA.

Aim: To evaluate treatment patterns and overall survival (OS) in real world metastatic non-squamous non-small-cell lung cancer (NSQ-NSCLC) patients that received pembrolizumab plus pemetrexed-platinum (pembro+pem+plat) aligned with KEYNOTE-189. Materials & methods: OS was evaluated for the overall cohort and maintenance therapy (MT) subgroups and analyzed using Kaplan-Meier estimates and Cox proportional hazards model. Results: Of 2488 patients that received first-line treatment, 45.1% received less than four cycles of pembro+pem+plat, 43.9% received four cycles plus MT with pembro and/or pem, and 11.1% received four cycles without continuing on MT. The median OS was 21.0 months and 9.1 months in patients that continued and did not continue MT. Conclusion: Real world patients that received KEYNOTE-189-aligned treatment had similar OS benefits.

What is this article about? KEYNOTE-189 was a research study (i.e., clinical trial) that compared two different combinations of medicine to treat patients with advanced non-squamous (NSQ) non-small-cell lung cancer (NSCLC). This was the first treatment after being diagnosed for all patients, and they received one of two combinations ­ either pembrolizumab, pemetrexed, plus a platinum-based chemotherapy (pembro+pem+plat) or placebo plus pemetrexed plus a platinum-based chemotherapy. After receiving these combinations four-times, patients were switched to maintenance therapy with pembro and/or pem. In general, patients first treated with pembro+pem+plat survived longer than those treated with placebo plus pemetrexed-platinum. In the current study, researchers wanted to learn if the same results can be expected for patients being treated in the community. What are the results? Patients who completed four sessions of pembro+pem+plat and continued on maintenance therapy survived for 21.0 months and those who completed four sessions of pembro+pem+plat but did not continue on maintenance therapy survived for 9.1 months. What do the results of the study mean? Patients in the community who were treated with pembro+pem+plat and continued on maintenance therapy survived as long as those in the KEYNOTE-189 study.

A network meta-analysis of immunotherapy-based treatments for advanced nonsquamous non-small cell lung cancer.

Introduction: In the absence of head-to-head trials comparing immunotherapies for advanced nonsquamous non-small-cell lung cancer (NsqNSCLC), a network meta-analysis (NMA) was conducted to compare the relative efficacy of these treatments. Materials & methods: A systematic literature review of randomized controlled trials evaluating first-line-to-progression and second-line treatments for advanced NsqNSCLC informed Bayesian NMAs for overall survival (OS) and progression-free survival (PFS) end points. Results: Among first-line-to-progression treatments, pembrolizumab + pemetrexed + platinum showed the greatest OS benefit versus other regimens and a PFS benefit versus all but three regimens. Among second-line treatments, an OS benefit was seen for atezolizumab, nivolumab and pembrolizumab versus docetaxel. Conclusion: Pembrolizumab + pemetrexed + platinum showed the maximum OS benefit in the first-line setting. In the second-line setting, anti-PD-1/anti-PD-L1 monotherapies were better than docetaxel.

Hypersensitivity Reactions to Selpercatinib Treatment With or Without Prior Immune Checkpoint Inhibitor Therapy in Patients With NSCLC in LIBRETTO-001.

INTRODUCTION: Immune checkpoint inhibitor (ICI) therapy has been found to increase the risk/severity of immune-mediated adverse events with subsequent kinase inhibitor treatment in oncogenically driven cancers. We explored the risk for hypersensitivity with selpercatinib, a first-in-class highly selective and potent, central nervous system-active RET inhibitor, in prior ICI-treated patients with RET fusion-positive NSCLC compared with their ICI-naive counterparts. METHODS: Data from patients enrolled by December 16, 2019, in the ongoing phase 1/2 LIBRETTO-001 (NCT03157128) trial were analyzed for hypersensitivity reactions reported using preferred terms of hypersensitivity/drug hypersensitivity and defined as a constellation of symptoms/findings characterized by maculopapular rash, often preceded by fever with arthralgias/myalgias, followed by greater than or equal to 1 of the following signs/symptoms: thrombocytopenia, increased aspartate aminotransferase or alanine aminotransferase, hypotension, tachycardia, or increased creatinine. RESULTS: Of 329 patients, 22 (7%) who experienced a grade 1 to 3 hypersensitivity reaction that met the defined constellation of events were attributed to selpercatinib by investigators, and more often in prior ICI-treated (n = 17, 77%) than ICI-naive (n = 5, 23%) patients. There were 19 patients with selpercatinib-related hypersensitivity who resumed selpercatinib post-hypersensitivity with dose modification/supportive care. Furthermore, 17 patients, of whom 14 received prior ICI therapy, were still on treatment at twice daily doses of 40 mg (n = 5), 80 mg (n = 4), 120 mg (n = 4), and 160 mg (n = 4). CONCLUSIONS: Rates of selpercatinib-related hypersensitivity were low overall and, as with other kinase inhibitors, occurred predominantly in prior ICI-treated patients. Hypersensitivity to selpercatinib can be managed with supportive care measures regardless of prior ICI status and is reversible.

Safety of pemetrexed plus platinum in combination with pembrolizumab for metastatic nonsquamous non-small cell lung cancer: A post hoc analysis of KEYNOTE-189.

OBJECTIVES: This post hoc analysis assessed the safety of pemetrexed and platinum in combination with pembrolizumab, including time-to-onset and time-to-resolution of all-cause any-grade and grade ≥3 adverse events (AEs) and renal AEs. MATERIALS AND METHODS: Patient-level data from KEYNOTE-189 were analyzed in the all-subjects-as-treated population (pembrolizumab arm, n = 405; placebo arm, n = 202), and among patients who received ≥5 cycles of pemetrexed (pemetrexed/pembrolizumab/platinum arm, n = 310; pemetrexed/placebo/platinum arm, n = 135). All-cause AEs were selected based on ≥2 % incidence from previously reported KEYNOTE-189 data and included neutropenia, febrile neutropenia, anemia, thrombocytopenia, asthenia, fatigue, dyspnea, diarrhea, nausea, vomiting, pneumonitis, and renal events. Descriptive statistics summarized all-cause AEs. Medians and interquartile ranges were used to examine time-to-onset and time-to-resolution. The data cutoff was November 8, 2017. RESULTS: In both treatment arms, most non-hematologic (nausea, vomiting, diarrhea, and asthenia), and hematologic (febrile neutropenia, thrombocytopenia, and neutropenia) grade ≥3 AEs with ≥2 % incidence had a median time-to-onset within the first 4 cycles, and a median time-to-resolution of within 2 weeks from onset. A small number of AEs had longer median time-to-onset (pneumonitis and fatigue) and median time-to-resolution (pneumonitis, fatigue, acute kidney injury, and anemia). Among patients who received ≥5 cycles of pemetrexed, the incidence of any-grade renal toxicity in the pemetrexed/pembrolizumab/platinum arm was 2.3 % in Cycles 1-4, 4.8 % in Cycles 5-8, 2.6 % in Cycles 9-12, and 2.5 % in Cycles ≥13; and, in the pemetrexed/placebo/platinum arm, 0.7 % in Cycles 1-4, 1.5 % in Cycles 5-8, 1.3 % in Cycles 9-12, and 2.0 % in Cycles ≥13. CONCLUSION: Pemetrexed/pembrolizumab/platinum has manageable toxicity with longer duration of treatment. While the incidence of renal toxicity was slightly higher in the pembrolizumab combination as compared to pemetrexed, the incidence did not increase in later treatment cycles. These results support the safe use of the KEYNOTE-189 regimen in clinical practice. CLINICAL TRIAL REGISTRATION NUMBER: NCT02578680 (clinicaltrials.gov).

KRAS mutation as a prognostic factor and predictive factor in advanced/metastatic non-small cell lung cancer: A systematic literature review and meta-analysis.

KRAS (Kirsten Rat Sarcoma) is the most common oncogenic mutation detected in patients with non-small cell lung cancer (NSCLC). However, the role of KRAS as either a prognostic factor or predictive factor (modifier of treatment effects) in NSCLC is not well established at this time. This systematic literature review (SLR) and meta-analysis synthesized the available evidence regarding the role of KRAS mutation as a predictive factor and/or prognostic factor of survival and response outcomes in patients with advanced/metastatic (stage IIIB-IV) NSCLC. Relevant clinical trials and observational studies were identified by searching MEDLINE, Embase and Cochrane Register of Controlled Trials. Meta-analyses were performed using data extracted from multivariable and univariable analyses from clinical studies to assess the empirical evidence of KRAS mutation status as a prognostic or/and predicitive factor. 43 selected studies were identified by the SLR and included in this meta-analysis. Pairwise meta-analyses of hazard ratios (HRs) reported in randomized controlled trials (RCTs) did not demonstrate a significant prognostic effect of mutant KRAS on overall survival (OS) (HR=1.10; 95% CI [0.88, 1.38]) or progression free survival (PFS) (HR=1.03; 95% CI [0.80, 1.33]). However, when conducting meta-analyses on HRs reported in observational studies, a statistically significant negative prognostic effect of mutant KRAS was observed (OS HR=1.71; 95% CI [1.07, 2.84]; PFS HR=1.18; 95% CI [1.02, 1.36]). Meta-analyses of objective response rate (ORR) in RCTs demonstrated a negative prognostic effect of mutant KRAS (RR=0.38; 95% CI [0.16, 0.63]). Limited data were available to evaluate the role of KRAS mutation as a predictive factor. In conclusion, this research offers evidence that KRAS mutation may be a negative prognostic factor for survival and response outcomes in patients with advanced/metastatic NSCLC, but further research is needed to address conflicting results on the importance of KRAS mutations as a predictive factor.

Treatment Decisions for Advanced Non-Squamous Non-Small Cell Lung Cancer: Patient and Physician Perspectives on Maintenance Therapy.

INTRODUCTION: Advanced non-small cell lung cancer (NSCLC) is a severe disease with burdensome symptoms and traditionally poor outcomes. The treatment of advance disease is based on chemotherapy, with the recent addition of immunotherapy. Patients who respond to initial treatment can opt to receive maintenance therapy (MT). It is important to understand why patients with advanced NSCLC choose to accept or refuse therapy, and how physician recommendations play into this decision-making process. This study characterized patient and physician decision-making regarding treatment for patients with advanced non-squamous NSCLC in the USA using the example of MT. METHODS AND MATERIALS: This study employed multiple approaches: patient interviews, a patient survey, and a physician survey. Qualitative interviews were conducted among patients who had been offered MT to identify factors influencing treatment decision-making. The patient survey explored the decision-making process and quantified challenges and motivators for receiving MT. The physician survey included a discrete choice experiment to understand the relationship between physician treatment recommendations and patient characteristics. RESULTS: Interviewed patients (n = 10) were motivated to receive MT in the hope of extending their lives and being proactive against their cancer, and they anticipated reduced adverse effects compared with first-line therapy. Surveyed patients (n = 77) described several deterrents to receiving therapy; the most prominent was severity of adverse effects, which was an influencing factor for 34% of patients. The major motivator for receiving therapy was the potential to extend life, which influenced 97% of patients. A total of 100 oncologists participated in the physician survey. Patients' lack of treatment motivation/inconvenience, disease progression, presence of severe renal co-morbidities, and older age decreased the likelihood of physicians recommending the use of MT. CONCLUSION: This study identified challenges and motivators influencing advanced NSCLC patients' decisions to accept or refuse therapy, as well as patient and disease characteristics associated with physician's treatment recommendations for MT.

Treatment patterns, duration and outcomes of pemetrexed maintenance therapy in patients with advanced NSCLC in a real-world setting.

OBJECTIVES: In patients with non-squamous non-small-cell lung cancer (NSCLC), maintenance therapy regimens, including pemetrexed, have been shown to prolong overall survival (OS) and progression-free survival (PFS). The purpose of this study was to describe real-world maintenance use of pemetrexed and associated outcomes in patients with advanced NSCLC. METHODS: This was a retrospective, observational study that used longitudinal, demographically and geographically diverse electronic health record data in the United States. Eligible patients were adults with advanced non-squamous NSCLC who had received maintenance treatment with pemetrexed monotherapy or pemetrexed plus bevacizumab. Descriptive statistics were used to describe the patient population and multivariable logistic regression was used to identify the factors associated with duration of maintenance therapy. Kaplan-Meier curves and Cox regression models were used for time-to-event analysis. RESULTS: Patients receiving pemetrexed maintenance therapy were treated with either pemetrexed monotherapy (66.0%) or pemetrexed plus bevacizumab (34.0%). Carboplatin and pemetrexed (37.9%) or carboplatin, pemetrexed and bevacizumab (36.1%) were the most commonly used first-line therapies observed. The majority (84.9%) of these maintenance patients responded to first-line therapy. The median duration of maintenance therapy was 6.0 months for pemetrexed and bevacizumab and 4.1 months for pemetrexed monotherapy. The median OS from the start of first-line therapy of the total study cohort was 21.5 months (95% CI 20.0, 22.9). CONCLUSION: Real-world effectiveness of pemetrexed maintenance therapy is similar to that observed in published randomized controlled trials, confirming a role for pemetrexed maintenance in eligible patients in clinical practice.

Treatment Patterns by EGFR Mutation Status in Non-Small Cell Lung Cancer Patients in the USA: A Retrospective Database Analysis.

INTRODUCTION: Targeted therapies, including tyrosine kinase inhibitors (TKIs) that target the sensitizing epidermal growth factor receptor (EGFR) gene are recommended for patients with non-small cell lung cancer (NSCLC). Most patients with NSCLC who test positive for the EGFR mutation and receive TKIs develop resistance to these drugs. Questions remain regarding which treatment sequence is optimal for patients with EGFR-mutant NSCLC, and few studies have evaluated patterns of TKI treatment use in NSCLC, irrespective of EGFR mutation status, in a real-world setting. This population-based study aimed to evaluate treatment patterns at a national level in the USA. METHODS: This retrospective observational study used data from the US Oncology Network's iKnowMed database. Patients with advanced NSCLC who initiated first-line therapy with erlotinib and/or intravenous chemotherapy between January 1, 2012 and June 30, 2015 and met all other study criteria were included. Descriptive analyses assessed demographic and clinical characteristics and treatment patterns among the overall study cohort, as well as for specific erlotinib treatment subgroups, stratified by EGFR status. RESULTS: Among the 3108 patients identified, 18.5% were EGFR positive, 49.8% were EGFR negative, and 31.7% were EGFR documented unknown. For the overall cohort, 18.4% received first-line erlotinib monotherapy, fewer than 1% received first-line combination therapy (erlotinib plus chemotherapy), 4.7% received second-line erlotinib monotherapy, and 3.3% received second-line combination therapy. First-line erlotinib monotherapy was used in 77.8% of all EGFR positive patients. Almost two-thirds of the overall cohort were not observed to have advanced to second-line therapy. CONCLUSIONS: As treatment options evolve, this study provides real-world treatment patterns that suggest concordance with NCCN guidelines and confirm the remaining need to understand sequencing of therapies and related outcomes. FUNDING: Eli Lilly and Company.

An exploratory subgroup analysis of race and gender in squamous cancer of the head and neck: inferior outcomes for African American males in the LORHAN database.

OBJECTIVES: Previous retrospective analyses show poor outcomes for African American (AA) patients with head and neck carcinoma (HNC). Such racial disparities are not well understood, and generally studies have been too small to investigate subgroups and interactions related to race. MATERIALS AND METHODS: The longitudinal oncology registry of head and neck carcinoma registry was used to identify patients ⩾18 years of age with squamous cell carcinoma of the head and neck, with no baseline metastases, and with an adequate record of survival time. Patient demographic and treatment characteristics were evaluated as a function of race and other known potential confounders of outcome. Associations between patient characteristics, including smoking, stage, performance status, and overall survival (OS) and progression-free survival (PFS) outcomes were also examined. RESULTS: Analysis of OS and PFS confirmed prior reports of inferior outcomes in AA patients vs. Whites with median OS/3-yr rate 41.7 mo/52% in AAs vs. 56.6 mo/70% in Whites (hazard ratio: 1.69 [95% confidence interval: 1.42, 2.01]). The elevated risk for worse OS and PFS in AAs remained, after multivariate adjustment. African American males incurred most of the excess risk compared to AA females. CONCLUSION: This exploratory study confirmed a worse OS and PFS prognosis for AA patients, and it documents that most of the excess risk occurs in AA males. Future studies should confirm these findings and should investigate biological and other factors that account for such profound differences in outcomes.

Healthcare costs and workloss burden of patients with chemotherapy-associated peripheral neuropathy in breast, ovarian, head and neck, and nonsmall cell lung cancer.

Objective. Chemotherapy-associated peripheral neuropathy (CAPN) is a painful side-effect of chemotherapy. This study assesses healthcare and workloss costs of CAPN patients with breast, ovarian, head/neck, or non-small cell lung cancer (NSCLC) from a third-party payor/employer perspective. Research Design and Methods. Patients with qualifying tumors, and claims for chemotherapy and services indicative of peripheral neuropathy (PN) within 9-months of chemotherapy (cases) were identified in a administrative claims database. Cases were matched 1 : 1 to controls with no PN-related claims based on demographics, diabetes history and propensity for having a diagnosis of PN during the study period (based on resource use and comorbidities in a 3-month baseline period). Average all-cause healthcare costs, resource use and workloss burden were determined. Results. Average healthcare costs were $17,344 higher for CAPN cases than their non-CAPN controls, with outpatient costs being the highest component (with cases having excess costs of $8,092). On average, each CAPN case had 12 more outpatient visits than controls, and spent more days in the hospital. Workloss burden was higher for cases but not statistically different from controls. Conclusion. This study establishes that breast, ovarian, head/neck, or NSCLC patients with CAPN have significant excess healthcare costs and resource use.

Evaluation of the Reliability of Electronic Medical Record Data in Identifying Comorbid Conditions among Patients with Advanced Non-Small Cell Lung Cancer.

Background. Traditional methods for identifying comorbidity data in EMRs have relied primarily on costly and time-consuming manual chart review. The purpose of this study was to validate a strategy of electronically searching EMR data to identify comorbidities among cancer patients. Methods. Advanced stage NSCLC patients (N = 2,513) who received chemotherapy from 7/1/2006 to 6/30/2008 were identified using iKnowMed, US Oncology's proprietary oncology-specific EMR system. EMR data were searched for documentation of comorbidities common to advanced stage cancer patients. The search was conducted by a series of programmatic queries on standardized information including concomitant illnesses, patient history, review of systems, and diagnoses other than cancer. The validity of the comorbidity information that we derived from the EMR search was compared to the chart review gold standard in a random sample of 450 patients for whom the EMR search yielded no indication of comorbidities. Negative predictive values were calculated. Results. The overall prevalence of comorbidities of 22%. Overall negative predictive value was 0.92 in the 450 patients randomly sampled patients (36 of 450 were found to have evidence of comorbidities on chart review). Conclusion. Results of this study suggest that efficient queries/text searches of EMR data may provide reliable data on comorbid conditions among cancer patients.

Cost-effectiveness of pemetrexed as first-line maintenance therapy for advanced nonsquamous non-small cell lung cancer.

INTRODUCTION: The primary objective was to estimate the cost-effectiveness of maintenance therapy with pemetrexed (Pem) compared with observation, each with best supportive care, in patients with advanced non-small cell lung cancer (NSCLC) who have completed, without progression, at least four cycles of first-line platinum chemotherapy, particularly in those with nonsquamous cell histology. Secondary comparisons included Pem with erlotinib (Erl) or Pem with bevacizumab (Bev). METHODS: A semi-Markov model was developed to compare the 3-year impact of Pem with three other alternatives for maintenance therapy from a United States payer perspective. Data from randomized controlled clinical trials provided clinical inputs. Medicare reimbursement rates were used to determine drug costs. A retrospective claims database analysis was used to obtain estimates of other direct NSCLC-related costs. RESULTS: In the prespecified subset of patients with nonsquamous cell histology only, the incremental cost per life-year gained was $122,371 for Pem to observation and $150,260 for Pem to Erl, and Bev was dominated by Pem. In all patients with advanced NSCLC regardless of histologic subtype, using Pem as maintenance therapy led to an incremental cost per life-year gained of $205,597 compared with observation and $312,341 compared with Erl. CONCLUSIONS: Compared with observation and other agents used and/or reimbursed for maintenance therapy in advanced NSCLC, Pem may be considered cost-effective, particularly in patients with nonsquamous cell histology. This analysis is the first to evaluate the cost-effectiveness of maintenance therapy in advanced NSCLC and emphasizes the importance of histology in identifying the appropriate patient for Pem maintenance therapy.

Neutropenia-related costs in patients treated with first-line chemotherapy for advanced non-small cell lung cancer.

BACKGROUND: Neutropenia is a major adverse event often associated with chemotherapy administration. Neutropenia-related complications often lead to increased use of costly health care including inpatient and outpatient services. Monitoring and treatment of neutropenia thus place an economic burden on the health care system. OBJECTIVES: To evaluate (a) costs and medical resource use for chemotherapy- related afebrile and febrile neutropenia in an elderly population with Stage IIIB or Stage IV non-small cell lung cancer (NSCLC), and (b) costs unrelated to neutropenia and total all-cause health care costs during first-line chemotherapy. METHODS: Study patients in this retrospective database analysis were aged 65 years or older with a diagnosis of Stage IIIB or Stage IV NSCLC in the Surveillance, Epidemiology and End Results (SEER) cancer registry from 1998 through 2002. Neutropenia was identified by the presence of a primary or secondary diagnosis code for diseases of white blood cells (ICD-9-CM = 288.xx) during a period of first-line chemotherapy treatment. Febrile neutropenia was defined by (a) an inpatient hospitalization with a primary or secondary diagnosis for neutropenia occurring at any time during first-line chemotherapy or (b) intravenous or intramuscular antibiotic administration occurring after the initial neutropenia diagnosis and during first-line chemotherapy. Patients with neutropenia without these events were considered to have afebrile neutropenia. Patients were followed in the SEER-Medicare database to evaluate costs (defined as all Medicare payments, primary insurer payments, and patient copayments and deductibles) and resource use associated with afebrile or febrile neutropenia while on first-line chemotherapy. If a patient switched to second-line chemotherapy, the day prior to the switch was defined as the end of first-line treatment. If a switch to second-line therapy did not occur, then first-line therapy was assumed to end 30 days following administration of the last first-line agent. Costs were summed for 2 main types of cost measures: neutropenia-related costs, defined as costs for claims with either a primary or secondary diagnosis of neutropenia, and costs unrelated to neutropenia. Costs were classified using ICD-9-CM diagnosis and procedure codes appearing on the claims, with confidence intervals [CIs] for cost measures estimated by using nonparametric bootstrapping methods. Group comparisons of patient characteristics, medical utilization, and cost study measures were made using 2-sided Pearson chi-square and t-test statistics for categorical and continuous measures, respectively. The no neutropenia group was used as the reference category for comparisons involving patient characteristic, medical utilization, and total all-cause health care cost study measures. For total neutropenia-related costs, afebrile and febrile neutropenia study groups were compared. RESULTS: Among elderly patients treated first-line for advanced NSCLC, 5,138 met inclusion criteria, of whom 1,228 (23.9%) developed afebrile (n = 740, 14.4%) or febrile neutropenia (n = 488, 9.5%) while on first-line chemotherapy. Mean per patient costs for treating neutropenia during first-line chemotherapy were $12,148 (standard deviation [SD] = $15,432, 95% confidence interval [CI] = $10,915-$13,607) for patients with febrile neutropenia and $3,099 (SD = $4,541, 95% CI = $2,796-$3,431) for patients with afebrile neutropenia (P<0.001), with mean (SD) length of follow-up (duration of first-line chemotherapy) of 4.5 (4.8) and 5.5 (7.0) months, respectively. Expressed as a percentage of total all-cause health care costs during first-line chemotherapy, neutropenia-related costs accounted for 32.2% of total costs for patients with febrile neutropenia (mean [SD] = $37,694 [$26,078]) and 9.1% of total costs for patients with afebrile neutropenia (mean [SD] = $34,204 [$26,317]). Mean neutropenia-related costs per patient per month (PPPM) during first-line chemotherapy were $2,700 for patients with febrile neutropenia and $563 for patients with afebrile neutropenia. PPPM costs unrelated to neutropenia for patients with afebrile neutropenia, febrile neutropenia, and no neutropenia, respectively, were $5,655, $5,677, and $6,146. In sensitivity analyses, results were highly sensitive to the definition of neutropenia (i.e., claims with primary diagnosis only vs. primary or secondary diagnosis) but insensitive to the type of chemotherapy regimen. CONCLUSION: Neutropenia is a major adverse event that places patients at an increased risk of infection and subsequent morbidity and mortality. For elderly patients undergoing first-line chemotherapy for NSCLC, neutropenia, particularly febrile neutropenia, is associated with substantially higher total all-cause health care costs.

Cost-effectiveness of pemetrexed plus cisplatin as first-line therapy for advanced nonsquamous non-small cell lung cancer.

INTRODUCTION: To estimate the cost-effectiveness of first-line cisplatin/pemetrexed (Cis/Pem) compared with cisplatin/gemcitabine (Cis/Gem), carboplatin/paclitaxel (Carb/Pac), and carboplatin/paclitaxel/bevacizumab (Carb/Pac/Bev) in patients with advanced non-small cell lung cancer (NSCLC), particularly in those with nonsquamous cell histology (i.e., adenocarcinoma, large cell carcinoma, or histology not otherwise specified). METHODS: A semi-Markov model was developed to compare the 2-year impact of Cis/Pem to three other first-line regimens from the U.S. payer perspective. Data from the randomized controlled clinical trial of Cis/Pem versus Cis/Gem and a mixed treatment comparison model (no head-to-head data were available for the Cis/Pem to Carb/Pac or Carb/Pac/Bev comparisons) provided clinical inputs. Medicare reimbursement rates were used to determine drug costs. A retrospective claims database analysis was used to obtain estimates of other direct NSCLC-related costs. RESULTS: In all patients with advanced NSCLC regardless of histologic subtype, using Cis/Pem as first-line chemotherapy led to an incremental cost per life-year gained (LYG) of $104,577 for Cis/Pem to Cis/Gem and $231,291 for Cis/Pem to Carb/Pac. In the prespecified subset of patients with nonsquamous cell histology, the incremental cost per LYG was $83,537 for Cis/Pem to Cis/Gem and $178,613 for Cis/Pem to Carb/Pac. The incremental cost per LYG for Carb/Pac/Bev to Cis/Pem was more than $300,000. CONCLUSIONS: Compared with commonly used and reimbursed regimens for first-line chemotherapy in advanced NSCLC, Cis/Pem may be considered cost-effective, particularly in patients with nonsquamous cell histology. This analysis emphasizes the importance of histology in identifying the appropriate patient for Cis/Pem first-line chemotherapy.

Outcomes after HLA-matched sibling transplantation or chemotherapy in children with B-precursor acute lymphoblastic leukemia in a second remission: a collaborative study of the Children's Oncology Group and the Center for International Blood and Marrow Transplant Research.

The best treatment approach for children with B-precursor acute lymphoblastic leukemia (ALL) in second clinical remission (CR) after a marrow relapse is controversial. To address this question, we compared outcomes in 188 patients enrolled in chemotherapy trials and 186 HLA-matched sibling transplants, treated between 1991 and 1997. Groups were similar except that chemotherapy recipients were younger (median age, 5 versus 8 years) and less likely to have combined marrow and extramedullary relapse (19% versus 30%). To adjust for time-to-transplant bias, treatment outcomes were compared using left-truncated Cox regression models. The relative efficacy of chemotherapy and transplantation depended on time from diagnosis to first relapse and the transplant conditioning regimen used. For children with early first relapse (< 36 months), risk of a second relapse was significantly lower after total body irradiation (TBI)-containing transplant regimens (relative risk [RR], 0.49; 95% confidence interval [CI] 0.33-0.71, P < .001) than chemotherapy regimens. In contrast, for children with a late first relapse (> or = 36 months), risks of second relapse were similar after TBI-containing regimens and chemotherapy (RR, 0.92; 95% CI, 0.49-1.70, P = .78). These data support HLA-matched sibling donor transplantation using a TBI-containing regimen in second CR for children with ALL and early relapse.