Daniel J. Becker

A Randomized, Phase 2 Trial of Docetaxel with or without PX-866, an Irreversible Oral Phosphatidylinositol 3-Kinase Inhibitor, in Patients with Relapsed or Metastatic Non–Small-Cell Lung Cancer

Introduction: The phosphotidylinositol-3 kinase/serine-threonine kinase (AKT)/mammalian target of rapamycin signaling pathway is frequently altered in non–small-cell lung cancer (NSCLC). PX-866 is an oral, irreversible, pan-isoform inhibitor of phosphotidylinositol-3 kinase. Preclinical models revealed synergy with docetaxel and a phase 1 trial demonstrated tolerability of this combination. This randomized phase 2 study evaluated PX-866 combined with docetaxel in patients with advanced, refractory NSCLC. Methods: Patients with locally advanced, recurrent, or metastatic NSCLC who had received at least one and no more than two prior systemic treatment regimens were randomized (1:1) to a combination of docetaxel (75 mg/m2 intravenous every 21 days) with or without PX-866 (8 mg orally daily; arms A and B, respectively). The primary end point was progression-free survival (PFS). Secondary end points included objective response rate, overall survival (OS), toxicity, and correlation of biomarker analyses with efficacy outcomes. Results: A total of 95 patients were enrolled. Median PFS was 2 months in arm A and 2.9 months in arm B (p = 0.65). Objective response rates were 6% and 0% in arms A and B, respectively (p = 0.4). There was no difference in OS between the two arms (7.0 versus 9.2 months; p = 0.9). Grade 3 or higher adverse events were infrequent, but more common in the combination arm with respect to diarrhea (7% versus 2%), nausea (4% versus 0%), and vomiting (7% versus 0%). PIK3CA mutations or PTEN loss were infrequently observed. Conclusion: The addition of PX-866 to docetaxel did not improve PFS, response rate, or OS in patients with advanced, refractory NSCLC without molecular preselection.

Clinical Utility of Liquid Diagnostic Platforms in Non-Small Cell Lung Cancer

UNLABELLEDn: A firmer understanding of the genomic landscape of lung cancer has recently led to targeted, therapeutic advances in non-small cell lung cancer. Historically, the reference standard for the diagnosis and genetic interrogation for advanced-stage patients has been tissue acquisition via computed tomography-guided core or fine needle aspiration biopsy. However, this process can frequently put the patient at risk and remains complicated by sample availability and tumor heterogeneity. In addition, the time required to complete the diagnostic assays can negatively affect clinical care. Technological advances in recent years have led to the development of blood-based diagnostics or liquid biopsies with great potential to quickly diagnose and genotype lung cancer using a minimally invasive technique. Recent studies have suggested that molecular alterations identified in cell-free DNA (cfDNA) or circulating tumor DNA can serve as an accurate molecular proxy of tumor biology and reliably predict the response to tyrosine kinase therapy. In addition, several trials have demonstrated the high accuracy of microRNA (miRNA) platforms in discerning cancerous versus benign nodules in high-risk, screened patients. Despite the promise of these platforms, issues remain, including varying sensitivities and specificities between competing platforms and a lack of standardization of techniques and downstream processing. In the present report, the clinical applications of liquid biopsy technologies, including circulating tumor cells, proteomics, miRNA, and cfDNA for NSCLC, are reviewed and insight is provided into the diagnostic and therapeutic implications and challenges of these platforms.nnnIMPLICATIONS FOR PRACTICEnAlthough tumor biopsies remain the reference standard for the diagnosis and genotyping of non-small cell lung cancer, they remain fraught with logistical complexities that can delay treatment decisions and affect clinical care. Liquid diagnostic platforms, including cell-free DNA, proteomic signatures, RNA (mRNA and microRNA), and circulating tumor cells, have the potential to overcome many of these barriers, including rapid and accurate identification of de novo and resistant genetic alterations, real-time monitoring of treatment responses, prognosis of outcomes, and identification of minimal residual disease. The present report provides insights into new liquid diagnostic platforms in non-small cell lung cancer and discusses the promise and challenges of their current and future clinical use.

Beyond PD-L1 testing-emerging biomarkers for immunotherapy in non-small cell lung cancer

Recently, a firmer understanding of tumor immunology and tumor escape mechanisms has led to the development of immune checkpoint inhibitors, antibodies against programmed death-1 (PD-1) and its ligand (PD-L1). Nivolumab, pembrolizumab, and atezolizumab have dramatically altered the treatment paradigm in non-small cell lung cancer (NSCLC) and have each demonstrated improvements in outcomes and quality of life when compared to chemotherapy. Enrichment strategies to better select those patients more likely to respond have identified PD-L1 staining by immunohistochemistry (IHC) to be a predictive biomarker in both treatment naïve and refractory patients. Unfortunately, many challenges exist with this strategy and underscore the need for further exploration for more reliable biomarkers. Multiple tissue and plasma-based enrichment strategies have been identified in the hope of identifying patients more likely to benefit from checkpoint inhibitors. These include tumor mutational load; the inflamed phenotype including tumor infiltrating lymphocytes (TILS) and immunoscore; T-cell receptor clonality; gene signatures, and several plasma biomarkers. Several studies have revealed many of these biomarkers to be reliable predictors of response to immune checkpoint inhibitors across multiple tumor types. Given the small nature of these studies, additional prospective studies are warranted to formalize and validate each of these enrichment strategies.

Uptake of Oxaliplatin and Bevacizumab for Treatment of Node-Positive and Metastatic Colon Cancer

PURPOSEnIn 2004, the US Food and Drug Administration approved bevacizumab and oxaliplatin for use in metastatic colon cancer and oxaliplatin for localized colon cancer. We investigated the diffusion and predictors of use of these medications in the year after approval.nnnPATIENTS AND METHODSnWe used the Surveillance, Epidemiology, and End Results-Medicare database to identify patients older than 65 years diagnosed with stages III and IV colon cancer in 2005. Characteristics of the treating oncologists were identified using the American Medical Association database. We used logistic regression and generalized estimating equations to analyze factors associated with bevacizumab and oxaliplatin use.nnnRESULTSnAmong 1,547 patients with stage III colon cancer who had claims submitted by oncologists, 801 (51.8%) received adjuvant chemotherapy, and of those, 432 (54.1%) received oxaliplatin, whereas 54 (6.7%) received off-label bevacizumab. Among 859 patients with stage IV disease who saw oncologists, 435 (50.6%) received chemotherapy, and of those, 310 (71.3%) received bevacizumab, 289 (66.4%) received oxaliplatin, and 357 (82.1%) received oxaliplatin and/or irinotecan. Older patient age and more comorbidities were associated with nonreceipt of oxaliplatin for stage III disease and oxaliplatin and/or irinotecan for stage IV disease. Having a physician who graduated medical school after 1975 predicted receipt of both adjuvant oxaliplatin (odds ratio [OR], 1.65; 95% CI, 1.11 to 2.45) and oxaliplatin and/or irinotecan for stage IV disease (OR, 2.43; 95% CI, 1.47 to 4.01). None of the factors analyzed predicted bevacizumab receipt.nnnCONCLUSIONnUptake of new chemotherapy drugs for patients diagnosed with stages III and IV colon cancer in 2005 was rapid. Physician characteristics were consistently associated with this uptake.

Exploration of the ASCO and ESMO Value Frameworks for Antineoplastic Drugs

PURPOSEnIn 2015, both ASCO and the European Society for Medical Oncology (ESMO) proposed frameworks to quantify the benefit of antineoplastic drugs in the face of rising costs. We applied these frameworks to drugs approved by the US Food and Drug Administration over the past 12 years and examined relationships between costs and benefits.nnnMETHODSnWe searched FDA.gov for drugs that received initial approval for solid tumors from 2004 to 2015 and calculated the ASCO Net Health Benefit version 2016 (NHB16) and 2015 (NHB15) and the ESMO Magnitude of Clinical Benefit Scale scores for each drug. We calculated descriptive statistics and explored correlations and associations among benefit scores, cost, and independent variables.nnnRESULTSnWe identified 55 drug approvals supported by phase II (18.2%) and III (81.8%) trials, with primary outcomes of overall survival (36.4%), progression-free survival (43.6%), or response rate (20.0%). No significant association was found between NHB16 and year of approval ( P = .81), organ system ( P = .20), or trial comparator arm ( P = .17), but trials with progression-free survival outcomes were associated with higher scores ( P = .007). Both NHB15 and Magnitude of Clinical Benefit Scale scores were approximately normally distributed, but only a moderate correlation existed between them ( r = 0.40, P = .006). No correlation between benefit score and cost (NHB16, r = 0.19; ESMO, r = -0.07) was found. Before 2010, two (15.3%) of 13 approved drugs exceeded

The utilization of MGMT promoter methylation testing in United States hospitals for glioblastoma and its impact on prognosis

500/NHB point × month compared with 10 (25.0%) of 40 drugs subsequently approved.nnnCONCLUSIONnOur analysis of the ASCO and ESMO value frameworks illuminates the heterogeneous benefit of new medications and highlights challenges in constructing a unified concept of drug value. Drug benefit does not correlate with cost, and the number of high cost/benefit outliers has increased.

Survival of Asian Females With Advanced Lung Cancer in the Era of Tyrosine Kinase Inhibitor Therapy

Multiple studies have identified O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status to be an important prognostic factor in glioblastoma (GBM). We used the National Cancer Data Base (NCDB) to analyze completeness of coding for MGMT as well as to compare outcomes of GBM patients treated with adjuvant chemoradiation based on MGMT promoter methylation status (positive, negative, unknown). Patients diagnosed with GBM from 2010 to 2012 who received adjuvant chemoradiation were identified. MGMT promoter methylation status was obtained. The Kaplan-Meier method was used to assess overall survival (OS) by coding status of MGMT promoter methylation (positive, negative, unknown) and Cox regression analysis was used to assess impact of covariables on OS. There were 12,725 patients who met the study criteria, of which 626 (4.9%) were MGMT+, 1,037 (8.1%) were MGMT- and 11.062 (86.9%) were coded as unknown/not coded. Treatment at academic centers was strongly associated with MGMT promoter status testing (OR 2.23, pu202f<u202f0.001), as well as hospital facility within the Northeast (OR 1.55, pu202f<u202f0.001). The median and 2-year OS was 20u202fmonths and 40.2% for MGMT+ compared to 15u202fmonths and 24.1% for MGMT-, respectively (pu202f<u202f0.001). For those coded as MGMT unknown, median and 2-year OS was 14.6u202fmonths and 27.5%, which was significantly worse compared to MGMT+ (pu202f<u202f0.001) but not compared to MGMT- (pu202f=u202f0.78). On multivariable analysis, MGMT+ was strongly associated with improved OS (HR 0.74, pu202f<u202f0.001). Despite convincing evidence that MGMT promoter methylation status has a strong influence on prognosis; it appears to be a highly underutilized test in United States hospitals.

Patterns of care and survival outcomes of palliative radiation for prostate cancer with bone metastases: comparison of ≤5 fractions to ≥10 fractions

Introduction: We examined the effect of access to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy on survival for Asian female (AF) EGFR mutation‐enriched patients with advanced lung adenocarcinoma. Materials and Methods: We used the Surveillance Epidemiology and End Results database to study patients with stage IV lung adenocarcinoma diagnosed from 1998 to 2012. We compared survival (lung cancer‐specific survival [LCSS] and overall survival) between AFs and non‐Asian males (NAMs), an EGFR mutation‐enriched and EGFR mutation‐unenriched population, respectively, with a diagnosis in the pre‐EGFR TKI (1998–2004) and EGFR TKI (2005–2012) eras. We used Cox proportional hazards models to examine the interaction of access to TKI treatment and EGFR enrichment status. Results: Among 3029 AF and 35,352 NAM patients, we found that LCSS was best for AFs with a diagnosis in the TKI era (median, 14 months), followed by AFs with a diagnosis in the pre‐TKI era (median, 8 months), NAMs with a diagnosis in the TKI era (median, 5 months), and NAMs with a diagnosis in the pre‐TKI era (median, 4 months; log‐rank P < .0001). In a multivariable model, the effect of a diagnosis in the TKI era on survival was greater for AFs than for NAMs (LCSS, P = .0020; overall survival, P = .0007). A lung cancer diagnosis in the TKI era was associated with an overall mortality decrease of 26% for AFs (hazard ratio, 0.740; 95% confidence interval, 0.682–0.80) and 15.9% for NAMs (hazard ratio, 0.841; 95% confidence interval, 0.822–0.860). Conclusions: We found increased survival for lung adenocarcinoma diagnoses made after widespread access to EGFR TKIs, with the greatest increase among AF patients enriched for EGFR mutations. The present analysis eliminated the effect of crossover, which has complicated assessments of the survival advantage in EGFR TKI randomized trials. Micro‐Abstract: It has been difficult to prove a survival advantage for epidermal growth factor receptor (EGFR) inhibitors in lung cancer patients with EGFR mutations. Among 38,381 patients, we found that the introduction of EGFR inhibitors was associated with a survival increase among Asian female patients that was not matched by non‐Asian male patients. Our study adds population‐based data to support that the use of EGFR inhibitors extends lives.

Effect of Thoracic Radiotherapy Timing and Fractionation on Survival in Nonmetastatic Small Cell Lung Carcinoma

BACKGROUNDnTo review the palliative radiation fractionation regimens, trends and survival of men within the National Cancer Database (NCDB) diagnosed with prostate cancer and bony metastases.nnnMETHODSnA total of 3,871 patients from the NCDB were included in the analysis (patients treated from 2004-2012). The following fractionation regimens were analyzed [8 Gy × 1, 4 Gy × 5 (short course radiation therapy)], were compared to 3 Gy × 10, 2.50 Gy × 14-15 and 2 Gy × 20-30 (long course radiation therapy). Descriptive statistics, multivariable logistic regression and multivariable cox regression analysis were utilized to assess the data.nnnRESULTSnLonger fractionation schemes were used for 91.7% of patients. Treatment at an academic center (OR, 2.93), increasing distance from treatment center (OR, 1.48-1.59), treatment to the ribs (OR, 2.47), and year of diagnosis 2009 or later (OR, 2.31-3.26) were associated with an increased likelihood of receiving short course radiation, while treatment to the spine (OR, 0.34) was associated with a decreased likelihood of short course radiation. On multivariable analysis, longer course of radiation was associated with increased overall survival (HR =0.66; 95% CI: 0.56-0.78, P<0.001.). However, on landmark analysis this difference disappeared once limiting the survival analysis to men who survived ≥18 months [HR =0.83; 95% CI: 0.62-1.11, P=0.21].nnnCONCLUSIONSnFractionation schemes of ≥10 treatments remain the dominant palliative course of radiation therapy offered for metastatic prostate cancer. However, utilization of ≤5 fractions is slowly increasing, particularly at academic centers.

Patterns of care and outcomes for glioblastoma in patients with poor performance status

Background The optimal timing of thoracic radiation therapy (RT) in relation to chemotherapy is unknown in the treatment of nonmetastatic small cell lung cancer (SCLC). We analyzed the National Cancer Data Base (NCDB) to assess the effect on overall survival (OS) of RT timing with chemotherapy for patients with SCLC. Materials and Methods The NCDB was queried for patients diagnosed with nonmetastatic SCLC from 1998 to 2011 who had undergone definitive chemoradiation. The patients were stratified into quartiles according to the interval between the start of chemotherapy and the start of RT. The first and second quartiles (RT started 0‐20 days after chemotherapy) were classified as “early” RT and the third and fourth quartiles (RT started 21‐126 days after chemotherapy) as “late” RT. Patients were included if they had received hyperfractionated 45 Gy in 30 fractions or standard fractionation of ≥ 60 Gy in 1.8‐ to 2‐Gy fractions. Kaplan‐Meier analyses of OS were performed, and multivariable Cox regression analysis was conducted to assess the effect of the covariates on OS. Results A total of 8391 patients were included (50.5% had received early RT). Early RT was associated with significant improvement in survival (5‐year OS, 21.9% vs. 19.1%; P = .01). On subgroup analysis, the survival advantage for early RT was significant for patients receiving hyperfractionated RT (5‐year OS, 28.2% vs. 21.2%; P = .004) but not for those receiving standard fractionation (19.8% vs. 18.4%; P = .29). On multivariable Cox regression analysis, hyperfractionated RT was associated with reduced mortality (hazard ratio [HR], 0.90; 95% confidence interval [CI], 0.85‐0.96; P = .001), but early RT was not (HR, 0.98; 95% CI, 0.94‐1.04; P = .53). Conclusion These data support the early initiation of hyperfractionated thoracic RT for nonmetastatic SCLC. Micro‐Abstract The present study examined the National Cancer Data Base to assess the practice patterns and survival stratified by thoracic radiation therapy (RT) timing in relation to chemotherapy for nonmetastatic small cell lung carcinoma. The early initiation of thoracic RT was associated with improved survival compared with late initiation, in particular, when hyperfractionated RT was used.