Cheryl Ho

Randomized, Double-Blind Trial of Carboplatin and Paclitaxel With Either Daily Oral Cediranib or Placebo in Advanced Non–Small-Cell Lung Cancer: NCIC Clinical Trials Group BR24 Study

PURPOSE This phase II/III double-blind study assessed efficacy and safety of cediranib with standard chemotherapy as initial therapy for advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Paclitaxel (200 mg/m(2)) and carboplatin (area under the serum concentration-time curve 6) were given every 3 weeks, with daily oral cediranib or placebo at 30 mg (first 45 patients received 45 mg). Progression-free survival (PFS) was the primary outcome of the phase II interim analysis; phase III would proceed if the hazard ratio (HR) for PFS < or = 0.77 and toxicity were acceptable. Results A total of 296 patients were enrolled, 251 to the 30-mg cohort. The phase II interim analysis demonstrated a significantly higher response rate (RR) for cediranib than for placebo, HR of 0.77 for PFS, no excess hemoptysis, and a similar number of deaths in each arm. The study was halted to review imbalances in assigned causes of death. In the primary phase II analysis (30-mg cohort), the adjusted HR for PFS was 0.77 (95% CI, 0.56 to 1.08) with a higher RR for cediranib than for placebo (38% v 16%; P < .0001). Cediranib patients had more hypertension, hypothyroidism, hand-foot syndrome, and GI toxicity. Hypoalbuminemia, age > or = 65 years, and female sex predicted increased toxicity. Survival update (N = 296) 10 months after study unblinding favored cediranib over placebo (median of 10.5 months v 10.1 months; HR, 0.78; 95% CI, 0.57 to 1.06; P = .11). Causes of death in the cediranib 30-mg cohort were NSCLC (81%), protocol toxicity +/- NSCLC (13%), and other (6%); for the placebo group, they were 98%, 0%, and 2%, respectively. CONCLUSION The addition of cediranib to carboplatin/paclitaxel results in improved response and PFS, but does not appear tolerable at a 30-mg dose. Consequently, the National Cancer Institute of Canada Clinical Trials Group and the Australasian Lung Cancer Trials Group initiated a randomized, double-blind, placebo-controlled trial of cediranib 20 mg with carboplatin and paclitaxel in advanced NSCLC.

Intermittent Erlotinib in Combination with Pemetrexed: Phase I Schedules Designed to Achieve Pharmacodynamic Separation

Introduction: Epidermal growth factor receptor tyrosine kinase inhibitors given concurrently with chemotherapy do not improve patient outcomes compared with chemotherapy alone in advanced non-small cell lung cancer (NSCLC). Pharmacodynamic separation by intermittent delivery of epidermal growth factor receptor tyrosine kinase inhibitors with chemotherapy may increase efficacy by overcoming hypothesized antagonism. Methods: Two dose-escalating phase I trials (arm A and arm B) were conducted simultaneously. Pemetrexed was given every 21 days (500 mg/m2 intravenously). In arm A, erlotinib was given weekly on days 2, 9, and 16 (800–1400 mg). In arm B, erlotinib was given on days 2 to 16 (150–250 mg). Patients continued therapy until disease progression or unacceptable toxicity. Results: Forty-two patients with advanced solid tumors, including 16 NSCLC, were treated. Patient characteristics included median age of 63 (range, 29–77), 19 males, and Karnofsky performance status ≥90/<90 = 27/15. The median number of cycles was 2. Treatment was well tolerated. Planned dose escalation was completed without reaching a maximum tolerated dose. Dose-limiting toxicities included grade 3 infection/fever (arm A: 500/1200) and grade 3 infection/neutropenia (arm B: 500/150). Rash frequency was 55% in arm A and 90% in arm B. There were six partial responses (four lung, one head and neck, one breast) and 16 stable diseases. Four patients with NSCLC remained on therapy for 9, 16, 16, and 22 cycles. Conclusions: We report the first clinical trial to test intermittent erlotinib plus pemetrexed. Pemetrexed 500 mg/m2 and weekly erlotinib 1400 mg (arm A) or pemetrexed 500 mg/m2 and erlotinib 250 mg on days 2 to 16 (arm B) are feasible and well tolerated. Arm B efficacy is being examined in a randomized phase II trial for second-line NSCLC.

Correlations of EGFR mutations and increases in EGFR and HER2 copy number to gefitinib response in a retrospective analysis of lung cancer patients

BackgroundGefitinib, a small molecule tyrosine kinase inhibitor of the Epidermal Growth Factor Receptor (EGFR), has shown limited efficacy in the treatment of lung cancer. Recognized clinical predictors of response to this drug, specifically female, non-smoker, Asian descent, and adenocarcinoma, together suggest a genetic basis for drug response. Recent studies have addressed the relationship between response and either sequence mutations or increased copy number of specific receptor tyrosine kinases. We set out to examine the relationship between response and the molecular status of two such kinases, EGFR and HER2, in 39 patients treated with gefitinib at the BC Cancer Agency.MethodsArchival patient material was reviewed by a pathologist and malignant cells were selectively isolated by laser microdissection or manual recovery of cells from microscope slides. Genomic DNA was extracted from 37 such patient samples and exons 18–24, coding for the tyrosine kinase domain of EGFR, were amplified by PCR and sequenced. EGFR and HER2 copy number status were also assessed using FISH in 26 samples. Correlations between molecular features and drug response were assessed using the two-sided Fishers exact test.ResultsMutations previously correlated with response were detected in five tumours, four with exon 19 deletions and one with an exon 21 missense L858R point mutation. Increased gene copy number was observed in thirteen tumours, seven with EGFR amplification, three with HER2 amplification, and three with amplification of both genes. In our study cohort, a correlation was not observed between response and EGFR mutations (exon 19 deletion p = 0.0889, we observed a single exon 21 mutation in a non-responder) or increases in EGFR or HER2 copy number (p = 0.552 and 0.437, respectively).ConclusionNeither mutation of EGFR nor increased copy number of EGFR or HER2 was diagnostic of response to gefitinib in this cohort. However, validation of these features in a larger sample set is appropriate. Identification of additional predictive biomarkers beyond EGFR status may be necessary to accurately predict treatment outcome.

Lessons learned from the application of whole-genome analysis to the treatment of patients with advanced cancers

Given the success of targeted agents in specific populations it is expected that some degree of molecular biomarker testing will become standard of care for many, if not all, cancers. To facilitate this, cancer centers worldwide are experimenting with targeted “panel” sequencing of selected mutations. Recent advances in genomic technology enable the generation of genome-scale data sets for individual patients. Recognizing the risk, inherent in panel sequencing, of failing to detect meaningful somatic alterations, we sought to establish processes to integrate data from whole-genome analysis (WGA) into routine cancer care. Between June 2012 and August 2014, 100 adult patients with incurable cancers consented to participate in the Personalized OncoGenomics (POG) study. Fresh tumor and blood samples were obtained and used for whole-genome and RNA sequencing. Computational approaches were used to identify candidate driver mutations, genes, and pathways. Diagnostic and drug information were then sought based on these candidate “drivers.” Reports were generated and discussed weekly in a multidisciplinary team setting. Other multidisciplinary working groups were assembled to establish guidelines on the interpretation, communication, and integration of individual genomic findings into patient care. Of 78 patients for whom WGA was possible, results were considered actionable in 55 cases. In 23 of these 55 cases, the patients received treatments motivated by WGA. Our experience indicates that a multidisciplinary team of clinicians and scientists can implement a paradigm in which WGA is integrated into the care of late stage cancer patients to inform systemic therapy decisions.

Toxicity and outcomes in combined modality treatment of head and neck squamous cell carcinoma: cisplatin versus cetuximab.

AIMS The standard of care for locally advanced head and neck squamous cell carcinoma (HNSCC) is radiation therapy (RT) with concurrent cisplatin (CIS). Patients with renal or cardiac dysfunction, hearing loss or poor performance status (PS) may receive RT and cetuximab (CET) at our institution. This study compares treatment toxicities and outcomes. METHODS AND MATERIALS All patients treated with curative intent RT and concurrent CIS (100 mg/m 2 Day 1, 22, 43) or CET (400 mg/m 2 Day -7, 250 mg/m 2 weekly during RT) between August 2007 and July 2010 were reviewed and toxicity and outcomes analyzed. RESULTS Among 349 subjects (262 RT-CIS, 87 RT-CET) characteristics were similar except in age, head and neck subsite and RT fractionation. RT-CIS required more dose reductions, delays, and unplanned admissions and received less intended systemic therapy (ST). Weight loss and gastrostomy-tube use were similar. RT-CIS caused more nausea/vomiting, while RT-CET was associated with more dermatitis and acneiform rash. With mean follow-up of 20 months and 16 months, RT-CIS subjects experienced improved 1-year locoregional control (LRC) (90% vs. 72%, P < 0.01), disease-free survival (DFS) (83% vs. 67%, P < 0.01) and overall survival (OS) (90% vs. 80%, P = 0.04). On multivariate analysis type of ST was associated with LRC and DFS, but not OS. CONCLUSIONS In patients with locally advanced HNSCC, CIS and CET were associated with different toxicity profiles. RT-CIS was associated with improved LRC and DFS, but similar OS compared to RT-CET.

Pan Canadian Rash Trial: A Randomized Phase III Trial Evaluating the Impact of a Prophylactic Skin Treatment Regimen on Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor–Induced Skin Toxicities in Patients With Metastatic Lung Cancer

PURPOSE Erlotinib is an epidermal growth factor receptor inhibitor approved for patients with advanced non-small-cell lung cancer (NSCLC) whose epidermal growth factor receptor expression status is positive or unknown. Although it is efficacious, erlotinib can cause skin toxicity. This prospective, randomized phase III trial examined the effect of prophylactic treatment of erlotinib-induced skin rash. PATIENTS AND METHODS Patients receiving erlotinib in the second- or third-line setting for advanced NSCLC were randomly assigned to prophylactic minocycline (100 mg twice per day for 4 weeks), reactive treatment (after rash developed, per grade of rash), or no treatment unless severe (grade 3). Rash incidence and severity, time to maximal rash, time to resolution, and overall survival (OS) were compared among treatment groups. RESULTS In all, 150 patients were randomly assigned, 50 to each of three treatment arms. The incidence of skin toxicity was 84% regardless of treatment arm. Prophylactic treatment with minocycline significantly lengthened the time to the most severe grade of rash. Grade 3 rash was significantly higher in the no-treatment arm. OS was not significantly different among treatment arms, but patients receiving prophylactic or reactive treatments had a longer OS (7.6 and 8 months, respectively) than those who received no rash treatment (6 months). Rash was not self-limiting. CONCLUSION The incidence of all grades of rash did not differ statistically among the three arms, so the trial was negative. The incidence of grade 3 skin toxicities was reduced in patients who were treated with prophylactic minocycline or reactive treatment. Efficacy was not compromised. Prophylactic minocycline and reactive treatment are both acceptable options for the necessary treatment of erlotinib-induced rash in the second- or third-line setting of metastatic NSCLC.

Phase I Study of Two Different Schedules of Bortezomib and Pemetrexed in Advanced Solid Tumors with Emphasis on Non-small Cell Lung Cancer

Introduction: Bortezomib and pemetrexed are approved anticancer agents with non-overlapping mechanisms of action and toxicity. We examined the safety and tolerability of pemetrexed in combination with two different schedules of bortezomib in patients with advanced solid tumors. Methods: Two separate dose-escalating arms (arm A and arm B) were conducted simultaneously. Patients received pemetrexed on day 1 (D1) (500–600 mg/m2 IV) every 21 days. In arm A, bortezomib was given twice weekly (0.7–1.3 mg/m2 on D1, 4, 8, and 11). In arm B, bortezomib was given weekly (1.0–1.6 mg/m2 on D1 and 8). Results: We treated 27 patients on four dose levels in arm A and three dose levels in arm B. Tumor types included lung (n = 16), adenoid cystic carcinoma (n = 2), prostate (n = 2), sarcoma (n = 2), breast (n = 1), thymus (n = 1), head and neck (n = 1), and gastrointestinal(n = 2). Dose-limiting toxicities were seen in arm A only; grade 3 asthenia (n = 2), grade 3 transaminitis and dehydration (n = 1). The most common grade 3/4 toxicity was neutropenia. Of 26 evaluable patients, 2 patients had partial response (1 in arm A and 1 in arm B), 13 had stable disease (7 in arm A and 6 in arm B), and 11 had progression (6 in arm A and 5 in arm B). Of the 16 patients with non-small cell lung cancer, 2 (12.5%) had partial response and 9 had stable disease, for a disease control rate of 68.8%. Recommended phase II dose for arm A is pemetrexed 500 mg/m2 and bortezomib 1.3 mg/m2 twice weekly. For arm B, the recommended dose is pemetrexed 500 mg/m2, bortezomib 1.6 mg/m2 weekly. Conclusions: Pemetrexed with bortezomib is feasible and tolerable at recommended single-agent doses. Based on the observed efficacy, a phase II study in non-small cell lung cancer is warranted.

EGFR mutation status on brain metastases from non-small cell lung cancer.

OBJECTIVES The purpose of this study was to examine the impact of EGFR mutations on the incidence of brain metastases in patients with advanced non-small cell lung cancer (NSCLC). MATERIALS AND METHODS A retrospective, population-based study was conducted using a provincial cancer registry to identify patients with metastatic NSCLC. Patients with diagnostic EGFR mutation testing were divided into EGFR mutation positive (EGFR+) and EGFR wild type (WT) cohorts. The primary endpoint was the incidence of brain metastases. Cumulative incidence curves were estimated using the competing risk method. The secondary endpoint was overall survival. RESULTS For 543 patients there were 121 EGFR+ and 422 EGFR WT. The cumulative incidence of brain metastases was 39.2% for EGFR+ patients compared to 28.2% for EGFR WT (p=0.038; HR 1.4). In multivariate analysis, younger age and EGFR+ status were significant factors for developing brain metastases. The median survival for the EGFR+ and EGFR WT cohorts were 22.4 and 7.9 months (p<0.001), respectively. In multivariate analysis, poor performance status and brain metastases were factors significant for worse survival. CONCLUSIONS There is a higher incidence of brain metastases for patients with EGFR+ metastatic NSCLC, even when adjusted for differences in survival, compared to EGFR WT. For patients with and without brain metastases, survival prognosis with stage IV NSCLC is much longer with EGFR+ disease.

Referral patterns in advanced non-small cell lung cancer: impact on delivery of treatment and survival in a contemporary population based cohort.

INTRODUCTION Chemotherapy improves overall survival (OS) in advanced non-small cell lung cancer (NSCLC), yet low rates of chemotherapy utilization have been observed. We sought to characterize the clinical effectiveness of chemotherapy in the general population by evaluating referral patterns, predictors of chemotherapy receipt and outcomes. METHODS All referred cases of stage IIIB/IV NSCLC in British Columbia from January 1 to December 31, 2009 were retrospectively reviewed. Patient demographics, tumor characteristics and treatments were extracted. OS was estimated using the Kaplan-Meier method. Cox Proportional Hazards modeling was used to control for confounding variables. Multiple logistic regression was used to assess factors that predicted for chemotherapy treatment. RESULTS 1373 patients were identified. Median age 70 years, 53% male, 37% ECOG ≥ 3. HISTOLOGY 34% non-squamous, 21% squamous and 46% NOS. 748 (54%) patients were assessed by medical oncology and 417 (30%) received chemotherapy. Predictors of chemotherapy treatment were younger age, ECOG 0-2, living in a rural area and not receiving radiotherapy. There was an improvement in OS in patients who received chemotherapy at 13.1 months versus best supportive care 5.4 months (p<0.0001). This remained statistically significant when controlling for ECOG, sex, age, histology (HR 0.68, CI 0.59-0.78). CONCLUSIONS In this population-based setting, 37% of patients had an ECOG ≥ 3 at the time of referral, 54% were assessed by a medical oncologist and only 30% received chemotherapy. This is despite the awareness that chemotherapy significantly improves survival. Strategies to optimize appropriate referral such that patients do not miss out on life-prolonging therapy should be evaluated.

EGFR-directed therapies to treat non-small-cell lung cancer.

Lung cancer is the leading cause of cancer death in men and women. In 2008, in the US > 200,000 patients were diagnosed with lung cancer and > 160,000 died from their disease. Over 80% of lung cancers are of the non-small cell type, for which chemotherapy has demonstrated modest survival benefits at all stages of disease. Agents that alter critical molecular cell growth pathways are a growing area of research and development including targeted therapies directed at the EGFR. Downstream effects of EGFR dimerization and activation include cell proliferation, differentiation and angiogenesis, key events in the malignant process. Two main classes of drugs have been developed, small molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies directed against the extracellular domain of the receptor. This review discusses clinical studies with several new therapies and the plans for drug development.