Virote Sriuranpong

Detection and Dynamic Changes of EGFR Mutations from Circulating Tumor DNA as a Predictor of Survival Outcomes in NSCLC Patients Treated with First-line Intercalated Erlotinib and Chemotherapy

Purpose: Blood-based circulating-free (cf) tumor DNA may be an alternative to tissue-based EGFR mutation testing in NSCLC. This exploratory analysis compares matched tumor and blood samples from the FASTACT-2 study. Experimental Design: Patients were randomized to receive six cycles of gemcitabine/platinum plus sequential erlotinib or placebo. EGFR mutation testing was performed using the cobas tissue test and the cobas blood test (in development). Blood samples at baseline, cycle 3, and progression were assessed for blood test detection rate, sensitivity, and specificity; concordance with matched tumor analysis (n = 238), and correlation with progression-free survival (PFS) and overall survival (OS). Results: Concordance between tissue and blood tests was 88%, with blood test sensitivity of 75% and a specificity of 96%. Median PFS was 13.1 versus 6.0 months for erlotinib and placebo, respectively, for those with baseline EGFR mut+ cfDNA [HR, 0.22; 95% confidence intervals (CI), 0.14–0.33, P < 0.0001] and 6.2 versus 6.1 months, respectively, for the EGFR mut− cfDNA subgroup (HR, 0.83; 95% CI, 0.65–1.04, P = 0.1076). For patients with EGFR mut+ cfDNA at baseline, median PFS was 7.2 versus 12.0 months for cycle 3 EGFR mut+ cfDNA versus cycle 3 EGFR mut− patients, respectively (HR, 0.32; 95% CI, 0.21–0.48, P < 0.0001); median OS by cycle 3 status was 18.2 and 31.9 months, respectively (HR, 0.51; 95% CI, 0.31–0.84, P = 0.0066). Conclusions: Blood-based EGFR mutation analysis is relatively sensitive and highly specific. Dynamic changes in cfDNA EGFR mutation status relative to baseline may predict clinical outcomes. Clin Cancer Res; 21(14); 3196–203. ©2015 AACR.

Effect of a Proposed Trastuzumab Biosimilar Compared With Trastuzumab on Overall Response Rate in Patients With ERBB2 (HER2)-Positive Metastatic Breast Cancer: A Randomized Clinical Trial.

Importance Treatment with the anti-ERBB2 humanized monoclonal antibody trastuzumab and chemotherapy significantly improves outcome in patients with ERBB2 (HER2)–positive metastatic breast cancer; a clinically effective biosimilar may help increase access to this therapy. Objective To compare the overall response rate and assess the safety of a proposed trastuzumab biosimilar plus a taxane or trastuzumab plus a taxane in patients without prior treatment for ERBB2-positive metastatic breast cancer. Design, Setting, and Participants Multicenter, double-blind, randomized, parallel-group, phase 3 equivalence study in patients with metastatic breast cancer. From December 2012 to August 2015, 500 patients were randomized 1:1 to receive a proposed biosimilar or trastuzumab plus a taxane. Chemotherapy was administered for at least 24 weeks followed by antibody alone until unacceptable toxic effects or disease progression occurred. Interventions Proposed biosimilar (n = 230) or trastuzumab (n = 228) with a taxane. Main Outcomes and Measures The primary outcome was week 24 overall response rate (ORR) defined as complete or partial response. Equivalence boundaries were 0.81 to 1.24 with a 90% CI for ORR ratio (proposed biosimilar/trastuzumab) and −15% to 15% with a 95% CI for ORR difference. Secondary outcome measures included time to tumor progression, progression-free and overall survival at week 48, and adverse events. Results Among 500 women randomized, the intention-to-treat population included 458 women (mean [SD] age, 53.6 [11.11] years) and the safety population included 493 women. The ORR was 69.6% (95% CI, 63.62%-75.51%) for the proposed biosimilar vs 64.0% (95% CI, 57.81%-70.26%) for trastuzumab. The ORR ratio (1.09; 90% CI, 0.974-1.211) and ORR difference (5.53; 95% CI, −3.08 to 14.04) were within the equivalence boundaries. At week 48, there was no statistically significant difference with the proposed biosimilar vs trastuzumab for time to tumor progression (41.3% vs 43.0%; −1.7%; 95% CI, −11.1% to 6.9%), progression-free survival (44.3% vs 44.7%; −0.4%; 95% CI, −9.4% to 8.7%), or overall survival (89.1% vs 85.1%; 4.0%; 95% CI, −2.1% to 10.3%). In the proposed biosimilar and trastuzumab groups, 239 (98.6%) and 233 (94.7%) had at least 1 adverse event, the most common including neutropenia (57.5% vs 53.3%), peripheral neuropathy (23.1% vs 24.8%), and diarrhea (20.6% vs 20.7%). Conclusions and Relevance Among women with ERBB2-positive metastatic breast cancer receiving taxanes, the use of a proposed trastuzumab biosimilar compared with trastuzumab resulted in an equivalent overall response rate at 24 weeks. Further study is needed to assess safety and long-term clinical outcome. Trial Registration clinicaltrials.gov Identifier: NCT02472964; EudraCT Identifier: 2011-001965-42

Serum NT-proBNP in the early detection of doxorubicin-induced cardiac dysfunction.

Cardiac dysfunction is a major limitation of anthracycline treatment in cancer patients. There are several useful serum markers in other types of cardiomyopathy, including N‐terminal pro‐brain‐natriuretic peptide (NT‐proBNP), troponin‐T and creatine kinase MB isoform. We investigated the potential application of these serum biomarkers in cancer patients receiving treatment with anthracycline.

Epithelial-Specific Methylation Marker: A Potential Plasma Biomarker in Advanced Non-small Cell Lung Cancer

Background: Under physiological conditions, leukocytes contribute the majority of circulating DNA in plasma. Therefore, detection of methylation at the SHP-1 promoter 2 (SHP1P2) in plasma, which represents epithelial tumor-derived circulating nucleic acids, may serve as a potential noninvasive biomarker for non-small cell lung cancer (NSCLC). Materials and Method: A quantitative polymerase chain reaction-based assay was used to determine the level of SHP1P2 methylation in plasma. Blood samples were prospectively collected from 58 patients with advanced NSCLC, 20 patients with early NSCLC, and 52 healthy volunteers. Results: Most of the healthy volunteers exhibited undetectable levels of SHP1P2 methylation. In contrast, the pretreatment levels of SHP1P2 methylation in the patients with NSCLC were readily detectable, with a median value of 770 pg ml−1 (0–26,500 pg ml−1), which was significantly higher than that of the healthy controls. Furthermore, the patients with advanced NSCLC who presented baseline levels of SHP1P2 methylation of less than 700 pg ml−1 exhibited enhanced median progression-free survival (5.2 versus 2.6 months, p = 0.009) and improved median overall survival (12.6 versus 7.6 months, p = 0.01) compared with patients who exhibited SHP1P2 methylation levels greater than 700 pg ml−1. From a multivariate analysis, the levels of SHP1P2 methylation were significantly associated with survival rates in advanced NSCLC. Conclusion: Measurement of the level of SHP1P2 methylation in plasma serves as a potential noninvasive biomarker for the prognostic assessment of patients with lung cancer. This biomarker can be used to develop risk-adaptive treatments for patients with lung cancer.

Tumor marker analyses from the phase III, placebo-controlled, FASTACT-2 study of intercalated erlotinib with gemcitabine/platinum in the first-line treatment of advanced non-small-cell lung cancer.

OBJECTIVES The FASTACT-2 study of intercalated erlotinib with chemotherapy in Asian patients found that EGFR mutations were the main driver behind the significant progression-free survival (PFS) benefit noted in the overall population. Further exploratory biomarker analyses were conducted to provide additional insight. MATERIALS AND METHODS This multicenter, randomized, placebo-controlled, double-blind, phase III study investigated intercalated first-line erlotinib or placebo with gemcitabine/platinum, followed by maintenance erlotinib or placebo, for patients with stage IIIB/IV non-small cell lung cancer (NSCLC). Provision of samples for biomarker analysis was encouraged but not mandatory. The following biomarkers were analyzed (in order of priority): EGFR mutation by cobas(®) test, KRAS mutation by cobas(®)KRAS test, HER2 by immunohistochemistry (IHC), HER3 by IHC, ERCC1 by IHC, EGFR gene copy number by fluorescence in-situ hybridization (FISH) and EGFR by IHC. All subgroups were assessed for PFS (primary endpoint), overall survival (OS), non-progression rate and objective response rate. RESULTS Overall, 256 patients provided samples for analysis. Considerable overlap was noted among biomarkers, except for EGFR and KRAS mutations, which are mutually exclusive. Other than EGFR mutations (p<0.0001), no other biomarkers were significantly predictive of outcomes in a treatment-by-biomarker interaction test, although ERCC1 IHC-positive status was predictive of improved OS for the erlotinib arm versus placebo in EGFR wild-type patients (median 18.4 vs 9.5 months; hazard ratio [HR] HR=0.32, 95% confidence intervals [CI]: 0.14-0.69, p=0.0024). CONCLUSION Activating EGFR mutations were predictive for improved treatment outcomes with a first-line intercalated regimen of chemotherapy and erlotinib in NSCLC. ERCC1 status may have some predictive value in EGFR wild-type disease, but requires further investigation.

Patient Management with Eribulin in Metastatic Breast Cancer: A Clinical Practice Guide

Eribulin, an antimicrotubule chemotherapeutic agent, is approved for the treatment of pretreated metastatic breast cancer (mBC) based on the positive outcomes of phase II and phase III clinical trials, which enrolled mainly Western patients. Eribulin has recently been approved in an increasing number of Asian countries; however, there is limited clinical experience in using the drug in certain countries. Therefore, we established an Asian working group to provide practical guidance for eribulin use based on our clinical experience. This paper summarizes the key clinical trials, and the management recommendations for the reported adverse events (AEs) of eribulin in mBC treatment, with an emphasis on those that are relevant to Asian patients, followed by further elaboration of our eribulin clinical experience. It is anticipated that this clinical practice guide will improve the management of AEs resulting from eribulin treatment, which will ensure that patients receive the maximum treatment benefit.

Sunrise in melanoma management: Time to focus on melanoma burden in Asia.

1Division ofHematology-Oncology, Department of InternalMedicine, ChangGungMemorial Hospital at Linkou, Taoyuan, Taiwan 2Immune-OncologyCenter of Excellence, Chang-GungMemorial Hospital, Taipei, Taiwan 3Department of Renal Cancer andMelanoma, PekingUniversity CancerHospital & Institute, Beijing, China 4Division ofHematology-Oncology, Department of InternalMedicine,MackayMemorial Hospital, Taipei, Taiwan 5Yonsei CancerCenter, Yonsei University College ofMedicine, Seoul, SouthKorea 6Division ofMedicalOncology, National CancerCentre Singapore, Singapore, Singapore 7YingChiHoAnthonyClinic, Central, HongKong 8UniversityMalayaMedical Centre, Kuala Lumpur,Malaysia 9NationalHospital ofDermatology andVenereology, Hanoi, Vietnam 10FortisHospital,Mumbai, India 11ChulalongkornUniversity and theKingChulalongkornMemorial Hospital, Bangkok, Thailand 12Cardinal SantosCancerCenter,Manila, the Philippines 13DharmaisNational CancerCenter, Jakarta, Indonesia 14Department ofDermatologicOncology, National CancerCenterHospital, Tokyo, Japan

Results of PROFILE 1029, a Phase III Comparison of First-Line Crizotinib versus Chemotherapy in East Asian Patients with ALK-Positive Advanced Non–Small Cell Lung Cancer

Introduction: The phase III randomized PROFILE 1014 study demonstrated superiority of crizotinib to first‐line chemotherapy in prolonging progression‐free survival (PFS) in previously untreated patients with ALK receptor tyrosine kinase gene (ALK)‐positive advanced nonsquamous NSCLC. This result was consistent with that in the smaller subset of East Asian patients in PROFILE 1014. The subsequent study reported here prospectively evaluated crizotinib in a larger East Asian patient population. Methods: In this open‐label phase III study (PROFILE 1029), patients were randomized 1:1 to receive orally administered crizotinib 250 mg twice daily continuously (3‐week cycles) or intravenously administered chemotherapy (pemetrexed 500 mg/m2, plus cisplatin 75 mg/m2, or carboplatin [at a dose to produce area under the concentration–time curve of 5–6 mg·min/mL]) every 3 weeks for a maximum of six cycles. PFS confirmed by independent radiology review was the primary end point. Results: Crizotinib significantly prolonged PFS (hazard ratio, 0.402; 95% confidence interval [CI]: 0.286–0.565; p < 0.001). The median PFS was 11.1 months with crizotinib and 6.8 months with chemotherapy. The objective response rate was 87.5% (95% CI: 79.6–93.2%) with crizotinib versus 45.6% (95% CI: 35.8–55.7%) with chemotherapy (p < 0.001). The most common adverse events were increased transaminase levels, diarrhea, and vision disorders with crizotinib and leukopenia, neutropenia, and anemia with chemotherapy. Significantly greater improvements from baseline in patient‐reported outcomes were seen in crizotinib‐treated versus chemotherapy‐treated patients. Conclusions: First‐line crizotinib significantly improved PFS, objective response rate, and patient‐reported outcomes compared with standard platinum‐based chemotherapy in East Asian patients with ALK‐positive advanced NSCLC, which is similar to the results from PROFILE 1014. The safety profiles of crizotinib and chemotherapy were consistent with those previously published.