Arunee Dechaphunkul

Osimertinib in Untreated EGFR-Mutated Advanced Non–Small-Cell Lung Cancer

Background Osimertinib is an oral, third‐generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‐TKI) that selectively inhibits both EGFR‐TKI–sensitizing and EGFR T790M resistance mutations. We compared osimertinib with standard EGFR‐TKIs in patients with previously untreated, EGFR mutation–positive advanced non–small‐cell lung cancer (NSCLC). Methods In this double‐blind, phase 3 trial, we randomly assigned 556 patients with previously untreated, EGFR mutation–positive (exon 19 deletion or L858R) advanced NSCLC in a 1:1 ratio to receive either osimertinib (at a dose of 80 mg once daily) or a standard EGFR‐TKI (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily). The primary end point was investigator‐assessed progression‐free survival. Results The median progression‐free survival was significantly longer with osimertinib than with standard EGFR‐TKIs (18.9 months vs. 10.2 months; hazard ratio for disease progression or death, 0.46; 95% confidence interval [CI], 0.37 to 0.57; P<0.001). The objective response rate was similar in the two groups: 80% with osimertinib and 76% with standard EGFR‐TKIs (odds ratio, 1.27; 95% CI, 0.85 to 1.90; P=0.24). The median duration of response was 17.2 months (95% CI, 13.8 to 22.0) with osimertinib versus 8.5 months (95% CI, 7.3 to 9.8) with standard EGFR‐TKIs. Data on overall survival were immature at the interim analysis (25% maturity). The survival rate at 18 months was 83% (95% CI, 78 to 87) with osimertinib and 71% (95% CI, 65 to 76) with standard EGFR‐TKIs (hazard ratio for death, 0.63; 95% CI, 0.45 to 0.88; P=0.007 [nonsignificant in the interim analysis]). Adverse events of grade 3 or higher were less frequent with osimertinib than with standard EGFR‐TKIs (34% vs. 45%). Conclusions Osimertinib showed efficacy superior to that of standard EGFR‐TKIs in the first‐line treatment of EGFR mutation–positive advanced NSCLC, with a similar safety profile and lower rates of serious adverse events. (Funded by AstraZeneca; FLAURA ClinicalTrials.gov number, NCT02296125.)

Buparlisib and paclitaxel in patients with platinum-pretreated recurrent or metastatic squamous cell carcinoma of the head and neck (BERIL-1): a randomised, double-blind, placebo-controlled phase 2 trial

BACKGROUND Phosphatidylinositol 3-kinase (PI3K) pathway activation in squamous cell carcinoma of the head and neck contributes to treatment resistance and disease progression. Buparlisib, a pan-PI3K inhibitor, has shown preclinical antitumour activity and objective responses in patients with epithelial malignancies. We assessed whether the addition of buparlisib to paclitaxel improves clinical outcomes compared with paclitaxel and placebo in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. METHODS In this multicentre, randomised, double-blind, placebo-controlled phase 2 study (BERIL-1), we recruited patients aged 18 years and older with histologically or cytologically confirmed recurrent and metastatic squamous cell carcinoma of the head and neck after disease progression on or after one previous platinum-based chemotherapy regimen in the metastatic setting. Eligible patients were enrolled from 58 centres across 18 countries and randomly assigned (1:1) to receive second-line oral buparlisib (100 mg once daily) or placebo, plus intravenous paclitaxel (80 mg/m2 on days 1, 8, 15, and 22) in 28 day treatment cycles. Randomisation was done via a central patient screening and randomisation system with an interactive (voice and web) response system and stratification by number of previous lines of therapy in the recurrent and metastatic setting and study site. Patients and investigators (including local radiologists) were masked to treatment assignment from randomisation until the final overall survival analysis. The primary endpoint was progression-free survival by local investigator assessment per Response Evaluation Criteria In Solid Tumors (version 1.1) in all randomly assigned patients. Efficacy analyses were done on the intention-to-treat population, whereas safety was analysed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment according to the treatment they received. This trial is registered with ClinicalTrials.gov, number NCT01852292, and is ongoing but no longer enrolling patients. FINDINGS Between Nov 5, 2013, and May 5, 2015, 158 patients were enrolled and randomly assigned to receive either buparlisib plus paclitaxel (n=79) or placebo plus paclitaxel (n=79). Median progression-free survival was 4·6 months (95% CI 3·5-5·3) in the buparlisib group and 3·5 months (2·2-3·7) in the placebo group (hazard ratio 0·65 [95% CI 0·45-0·95], nominal one-sided p=0·011). Grade 3-4 adverse events were reported in 62 (82%) of 76 patients in the buparlisib group and 56 (72%) of 78 patients in the placebo group. The most common grade 3-4 adverse events (occurring in ≥10% of patients in the buparlisib group vs the placebo group) were hyperglycaemia (17 [22%] of 76 vs two [3%] of 78), anaemia (14 [18%] vs nine [12%]), neutropenia (13 [17%] vs four [5%]), and fatigue (six [8%] vs eight [10%]). Serious adverse events (regardless of relation to study treatment) were reported for 43 (57%) of 76 patients in the buparlisib group and 37 (47%) of 78 in the placebo group. On-treatment deaths occurred in 15 (20%) of 76 patients in the buparlisib group and 17 (22%) of 78 patients in the placebo group; most were caused by disease progression and none were judged to be related to study treatment. INTERPRETATION On the basis of the improved clinical efficacy with a manageable safety profile, the results of this randomised phase 2 study suggest that buparlisib in combination with paclitaxel could be an effective second-line treatment for patients with platinum-pretreated recurrent or metastatic squamous cell carcinoma of the head and neck. Further phase 3 studies are warranted to confirm this phase 2 finding. FUNDING Novartis Pharmaceuticals Corporation.

A randomized phase III study evaluating the efficacy of single-dose NEPA, a fixed antiemetic combination of netupitant and palonosetron, versus an aprepitant regimen for prevention of chemotherapy-induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy (HEC)

Abstract Background Co-administration of multiple antiemetics that inhibit several molecular pathways involved in emesis is required to optimize chemotherapy-induced nausea and vomiting (CINV) control in patients receiving highly emetogenic chemotherapy (HEC). NEPA, a fixed combination of a highly selective NK1 receptor antagonist, netupitant (300 mg), and the pharmacologically distinct 5-HT3RA, palonosetron (PALO 0.50 mg), has shown superior CINV prevention compared with PALO in cisplatin and anthracycline/cyclophosphamide-based settings. This study is the first head-to-head comparison of NEPA versus an aprepitant (APR)/granisetron (GRAN) regimen. Patients and methods This randomized, double-blind phase III study conducted in Asia was designed with the primary objective to demonstrate non-inferiority of a single oral dose of NEPA compared with a 3-day oral APR/GRAN regimen in chemotherapy-naïve patients receiving cisplatin-based HEC. All patients also received oral dexamethasone (DEX) on days 1–4. The primary efficacy endpoint was complete response (CR: no emesis/no rescue medication) during the overall (0–120 h) phase. Non-inferiority was defined as a lower 95% CI greater than the non-inferiority margin set at − 10%. Secondary efficacy endpoints included no emesis, no rescue medication, and no significant nausea (NSN). Results Treatment groups were comparable for the 828 patients analyzed: predominantly male (71%); mean age 54.5 years; ECOG 0–1 (98%); lung cancer (58%). NEPA demonstrated non-inferiority to APR/GRAN for overall CR [NEPA 73.8% versus APR/GRAN 72.4%, 95% CI (−4.5%, 7.5%)]. No emesis [NEPA 75.0% versus APR/GRAN 74.0%, 95% CI (−4.8%, 6.9%)] and NSN rates [NEPA 75.7% versus APR/GRAN 70.4%, 95% CI (−0.6%, 11.4%)] were similar between groups, but significantly more NEPA patients did not take rescue medication [NEPA 96.6% versus APR/GRAN 93.5%, 95% CI (0.2%, 6.1%)]. NEPA was well tolerated with a similar safety profile to APR/GRAN. Conclusions In this first study comparing NK1RA regimens and DEX, NEPA administered only on day 1 was non-inferior to a 3-day oral APR/GRAN regimen in preventing CINV associated with HEC.

Clonal Evolutionary Analysis during HER2 Blockade in HER2-Positive Inflammatory Breast Cancer: A Phase II Open-Label Clinical Trial of Afatinib +/- Vinorelbine

Background Inflammatory breast cancer (IBC) is a rare, aggressive form of breast cancer associated with HER2 amplification, with high risk of metastasis and an estimated median survival of 2.9 y. We performed an open-label, single-arm phase II clinical trial (ClinicalTrials.gov NCT01325428) to investigate the efficacy and safety of afatinib, an irreversible ErbB family inhibitor, alone and in combination with vinorelbine in patients with HER2-positive IBC. This trial included prospectively planned exome analysis before and after afatinib monotherapy. Methods and Findings HER2-positive IBC patients received afatinib 40 mg daily until progression, and thereafter afatinib 40 mg daily and intravenous vinorelbine 25 mg/m2 weekly. The primary endpoint was clinical benefit; secondary endpoints were objective response (OR), duration of OR, and progression-free survival (PFS). Of 26 patients treated with afatinib monotherapy, clinical benefit was achieved in 9 patients (35%), 0 of 7 trastuzumab-treated patients and 9 of 19 trastuzumab-naïve patients. Following disease progression, 10 patients received afatinib plus vinorelbine, and clinical benefit was achieved in 2 of 4 trastuzumab-treated and 0 of 6 trastuzumab-naïve patients. All patients had treatment-related adverse events (AEs). Whole-exome sequencing of tumour biopsies taken before treatment and following disease progression on afatinib monotherapy was performed to assess the mutational landscape of IBC and evolutionary trajectories during therapy. Compared to a cohort of The Cancer Genome Atlas (TCGA) patients with HER2-positive non-IBC, HER2-positive IBC patients had significantly higher mutational and neoantigenic burden, more frequent gain-of-function TP53 mutations and a recurrent 11q13.5 amplification overlapping PAK1. Planned exploratory analysis revealed that trastuzumab-naïve patients with tumours harbouring somatic activation of PI3K/Akt signalling had significantly shorter PFS compared to those without (p = 0.03). High genomic concordance between biopsies taken before and following afatinib resistance was observed with stable clonal structures in non-responding tumours, and evidence of branched evolution in 8 of 9 tumours analysed. Recruitment to the trial was terminated early following the LUX-Breast 1 trial, which showed that afatinib combined with vinorelbine had similar PFS and OR rates to trastuzumab plus vinorelbine but shorter overall survival (OS), and was less tolerable. The main limitations of this study are that the results should be interpreted with caution given the relatively small patient cohort and the potential for tumour sampling bias between pre- and post-treatment tumour biopsies. Conclusions Afatinib, with or without vinorelbine, showed activity in trastuzumab-naïve HER2-positive IBC patients in a planned subgroup analysis. HER2-positive IBC is characterized by frequent TP53 gain-of-function mutations and a high mutational burden. The high mutational load associated with HER2-positive IBC suggests a potential role for checkpoint inhibitor therapy in this disease. Trial Registration ClinicalTrials.gov NCT01325428

Phase 2 Study of Erlotinib in Combination With Linsitinib (OSI-906) or Placebo in Chemotherapy-Naive Patients With Non–Small-Cell Lung Cancer and Activating Epidermal Growth Factor Receptor Mutations

Introduction: First‐line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor treatment of advanced non–small‐cell lung cancer with EGFR‐activating mutations improves outcomes compared with chemotherapy, but resistance develops in most patients. Compensatory signaling through type 1 insulin‐like growth factor 1 receptor (IGF‐1R) may contribute to resistance; dual blockade of IGF‐1R and EGFR may improve outcomes. Patients and Methods: We performed a randomized, double‐blind, placebo‐controlled phase II study of linsitinib, a dual IGF‐1R and insulin receptor tyrosine kinase inhibitor, plus erlotinib versus placebo plus erlotinib in chemotherapy‐naive patients with EGFR‐mutation positive, advanced non–small‐cell lung cancer. Patients received linsitinib 150 mg twice daily or placebo plus erlotinib 150 mg once daily on continuous 21‐day cycles. The primary end point was progression‐free survival. Results: After randomization of 88 patients (44 each arm), the trial was unblinded early owing to inferiority in the linsitinib arm. The median progression‐free survival for the linsitinib versus the placebo group was 8.4 months versus 12.4 months (hazard ratio, 1.37; P = .29). Overall response rate (47.7% vs. 75.0%; P = .02) and disease control rate (77.3% vs. 95.5%; P = .03) were also inferior. Whereas most adverse events were ≤ grade 2, linsitinib plus erlotinib was associated with increased adverse events that led to decreased erlotinib exposure (median days, 228 vs. 305). No drug‐drug interaction was suggested by pharmacokinetic and pharmacodynamic results. Conclusion: Adding linsitinib to erlotinib resulted in inferior outcomes compared with erlotinib alone. Further understanding of the signaling pathways and a biomarker that can predict efficacy is needed prior to further clinical development of IGF‐1R inhibitors in lung cancer. Micro‐Abstract: This was a phase II study of linsitinib plus erlotinib versus placebo plus erlotinib in chemotherapy‐naive patients with epidermal growth factor receptor‐mutation positive, advanced, non–small‐cell lung cancer. Linsitinib plus erlotinib resulted in inferior outcomes compared with erlotinib alone. Linsitinib combination was associated with increased adverse events that led to decreased erlotinib exposure. Results highlight the complexity of targeting insulin‐like growth factor‐1 receptor signaling.

Small cell carcinoma of the genitourinary tract: A 10-year single institution experience.

312 Background: Small cell carcinoma (SCC) of the genitourinary (GU) tract is rare and there is no standard treatment strategy for managing these patients. The objective of this study is to report the clinical experience and management of patients with SCC of the GU tract, treated in the Cross Cancer Institute, Edmonton, AB, Canada from 1999 to 2009. METHODS A retrospective chart review of all patients diagnosed with SCC of the GU tract between 1999 to 2009 was undertaken. Data was collected on demographics, clinical and pathological characteristics, and patient outcomes. RESULTS Fifty-eight patients were identified with primary sites as follows: urinary bladder (UB) 35 (60%), prostate 17 (29%) and upper urinary tract (UUT) 6 (11%). Mean age for the entire group was 68 years; 12/58 were female and 46/58 were male. Sixty-six percent (37/58) had pure SCC; the rest had mixed histology. Seventy percent (41/58) were positive for at least one neuroendocrine marker. Overall, 27/58 had limited stage disease, 25/58 had extensive disease and six were unknown. Treatment of limited stage patients was 10/27 (37%) concurrent chemotherapy with radiation, 5/27 (19%) surgery +/- adjuvant chemotherapy, 5/27 (19%) chemotherapy alone, 2/27 (7%) radiation alone and 5/27 (19%) supportive care only. For extensive stage patients, 5/25 (20%) received chemotherapy alone, 3/25 (12%) received radiation alone, 4/25 (16%) received RT and chemotherapy, 4/25 (16%) surgery alone and 9/25 (36%) supportive care only. One patient with limited stage disease received prophylactic cranial irradiation. Despite this, only one patient in the entire cohort presented with brain metastases as the site of initial relapse. Median survival for the entire cohort was 24 months (28 months for limited stage disease and 7 months for extensive). Prostate patients tended to do worse, with a survival of only eight months. CONCLUSIONS SCC of the GU tract is aggressive with an overall poor prognosis. As there is no standard of care for these patients, they are treated according to local protocols. Further efforts should be made to develop more effective treatments and the role of PCI should be investigated in the setting of a clinical trial, in conjunction with other extrapulmonary SCCs.

Common Presentation in an Uncommon Disease: Case Report of a Patient With Primary Diffuse Leptomeningeal Melanocytosis

Case Report A 17-year-old male was referred to our hospital with a 6-month history of uncontrolled generalized tonic clonic seizures. He denied fever, headache, or other constitutional symptoms. After the postictal stage, consciousness was fully regained without residual focal neurological deficit. He was compliant with his antiepileptic drugs (AEDs), including topiramate 50 mg/day and sodium valproate 1,000 mg/day. His medical history was otherwise unremarkable. Physical examination was completely normal. Specifically, he had no fever, lymphadenopathy, concerning skin lesions, or neurologic findings. Magnetic resonance imaging (MRI) of the brain demonstrated diffuse leptomeningeal enhancement without intracranial abnormality (Figs 1A and 1B). Lumbar puncture (LP) was performed, and revealed increased opening pressure at 30 cm H2O. Cerebrospinal fluid (CSF) analysis revealed a minimally increased WBC count (6 cells: 100% mononuclear cells), high protein (143.3 mg/100 mL), and normal CSF/blood glucose ratio (56 mg/100 mL/94 mg/100 mL). Further CSF analysis including gram stain, acid fast bacilli, modified acid fast bacilli, india ink, and CSF cultures did not support an infectious etiology. Subsequently, the patient underwent craniotomy and meningeal biopsy. Intraoperatively, dark pigmentation of the subarachnoid space was detected (Fig 2). Histopathologic and immunohistochemical examinations confirmed the presence of a primary diffuse leptomeningeal melanocytosis. The tumor was composed of an abundance of uniform polygonal cells containing extensive melanin pigment within the arachnoid space but without brain invasion. The tumor cells had nonprominent nucleolus with no atypia. (Fig 3). These cells displayed diffuse and strong staining for the melanocytic marker human melanoma black-45 (HMB-45) (Fig 4). On the basis of a benign histology and diffuse leptomeningeal involvement, there was no definitive treatment available to him. He was treated symptomatically with AEDs adjustment by the neurologist. At the time of this report, 2 years from initial presentation, the patient remains symptomatically well with good seizures control.

Clinical Characteristics and Treatment Outcomes of Patients with Primary Mediastinal Germ Cell Tumors: 10-Years' Experience at a Single Institution with a Bleomycin-Containing Regimen.

Background: Cisplatin-based chemotherapy followed by surgical resection of the residual tumor remains the standard of care for patients with mediastinal germ cell tumors (MGCTs). To prevent pulmonary complications, a non-bleomycin-containing regimen is generally preferred. This study aims to review the clinical characteristics and outcomes of these patients. Methods: A retrospective chart review was undertaken in patients treated for MGCTs between 2003 and 2013. Results: A total of 40 patients were enrolled; 7 patients were diagnosed with seminoma, while 33 patients had non-seminoma. 92% of patients received chemotherapy as a first treatment modality: 87% bleomycin, etoposide and cisplatin; 13% etoposide and cisplatin, with an objective response rate of 61.3%. Among these, 44% achieved a complete serological response. 17 patients underwent surgical resection of the residual tumor. No patient suffered from pulmonary complications after surgery. The 5-year overall survival (OS) was 71.4 and 27.3% in seminoma and non-seminoma patients, respectively (p = 0.051). For those who received chemotherapy followed by surgical resection with no viable tumor or only mature teratoma detected, the 5-year OS was 72.7% compared with 20.7% in patients not treated with surgery (p = 0.02). Conclusion: Our study confirmed the importance of a multimodality approach with primary chemotherapy followed by surgical resection of the residual tumor. A bleomycin-containing regimen can be safely used in this setting.

Osimertinib versus Standard of Care EGFR TKI as First-Line Treatment in Patients with EGFRm Advanced NSCLC: FLAURA Asian Subset

Introduction: Here we report efficacy and safety data of an Asian subset of the phase III FLAURA trial (NCT02296125), which compares osimertinib with standard of care (SoC) EGFR tyrosine kinase inhibitors (TKIs) in patients with previously untreated advanced NSCLC with tumors harboring exon 19 deletion (Ex19del)/L858R EGFR TKI–sensitizing mutations. Methods: Eligible Asian patients (enrolled at Asian sites) who were at least 18 years of age (≥20 years in Japan) and had untreated EGFR‐mutated advanced NSCLC were randomized 1:1 to receive osimertinib (80 mg, orally once daily) or an SoC EGFR TKI (gefitinib, 250 mg, or erlotinib, 150 mg, orally once daily). The primary end point was investigator‐assessed progression‐free survival (PFS). The key secondary end points were overall survival, objective response rate, central nervous system efficacy, and safety. Results: The median PFS was 16.5 versus 11.0 months for the osimertinib and SoC EGFR TKI groups, respectively (hazard ratio = 0.54, 95% confidence interval: 0.41–0.72, p < 0.0001). The overall survival data were immature (24% maturity). The objective response rates were 80% for osimertinib and 75% for an SoC EGFR TKI. The median central nervous system PFS was not calculable for the osimertinib group and was 13.8 months for the SoC EGFR TKI group (hazard ratio = 0.55, 95% confidence interval: 0.25–1.17, p = 0.118). Fewer adverse events of grade 3 or higher (40% versus 48%) and fewer adverse events leading to treatment discontinuation (15% versus 21%) were reported with osimertinib versus with an SoC EGFR TKI, respectively. Conclusion: In this Asian population, first‐line osimertinib demonstrated a clinically meaningful improvement in PFS over an SoC EGFR TKI, with a safety profile consistent with that for the overall FLAURA study population.