P2.03-044 OSCILLATE - Phase 2 Trial of Alternating Osimertinib with Gefitinib in Patients with EGFR-T790M Mutation Positive Advanced NSCLC

S2144 Background: In this study (NCT02206763), momelotinib, an inhibitor of Janus kinases 1 and 2, was administered in combination with erlotinib, a tyrosine kinase inhibitor (TKI) in patients with TKI-naïve epidermal growth factor receptor (EGFR)-mutated metastatic nonsmall cell lung cancer (NSCLC), to determine the maximum tolerated dose and safety of momelotinib in combination with erlotinib. As previously reported, dose limiting toxicities (DLTs) of grade 3 diarrhea (n¼1) and grade 4 neutropenia (n¼1) without fever were seen at dose level (DL) 2B and trial enrollment was halted. Here, we report the final results. Method: Patients received oral erlotinib 150 mg QD (including 11-31 day run-in). Momelotinib was administered orally in a standard 3+3 dose-escalation design: DL1, momelotinib 100 mg QD; DL2A, 200 mg QD; and DL2B, 100 mg BID. DLTs were evaluated in the first 28 days. Plasma samples were collected for PK/PD analyzes. Result: Eleven patients enrolled: 3 in DL1, 3 in DL2A, and 5 in DL2B. The median duration of exposure to momelotinib was 40 weeks (range 2.4-63.1) and median number of cycles was 10 (range 0.615.8). Treatment was discontinued for progressive disease (n¼7), adverse event (n¼3), and patient decision (n¼1). The objective response rate was 54.5% (90% CI: 27.1%e80.0%) and all responses (n¼6) were partial responses; 4 patients had stable disease and 1 patient had progressive disease. The median duration of response was 7.1 (90% CI: 4.4e9.6) months. The median progression-free survival was 9.2 (90% CI: 6.2e12.4) months. The estimated median overall survival was not reached. The most common treatment-emergent adverse events (TEAEs) were decreased appetite, dry skin, and fatigue (7 patients each) and diarrhea (6 patients). In addition to the patient with grade 4 neutropenia (DLT), decreased neutrophil count was recorded in 4 additional patients (grade 1-2 [n¼3], grade 3 [n¼1]); median time to first neutrophil abnormality was 0.5 (range 0.5e3.7) months. Momelotinib-related TEAEs of interest (one patient each) included grade 1 sensory peripheral neuropathy, grade 1 paresthesia, and reactivation of hepatitis B. There was one momelotinib-related serious adverse event, grade 3 pneumonitis. There was no PK interaction between momelotinib and erlotinib. Conclusion: The combination of momelotinib and erlotinib had more toxicity than expected at DL2B. Neutropenia was common. Although the small number of patients in this phase 1 study limits our ability to make a definitive conclusion regarding efficacy, the response rate and progression-free survival was similar to previous reports with erlotinib alone. Keywords: Targeted therapy, non-small cell lung cancer, chemotherapy

P2.03-044 OSCILLATE - Phase 2 Trial of Alternating Osimertinib with Gefitinib in Patients with EGFR-T790M Mutation Positive Advanced NSCLC B. Solomon,1 P. Kok,2 A. Livingstone,2 S. Yip,2 C. Brown,2 S. Dawson,1 S. Wong,1 N. Pavlakis,3 M. Stockler2 1Medical Oncology, Peter MacCallum Cancer Centre, Melbourne/AU, 2Medical Oncology, Nhmrc Clinical Trials Centre, the University of Sydney, Camperdown/AU, 3 Royal North Shore Hospital, St Leonards/AU Background: Activating mutations of the epidermal growth factor receptor (EGFR) are key drivers of non-small cell lung cancer (NSCLC) in approximately 10-15% of Western patients and 30-35% of Asian patients. Patients with common activating mutations (L858R and del19) typically have objective tumor response rates (OTRR) of 56-74% and median progression free survival (PFS) of 9-13 months with first-generation EGFR tyrosine kinase inhibitors (TKI) such as erlotinib or gefitinib. The most common mechanism of acquired resistance to first generation EGFR TKI is the T790M mutation (50-

Journal of Thoracic Oncology

Vol. 12 No. 11S2

60% of cases). Osimertinib is an irreversible EGFR TKI effective against the T790M resistance mutation with OTRR of 51-71% in T790M positive disease. However, acquired resistance invariably develops, and median PFS is approximately 10 months. Mechanisms of resistance include C797S mutations and loss of T790M. Novel strategies that prevent or delay resistance to osimertinib are likely to enhance its durability of response and clinical benefit in EGFR-T790M positive NSCLC. Method: DESIGN: Open-label, single arm, multi-center, phase 2 trial with safety run in. ELIGIBILITY: Adults with advanced, EGFR mutated NSCLC, acquired resistance to first or second generation EGFR TKIs, and mutation of T790M. ENDPOINTS: PFS rate at 12 months, feasibility of alternating osimertinib and gefitinib, time to progression and PFS time, objective tumor response rate, overall survival and adverse events. Tertiary correlative objectives include changes in plasma cfDNA levels for activating EGFR mutations and T790M over time, their relationships with OTRR and the mechanism of resistance. TREATMENT: Osimertinib 80mg daily for 8 weeks (2 cycles), then gefitinib 250mg daily for 4 weeks alternating with osimertinib 80mg daily for 4 weeks (i.e. alternating 4 weekly cycles of each drug) until disease progression or prohibitive toxicity. STATISTICS: A total of 45 participants provides 90% power, with a 1-sided type 1 error rate of 10%, to distinguish the observed proportion alive and progression free at 12 months from true rates of 45% (not worthy of pursuit) and 65% (worthy of pursuit) using a Simon, 2-stage, minimax design allowing for 4 ineligible or inevaluable participants. ASSESSMENT: CT scans 8-weekly until disease progression. Plasma collections at baseline and at the start of each 4week cycle. OSCILLATE is an investigator-initiated cooperative-group trial led by ALTG, in collaboration with NHMRC Clinical Trials Centre, University of Sydney, with support from Astra-Zeneca. Result: Not applicable. Conclusion: Not applicable. Keywords: osimertinib, T790M, EGFR

P2.03-045 Updated Results of Phase II, Liquid Biopsy Study in EGFR Mutated NSCLC Patients Treated with Afatinib (WJOG 8114LTR) H. Hayashi,1 H. Akamatsu,2 Y. Koh,2 S. Morita,3 D. Fujimoto,4 I. Okamoto,5 A. Bessho,6 K. Azuma,7 K. Nakagawa,1 N. Yamamoto2 1 Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayama/JP, 2Department of Internal Medicine, Wakayama Medical University, Wakayama/JP, 3Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto/JP, 4Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe-City/JP, 5Kyushu University, Fukuoka/JP, 6 Respiratory Medicine, Japanese Red Cross Okayama Hospital, Okayama/JP, 7Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Kurume/JP Background: Liquid biopsy has been approved as an optional method to detect clinically relevant EGFR mutations in NSCLC. WJOG8114LTR is a prospective, multi-institutional study of liquid biopsy in EGFR mutated NSCLC patients. Previously, we reported that complete molecular response at 4 weeks could be an early surrogate marker of durable efficacy. Here, we report updated results. Method: Chemotherapy naïve, advanced NSCLC patients with EGFR-sensitizing mutation received afatinib monotherapy (40 mg/body) until progressive disease (PD) or unacceptable toxicity. Plasma DNA was obtained from patients at baseline, weeks 2, 4, 8, 12, 24, 48, and at PD. Three types of clinically relevant EGFR mutations (exon 19 deletion, exon 20 T790M and exon 21 L858R) will be analyzed using plasma