Abstract CT342: Phase I/II study of gefitinib in combination with vorinostat in patients with advanced non-small cell lung cancer (NSCLC) who progressed on prior chemotherapy

Background: Gefitinib has shown marked efficacy in EGFR-mutant NSCLC. However, the development of acquired resistance is inevitable. Additionally, its therapeutic effect in EGFR-wild type NSCLC is controversial. Vorinostat, a histone deacetylase inhibitor, has shown to overcome resistance to gefitinib. We performed a phase I/II study combining gefitinib with vorinostat in previously treated patients with advanced NSCLC. Methods: A 3+3 dose-escalation design was used to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D). Three dose levels were tested: gefitinib 250/day on days 1 through 28 and vorinostat on days 1-7 and 15-21 at 200, 300 and 400mg/day every 28 days. Phase II eligibility included advanced NSCLC, ≤2 line prior therapy, PS 0-2, adequate organ function. The primary endpoint was to determine the median progression-free survival (PFS) (null hypothesis 3.5 months, alternative hypothesis 6.5 months). Results: Planned dose escalation was completed without reaching the MTD. The RP2D was gefitinib 250mg and vorinostat 400mg. Fifty-two patients were enrolled and treated in this study (43 in phase II). The median age was 59 years (range, 39 to 79 years), 30 were male, 48 had adenocarcinoma, 29 were never smokers, 31 had one prior regimen and 12 had two prior regimens; 21 had sensitive EGFR mutations, 3 had resistant exon 20 mutations and 5 had KRAS mutations. The most common adverse events were mild or moderate diarrhea, anorexia and anemia. In 43 assessable patients in phase II, there were 16 partial responses, 6 stable disease. The median PFS was 3.4 months; overall survival (OS) was 20.3 months. In patient harboring EGFR mutations, response rate (RR) was 88%, median PFS was 9.3 months and median OS was 22.6 months. Conclusions Gefitinib 250mg daily with biweekly vorinostat 400 mg/day was feasible and well tolerated. In unselected patient population, this combination dose not improved PFS compared with historical control of single gefitinib. However, in EGFR-mutant NSCLC, this combination may improve RR and survival compared with historical control of gefitinib in previously treated EGFR-mutant NSCLC. Citation Format: Ji-Youn Han, Soo Hyun Lee, Tak Yun, Young Jooo Lee, Kum Hui Hwang, Sunah Ryu, Heung Tae Kim, Jin Soo Lee. Phase I/II study of gefitinib in combination with vorinostat in patients with advanced non-small cell lung cancer (NSCLC) who progressed on prior chemotherapy. [abstract]. In: Proceedings of the 105th