Julie Switzky

8009 Background: Activating BRAF V600E mutations in NSCLC are present in < 2% of tumors, primarily adenocarcinoma. The BRAF inhibitor dabrafenib has demonstrated clinical activity in BRAF V600 mutation–positive melanoma. Here we report interim efficacy and safety data obtained in 17 BRAF V600E–mutant NSCLC patients enrolled in dabrafenib phase II study BRF113928. Methods: Single-arm, 2-stage, phase II study in stage IV BRAF V600E mutation–positive NSCLC pts who failed at least 1 line of chemotherapy. Dabrafenib dosed at 150 mg orally twice daily. The primary endpoint was investigator-assessed overall response rate (ORR) per RECIST 1.1 criteria. Results: The median age of the 17 pts was 69 years (range, 51-77 years). Most pts (12/17) were male, all were white with adenocarcinoma, and 13 were former smokers. All pts had failed at least 1 line of prior anticancer therapy, and 5 subjects had failed ≥ 2. At the time of reporting, 11 pts remain on therapy, and 6 have stopped therapy (5 with PD and 1 due to an AE). Thirteen pts were evaluable for efficacy. The best response for these pts included 7 PRs (5 confirmed PRs), 1 SD, and 4 PD; 1 pt discontinued due to an SAE (hypersensitivity reaction) prior to response assessment (ORR, 54%). The median duration of treatment for all 17 pts is approximately 9 weeks (range, 1-69 weeks). Among the 5 pts with confirmed PRs, duration of response was 29 and 49 weeks for the 2 pts who progressed, while the remaining 3 pts were responding for 6+ to 24+ weeks. The safety of dabrafenib in NSCLC pts appears to be generally consistent with what has been previously observed. The most common AEs were decreased appetite, fatigue, asthenia, dyspnea, and nausea, mostly grade 1 or 2. Five pts (29%) had a grade 3 AE, and 1 pt (6%) had a grade 4 SAE (hemorrhage). Conclusions: Dabrafenib shows early antitumor activity in BRAF V600E mutation–positive pretreated NSCLC pts, with an ORR of 54% and with the longest duration of response of 49 weeks thus far. Dabrafenib is generally well tolerated, and the study has met the minimum response rate (≥ 3 of first 20 pts) to continue into the second stage. This study represents the first clinical evidence of BRAF as a therapeutic target in NSCLC. Clinical trial information: NCT01336634.

PURPOSE: Bromodomain and extraterminal (BET) proteins are key epigenetic transcriptional regulators, inhibition of which may suppress oncogene expression. We report results from 2 independent first-in-human phase 1/2 dose-escalation and expansion, safety and tolerability studies of BET inhibitors INCB054329 (study INCB 54329-101; NCT02431260) and INCB057643 (study INCB 57643-101; NCT02711137). PATIENTS AND METHODS: Patients (≥18 years) with advanced malignancies, ≥1 prior therapy, and adequate organ functions received oral INCB054329 (monotherapy) or INCB057643 (monotherapy or in combination with standard-of-care) in 21-day cycles (or 28-day cycles depending on standard-of-care combination). Primary endpoints were safety and tolerability. RESULTS: Sixty-nine and 134 patients received INCB054329 and INCB057643, respectively. Study INCB 54329-101 has been completed; INCB 57643-101 is currently active, but not recruiting (no patients were receiving treatment as of January 8, 2019). Terminal elimination half-life was shorter for INCB054329 versus INCB057643 (mean [SD], 2.24 [2.03] vs. 11.1 [8.27] hours). INCB054329 demonstrated higher interpatient variability in oral clearance versus INCB057643 (CV%, 142% vs. 45.5%). Most common (>20%) any-grade treatment-related adverse events were similar for both drugs (INCB054329; INCB057643): nausea (35%; 30%), thrombocytopenia (33%; 32%), fatigue (29%; 30%), decreased appetite (26%; 22%). Two confirmed complete responses and 4 confirmed partial responses with INCB057643 were reported as best responses. CONCLUSIONS: INCB057643 exhibited a more favorable PK profile versus INCB054329; exposure-dependent thrombocytopenia was observed with both drugs which limited the target inhibition that could be safely maintained. Further efforts are required to identify patient populations that can benefit most, and an optimal dosing scheme to maximize therapeutic index.

Dabrafenib is a BRAF kinase inhibitor indicated for the treatment of BRAF V600E mutation-positive melanoma. The population pharmacokinetics of dabrafenib, including changes over time and relevant covariates, were characterized based on results from four clinical studies using a nonlinear mixed effects model with a full covariate approach. Steady-state exposures of dabrafenib metabolites (hydroxy-, carboxy-, and desmethyl-dabrafenib) were characterized separately. The pharmacokinetics of dabrafenib were adequately described by non-inducible and inducible apparent clearance that increased with dose and time. Total steady-state clearance (CL/F) at 150 mg BID dose was 34.3 L/h. Based on the induction half-life (67 hours), steady state should be achieved within 14 days of dosing. Capsule shell was the most significant covariate (55%) while sex and weight had only a small impact on exposure (<20%). The AUC ratio (hypromellose:gelatin capsule) is predicted to be 1.80 and 1.42 following single and repeat dosing, respectively. Age, renal (mild and moderate), and hepatic (mild) impairment were not significant covariates. Steady-state pre-dose concentration (%CV) of dabrafenib and of hydroxy-, carboxy-, and desmethyl-dabrafenib at 150 mg BID were 46.6 ng/mL (83.5%), 69.3 ng/mL (64.1%), 3608 ng/mL (14.7%), and 291 ng/mL (17.2%), respectively. Capsule shell, concomitant medications, older age, and weight were predictors of metabolite exposure.

BACKGROUND: The Janus kinase/signal transducer and activator of transcription (JAK-STAT) signaling pathway plays a key role in the systemic inflammatory response in many cancers, including colorectal cancer (CRC). This study evaluated the addition of ruxolitinib, a potent JAK1/2 inhibitor, to regorafenib in patients with relapsed/refractory metastatic CRC. METHODS: In this two-part, multicenter, phase 2 study, eligible adult patients had metastatic adenocarcinoma of the colon or rectum; an Eastern Cooperative Oncology Group performance status of 0-2; received fluoropyrimidine, oxaliplatin, and irinotecan-based chemotherapy, an anti-vascular endothelial growth factor therapy (if no contraindication); and if KRAS wild-type (and no contraindication), an anti-epidermal growth factor receptor therapy; and progressed following the last administration of approved therapy. Patients who received previous treatment with regorafenib, had an established cardiac or gastrointestinal disease, or had an active infection requiring treatment were excluded. The study was conducted in 95 sites in North America, European Union, Asia Pacific, and Israel. After an open-label, safety run-in phase (part 1; ruxolitinib 20 mg twice daily [BID] plus regorafenib 160 mg once daily [QD]), the double-blind, randomized phase (part 2) was conducted wherein patients were randomized 1:1 to receive ruxolitinib 15 mg BID plus regorafenib 160 mg QD [ruxolitinib group] or placebo plus regorafenib 160 mg QD [placebo group]. Part 2 included substudy 1 (patients with high systemic inflammation, ie, C-reactive protein [CRP] >10 mg/L) and substudy 2 (patients with low systemic inflammation, ie, CRP ≤10 mg/L); the primary endpoint was overall survival (OS). RESULTS: The study was terminated early; substudy 1 was terminated for futility at interim analysis and substudy 2 was terminated per sponsor decision. Ruxolitinib 20 mg BID was well tolerated in the safety run-in (n = 11). Overall, 396 patients were randomized (substudy 1: n = 175 [ruxolitinib group, n = 87; placebo group, n = 88]; substudy 2: n = 221 [ruxolitinib group, n = 110; placebo group, n = 111]). There was no significant difference in OS or progression-free survival (PFS) between treatments in substudy 1 (OS: hazard ratio [HR] = 1.040 [95% confidence interval: 0.725-1.492]; PFS: HR = 1.004 [0.724-1.391]) and substudy 2 (OS: HR = 0.767 [0.478-1.231]; PFS: HR = 0.787 [0.576-1.074]). The most common hematologic adverse event was anemia. No new safety signals with ruxolitinib were identified. CONCLUSIONS: Although addition of ruxolitinib to regorafenib did not show increased safety concerns in patients with relapsed/refractory metastatic CRC, this combination did not improve OS/PFS vs. regorafenib plus placebo.