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H.R. Kim
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P2.06 - Poster Session with Presenters Present (ID 467)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.06-003 - A Phase Ib Study of the Combination of Afatinib and Ruxolitinib in EGFR Mutant Non-Small Cell Lung Cancer (NSCLC) Progressed on EGFR-TKI (ID 5453)
14:30 - 14:30 | Author(s): H.R. Kim
- Abstract
Background:
In non-small cell lung cancer (NSCLC) patients treated with EGFR tyrosine kinase inhibitors (TKIs), acquired resistance is attributed to the T790M mutation in exon 20 in approximately 50% of cases. Despite promising preclinical findings, afatinib did not improve survival of patients with the T790M mutation. In a recent preclinical study, we demonstrated that autocrine IL-6 induced JAK/STAT3 signaling pathway activation mediated adaptive resistance to afatinib in H1975 and PC9-GR cells harboring T790M mutations. Knockdown of STAT3 with siRNA or pharmacologic JAK1 inhibition increased the anti-tumor activity of afatinib in T790M-positive NSCLC cells. Based on the promising preclinical results, we conducted a phase Ib study to evaluate the safety and efficacy of the combination of afatinib and ruxolitinib, a selective JAK inhibitor, in NSCLC patients who had progressed on EGFR-TKIs.
Methods:
For dose escalation with the classical 3+3 design, patients with histologically diagnosed, EGFR mutant stage IV NSCLC were considered eligible. Patients should have documented disease progression on EGFR-TKIs with clinical definition of acquired resistance. Afatinib was administered alone once daily from day 1 through day 8 (run-in period), then ruxolitinib was orally administered twice daily concomitantly with afatinib until progression. The primary endpoint was to determine RP2D and DLT.
Results:
As of July 13, 2016, 15 patients (8 with exon19 deletion, 7 with exon21 L858R) were enrolled in the dose escalation cohort, 8 of which had T790M mutations. Patients were previously treated with erlotinib (n=5) or gefitinib (n=10). Patients received a median of 3 (range, 1-4) lines of chemotherapy. No DLT was observed at the highest dose level (afatinib 50 mg once daily plus ruxolitinib 25 mg twice daily). Frequent AEs included paronychia (G1 in 7 cases), diarrhea (G1 in 6 cases, G2 in 1 case), acneiform rash (G1 in 5 cases), and oral mucositis (G1 in 1 case, G2 in 3 cases). SAEs were reported in 4 patients, which were not related to the investigational products. Partial responses were observed in 6 patients (40%) with disease control rate (CR+PR+SD) of 86.7%. Median PFS was 8.8 months (95% CI, 1.8-15.8) and 6 patients remain on study. Dose expansion with pharmacodynamic study at the RP2D will be open for NSCLC patients with EGFR T790M.
Conclusion:
The combination of afatinib with ruxolitinib was well tolerated and had promising clinical activity with durable disease control in NSCLC with acquired resistance to EGFR-TKIs (NCT02145637).
