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J. Kawashima
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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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P2.06-004 - A Phase 1b Study of Erlotinib and Momelotinib for EGFR TKI Naïve EGFR Mutated Metastatic Non-Small Cell Lung Cancer (ID 4778)
14:30 - 14:30 | Author(s): J. Kawashima
- Abstract
Background:
Momelotinib (MMB) is a selective ATP-competitive small-molecule inhibitor of Janus kinases (JAK) 1 and 2. The JAK signal transduction pathway is hyperactivated in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). Erlotinib, a tyrosine kinase inhibitor (TKI), is a standard of care treatment for EFGR-mutated NSCLC. However, patients eventually develop resistance to single agent EGFR TKI and thus this combination trial was designed. The primary objective of this phase 1b study (NCT02206763) was to determine the maximum tolerated dose and safety of MMB in combination with erlotinib. Other objectives included pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy.
Methods:
Eligible patients had metastatic EGFR-mutated NSCLC (exon 19 deletion or exon 21 [L858R] substitution). Oral erlotinib 150 mg was administered once daily. MMB was dose escalated in a standard 3+3 design as follows: MMB 100 mg once daily (Dose Level [DL] 1), 200 mg once daily (DL2A), and 100 mg twice daily (DL2B). Dose limiting toxicities (DLTs) were evaluated in the first 28 days. Plasma samples for PK/PD analyses were serially collected up to 24 hours postdose.
Results:
Eleven patients enrolled: 3 in DL1, 3 in DL2A, and 5 in DL2B. Seven were female and median age was 55 years. DLTs of grade 3 diarrhea (n=1) and grade 4 neutropenia (n=1) without fever were seen at DL2B, and trial enrollment was halted. Decreased neutrophil count was recorded in 4 additional patients (grade 1-3; only one grade 3). The most common treatment-emergent adverse events were diarrhea and fatigue, each reported by 7 patients. One patient reported grade 1 peripheral neuropathy (sensory). No deaths were reported. Mean MMB systemic exposure was dose proportional between DL1 and DL2A, and comparable between DL2A and DL2B (200 mg total daily dose). MMB did not affect erlotinib PK. Mean blood pSTAT3 was maximally decreased by 34.9% at 1 hour postdose and was not dose dependent. As observed for MMB in myelofibrosis, inflammatory cytokines such as CRP, IL-10 and IL-12/-23p40 were reduced, whereas IL-8 was increased. The overall response rate was 54.5% (n=6; all partial responses).
Conclusion:
MMB administered in combination with erlotinib had more toxicity than expected at DL2B, including one grade 4 neutropenia. However, grade 2-3 neutropenia without fever was seen in 2 additional patients. The response rate was similar to previous reports with erlotinib, but it is too early in the study to provide progression-free survival with this treatment combination.
