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E. Schaefer
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P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.01-026 - Proactive Management of Potential Gastrointestinal Adverse Reactions with Ceritinib in Patients with Advanced ALK+ NSCLC (ID 1764)
09:30 - 09:30 | Author(s): E. Schaefer
- Abstract
Background:
Anaplastic lymphoma kinase (ALK) gene fusions are implicated in the pathogenesis of non-small cell lung cancer (NSCLC), occurring in 3–7% of cases. Crizotinib, a first-in-class ALK inhibitor, was granted US FDA approval in 2011 to treat metastatic ALK-positive (ALK+) NSCLC. However, intrinsic and acquired resistance limits its duration of use. Ceritinib, an ALK inhibitor with activity against crizotinib-resistant NSCLC and brain metastases, was granted accelerated approval by the US FDA in 2014 for treating crizotinib-resistant ALK+ NSCLC. Adverse events (AEs), particularly gastrointestinal (GI) AEs, are commonly experienced at the recommended dose of 750 mg/day (Shaw A et al. NEJM 2014;370:1189–1197) and around 60% of patients require dose interruption or reduction. This report details our experience with the use of proactive GI AE management regimens with ceritinib.
Methods:
Proactive regimens A and B were implemented in patients with metastatic ALK+ NSCLC treated with ceritinib to manage drug-related GI AEs. Regimen A comprised ondansetron and diphenoxylate/atropine or loperamide, taken 30 minutes prior to dosage. Regimen B included dicyclomine, taken with the first ceritinib dose, ondansetron, taken 30 minutes prior to dosage for the first 7 doses, and loperamide, taken as needed with the onset of diarrhea. The proactive medications were tapered off depending on patient tolerability to ceritinib. We report a case series comprising 9 patients treated at two sites with ceritinib (750 mg/day) for whom these proactive GI AE management programs were successfully implemented.
Results:
The 9 patients presented had discontinued crizotinib due to disease progression or intolerance, and received ceritinib as their 2[nd]–5[th] line of treatment (Table). Rapidly starting regimens A or B before the first dose of ceritinib, or as soon as GI symptoms were encountered, prevented the need for dose reduction due to GI toxicity in 8/9 patients. One patient discontinued therapy due to GI toxicities despite prophylaxis. One patient required dose reduction to 600 mg/day due to Grade 3 transaminitis. Using these regimens, 78% of patients were able to remain on 750 mg/day fasting. Two patients have completed 16 and 12 months of therapy, and remain on ceritinib 750 and 600 mg/day, respectively. Figure 1
Conclusion:
Although not currently recommended or implemented in clinical studies, based on the patients evaluated here, upfront or proactive treatment plans that address AEs early on can allow the majority of patients to remain on the approved 750-mg/day ceritinib dose.
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P2.01-085 - Abemaciclib in Combination with Single Agent Options in Stage IV NSCLC, a Phase 1b Study (ID 125)
09:30 - 09:30 | Author(s): E. Schaefer
- Abstract
Background:
Abemaciclib, a cell cycle inhibitor selective for CDK4/6, demonstrated acceptable safety and early clinical activity in metastatic NSCLC, given orally as monotherapy on a continuous schedule. Combinations of abemaciclib showed greater activity compared with monotherapy in KRAS-mutant NSCLC preclinical models. Primary aim of study NCT02079636 was safety/tolerability of combination therapy with abemaciclib; secondary aims included pharmacokinetics and antitumor activity.
Methods:
In this open-label 3+3 dose-escalation study with expansion cohorts, eligibility included stage IV NSCLC, measurable or nonmeasurable disease (RECISTv1.1), ECOG PS ≤1, and 1-3 prior therapies. Abemaciclib was combined with pemetrexed (Part A, nonsquamous, 500 mg/m[2] IV day 1), gemcitabine (Part B, 1250 mg/m[2] IV days 1 and 8), ramucirumab (Part C, 10 mg/kg IV day 1, or 8 or 10 mg/kg IV days 1 and 8) (Q21), or LY3023414 (dual PI3K-mTOR inhibitor) (Part D, 100 mg, 150 mg or 200 mg orally Q12H). In escalation, patients were dosed continuously until progression with abemaciclib at 100 mg (Part D), 150 mg or 200 mg orally Q12H.
Results:
As of February 27, 2015, 70 patients (Parts A-C) received ≥1 dose; 15 patients at 150 mg and 55 patients (including all 39 patients in expansion) at 200 mg Q12H abemaciclib. The MTD was established at 200 mg Q12H abemaciclib for Parts A-C. See Table 1 for treatment-emergent adverse events (TEAEs). Stable disease was observed in 13/23 patients in Part A; 7 unknown, 4/24 patients in Part B; 10 unknown, and 7/23 patients in Part C; 12 unknown. In Parts A-C, 18/70 (26%) patients started ≥4 cycles (Part A=9, Part B=3, Part C=6). Three confirmed PRs were observed: Part B, 1 patient with squamous histology (unknown mutation status), Part C, 1 patient with nonsquamous histology (KRAS mutation positive; EGFR mutation negative), and 1 patient with squamous histology (unknown mutation status). Updated analyses will be presented including Part D and longer term follow-up for Parts A-C through approximately June 2015. Table 1. TEAEs related to treatment (≥20% in ≥1 part)% All grades (% Gr3/4) Part A (n=23) Part B (n=24) Part C (n=23) Diarrhea 65 (4) 50 (17) 52 (9) Fatigue 57 (9) 63 (8) 17 (4) Nausea 35 (0) 50 (4) 48 (9) Neutropenia 61 (61) 50 (33) 17 (4) Anemia 57 (26) 33 (17) 9 (0) Thrombocytopenia 39 (9) 38 (8) 17 (13) Decreased appetite 30 (0) 25 (0) 22 (0) Vomiting 9 (0) 21 (0) 35 (0) Blood creatinine increased 30 (0) 8 (0) 17 (4) Leukopenia 30 (22) 17 (8) 9 (4)
Conclusion:
Abemaciclib combined with single-agents with acceptable toxicity. Safety findings observed in Parts A and B are consistent with AEs expected when combining myelosuppressive compounds with abemaciclib, resulting in an increased myelosuppressive effect. In Part C, safety findings are consistent with those of single-agents. Tumor responses were observed in Parts B and C.
