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T.M. Bauer
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OA 05 - Next Generation TKI (ID 657)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:James Chih-Hsin Yang, Fiona Blackhall
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 301 + 302
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OA 05.06 - Phase 2 Study of Lorlatinib in Patients with Advanced ALK<sup>+</sup>/ROS1<sup>+</sup> Non-Small-Cell Lung Cancer (ID 8573)
16:40 - 16:50 | Author(s): T.M. Bauer
- Abstract
- Presentation
Background:
Lorlatinib, a selective, potent, brain-penetrant ALK/ROS1 TKI, is active against most known ALK kinase domain mutations. In phase 1 of this ongoing study (NCT01970865), lorlatinib displayed robust clinical activity among patients with ALK[+]/ROS1[+] non-small-cell lung cancer (NSCLC), most of whom were heavily pretreated and had CNS metastases. Phase 2 evaluated efficacy (overall and intracranial), according to prior treatment, and safety at the recommended phase 2 dose (100 mg QD).
Method:
Patients with NSCLC ± asymptomatic CNS metastases enrolled in 6 cohorts (EXP1–5, ALK[+]; EXP6, ROS1[+]). The primary endpoint was objective response rate (ORR) and intracranial ORR by independent central review. Safety, patient-reported outcomes and molecular profiling were also assessed.
Result:
As of 15-March-2017, 227 ALK[+] patients were evaluated for ORR (Table), including 140 with CNS involvement who were evaluated for intracranial ORR.
Of 219 ALK+ patients analyzed for ALK kinase domain mutations at baseline, 46/219 (21%) had ≥1 mutation detected in circulating free DNA; most derived treatment benefit with an ORR of (27/46) 59%. Across all cohorts (N=275), the most common treatment-related adverse events (AEs) and grade 3/4 treatment-related AEs were hypercholesterolemia (81%/16%) and hypertriglyceridemia (60%/16%); 30% and 22% of patients had treatment-related AEs associated with dose interruptions and reductions, respectively. No treatment-related deaths occurred; 7 patients (3%) had treatment-related AEs leading to treatment discontinuation. 157/275 (57%) patients remained on treatment at data cutoff. Most patients reported stable/improved global quality of life (40%/43%).Confirmed ORR Confirmed IC-ORR N n (%) N n (%) ALK[+] cohorts EXP1 (treatment-naïve, no prior ALK-TKIs or CT) 30 27 (90) 8 6 (75) EXP2 (prior crizotinib only) 27 20 (74) 17 10 (59) EXP3 (1 prior ALK TKI ± CT) 59 30 (51) 32 20 (63) EXP3A (prior crizotinib + CT) 32 21 (66) 20 15 (75) EXP3B (any 1 other ALK TKI ± CT) 27 9 (33) 12 5 (42) EXP4 (2 prior ALK TKIs ± CT) 65 27 (42) 45 25 (56) EXP5 (3 prior ALK TKIs ± CT) 46 16 (35) 38 (15 (39) CT, chemotherapy; IC, intracranial.
Conclusion:
Lorlatinib showed clinically meaningful activity, including substantial intracranial efficacy, among ALK[+]/ROS1[+] patients who were either treatment-naïve or failed ≥1 prior ALK TKI. Overall lorlatinib was well tolerated and when needed, AEs were managed by dose delay/reduction or standard medical therapy.
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OA 12 - Emerging Genomic Targets (ID 679)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:H. Akita, Maurice Pérol
- Coordinates: 10/18/2017, 11:00 - 12:30, F203 + F204 (Annex Hall)
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OA 12.07 - LOXO-292, a Potent, Highly Selective RET Inhibitor, in MKI-Resistant RET Fusion-Positive Lung Cancer Patients with and without Brain Metastases (ID 10955)
12:00 - 12:10 | Author(s): T.M. Bauer
- Abstract
- Presentation
Background:
RET fusions are validated therapeutic targets in human lung cancers. However, the clinical activity of multikinase inhibitors (MKIs) with anti-RET activity is limited by a narrow therapeutic index from off-target effects and poor pharmacokinetics (PK). Moreover, MKIs have limited RET inhibition in the central nervous system (CNS), and patients often experience disease progression in the brain. LOXO-292 is a potent and highly selective RET inhibitor, with >100-fold selectivity versus important off-targets, and anti-tumor activity in the brain and periphery in RET-dependent tumor models in vivo.
Method:
Two RET fusion-positive lung cancer patients were treated with LOXO-292: a patient with CCDC6-RET-rearranged lung cancer with acquired resistance to RXDX-105; and a patient with KIF5B-RET-rearranged lung cancer with progressive disease in the brain while on alectinib treated under a single patient protocol with real-time, PK- guided intra-patient dose titration.
Result:
The first patient was enrolled on cohort 1 of the Phase 1 trial (20 mg daily) and was the first lung cancer patient to receive LOXO-292. She achieved a rapid, confirmed partial response (PR) by RECIST 1.1, with a 44% reduction in target lesion size. The second patient, the first to receive LOXO-292 in the setting of brain metastases, achieved a PR with escalating doses of LOXO-292 (20-60-100 mg twice daily) that included target lesion responses in both the lungs and brain (Figure 1), and resolution of cancer-related CNS symptoms. Early clinical experience with LOXO-292 has already established drug exposures that are consistent with significant RET inhibition in vitro and RET-dependent tumor regression in vivo. Importantly, LOXO-292 has been well-tolerated, with the majority of treatment-emergent adverse events reported as Grade 1-2, and none attributed to LOXO-292.
Conclusion:
LOXO-292 has demonstrated proof-of-concept tolerability, significant exposure, and efficacy in two patients with MKI-resistant, RET-dependent cancers, including a patient with progressive brain metastases after alectinib.Figure 1
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