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OA 12 - Emerging Genomic Targets (ID 679)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
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)
11:00 - 12:30 | Author(s): V. Subbiah
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.
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.
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.
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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P1.03 - Chemotherapy/Targeted Therapy (ID 689)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
P1.03-044 - Exploratory Analysis of Lung Cancer Patients in a Phase Ib/II Trial of NC-6004 (Nanoparticle Cisplatin) plus Gemcitabine (ID 10174)
09:30 - 16:00 | Author(s): V. Subbiah
NC-6004 is a polymeric micelle exhibiting sustained release of cisplatin and selective distribution to tumors, reducing plasma C~max~ and increasing AUC. Preclinical data showed less neuro- and nephrotoxicity with greater anti-tumor activity versus cisplatin. A previous trial evaluated NC-6004 and gemcitabine defining a recommended phase 2 dose of 90 mg/m. A Bayesian continual reassessment method (N-CRM) design evaluated escalating doses of NC-6004 in combination with gemcitabine at 1250 mg/m.
Patients with refractory solid tumors were enrolled at four US sites. NC-6004 was administered intravenously (IV) at 60-180 mg/m over 1 hour on Day 1 with gemcitabine at 1250 mg/m IV over 30 mins on Day 1 and Day 8 every 3 weeks. All patients were administered a hydration regimen. Escalation of NC-6004 began with a single patient run-in, escalating by 15 mg/m until a dose limiting toxicity (DLT) occurred at 180 mg/m. Cohorts of four patients were then enrolled at each dose predicted by the N-CRM design. The maximum tolerated dose (MTD) was defined as the dose with the greatest posterior probability of target toxicity < 25%.
Among 22 patients enrolled in Phase 1b, 11 patients (six male, five female) had lung cancer. Non-squamous non-small cell lung cancer (NSCLC) was the most common subtype in 8/11 (72%) followed by squamous NSCLC, SCLC and large cell neuroendocrine histology in 1/11 (9%) of each type. Patients received a mean of 1.7 (range, 1-5) prior lines of therapy with 82% receiving a prior platinum agent. Common Grade 3/4 hematologic adverse events (AEs) among all patients were leukopenia (27%), thrombocytopenia (27%), anemia (18%) and neutropenia (18%). All AEs/DLTs were manageable and resolved. Of the four lung cancer patients treated at the MTD (135 mg/m), the mean number of cycles received was 6 (range, 2-17). The total cumulative doses were 120-2340 mg/m. Of ten patients evaluable, partial response was observed in 2/10 and stable disease in 7/10. Tumor shrinkage was observed in 6/10.
The nanoparticle formulation allowed greater cisplatin equivalent doses with no clinically significant neuro-, oto- or nephrotoxicity allowing patients to receive treatment for a longer duration. Activity was observed in heavily pretreated platinum exposed lung cancer patients with a majority of patients exhibiting tumor regression or stable disease. NC-6004 with gemcitabine demonstrated promising activity and tolerability in heavily pretreated lung cancer patients in this trial and warrants further investigation.