Virtual Library
Start Your Search
V. Subbiah
Author of
-
+
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)
-
+
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): V. Subbiah
- 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
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
P1.03 - Chemotherapy/Targeted Therapy (ID 689)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- 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 - 09:30 | Author(s): V. Subbiah
- Abstract
Background:
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[2]. A Bayesian continual reassessment method (N-CRM) design evaluated escalating doses of NC-6004 in combination with gemcitabine at 1250 mg/m[2].
Method:
Patients with refractory solid tumors were enrolled at four US sites. NC-6004 was administered intravenously (IV) at 60-180 mg/m[2] over 1 hour on Day 1 with gemcitabine at 1250 mg/m[2] 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[2] until a dose limiting toxicity (DLT) occurred at 180 mg/m[2]. 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%.
Result:
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[2]), the mean number of cycles received was 6 (range, 2-17). The total cumulative doses were 120-2340 mg/m[2]. Of ten patients evaluable, partial response was observed in 2/10 and stable disease in 7/10. Tumor shrinkage was observed in 6/10.
Conclusion:
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.
