Start Your Search
Monika A Davare
P1.14 - Targeted Therapy (ID 182)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 2
- Now Available
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
P1.14-12 - A Novel Activating MAP2K1 In-Frame Deletion Mediates Acquired Resistance to ROS1 TKIs in a Patient with ROS1 Fusion-Positive NSCLC (ID 2450)
09:45 - 18:00 | Author(s): Monika A Davare
ROS1 tyrosine kinase inhibitors (TKIs) such as crizotinib, entrectinib and lorlatinib provide significant benefit in non-small cell lung cancer (NSCLC) patients with ROS1 fusions. As observed with all targeted therapies however, resistance arises. With the widespread adoption of large panel next generation sequencing (NGS) at the time of acquired resistance (AR), our appreciation of novel off-target mechanisms continues to grow. Detecting additional mechanisms of acquired resistance (AR) is crucial to find novel therapies and improve patient outcomes.Method
We reviewed targeted large-panel sequencing data (using the MSK-IMPACT assay) of paired pre-treatment and post-progression samples from patients treated with ROS1 TKIs. Genetic alterations hypothesized to confer AR were modeled in a patient-derived cell line (LUAD-0003, expressing EZR/ROS1) as well as isogenic human (HBEC) and murine (NIH-3T3) cell lines. ROS1 fusions were expressed in these cells either by cDNA overexpression (CD74/ROS1, SLC34A2/ROS1) or CRISPR-Cas9-mediated genomic engineering (EZR/ROS1). Using these cell line models, alterations in drug sensitivity and downstream signal pathways were examined. We also explored possible therapeutic strategies to overcome the drug resistance caused by the novel AR mechanisms examined in this study.Result
We identified a patient with NSCLC harboring a MAP2K1 (MEK1) variant encoding an in-frame deletion of amino acids E41-L54 (MEK1del) in a sample taken at the time of resistance to lorlatinib (after 9 months’ treatment). This mutation was not detected in the pre-TKI sample. Induction of ROS1 fusions in HBEC and NIH-3T3 cells increased the sensitivity of these cells to ROS1 TKIs and stimulated activation of MEK/ERK signaling in comparison with AKT signaling, suggesting the importance of the RAS-MAPK pathway in driving ROS1 fusion-positive cancers. Underscoring the importance of the RAS-MAPK pathway in ROS1-mediated tumorigenesis, we identified three patients (pancreatic, salivary, and breast cancer) with a ROS1 fusion and NF1 loss-of-function mutation concurrently, in TKI-naïve samples. Expression of MEK1del in HBEC and NIH-3T3 cells harboring ROS1 fusions, and knockdown of NF1 in LUAD-0003, activated ERK signaling and conferred resistance to ROS1 TKIs. Combined targeting of ROS1 (crizotinib, lorlatinib) and MEK (selumetinib, trametinib) inhibited growth of cells expressing both ROS1 fusion and MEK1del.Conclusion
Our results suggest that the activation of the RAS-MAPK pathway plays a critical role in tumorigenesis mediated by ROS1 fusions, and that activating mutations in this pathway can drive AR to ROS1 TKIs. Combined inhibition of ROS1 and MEK is a potential therapeutic strategy that should be explored clinically.
P1.14-50 - A Phase 2 Trial of Cabozantinib in ROS1-Rearranged Lung Adenocarcinoma (Now Available) (ID 2753)
09:45 - 18:00 | Author(s): Monika A Davare
To date, no ROS1 inhibitor is approved for the treatment of ROS1-rearranged lung cancers after progression on crizotinib. Progression on crizotinib can be mediated by the acquisition of ROS1 kinase domain mutations (e.g. ROS1G2032R or ROS1D2033N). Cabozantinib is a highly potent ROS1 tyrosine kinase inhibitor that has superior activity over lorlatinib against these mutations. We evaluated the activity of cabozantinib in patients with ROS1-rearranged lung cancers on a phase 2 trial.Method
In this single-center, open-label, Simon two-stage, phase 2 study, eligible patients had ROS1-rearranged unresectable/metastatic non-small cell lung cancer, a Karnofsky performance status >70%, and measurable disease. ROS1 fusion was identified by local testing in a CLIA-compliant environment. Cabozantinib was dosed at 60 mg once daily. The primary endpoint was objective response (RECIST v1.1). In the first stage of this trial, 1 response was required to move to the second stage. Secondary endpoints included safety.Result
Six patients received cabozantinib in the ongoing first stage of this study. All patients had >1 prior ROS1 inhibitor. The median age was 59 years; all were never smokers. The best response to therapy was: 1 partial response (-92%, confirmed), 1 unconfirmed partial response (-31%), and 4 stable disease. All patients had disease regression (-7 % to -92%); no patients had primary progressive disease. The only patient with a confirmed partial response was a patient whose cancer acquired a ROS1D2033N solvent front mutation after crizotinib. None of the other five ROS1 inhibitor pre-treated patients (who did not have a confirmed response) had a known on-target acquired resistance mutation in their cancer. After progression on cabozantinib (9.1 months after therapy initiation), the patient whose cancer harbored the ROS1D2033N mutation acquired a METD1228N kinase domain mutation on paired sequencing of pre-cabozantinib and post-progression tumor. The most common grade 3 treatment-related adverse events were hypertension (50%), and mucositis, palmar-plantar erythrodysesthesia, and hypophosphatemia (each in 17%). Most patients (83%) required a dose reduction.Conclusion
Cabozantinib can re-establish disease control in ROS1-rearranged lung cancers after progression on a prior ROS1 inhibitor. The first stage of this ongoing trial met its prespecified endpoint for efficacy to move into the second stage. Response was only observed in the setting of a known ROS1 kinase domain resistance mutation.
Only Active 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 or select "Add to Cart" and proceed to checkout.