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S.T. Neuteboom
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P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.01-048 - CBL Mutations as Potential Mediators of EGFR TKI Resistance Effectively Treated with Sitravatinib (ID 9560)
09:30 - 09:30 | Author(s): S.T. Neuteboom
- Abstract
Background:
Third generation EGFR inhibitors are efficacious in patients with NSCLC harboring EGFR sensitizing mutations. Acquired resistance includes alternative mechanisms of EGFR activation and activation of other signaling pathways. Here we report a patient with a CBL mutation as a potential mechanism of acquired resistance to 3[rd] generation EGFR TKI effectively treated with sitravatinib, a spectrum-selective RTK inhibitor of TAM receptors (comprised of TYRO3, AXL, and MER), PDGFRA, KIT, and MET.
Method:
In Study 516-001, a phase 1/1b study of sitravatinib in patients with advanced solid tumor malignancies, patients are selected based on mutations in targeted pathways. Eligible genetic alterations include inactivating mutations of CBL, which encodes an E3-ubiquitin ligase that regulates degradation of activated RTKs that include EGFR, TAM receptors, PDGFRA, KIT, and MET and which account for ~2-3% of NSCLC. Based on overlap of sitravatinib and CBL RTK targets and supporting cancer cell line and tumor model data, we hypothesize that inactivating CBL mutations predict response to sitravatinib.
Result:
After Phase 1, patients were enrolled by mutational profile, and here we report on a patient enrolled into the CBL mutation cohort. The patient is a 77 year-old female, lifelong non-smoker with metastatic lung adenocarcinoma characterized by EGFR exon19del initially treated with erlotinib with a partial response (PR) of 9 months. Upon disease progression (PD), a new EGFR T790M mutation led to treatment with rociletinib (an experimental inhibitor of EGFR T790M) with stable disease for 11 months. Upon PD she was treated with osimertinib without response. She then received carboplatin/pemetrexed with a PR. Brief erlotinib re-challenge resulted in PD, with post-progression NGS revealing loss of EGFR T790M, presence of the original EGFR exon19del, and a new CBL C384R, a mutation located in the RING domain and predicted to result in the loss of CBL ligase adaptor function resulting in sustained activation of relevant RTKs. The patient then started sitravatinib treatment in Study 516-001. After 36 days on-study, restaging demonstrated PR, which was later confirmed with a maximum decrease in unidimensional target lesion measurement of 77%. She remains on-study.
Conclusion:
Loss of function mutations in CBL represent a unique class of mutations that may be responsible for acquired resistance to 3[rd] generation EGFR TKI. Sitravatinib has demonstrated clinical activity in a patient with NSCLC characterized by EGFR exon19del and CBL C384R mutations. The clinical trial with sitravatinib is currently enrolling patients with CBL loss of function mutations. (NCT02219711).
