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J.G. Christensen
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MA 02 - Emerging Targets (ID 656)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:Ravi Salgia, Shun Lu
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 511 + 512
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MA 02.01 - Evidence of Clinical Activity of Sitravatinib in Combination with Nivolumab in NSCLC Patients Progressing on Prior Checkpoint Inhibitors (ID 9720)
11:00 - 11:05 | Author(s): J.G. Christensen
- Abstract
- Presentation
Background:
Combination therapy with agents that target the molecular and cellular mechanisms of resistance to checkpoint inhibitor therapy (CIT) is a rational approach to restoring or improving the efficacy of CIT in patients with immunotherapy resistant NSCLC. Sitravatinib is a spectrum-selective TKI which targets TAM receptors (Axl, MER), split family receptors (VEGFR2 and KIT), and MET. Inhibition of these target classes by sitravatinib may enhance anti-tumor activity through targeted depletion of immunosuppressive Type 2 tumor associated macrophages, regulatory T cells and myeloid-derived suppressor cells (MDSCs) and increasing antigen presentation capacity of dendritic cells in the tumor microenvironment (TME) thereby enhancing anti-tumor T effector and NK cell responses. Given these pleiotropic immune activating effects, the combination of sitravatinib with nivolumab is a rational approach to restoring or enhancing the clinical activity of CIT in patients with immunotherapy resistant NSCLC.
Method:
MRTX-500 is a Phase 2 Study of sitravatinib in combination with nivolumab in non-squamous NSCLC patients who have experienced progression of disease on or after treatment with CIT. The primary objective is to assess the clinical activity of the combination using ORR by RECIST 1.1. Enrollment into the Phase 2 treatment arm is stratified by prior outcome of CIT (e.g., clinical benefit versus progression of disease in ≤12 weeks). The investigational agent sitravatinib is administered orally in continuous regimen; nivolumab is administered intravenously, 240 mg every 2 weeks. The sample sizes for the treatment arms are based on two-stage Simon Optimal Design.
Result:
The recommended phase 2 dose of the combination is 120 mg of sitravatinib orally, once daily with nivolumab given at a flat dose of 240 mg IV Q 2 weeks. As of June 20, 2017, the study has enrolled 11 patients and 6/11 patients have had at least one on-study tumor assessment. Two patients out of 6 have achieved PR by RECIST. The first patient is a 72 yo female with pan-wild type metastatic NSCLC with history of treated brain metastases with multiple prior therapies who previously received pembrolizumab (stable disease for 14 months) and obtained confirmed PR at first disease evaluation. The second patient is a 71 yo female with pan-wild type metastatic NSCLC with multiple prior therapies who previously received nivolumab (progressive disease as best overall response) but who obtained unconfirmed PR at first disease evaluation. Treatment has been associated with manageable side effects to date.
Conclusion:
This study is ongoing and actively accruing patients.
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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): J.G. Christensen
- 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).
