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Viive M Howell
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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-129 - Preclinical Genetic Evaluation of Alternating ALK TKI Therapy Versus Continuous Dosing in ALK NSCLC to Inform the ALKternate Clinical Trial (ID 2074)
09:45 - 18:00 | Author(s): Viive M Howell
- Abstract
Background
Despite recent advances in the management of advanced ALK-rearranged NSCLC, with high objective response rates to ALK TKI therapy and survival gain, resistance to TKIs remains inevitable. Mechanisms of ALK-dominant and non-dominant resistance are being increasingly recognized, although in a many patients the underlying cause of drug resistance is unexplained.
ALKternate is a clinical trial recruiting pre-treated patients, testing the hypothesis that with fixed alternating TKI therapy, the emergence of ALK resistant clones can be suppressed through applying variable selection pressure compared to continuous treatment with a TKI. This has been tested pre-clinically with a human cell line to complement the clinical trial in progress, ALKternate (Abstract #2043). Proteomic pathway profiling to complement these data are presented in #2072.
Method
The H3122 human cell line (EML4(13)-ALK(20) variant 1 fusion) was treated with continuous ceritinib to induce resistance as confirmed by triplicate cytotoxicity assays. Once ceritinib resistance had developed, treatment continued with either continuous lorlatinib (‘CONT’ arm) or alternating continuous lorlatinib intercalated with crizotinib (‘ALT’ arm) to recapitulate ALKternate. Treatment continued for 17 cycles. Total nucleic acid was extracted from cells after cycles 5,11 and 17 of treatment and targeted next generation sequencing performed using the Oncomine Lung total nucleic acid assay on the Ion S5 system (Thermo-Fisher Scientific). Results were compared between treatment arms and over time.
Result
The genetic changes are detailed in Figure 1. The number of mutations identified increased with treatment duration.
Figure 1: Mutations and copy number gains (CNV) identified.
Conclusion
In keeping with the hypothesis, the genetic profiles identified demonstrate the emergence of different clones over time and between treatment strategies. This supports further investigation into the novel strategy of alternating therapy as planned in the ALKternate trial.
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P1.01-24 - Preclinical Proteomic Evaluation of Alternating ALK TKI Therapy Versus Continuous Dosing in ALK NSCLC to Inform the ALKternate Clinical Trial (ID 2072)
09:45 - 18:00 | Author(s): Viive M Howell
- Abstract
Background
Despite recent advances in the management of advanced ALK-rearranged NSCLC, with high objective response rates to ALK TKI therapy and survival gain, resistance to TKIs is inevitable. Mechanisms of ALK-dominant and non-dominant resistance are being increasingly recognized, although in many patients the underlying cause of drug resistance is unexplained.
ALKternate is a clinical trial recruiting pre-treated patients, testing the hypothesis that with fixed alternating TKI therapy, the emergence of ALK resistant clones can be suppressed through applying variable selection pressure compared to continuous treatment with a TKI. This has been tested pre-clinically with a human cell line to complement the clinical trial in progress, ALKternate (Abstract #2043). Genetic profiling to complement these data are presented in #2074.
Method
ALK TKI treatment was conducted on resistant ALK-rearranged cell lines (methods in Abstract #2074). Protein profiling was performed using the SWATH-MS 2.0 algorithm, conducted on the Sciex 6600 TripleTOF on cell pellets collected prior to treatment and at cycles (C) 5, 11 and 17 of both alternating lorlatinib with crizotinib (ALT) and continual lorlatinib (CONT) treatment arms.
Result
Figure 1: Significantly different proteins and pathways identified by proteomic profiling
Overall, LC-MS/MS data was extracted for 3850 proteins. Significantly differentially expressed proteins (SDEPs) identified between CONT/ALT cell lines (FC>1.5, p<0.05) are shown in Figure 1. There was significant enrichment of a number of pathways between the treatment arms. At cycle 5, the EIF pathway, which helps to drive tumour invasion and progression, was the most dysregulated.
At C11, elevated activity of cholesterol biosynthesis was observed in the ALT treatment arm. It is notable that hypercholesterolemia is a known side effect of lorlatinib treatment.
At the end of C17, the top dysregulated pathways in the CONT line involved sirtuin/integrin signalling, EMT remodelling, while all of the dysregulated pathways for the ALT line were related to cholesterol biosynthesis.
Conclusion
This study represents the first of proteomics used to identify resistance mechanisms to ALK TKIs. Data from this in vitro work will inform the ALKternate clinical trial.
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P2.01 - Advanced NSCLC (ID 159)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.01-11 - ALKternate: A Proof of Concept Study in ALK-Rearranged NSCLC Alternating Lorlatinib with Crizotinib After Disease Progression (Now Available) (ID 2043)
10:15 - 18:15 | Author(s): Viive M Howell
- Abstract
Background
Standard frontline therapy for patients with advanced ALK-NSCLC has rapidly evolved to 2nd generation ALK TKIs based on superior survival. Regardless, resistance to treatment is inevitable. Most will receive multiple lines of TKIs +/- chemotherapy before eventually dying from the disease.
Lorlatinib is a 3rd generation ALK TKI active against a broad range of acquired ALK kinase domain (KD) resistance mutations. A recent report demonstrated re-sensitisation to crizotinib by the lorlatinib ALK resistance mutation L1198F. Increased knowledge of resistance mechanisms is key to overcoming and preventing its emergence.
Based on knowledge of the varying patterns of resistance to different ALK TKIs, ALKternate will test the hypothesis that treatment with alternating TKIs will re-equilibrate the selection pressure for enrichment of resistant clones. This hypothesis has been tested preclinically in accompanying abstracts #2072 and #2074.
Method
ALKternate is a proof of concept open label multi-centre translational study alternating lorlatinib (100mg OD) with crizotinib (250mg BD) (Figure 1. including eligibility).
The aim is to identify whether this fixed alternating schedule of ALK TKI is: safe; feasible and active, resulting in prolonged systemic and intracranial disease control via delaying the emergence of ALK TKI resistance. A secondary aim is to investigate whether plasma ALK-dependent and independent resistance profiles can be used to monitor therapy effectiveness.
The primary outcome measure is time to treatment failure (TTTF) with alternating therapy. Secondary end points include best OR, PK analysis, PFS, DCR (systemic and CNS) after lorlatinib induction and the first cycle of alternating therapy, OS, toxicity, PROs and QOL measures. Plasma ctDNA and proteomic biomarkers will be analysed.
Enrolled patients must demonstrate disease control after induction lorlatinib to continue alternating therapy. Imaging occurs more frequently initially (Figure 1.), before 12 weekly after two alternating cycles in those with disease control.
Status: Trial in Progress. Enrollment began Q3 2019, ethics approval NSLHD ETH00389.
Figure 1. ALKternate trial schema
Result
Section not applicable
Conclusion
Section not applicable
