Lorlatinib is currently the only approved treatment for patients with ALK-positive NSCLC whose cancers have progressed on prior ALK drugs, and for those whose tumors develop resistance, there is a lack of other treatment options other than chemotherapy. In this study, Dr. Qin will evaluate a novel drug called gilteritinib as a treatment in patients with ALK-positive NSCLC whose tumors have developed a resistance to lorlatinib.
Research Summary
Lorlatinib is the only approved ALK-targeted drug for patients with ALK-positive non-small cell lung cancer (ALK NSCLC) who progressed on prior ALK drugs. The average duration of benefit from lorlatinib is seven months before resistance develops. There are currently no approved ALK-directed therapies after lorlatinib.
Our understanding of lorlatinib resistance mechanisms remains limited. However, we know that 1) cancer cells can develop two ALK mutations that block lorlatinib action and 2) cancer cells can activate other pathways so that cancers no longer exclusively rely on ALK.
This proposal addresses ALK resistance directly, with the goal of opening a clinical trial using a novel drug called gilteritinib. Preliminary tests show gilteritinib prevents ALK NSCLC from using alternative pathways to overcome ALK inhibition. First, we propose to obtain tumor-containing samples from patients who are progressing on lorlatinib and perform in-depth sequencing of these cancer cells to thoroughly describe resistance mechanisms in all detectable cancer clones. Next, we will perform drug sensitivity testing on these cancer cells using approved and experimental drugs, including gilteritinib. Finally, we will open a clinical trial using gilteritinib, already approved for treatment of a blood cancer (FLT3+ acute myeloid leukemia). In multiple pre-clinical studies, gilteritinib was able to kill lorlatinib-resistant cells, but this drug has not been given to patients with ALK NSCLC. Our proposal focuses on bringing knowledge obtained from patients’ cancer cells through extensive analysis directly into a clinical trial with a novel drug, maximizing the impact to patients.
Technical Abstract
Lorlatinib is currently the only approved ALK TKI (tyrosine kinase inhibitor) for patients with ALK NSCLC that have progressed on prior lines of therapy. The clinical benefit of lorlatinib is modest in previously-treated patients with a median PFS of 7 months (1). Mechanisms of lorlatinib resistance are diverse and include novel ALK mutations, compound ALK mutations, and activation of bypass pathways including AXL. Gilteritinib is a dual inhibitor of FLT3/AXL that is approved for relapsed/refractory FLT3+ acute myeloid leukemia (AML). Pre-clinical work using ALK fusion positive cell lines (including those containing compound mutations), patient-derived tumor cells, and in vivo mouse studies all demonstrate the anti-tumor activity of gilteritinib specifically against lorlatinib-resistant ALK NSCLC.
We will recruit patients with ALK NSCLC with progression on lorlatinib and collect patient-derived tumor samples. In addition to surgical, biopsy, or effusion fluid samples, plasma will be collected for isolation of circulating tumor DNA and circulating tumor cells. Whole exome sequencing (WES) will be used to identify molecular alterations that define resistance mechanisms. Ex vivo drug testing will be conducted using our existing platform and will include ALK inhibitors and inhibitors of pathways implicated in resistance such as AXL, MET, mTOR, and MAPK. Results of ex vivo drug testing will be correlated with findings from WES.
Simultaneously, we will open a phase I clinical trial to assess the safety and preliminary efficacy of gilteritinib in patients with lorlatinib-resistant ALK NSCLC. Crucially, clinical endpoints will be correlated with sequencing data and ex vivo drug testing results.