Patients with EGFR-mutant lung cancer derive significant therapeutic benefit from treatment with EGFR tyrosine kinase inhibitors (TKI). Unfortunately, acquired resistance is an inevitable consequence ...of this treatment strategy, with a broad variety of resistance mechanisms including acquired EGFR mutations (e.g., T790M) and activation of bypass signaling pathways, such as MET and HER2. Several therapeutic strategies hypothesized to delay or overcome resistance have been tested in clinical trials, including "next-generation" EGFR TKIs and rational combinations of targeted agents. However, to date, there are no FDA-approved therapies for patients with acquired resistance to first-line EGFR TKI therapy. There remains a critical need for more effective and better tailored treatments in this setting to match treatments to the individual patient and specific resistance mechanism at hand. In this review, we discuss known mechanisms of resistance to first-line EGFR TKI therapy and describe previous and ongoing strategies to overcome resistance.
Oncogenic tyrosine kinase fusions involving the anaplastic lymphoma kinase (ALK) are detected in numerous tumor types. Although more than 30 distinct 5' fusion partner genes have been reported, ...treatment of
-rearranged cancers is decided without regard to which 5' partner is present. There is little data addressing how the 5' partner affects the biology of the fusion or responsiveness to ALK tyrosine kinase inhibitors (TKI). On the basis of the hypothesis that the 5' partner influences the intrinsic properties of the fusion protein, cellular functions that impact oncogenic potential, and sensitivity to ALK TKIs, clonal 3T3 cell lines stably expressing seven different ALK fusion variants were generated. Biochemical and cellular assays were used to assess the efficacy of various ALK TKIs in clinical use, transformative phenotypes, and biochemical properties of each fusion. All seven ALK fusions induced focus formation and colonies in soft agar, albeit to varying degrees. IC
s were calculated for different ALK TKIs (crizotinib, ensartinib, alectinib, lorlatinib) and consistent differences (5-10 fold) in drug sensitivity were noted across the seven ALK fusions tested. Finally, biochemical analyses revealed negative correlations between kinase activity and protein stability. These results demonstrate that the 5' fusion partner plays an important biological role that affects sensitivity to ALK TKIs.
This study shows that the 5' ALK fusion partner influences ALK TKI drug sensitivity. As many other kinase fusions are found in numerous cancers, often with overlapping fusion partners, these studies have ramifications for other kinase-driven malignancies.
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Evaluate safety and determine the recommended phase II dose (RP2D) of ensartinib (X-396), a potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), and evaluate preliminary ...pharmacokinetics and antitumor activity in a first-in-human, phase I/II clinical trial primarily in patients with non-small cell lung cancer (NSCLC).
In dose escalation, ensartinib was administered at doses of 25 to 250 mg once daily in patients with advanced solid tumors; in dose expansion, patients with advanced
-positive NSCLC were administered 225 mg once daily. Patients who had received prior ALK TKI(s) and patients with brain metastases were eligible.
Thirty-seven patients enrolled in dose escalation, and 60 enrolled in dose expansion. The most common treatment-related toxicities were rash (56%), nausea (36%), pruritus (28%), vomiting (26%), and fatigue (22%); 23% of patients experienced a treatment-related grade 3 to 4 toxicity (primarily rash and pruritus). The maximum tolerated dose was not reached, but the RP2D was chosen as 225 mg based on the frequency of rash observed at 250 mg without improvement in activity. Among the
-positive efficacy evaluable patients treated at ≥200 mg, the response rate (RR) was 60%, and median progression-free survival (PFS) was 9.2 months. RR in ALK TKI-naïve patients was 80%, and median PFS was 26.2 months. In patients with prior crizotinib only, the RR was 69% and median PFS was 9.0 months. Responses were also observed in the central nervous system, with an intracranial RR of 64%.
Ensartinib was active and generally well tolerated in patients with
-positive NSCLC.
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Mutant-selective EGFR tyrosine kinase inhibitors (TKI), such as osimertinib, are active agents for the treatment of
-mutant lung cancer. Specifically, these agents can overcome the effects of the ...T790M mutation, which mediates resistance to first- and second-generation EGFR TKI, and recent clinical trials have documented their efficacy in patients with
-mutant lung cancer. Despite promising results, therapeutic efficacy is limited by the development of acquired resistance. Here we report that Src family kinases (SFK) and focal adhesion kinase (FAK) sustain AKT and MAPK pathway signaling under continuous EGFR inhibition in osimertinib-sensitive cells. Inhibiting either the MAPK pathway or the AKT pathway enhanced the effects of osimertinib. Combined SFK/FAK inhibition exhibited the most potent effects on growth inhibition, induction of apoptosis, and delay of acquired resistance. SFK family member
was amplified in osimertinib-resistant
-mutant tumor cells, the effects of which were overcome by combined treatment with osimertinib and SFK inhibitors. In conclusion, our data suggest that the concomitant inhibition of both SFK/FAK and EGFR may be a promising therapeutic strategy for
-mutant lung cancer.
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Mutated anaplastic lymphoma kinase (ALK) drives the development of multiple tumor types, and ALK tyrosine kinase inhibitors such as crizotinib have been validated as targeted therapeutics. ...Unfortunately, as with other oncogene-driven tumors, therapeutic resistance invariably develops. In Science Translational Medicine, two recent studies provide new insight into mechanisms of resistance to ALK tyrosine kinase inhibitors and possible strategies to overcome this resistance.
ALK rearrangement-positive lung cancers can be effectively treated with ALK inhibitors. However, the magnitude and duration of response is heterogeneous. In addition, acquired resistance limits the ...efficacy of ALK inhibitors, with most upfront resistance mechanisms being unknown.
By making use of the Ba/F3 cell line model, we analyzed the cytotoxic efficacy of ALK kinase inhibitors as a function of different EML4-ALK fusion variants v1, v2, v3a, and v3b as well as of three artificially designed EML4-ALK deletion constructs and the ALK fusion genes KIF5b-ALK and NPM1-ALK. In addition, the intracellular localization, the sensitivity to HSP90 inhibition and the protein stability of ALK fusion proteins were studied.
Different ALK fusion genes and EML4-ALK variants exhibited differential sensitivity to the structurally diverse ALK kinase inhibitors crizotinib and TAE684. In addition, differential sensitivity correlated with differences in protein stability in EML4-ALK-expressing cells. Furthermore, the sensitivity to HSP90 inhibition also varied depending on the ALK fusion partner but differed from ALK inhibitor sensitivity patterns. Finally, combining inhibitors of ALK and HSP90 resulted in synergistic cytotoxicity.
Our results might explain some of the heterogeneous responses of ALK-positive tumors to ALK kinase inhibition observed in the clinic. Thus, targeted therapy of ALK-positive lung cancer should take into account the precise ALK genotype. Furthermore, combining ALK and HSP90 inhibitors might enhance tumor shrinkage in EML4-ALK-driven tumors.
The third-generation EGFR inhibitor, osimertinib, is the first mutant-selective inhibitor that has received regulatory approval for the treatment of patients with
-mutant lung cancer. Despite the ...development of highly selective third-generation inhibitors, acquired resistance remains a significant clinical challenge. Recently, we and others have identified a novel osimertinib resistance mutation, G724S, which was not predicted in
screens. Here, we investigate how G724S confers resistance to osimertinib.
We combine structure-based predictive modeling of G724S in combination with the 2 most common EGFR-activating mutations, exon 19 deletion (Ex19Del) and L858R, with
drug-response models and patient genomic profiling.
Our simulations suggest that the G724S mutation selectively reduces osimertinib-binding affinity in the context of Ex19Del. Consistent with our simulations, cell lines transduced with Ex19Del/G724S demonstrate resistance to osimertinib, whereas cells transduced with L858R/G724S are sensitive to osimertinib. Subsequent clinical genomic profiling data further suggest G724S occurs with Ex19Del but not L858R. Furthermore, we demonstrate that Ex19Del/G724S retains sensitivity to afatinib, but not to erlotinib, suggesting a possible therapy for patients at the time of disease relapse.
Altogether, these data suggest that G724S is an allele-specific resistance mutation emerging in the context of Ex19Del but not L858R. Our results fundamentally reframe the problem of targeted therapy resistance from one focused on the "drug-resistance mutation" pair to one focused on the "activating mutation-drug-resistance mutation" trio. This has broad implications across clinical oncology.
An ASCO provisional clinical opinion offers timely clinical direction to ASCO's membership following publication or presentation of potentially practice-changing data from major studies. This ...provisional clinical opinion addresses the appropriate use of tumor genomic testing in patients with metastatic or advanced solid tumors.
An increasing number of therapies are approved to treat cancers harboring specific genomic biomarkers. However, there is a lack of clarity as to when tumor genomic sequencing should be ordered, what type of assays should be performed, and how to interpret the results for treatment selection.
Patients with metastatic or advanced cancer should undergo genomic sequencing in a certified laboratory if the presence of one or more specific genomic alterations has regulatory approval as biomarkers to guide the use of or exclusion from certain treatments for their disease. Multigene panel-based assays should be used if more than one biomarker-linked therapy is approved for the patient's disease. Site-agnostic approvals for any cancer with a high tumor mutation burden, mismatch repair deficiency, or neurotrophic tyrosine receptor kinase (
) fusions provide a rationale for genomic testing for all solid tumors. Multigene testing may also assist in treatment selection by identifying additional targets when there are few or no genotype-based therapy approvals for the patient's disease. For treatment planning, the clinician should consider the functional impact of the targeted alteration and expected efficacy of genomic biomarker-linked options relative to other approved or investigational treatments.Additional information is available at www.asco.org/assays-and-predictive-markers-guidelines.
Correspondence to Dr Christine M. Lovly; christine.lovly@vumc.org Introduction Cell-free DNA (cfDNA) is DNA present in the cell-free component of blood (plasma and serum) or other human bodily ...fluids.1 In patients diagnosed with cancer, a component of this cfDNA includes tumor-derived DNA arising from primary or metastatic cancer sites, also known as circulating tumor DNA (ctDNA).2 Since ctDNA may harbor the same somatic genomic alterations as the tumor,3 ctDNA detection may have utility in screening and diagnosis, assessing therapeutic response, monitoring for therapeutic resistance, and quantitatively assessing molecularly measurable/minimal residual disease (MRD).4 In the article highlighted by this viewpoint, Semenkovich et al provide a comprehensive review of the various sources, laboratory techniques, clinical applications, and challenges with utilization of ctDNA. The ctDNA dynamics may provide early assessment of treatment efficacy, differentiation of true progression from pseudoprogression, and opportunity to alter or escalate treatment prior to clinical progression.8 Standardization and identification of optimal strategies (tumor informed vs tumor agnostic tests) and thresholds for monitoring and timing for ctDNA-based response prediction are necessary to determine best practices for clinical application. ...analysis of alternative sources of ctDNA (such as other bodily fluids proximal to the primary cancer site) and evaluation of other analytes in the blood (DNA methylation signatures, RNA, exosomes, and circulating tumor cells), both of which may provide complementary approaches to increase sensitivity and optimize liquid biopsy technology for clinical utility. ...ctDNA has the potential to truly enable precision oncology where early screening, diagnostic, response prediction, monitoring and surveillance can be performed to tailor the right treatments to our patients at the right time.
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