EML4-ALK fusion

Between January 2020 and February 2024, we identified four patients with either EML4-ALK fusions (2/4) or EGFR mutations (2/4) who underwent treatment with brigatinib or osimertinib before surgery. This case series highlights the potential of targeted therapies for resectable NSCLC in the neoadjuvant setting. Further research is required to confirm their benefits, assess their safety and efficacy, and determine optimal timing and sequencing.

P2, N=109, Completed, Pfizer | Active, not recruiting --> Completed

Interlaboratory studies using the EML4-ALK RMs and potential RMP showed that participating laboratories can produce consistent copy concentrations of fusion variant and ALK-ref as well as the ratio of EML4-ALK/ALK-ref. The established potential RMP with high specificity and accuracy can be used to characterize the EML4-ALK RMs, and the potential RMP and RM are useful to establish the traceability of EML4-ALK fusion measurement to improve the comparability and consistency in clinical tests.

Based on the genomic analysis, we treated the patient with brigatinib, an ALK inhibitor. We describe here a patient with LCNEC who responded significantly to brigatinib without serious adverse events.

Despite two cycles of adjuvant chemotherapy consisting of carboplatin and gemcitabine, CT revealed that the pleural effusion had increased from it before chemotherapy, and the shortness of breath worsened...Treatment with alectinib, a second-generation ALK-tyrosine kinase inhibitor, led to a partial response of 18 months' duration, and the shortness of breath improved...Variations in the drug response among EML4-ALK fusion variants highlight the importance of understanding their molecular structure. Further investigation is warranted to refine fusion gene detection methods and assess the therapeutic implications of rare fusion variants.

V3 patients had poor outcomes regardless of PD-L1 status, while V1 patients with PD-L1 negativity had better outcomes. These biomarkers offer key insights into treatment outcomes for ALK-positive patients.

The patient was treated with lorlatinib as the first-line treatment. This case is the first to describe the effectiveness of lorlatinib in treating an advanced high-grade PMEC with EML4-ALK fusion V2 mutation patient.

Consistently, combination of the ALK TKI alectinib with the MET TKI capmatinib and/or the integrin inhibitor cilengitide was significantly more efficacious than single agent treatment in suppressing tumor growth using an in vivo EML4-ALK -dependent allograft mouse model of NSCLC. In summary, these findings emphasize the complexity of resistance-associated crosstalk between CAFs and cancer cells, which can involve multiple concurrent signaling pathways, and illustrate how comprehensive elucidation of paracrine and juxtacrine resistance mechanisms can inform on more effective therapeutic approaches.

Yet, to our knowledge, we present herein the first case of ALK + NSCLC rapidly progressing on 1 st line Brigatinib treatment due to de novo MET- amplification. The recognition of this mechanism of ALK-TKI resistance by FISH, especially in NGS-negative cases, should be considered before initiating 1 st line treatment. This is of clinical importance, as effective combined therapy with ALK-TKI and MET-inhibitor is feasible.

Some atypical fusion partners were observed in white and BAA that were not observed in other races. These data emphasize the importance of testing lung cancer patients with assays that allow for unbiased fusion detection and identification of novel fusion partners across racially diverse populations to better understand racial and ethnic differences in ALK-rearranged lung cancers.

Initially, she received three cycles of Nabpaclitaxel and carboplatin and upon progression plasma ctDNA NGS was ordered and reported EML4-ALK fusion (0.7% VAF) in Nov 2022 resulting in treatment with alectinib. ctDNA CGP can provide genotyping at fast TAT for effective management of aBC. Fusions, though rare in aBC, should be considered for detection for targeted therapy.

P3 | "In ALINA, DFS benefit with alectinib was seen regardless of EML4-ALK variant. Pts with WT TP53 at baseline showed a trend for improved DFS with alectinib vs mutated TP53."

P2, N=85, Completed, M.D. Anderson Cancer Center | Active, not recruiting --> Completed | Trial completion date: Sep 2024 --> May 2024 | Trial primary completion date: Sep 2024 --> May 2024

A case of EML4-ALK fusion mutation in invasive lung adenocarcinoma has been reported. Multiple cystic changes occurred repeatedly in both kidneys, right rectus muscle, and psoas major muscle after treatment with crizotinib, and spontaneous absorption and resolution after discontinuation of the drug.

Combination treatment with lorlatinib and erlotinib significantly reduced HRG1-induced activation of RTK signaling in ALK-positive NSCLC cells. HER3 overexpression has potential as a prognostic marker in ALK-positive NSCLCs, including ALK-TKI naïve and treated cases, especially those with EML4-ALK V1/V2. Assessing HER3 expression may be crucial for treatment planning and outcome prediction in these patients.

Intriguingly, we also found that expression of Eg5-S1033D led to cells expressing EML4-ALK V1 adopting a more mesenchymal-like morphology. Taken together, we propose Eg5 acts as a substrate of NEK7 in cells expressing EML4-ALK V3 and that Eg5 phosphorylation promotes the altered morphology typical of these cells.

Both fluorouracil, leucovorin, and oxaliplatin (FOLFOX) and bevacizumab combined with 5-fluorouracil, l-leucovorin, and irinotecan (FOLFIRI) proved ineffective against the disease...The patient was initially treated with ensartinib monotherapy for 9 months, then with ensartinib combined with local radiotherapy and fruquintinib for another 4 months for isolated hilar hepatic lymph node metastasis. The patient experienced disease progression with an acquired ALK G1202R resistance mutation that responded well to lorlatinib...However, the patient responded remarkably well to alectinib. Our report emphasizes the importance of gene detection in the treatment of malignant tumors, and the significance of ALK mutations in CRC.

In this study, we systematically explored the validity of sequential ALK inhibitors (alectinib, lorlatinib, crizotinib, ceritinib and brigatinib) for a heavy-treated patient with EML4-ALK fusion via developing an in vitro and in vivo drug testing system based on patient-derived models. In summary, our results delineate clinical responses of sequential ALK-TKIs treatments and provide insights into the mechanisms underlying the superior effects of brigatinib in patients harboring ALKG1269A mutation and resistant towards alectinib, lorlatinib and crizotinib. The molecular signatures model based on the combination of IL6, CXCL1 and CXCL5 has the potential to predict prognosis of EML4-ALK positive NSCLC patients.

Furthermore, dEALK1 also exerts a potent antitumor activity against EML4-ALK-positive xenograft tumors without or with harboring ceritinib-resistant EML4-ALK mutations in vivo. Our study suggests that dEALK1-induced degradation of EML4-ALK fusion proteins is a promising therapeutic strategy for treatment of ALK-rearranged lung cancer with ceritinib resistance.

Consistently, mouse squamous tumors or LUAD with squamous signature display certain resistance to ALK inhibitor, which can be overcome by combined JAK1/2 inhibitor treatment. This study uncovers strong plasticity of ALK-rearranged tumors in orchestrating phenotypic transition and drug resistance and proposes a potentially effective therapeutic strategy.

These findings highlight the complexity of drug selection when treating patients harboring resistance mutations and suggest that the F1174S mutation in EML4-ALK variant 1 is likely not a potent oncogenic driver. Additional oncogenic driver or other resistance mechanisms should be considered in the case of EML4-ALK variant 1 with F1174S mutation.

This study affirms the efficacy of lorlatinib in patients with ALK-positive SCLC transformation harboring the V1180L mutation. Furthermore, it underscores the imperative of conducting genetic testing in patients who transition to SCLC following ALK-TKI resistance, as targeted therapies may remain efficacious if a genetic driver is identified.

Whole-transcriptome sequencing allowed the identification of actionable fusions with the potential to affect clinical decisions regarding therapy in 2.8% of RCC patient tumors. In addition, one patient was found to have a fusion that is characteristic of a solitary fibrous tumor, demonstrating the power of genomic profiling to aid diagnosis.

Conclusion  Oncogenic driver mutations are present in Indian NSCLC patients. Molecular testing should be performed for all patients of advanced NSCLC to identify those that can benefit from newer generation of targeted or immunotherapies.

ALK inhibitors first-line crizotinib, second-line ceritinib, and alectinib are effective against NSCLC patients with these rearrangements. Based on the Y1278-C1097 H-bond and E1167-K1150 salt bridge interaction, I1171N strongly promotes the constitutively active kinase independent of ATP. This structural mechanism study will aid in understanding the oncogenic activity of ALK and the basis for improving the ALK inhibitors.

By means of the diagnosis and treatment of this case, the characteristics and therapies of IMT are illustrated. In addition, it also provides a reference for the therapeutic strategy of IMT in the future.

Then, the patient received 1 cycle of chemotherapy with paclitaxel in combination with nedaplatin and subsequently received maintenance treatment involving lorlatinib. CONCLUSIONS This case demonstrates the potential advantage of lorlatinib as a neoadjuvant therapy in advanced ALK-positive NSCLC. It emphasizes the importance of identifying new therapeutic targets by next-generation sequencing (NGS) and implementing precise treatment strategies in clinical practice.

EML4-ALK fusion protein may enhance venous thrombogenicity by regulating coagulation factor TF expression. There was potential involvement of the pERK1/2-AP-1 pathway in this process.

Following corticosteroid treatment and discontinuation of alectinib, clinical presentations and CT scan gradually improved, but the primary lung lesions enlarged during the regular follow-up. The administration of crizotinib was then initiated and the disease was stable for 25 months without recurrence of primary lung lesions and ILD.

Multivariate Cox regression analysis revealed that harboring multiple ALK fusions had the potential to be an independent predictor of better PFS for ALK-positive NSCLC [hazard ratio (HR) =0.490; 95% confidence interval (CI): 0.229-1.049]. Harboring multiple ALK fusions could serve as an independent predictive marker of better clinical outcome for patients with NSCLC and ALK rearrangement who have received ALK-TKIs treatment.

No abstract available

Following corticosteroid treatment and discontinuation of alectinib, clinical presentations and CT scan gradually improved, but the primary lung lesions enlarged in the regular follow-up. The administration of a first-generation ALK inhibitor crizotinib was then initiated and the disease was stable for 25 months without recurrence of ILD.

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Brigatinib, a tyrosine kinase inhibitor (TKI) with specificity for gene rearranged anaplastic lymphoma kinase (ALK), such as the EML4-ALK, has shown a potential to inhibit mutated epidermal growth factor receptor (EGFR). The tumor-to-blood ratio in H2228 xenografts could be reduced by pretreatment with ALK inhibitor crizotinib. Tracer uptake in EGFR Del19 mutated HCC827 and EML4-ALK fusion A549 was not significantly different from uptake in A549 xenografts.

One expansion cohort of J-ALTA enrolled patients previously treated with ALK tyrosine kinase inhibitors (TKIs); the main cohort included patients with prior alectinib ± crizotinib. Exploratory analyses of baseline circulating tumor DNA in ALK TKI-pretreated NSCLC showed associations between poor PFS and EML4-ALK fusion variant 3 and TP53. Brigatinib is an important treatment option for Japanese patients with ALK+ NSCLC, including patients previously treated with alectinib.

NGS recommended an FDA-approved drug or clinical trial in 85.71% of cases; patients with only CTs available had the worst PFS; Our study provides results that suggest NGS may guide therapeutic decisions and potentially improve patient outcomes. Further research with larger sample sizes is needed to validate our findings and expand our understanding of the genomic landscape of lung cancer in Mexico.

Secondary rearrangement involving EML4-ALK which places the fusion gene under control of a new promoter may be a novel mechanism of resistance to crizotinib in IMT (and potentially other ALK-fusion-driven malignancies). Alectinib, a more potent ALK inhibitor, overcame resistance in this case. More broadly, this study exemplifies the importance of molecular testing in the setting of resistance to targeted therapy to inform clinical decision making.

Due to significant loculation, he was transferred to a tertiary center, underwent bronchoscopy however was a poor candidate for stenting/VATS, received oral salvage chemotherapy with Lorbrena...Next-generation ALK inhibitors like Alectinib and Brigatinib, have demonstrated clinical improvement and overall survival benefits in ALK-positive tumors when compared to chemotherapy... With this case, we emphasise the role of NGS, identification of EML4-ALK fusion in NSCLC and the potential role of tyrosine-kinase inhibitors in personalizing lung cancer therapy. Using combination therapy with ALK-TKIs and anti-PD1/PD-L1 antibodies in ALK positive NSCLC is an option that has not been sufficiently studied however is worth exploring in patients with resistant NSCLC [3].

To date, the detection of gene mutation using RNA from sputum samples is considered practically difficult. We report a case in which the EML4-ALK fusion gene was successfully detected from a sputum sample using the LCCP that was just released in Japan as a new next-generation sequencing lung cancer panel, CDx.

This trial is evaluating T-DXd alone or in combination with durvalumab (durva) or MEDI5752 (a PD-1/CTLA-4 bispecific antibody) with or without chemotherapy in pts with unresectable/metastatic, HER2-OE, nonsquamous NSCLC...In part 1 (enrollment completed), pts with disease progression after 1 or 2 lines of systemic therapy in the recurrent/metastatic setting receive T-DXd monotherapy or T-DXd + durva in combination with cisplatin, carboplatin, or pemetrexed...The primary endpoint is the frequency of adverse events (AEs) and serious AEs (SAEs) with T-DXd + durva + chemotherapy (part 1) or T-DXd + MEDI5752 ± chemotherapy (part 3). Secondary endpoints include confirmed objective response rate, duration of response, disease control rate, progression-free and overall survival, pharmacokinetics, and immunogenicity in all arms as well as the frequency of AEs and SAEs with T-DXd monotherapy (part 1).

Legal entity responsible for the study Fondazione Policlinico Universitario A Gemelli – IRCCS. In post-lorlatinib NGS-assay, 2 pts had ALK-compound mutations, while 4 pts had newly off-target alterations (CDKN2A/B CDKN2B loss, NF1 deletion, DNMT3A/ARID1A/CHECK2 M+). Conclusions Implementation of longitudinal genomic assessment is required in order to provide an extensive overview of resistance mechanisms and clinical outcomes according to current ALK-inhibitors treatment sequences.

Conclusions CGP tests are being utilized in precision oncology, but NGS workflows and bioinformatics pipelines can be difficult to implement. The AVENIO CGP Tumor Tissue Kit is highly reproducible across sites and operators, achieving high sequencing quality metrics and diagnostic sensitivity.