ALK mutation

It follows that the farnesyltransferase inhibitor (FTI) lonafarnib in addition to ALK TKIs act synergistically in neuroblastoma, inducing apoptosis in vitro. In particular, on combined treatment of neuroblastoma patient derived xenografts with an FTI and an ALK TKI complete regression of tumour growth is observed although tumours rapidly regrow on cessation of therapy. Overall, our data suggests that combined use of ALK TKIs and FTIs, constitutes a therapeutic approach to treat high risk neuroblastoma although prolonged therapy is likely required to prevent relapse.

P1, N=102, Recruiting, Bayer | N=74 --> 102

The different imaging manifestations of mucinous adenocarcinoma are possibly due to the different amounts or viscosity of mucus produced, and the mechanisms of its formation may include (1) tumour cells in different shapes have different abilities to produce mucus; (2) tumours in different stages produce different amounts or viscosity of mucus; and (3) the TTF-1 and ALK genes affect the production of mucus.

P2, N=27, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2024 --> Mar 2025

Several anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have been developed for the treatment of echinoderm microtubule-associated protein-like 4 (EML4)-ALK-rearranged non-small cell lung cancer (NSCLC), with the newer generation agents brigatinib, alectinib and lorlatinib showing prolonged responses. The second ALK resistance mutation detected after a chemotherapy interval, the G1202R, is the most common resistance mutation after second generation ALK TKIs and has been associated with sensitivity to third generation TKIs, such as lorlatinib. This case of a patient with EML4-ALK-rearranged NSCLC shows that sequential treatment with next-generation ALK TKIs, including rechallenge, can induce profound remissions, even in heavily pretreated patients, and that ALK-targeted strategies may be personalized by considering the presence of distinct ALK resistance mutations.

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.

P2, N=122, Active, not recruiting, National Cancer Institute (NCI) | Terminated --> Active, not recruiting | Trial completion date: Jun 2022 --> Apr 2025

The results of the PEMBROREAL study have shown that the combined treatment of pembrolizumab with pemetrexed and platinum is effective for metastatic non-squamous NSCLC, even for patients with PD-L1 levels below 50%, despite the differences in patient demographics and pathological features compared to the Keynote-189 study. The adverse events reported during the study were more typical of chemotherapy treatment rather than immunotherapy, and physicians were able to manage them easily.

In vitro and in vivo analyses demonstrate that gilteritinib can overcome the L650F-mediated resistance to lorlatinib. In silico analysis suggests that introduction of the L650F mutation may attenuate lorlatinib-LTK binding. Our study provides preclinical evaluations of potential on-target resistance mutations to lorlatinib, and a novel strategy to overcome the resistance.

P3, N=720, Recruiting, Gilead Sciences | Trial completion date: Dec 2027 --> Sep 2027 | Trial primary completion date: Dec 2027 --> Sep 2027

P2, N=122, Terminated, National Cancer Institute (NCI) | Active, not recruiting --> Terminated; Inadequate accrual rate

The core autoregulatory transcriptional circuitry activity is reinforced by MYC binding to the enhancer regions associated with STAT3 and each of the core regulatory transcription factors. Thus, activation of STAT3 provides the crucial link between aberrant tyrosine kinase signaling and the core transcriptional machinery that drives tumorigenesis and creates therapeutic vulnerabilities in ALCL.

P1, N=115, Recruiting, Daiichi Sankyo | Trial completion date: Mar 2024 --> Aug 2025 | Trial primary completion date: Feb 2024 --> Dec 2024

A series of novel benzimidazole derivatives were designed and synthesised based on the structures of reported oral available ALK inhibitor and HDAC inhibitor, pracinostat...Compound 3b also inhibited various ALK mutants known to be involved in crizotinib resistance, including mutant L1196M (IC50, 4.9 nM)...At 20 mg/kg, 3b inhibited tumour growth by 85% yet had a negligible effect on mean body weight. These results suggest a attracting route for the further research and optimisation of dual ALK/HDAC inhibitors.

P1/2; Trial completion date: Apr 2027 --> Dec 2027 | Trial primary completion date: Apr 2027 --> Dec 2027

Our findings demonstrate that dual inhibition of the RTK/MAPK pathway and the CD47/SIRPa axis is a promising immunotherapeutic strategy. Our study provides strong rationale for testing this therapeutic combination in patients with lung cancers bearing driver mutations.

P4, N=15, Active, not recruiting, Galvanize Therapeutics, Inc. | Recruiting --> Active, not recruiting

P1, N=190, Completed, Astellas Pharma Global Development, Inc. | Phase classification: P1b --> P1

Mutations in the ALK gene are common in EIMS. Surgery is the mainstay of EIMS treatment, and patients benefit from a multidisciplinary combination that includes targeted therapies, with long-term prognosis remaining subject to ongoing follow-up.

Reciprocally, inhibition of the WNT pathway reduced expression of POSTN and growth of ALK/MYCN tumor cells. Thus, ALK drives neuroblastoma in part through a feedforward loop between POSTN and WNT signaling.

Among the 330 patients with undetected EGFR, ALK, ROS1, and BRAF V600E mutations at diagnosis, 81 patients (24.5%) had newly identified driver oncogenes. CGP assays could be useful to identify driver oncogenes in patients with advanced NSCLC, including those initially undetected, facilitating personalized treatment.

New EML4::ALK substitutions, L1198R, C1237Y and L1196P, were identified in the plasma of NSCLC ALK patients and characterized in a Ba/F3 cell model. Variants C1237Y and L1196P demonstrated pan-inhibitor resistance across 5 clinical and 2 investigational TKIs.

P2, N=40, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Feb 2024 --> Feb 2025 | Trial primary completion date: Feb 2024 --> Feb 2025

Currently, a fourth-generation (4G) ALK TKI, NVL-655, is being developed to attack some of the unmet needs such as compound resistance mutations in cis...Potentially, in the shifting landscape where lorlatinib should be the first-line ALK TKI of choice based on the CROWN trial, the central β-sheet #6 (Cβ6) mutation ALK L1256F will be the potential acquired resistance mutation to lorlatinib which may be resistant to current ALK TKIs. Here we opine on what additional capacities a putative fifth-generation (5G) ALK TKI will need to possess if it can be achieved in one single molecule. We propose randomized trial schemas targeting some of the intrinsic resistance mechanisms that will lead to approval of a prototypic fifth-generation (5G) ALK TKI and actually be beneficial to ALK+ NSCLC patients rather than just design a positive pivotal superiority trial for the sole purpose of drug approval.

P1/2, N=24, Active, not recruiting, Astellas Pharma Global Development, Inc. | Trial completion date: Dec 2027 --> Jun 2024 | Trial primary completion date: Dec 2027 --> Jun 2024

Future studies are needed to elucidate the ALK role in gastric cancer and to identify predictive biomarkers to improve patient selection for targeted therapy. Overall, ALK alterations are a relevant biomarker for gastric adenocarcinoma treatment and targeted therapies for ALK may improve patients' overall survival.

Ensartinib led to a favorable OS in patients with advanced, crizotinib-resistant, and ALK-positive NSCLC. Quantification of ctDNA levels also provided valuable prognostic information for risk stratification.

P1/2, N=4, Terminated, Asha Nayak | N=40 --> 4 | Unknown status --> Terminated; The study was terminated due to poor accrual.

P2, N=0, Withdrawn, Xinqiao Hospital of Chongqing | N=20 --> 0 | Unknown status --> Withdrawn

P4, N=0, Withdrawn, Xinqiao Hospital of Chongqing | N=20 --> 0 | Unknown status --> Withdrawn

V3 status is also associated with specific patterns of clinically important ALK resistance mutations. These tumor-intrinsic features may inform rational selection and optimization of first-line and consolidative therapy.

No demonstrable difference in survival or TTE was seen between receipt of upfront local therapy. Prospective studies are required to assist clinical decision making regarding optimal sequencing of local and systemic therapies.

Other approaches involving the promising potential of nanobodies, probodies, affibodies, and DARPINs targeting immune checkpoints are also described; these are under active research or clinical trials to mediate immune regulation and reduce cancer progression. This comprehensive review underscores the multifaceted nature, current state and future directions of NSCLC research and treatment.

A higher proportion of patients with ALK-positive lung cancer were CYFRA21-1 positive and had higher CYFRA21-1:CEA ratios compared with EGFR-positive lung cancer patients.

Standard chemotherapy involves gemcitabine-based therapies combined with cisplatin, oxaliplatin, capecitabine, or 5-FU with a dismal prognosis for most patients...Additionally, ceritinib and cisplatin synergistically reduced CCA cell viability. Our data show ceritinib as an effective treatment of CCA, which could be potentially explored in the other cancer types without ALK mutations.

P2, N=673, Completed, Genentech, Inc. | Phase classification: P2a --> P2

P1; Phase classification: P1b --> P1

P1/2, N=22, Active, not recruiting, Coherus Biosciences, Inc. | Recruiting --> Active, not recruiting | N=100 --> 22

Targeting yes-associated protein (YAP) and the mechanisms associated with YAP activation through Hippo-dependent or independent pathways, is desirable. Additionally, the exploration of liquid-liquid phase separation in fusion oncoproteins forming condensates in the cytoplasm for oncogenic signaling is a promising field for the development of new treatments.

This study underscores the efficacy of targeted consolidation therapy in enhancing PFS in LUAD patients with genetic mutations. It also shows that immune consolidation therapy provides similar survival benefits to mutant and wild-type patients. Future research should focus on optimizing these therapies for improved patient outcomes.

P4, N=15, Recruiting, Galvanize Therapeutics, Inc. | Trial primary completion date: Dec 2023 --> Jun 2024

P1, N=74, Recruiting, Bayer | Trial completion date: Oct 2026 --> Mar 2027 | Trial primary completion date: Feb 2026 --> Jul 2025