Search Results (91)

This case report highlights the management of a delayed bronchopleural fistula (BPF) following salvage pulmonary resection to achieve local control and no radiographic evidence of disease in a patient treated with serial tyrosine kinase inhibitors (TKIs) for stage IV anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC). The initial pulmonary resection was complicated by dense adhesions and an abnormally torturous pulmonary artery. Six weeks after the index surgery, the patient presented with a delayed BPF requiring decortication, repair of airway, and coverage of the bronchial stump with a serratus anterior muscle flap. Full article

Background/Objectives: Non-small cell lung cancer (NSCLC) constitutes over 84% of all lung cancer cases and is a leading cause of cancer-related mortality globally. Alectinib, a second-generation anaplastic lymphoma kinase (ALK) inhibitor, is effective in ALK-positive NSCLC; however, its clinical potential is hampered by poor aqueous solubility and limited oral bioavailability. This study aimed to develop Alectinib-loaded chitosan–alginate nanoparticles (ACANPs) to enhance its solubility, oral bioavailability, and therapeutic efficacy. Methods: ACANPs were synthesized using a novel combined solid/oil/water (s/o/w) emulsification technique with ionotropic gelation. Characterization was performed using Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), dynamic light scattering (DLS), and zeta potential measurements. A validated high-performance liquid chromatography (HPLC) method quantified the Alectinib. In vitro drug release studies compared free Alectinib with ACANPs. Cytotoxicity against NSCLC cell lines (A549 and H460) was assessed using MTT assays. Pharmacokinetic parameters were evaluated in rats using LC–MS/MS. Results: ACANPs showed a high encapsulation efficiency (~97%), an average particle size of 161 nm, and a positive zeta potential of +21 mV. In vitro release studies revealed a threefold increase in drug release from ACANPs over 48 h compared to free Alectinib. Cytotoxicity assays demonstrated significantly reduced IC₅₀ values for ACANPs. Pharmacokinetic analyses showed an enhanced maximum plasma concentration (C_max) and area under the curve (AUC), indicating a 78% increase in oral bioavailability. Conclusions: ACANPs substantially improved the solubility, cytotoxic efficacy, and oral bioavailability of Alectinib, suggesting their potential as a promising nanocarrier system for enhancing NSCLC treatment outcomes. Full article

Since epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors were introduced in 2004, various driver gene mutations have been identified in non-small cell lung cancer, particularly adenocarcinoma, where mutations are typically mutually exclusive. EGFR and Kirsten rat sarcoma viral oncogene (KRAS) mutations are most prevalent in Japan, with routine testing now standard. However, hematoxylin and eosin staining often fails to detect mutations, except in cases such as ALK fusion lung cancer. We report a 76-year-old non-smoking Japanese woman diagnosed with adenocarcinoma confirmed as KRAS G12D/S-positive. Histological features, including thanatosomes (hyaline globules), nuclear pleomorphism, and cytoplasmic clearing, may aid in identifying mutations. Numerous thanatosomes were identified, some containing nuclear dust. Thanatosomes revealed periodic acid–Schiff reactivity with diastase resistance, fuchsinophilia with Masson’s trichrome stain, and dark blue-black color with Mallory’s PTAH stain. This is the first report linking thanatosomes in KRAS-mutant pulmonary adenocarcinoma to apoptosis via cleaved caspase-3 staining. Full article

A subset of ALK+ non-small cell lung cancer (NSCLC) patients relapse on ALK inhibitor (ALKi) treatment due to on-target resistance mutations affecting the tyrosine kinase domain. Objective: In this study, we investigated the presence of minor resistant clones in pre-treatment tissue samples and assessed their predictive value for subsequent resistance mechanisms. Methods: Using the highly sensitive digital droplet (dd)PCR technique, we analyzed 40 tissue samples obtained from 17 patients who had developed on-target resistance mutations after receiving ALKi between 2013 and 2022. We focused on 10 on-target ALKi resistant mutations identified in our patient cohort. Results: Fifteen ALKi resistance mutations were detected in 13 samples from 11/17 patients. Among these, four mutations were observed as resistance mutations in follow-up biopsies taken after first or subsequent lines of ALKi. Comparison of the test results from two subsequent biopsies, before and directly after therapy, revealed presence of the resistance mutation identified upon relapse in the pre-treatment sample of three cases that were all taken from the same tumor location. In six cases taken from different tumor locations, the resistant mutations were not found in the pre-treatment sample. Conclusions: By using the highly sensitive ddPCR approach, we detected minor clones with on-target resistant mutations in both treatment-naive and relapse biopsies from ALK-positive NSCLC patients. The predictive value of these mutations as the potential resistance-causing mechanism was limited to relapses occurring at the same tumor location as the pre-treatment sample. Full article

Since the discovery of the first-generation ALK inhibitor, many other tyrosine kinase inhibitors have been demonstrated to be effective in the first line or further lines of treatment in patients with advanced non-small cell lung cancer with EMLA4-ALK translocation. This review traces the main milestones in the treatment of ALK-positive metastatic patients and the survival outcomes in the first-line and second-line settings with different ALK inhibitors. It presents the two options available for first-line treatment at the present time: sequencing different ALK inhibitors versus using the most potent inhibitor in front-line treatment. The efficacy outcomes of different ALK inhibitors in the first-line setting; the molecular profile of the disease, including mutation resistances and ALK variants and co-mutations; and patients’ co-morbidities and inhibitor toxicities should be taken into account to address the choice of the first-line treatment, as suggested in this review. Full article

The formulation process for some drugs can be challenging, due to their unfavorable physical and mechanical properties and poor water solubility. Powder technology has made a significant impact in regard to the modification of the particles in active pharmaceutical ingredients (APIs) to produce high-quality granules. Spherical particles are preferred over other shapes, due to their high tap and bulk density, reduced dustiness, better flowability, strong anti-caking properties, and better mechanical performance during tableting. The present study investigates the possibility of obtaining spherical crystals of ceritinib, a drug used for the treatment of anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer, which belongs to BCS class IV drugs and has a platy crystal shape. Ceritinib spheres were prepared by spherical agglomeration, in a ternary system, and quasi-emulsion solvent diffusion, with the addition of polyvinylpyrrolidone, as well as a combination of these two methods. With the combined method of spherical crystallization, crystals with the most favorable morphology and the narrowest distribution of particle sizes were obtained, which was the reason for further optimization. The influence of different impeller geometries and mixing rates on the morphology of the obtained crystals was examined and the optimal conditions for the process were selected. Using empirical correlations and a visual criterion, the process was scaled up from a 0.1 L to a 1 L batch crystallizer. The obtained crystals were characterized by light and scanning electron microscopy. The addition of a bridging liquid and/or a polymer additive did not change the internal structure of the ceritinib crystals, which was confirmed by X-ray powder diffraction. Full article

Molecular testing is recommended in patients with metastatic non-small cell lung cancer (NSCLC), but the extent of its use in Poland is unknown. The aim of the POL-MOL study was to investigate the frequency of using molecular testing in Polish patients with NSCLC. The invited Polish oncologists completed two questionnaires, and data for 1001 patients undergoing systemic treatment for NSCLC were collected. The use of molecular tests for the following genetic mutations was recorded: EGFR (del19, sub21), EGFR (other than del19/sub21), EGFR T790M, ALK (expression and rearrangement), RET, NTRK, ROS1, BRAF, HER2, and MET, as well as for immunochemical assessment of programmed cell death ligand 1 (PD-L1). Thanks to the weighting procedure, the results are representative of the population of Polish patients treated for NSCLC. Molecular tests were applied in 78% of patients with NSCL, 70% of patients with NSCLC not otherwise specified, and in 12% of patients with squamous cell carcinoma of the lung. The frequency of application increased with disease stage in all groups. In patients with squamous cell carcinoma, approximately 30% of tests for EGFR, ALK, and RET mutations were positive, which confirms the importance of testing at least a preselected subgroup of patients. Full article

The recent advent of tyrosine kinase inhibitors (TKIs) and immune checkpoint blockers (ICBs) in early-stage non-small cell lung cancer (NSCLC) has dramatically modified treatment strategies by improving the prognosis in this setting. Osimertinib and alectinib, both TKIs, have shown significant improvements in outcomes for patients with resected EGFR- and ALK-positive NSCLC, respectively, changing the standard of care in these subgroups. More recently, the LAURA trial showed the efficacy of osimertinib after chemoradiotherapy in patients with unresectable stage III NSCLC harboring EGFR mutations. Numerous trials are still ongoing to investigate neoadjuvant/perioperative TKIs in several oncogene-driven NSCLC. In addition, several ICBs have been tested and approved as adjuvant (atezolizumab and pembrolizumab), neoadjuvant (nivolumab), and perioperative treatments (pembrolizumab) for patients with resectable early-stage NSCLC. Despite these advances, many challenges remain regarding the use of TKIs and ICBs in this setting, including the optimal duration of adjuvant TKI or induction ICB therapy, the role of minimal residual disease to identify patients at high-risk of disease relapse and to guide adjuvant treatment decisions, and the role of adjuvant chemotherapy in resected oncogene-driven NSCLC. Furthermore, potential predictive biomarkers for efficacy are needed to eventually intensify the entire perioperative strategies. This review aims to summarize and discuss the available evidence, the ongoing trials, and the challenges associated with TKI- and ICB-based approaches in early-stage NSCLC. Full article

A pediatric dosage form for crizotinib (Xalkori) was commercialized using quality-by-design principles in a material-sparing fashion. The dosage form consists of spherical multiparticulates (microspheres or pellets) that are coated and encapsulated in capsules for opening. The crizotinib (Xalkori)-coated pellet product is approved in the US for pediatric patients 1 year of age and older and young adults with relapsed or refractory, systemic anaplastic large cell lymphoma (ALCL) and unresectable, recurrent, or refractory inflammatory myofibroblastic tumor (IMT) that is ALK-positive. The product is also approved in the US for adult patients with non-small cell lung cancer (NSCLC) who are unable to swallow intact capsules. The lipid multiparticulate is composed of a lipid matrix, a dissolution enhancer, and an active pharmaceutical ingredient (API). The API, which remains crystalline, is embedded within the microsphere at a 60% drug loading in the uncoated lipid multiparticulate to enable dose flexibility. The melt spray congealing technique using a rotary atomizer is used to manufacture the lipid multiparticulate. Following melt spray congealing, a barrier coating is applied via fluid bed coating. Due to their particle size and content uniformity, this dosage form provides the dosing flexibility and swallowability needed for the pediatric population. The required pediatric dose is achieved by opening the capsules and combining doses of different encapsulated dose strengths, followed by administration of the multiparticulates directly to the mouth. The encapsulation process was optimized through equipment modifications and by using a design of experiments approach to understand the operating space. A limited number of development batches produced using commercial-scale equipment were leveraged to design, understand, and verify the manufacturing process space. The quality by design and material-sparing approach taken to design the melt spray congeal and encapsulation manufacturing processes resulted in a pediatric product with exceptional content uniformity (a 95% confidence and 99% probability of passing USP <905> content uniformity testing for future batches). Full article

Lorlatinib has been FDA-approved as a systemic therapy for ALK/ROS1-positive non-small cell lung cancer (NSCLC) patients. However, it has been associated with an increased frequency of neurocognitive adverse events (NAEs). Therefore, we conducted a systematic review and meta-analysis to assess the NAEs related to lorlatinib therapy in NSCLC patients. PubMed, Scopus, the Cochrane Library, and prominent conference proceedings were searched for eligible studies of lorlatinib in NSCLC patients. NAEs included cognitive, mood, speech, and psychotic effects. A total of 1147 patients from 12 studies were included; 62% had brain metastases. A pooled analysis of NAEs showed frequencies of cognitive effects of 14.57% (95% CI, 8.37 to 24.14, I2 = 84%), mood effects of 11.17% (95% CI, 5.93 to 20.07, I2 = 84%), speech effects of 7.24% (95% CI, 3.39 to 15.20, I2 = 72%), and psychotic effects of 4.97% (95% CI, 3.27 to 7.49, I2 = 21%). Clinical trials reported a significantly higher frequency of mood effects than was indicated by real-world data. These results highlight the importance of educating patients and healthcare professionals about lorlatinib-related NAEs for early detection and management to improve NSCLC patients’ quality of life. Full article

Lorlatinib is a pharmaceutical ALK kinase inhibitor used to treat ALK driven non-small cell lung cancers. This paper analyses the intersection of past published data on the physiological consequences of two unrelated drugs from general medical practice—itraconazole and cilostazol—with the pathophysiology of ALK positive non-small cell lung cancer. A conclusion from that data analysis is that adding itraconazole and cilostazol may make lorlatinib more effective. Itraconazole, although marketed worldwide as a generic antifungal drug, also inhibits Hedgehog signaling, Wnt signaling, hepatic CYP3A4, and the p-gp efflux pump. Cilostazol, marketed worldwide as a generic thrombosis preventative drug, acts by inhibiting phosphodiesterase 3, and, by so doing, lowers platelets’ adhesion, thereby partially depriving malignant cells of the many tumor trophic growth factors supplied by platelets. Itraconazole may enhance lorlatinib effectiveness by (i) reducing or stopping a Hedgehog-ALK amplifying feedback loop, by (ii) increasing lorlatinib’s brain levels by p-gp inhibition, and by (iii) inhibiting growth drive from Wnt signaling. Cilostazol, surprisingly, carries minimal bleeding risk, lower than that of aspirin. Risk/benefit assessment of the combination of metastatic ALK positive lung cancer being a low-survival disease with the predicted safety of itraconazole-cilostazol augmentation of lorlatinib favors a trial of this drug trio in ALK positive lung cancer. Full article

Chemoresistance is a major obstacle in cancer treatment, often leading to disease progression and poor outcomes. It arises through various mechanisms such as genetic mutations, drug efflux pumps, enhanced DNA repair, and changes in the tumor microenvironment. These processes allow cancer cells to survive despite chemotherapy, underscoring the need for new strategies to overcome resistance and improve treatment efficacy. Crizotinib, a first-generation multi-target kinase inhibitor, is approved by the FDA for the treatment of ALK-positive or ROS1-positive non-small cell lung cancer (NSCLC), refractory inflammatory (ALK)-positive myofibroblastic tumors (IMTs) and relapsed/refractory ALK-positive anaplastic large cell lymphoma (ALCL). Crizotinib exists in two enantiomeric forms: (R)-crizotinib and its mirror image, (S)-crizotinib. It is assumed that the R-isomer is responsible for the carrying out various processes reviewed here The S-isomer, on the other hand, shows a strong inhibition of MTH1, an enzyme important for DNA repair mechanisms. Studies have shown that crizotinib is an effective multi-kinase inhibitor targeting various kinases such as c-Met, native/T315I Bcr/Abl, and JAK2. Its mechanism of action involves the competitive inhibition of ATP binding and allosteric inhibition, particularly at Bcr/Abl. Crizotinib showed synergistic effects when combined with the poly ADP ribose polymerase inhibitor (PARP), especially in ovarian cancer harboring BRCA gene mutations. In addition, crizotinib targets a critical vulnerability in many p53-mutated cancers. Unlike its wild-type counterpart, the p53 mutant promotes cancer cell survival. Crizotinib can cause the degradation of the p53 mutant, sensitizing these cancer cells to DNA-damaging substances and triggering apoptosis. Interestingly, other reports demonstrated that crizotinib exhibits anti-bacterial activity, targeting Gram-positive bacteria. Also, it is active against drug-resistant strains. In summary, crizotinib exerts anti-tumor effects through several mechanisms, including the inhibition of kinases and the restoration of drug sensitivity. The potential of crizotinib in combination therapies is emphasized, particularly in cancers with a high prevalence of the p53 mutant, such as triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSOC). Full article

Genomic mutations impact non-small cell lung cancer (NSCLC) biology. The influence of sex and age on the distribution of these alterations is unclear. We analyzed circulating-tumor DNA from individuals with advanced NSCLC from March 2018 to October 2020. EGFR, KRAS, ALK, ROS1, BRAF, NTRK, ERBB2, RET, MET, PIK3CA, STK11, and TP53 alterations were assessed. We evaluated the differences by sex and age (<70 and ≥70) using Fisher’s exact test. Of the 34,277 samples, 30,790 (89.83%) had a detectable mutation and 19,923 (58.12%) had an alteration of interest. The median age of the ctDNA positive population was 69 (18–102), 16,756 (54.42%) were female, and 28,835 (93.65%) had adenocarcinoma. Females had more alterations in all the assessed EGFR mutations, KRAS G12C, and ERBB2 ex20 ins. Males had higher numbers of MET amp and alterations in STK11 and TP53. Patients <70 years were more likely to have alterations in EGFR exon 19 del/exon 20 ins/T790M, KRAS G12C/D, ALK, ROS1, BRAF V600E, ERBB2 Ex20ins, MET amp, STK11, and TP53. Individuals ≥70 years were more likely to have alterations in EGFR L861Q, MET exon 14 skipping, and PIK3CA. We provided evidence of sex- and age-associated differences in the distribution of genomic alterations in individuals with advanced NSCLC. Full article

Anaplastic lymphoma kinase (ALK) fusions account for 5–7% of non-small cell lung cancer (NSCLC) patients, the therapeutic approaches for which have significantly evolved in the last few years. However, the response to target therapies remains heterogeneous, partially due to the many different ALK fusion variants reported to date. Rare fusion variants have also been discovered, but their role in influencing responses to ALK inhibitors (ALKis) remains poorly elucidated. Laboratory investigation at both the tissue and protein levels, and a molecular profile by next-generation sequencing (NGS) were performed on a lung biopsy sample from one patient with poorly differentiated adenocarcinoma. An in silico prediction model using ColabFold software v1.5.5 was used to model and predict the entire structure of the chimeric aberrant ALK protein. Here, we report a case of a former smoker, a 60-year-old man, diagnosed with NSCLC and undergoing ALK translocation. He received first-, second- and third-generation ALK protein inhibitors (ALKis), showing a clinical benefit for about 4 years. IHC analysis and the molecular examination of the tissue biopsy indicated a positive staining for ALK and a novel ALK gene fusion variant, involving the sperm antigen with calponin homology and coiled-coil domain 1-like (SPECC1L) gene with an unreported breakpoint in exon 7. The novel SPECCL1::ALK fusion was identified using Anchored Multiplex PCR (AMP)-NGS technology and was predicted to retain the Pkinase_Tyr domain at the carboxy-terminal region of the resulting chimeric protein. To the best of our knowledge, this is the first case of an ALK-positive NSCLC patient carrying the SPECC1L exon 7 fusion breakpoint and one of the few reports about clinical outcomes related to SPECC1L::ALK fusion. The in silico hypothesized biological role of this newly identified fusion variant corroborates the observed clinical response to multiple ALKis. The molecular findings also reinforce the utility of AMP-based NGS technology as a valuable tool for the identification of rare chromosomal events that may be related to the variability of patient outcomes to different ALKis treatments. Full article

Anaplastic thyroid cancer (ATC) is one of the deadliest human cancers and represents <2% of thyroid carcinomas. A therapeutic target for ATC is represented by anaplastic lymphoma kinase (ALK) rearrangements, involved in tumor growth. Crizotinib is an oral small-molecule tyrosine kinase inhibitor of the ALK, MET, and ROS1 kinases, approved in ALK-positive non-small cell lung cancer. Until now, the effect of crizotinib in “primary human ATC cells” (pATCs) with transforming striatin (STRN)–ALK fusion has not been reported in the literature. In this study, we aimed to obtain pATCs with STRN–ALK in vitro and evaluate the in vitro antineoplastic action of crizotinib. Thyroid surgical samples were obtained from 12 ATC patients and 6 controls (who had undergone parathyroidectomy). A total of 10/12 pATC cultures were obtained, 2 of which with transforming STRN–ALK fusion (17%). Crizotinib inhibited proliferation, migration, and invasion and increased apoptosis in 3/10 pATC cultures (2 of which with/1 without STRN–ALK), particularly in those with STRN–ALK. Moreover, crizotinib significantly inhibited the proliferation of AF cells (a continuous cell line obtained from primary ATC cells). In conclusion, the antineoplastic activity of crizotinib has been shown in human pATCs (with STRN–ALK) in preclinical studies in vitro, opening the way to future clinical evaluation in these patients. Full article