With increasingly effective systemic therapies for stage IV disease, the addition of local control strategies for a subset of patients with limited metastatic disease has contributed to improved disease control and life prolongation. While surgery has been the mainstay strategy for local control, stereotactic ablative body radiation and percutaneous ablation techniques are alternate methods that have been demonstrated to be safe and effective and offer options to those patients who are unresectable, inoperable, or who do not desire surgery. A hybrid approach combining surgery and radiotherapy can maximize the ability to treat more lesions.

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI), including brigatinib, are widely used to treat ALK-positive non-small cell lung cancer. However, severe adverse effects associated with brigatinib, such as interstitial pneumonia and liver dysfunction, may involve immune system activation. The precise mechanisms underlying these immune-related adverse effects remain unclear. In this study, we evaluated the direct activation of inflammasomes by brigatinib and other ALK TKI (crizotinib, alectinib, ceritinib) in differentiated THP-1 cells. Additionally, we analyzed the inflammasome-activating potential of supernatants from functional liver cell (FLC)-4 cells treated with these drugs. Our results demonstrate that brigatinib directly activates inflammasomes in THP-1 cells, inducing the production of interleukin-1β and the activation of caspase-1. In contrast, no inflammasome activation was observed with the other ALK TKIs. Furthermore, supernatants from FLC-4 cells, characterized by high drug-metabolizing activity, were shown to activate inflammasomes in differentiated THP-1 cells following treatment with brigatinib. Brigatinib treatment significantly increased the levels of damage-associated molecular patterns (DAMPs), including heat shock protein 90 and S100A6, in the supernatants of FLC-4 cells. These findings suggest that brigatinib induces the release of DAMPs from hepatocytes, which subsequently activate inflammasomes. This mechanism may be essential for brigatinib-induced immune system activation and the development of immune-related adverse events.

With the rapid advancements in second-generation gene sequencing technologies, a growing number of driver genes and associated therapeutic targets have been unveiled for lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). While they are clinically classified as non-small cell lung cancer (NSCLC), they display distinct genomic features and substantial variations in clinical efficacy, underscoring the need for particular attention. Hence, this review provides a comprehensive overview of the latest advancements in driver genes, epigenetic targets, chemotherapy, targeted therapy, and immunotherapy for LUAD and LUSC. Additionally, it delves into the distinctions in signaling pathways and pivotal facets of clinical management specific to these two categories of lung cancer. Moreover, we furnish pertinent details regarding clinical trials pertaining to driver genes and epigenetics, thus establishing a theoretical foundation for the realization of precision treatments for LUAD and LUSC.

Designing advanced biomimetic nanoplatforms that combine photothermal therapy (PTT) and immune activation represents a modern approach to addressing the challenges of cancer therapy. This study presents a nanobiomimetic hollow copper-sulfide (HCuS) platform for precise homotypic tumor targeting and melanoma treatment. The HCuS@OVA@CM (COC) nanoplatform-encapsulated ovalbumin (OVA) antigen protein within HCuS nanoparticles and was coated with melanoma cell membranes (B16F10). Importantly, this design facilitates specific tumor accumulation and achieves 16.0% photothermal conversion efficiency under 1064 nm NIR-II irradiation, which is a key factor for therapeutic success. In vitro studies have demonstrated that this nanoplatform induces immunogenic cell death (ICD), enhances antigen presentation, and stimulates dendritic cell (DCs) maturation. In vivo experiments confirmed that COC-mediated NIR-II photothermal treatment significantly suppressed tumor growth without notable body weight loss. This biomimetic nanoplatform approach offers a targeted, enhanced, and effective immune response for tumor photothermal immunotherapy, making it a promising candidate for advanced melanoma treatment and anticancer therapy.

Targeted therapy has achieved significant success in the treatment of non-small cell lung cancer (NSCLC), particularly in patients harboring common oncogenic driver mutations such as EGFR, KRAS, and ALK rearrangement. However, ~35-50% of NSCLC patients without tyrosine kinase mutation or rearrangement (non-mutated) cannot benefit from these targeted treatments, highlighting the urgent need for novel therapeutic strategies for this patient population. In this study, we report a non-canonical role of human secretory ribonuclease 1 (RNase1), which binds to and activates wild-type ALK in lung cancer cells, thereby triggering its downstream signaling pathway. RNase1-driven ALK-activation (RDAA) cells exhibit enhanced cell proliferation, migration, and colony formation. Additionally, RDAA facilitates tumor formation in fibroblast models, further underscoring its oncogenic potential in vivo. Importantly, RDAA lung cancer cells exhibit marked sensitivity to FDA-approved ALK inhibitors. Tumor growth suppression and survival were substantially improved in both RDAA-positive NSCLC cell line-derived and patient-derived xenograft tumor models treated with ALK inhibitors. Monoclonal antibodies against RNase1 and phosphorylated-ALK were used to analyze two different human NSCLC tissue cohorts by immunohistochemical staining identified 10.4% (5/48) and 8.5% (100/1173) patients who were RDAA positive, respectively. Notably, among the nine RDAA-positive NSCLC patients who accepted ALK inhibitor treatment, five achieved objective response including two who experienced complete response (CR). Together, the current study identifies RDAA as an oncogenic driver and proposes an effective targeted therapy strategy for non-mutated NSCLC patients.

Palliative interventions, such as chest tube drainage and radiotherapy for bone and brain metastases, are crucial for managing survival and quality of life in patients with advanced lung cancer.

This retrospective study analyzed 8171 patients with unresectable Stage IV lung cancer from the Japanese Joint Committee of Lung Cancer Registry (JJCLCR) database. At treatment initiation, 8.6% of patients underwent chest tube drainage, 9.9% underwent bone radiotherapy, and 11.5% underwent brain radiotherapy. In this study, associated factors for palliative interventions were evaluated, and their impact on patient survival was also assessed.

High-associated factors for upfront chest tube drainage included age ≥ 75 years, ECOG-PS ≥ 2, pleural nodules, and adenocarcinoma, while EGFR mutation, serum albumin ≥ 3.2 mg/dL, adrenal gland, and brain metastases were low-associated factors. For upfront brain radiotherapy, low-associated factors included malignant pleural effusion (MPE) and bone metastases, whereas ECOG-PS ≥ 2 was a high-associated factor. High-associated factors for upfront bone radiotherapy were serum albumin ≥ 3.2 mg/dL, ECOG-PS ≥ 2, adenocarcinoma, and squamous cell carcinoma, while pleural nodules, MPE, liver, and brain metastasis were low-associated factors. Patients receiving upfront bone radiotherapy had shorter survival, whereas survival did not significantly differ for those with or without upfront chest tube drainage or brain radiotherapy.

This study identified associated factors for palliative interventions in advanced lung cancer and their association with overall survival. Future prospective studies with more detailed data are necessary to confirm these findings and improve clinical decision-making.

Approval No. 15,321.

With the ongoing discovery of various oncogenic driver mutations in metastatic non-small cell lung cancer (mNSCLC), a precision medicine approach has emerged, characterized by targeted therapies for select patient populations. Randomized controlled trials (RCT) remain the gold standard for evaluating efficacy and safety of such therapies; however, RCTs evaluating treatments for rare oncogenic drivers still face limitations, given small populations, potentially long-time horizon for outcome events to occur, and underrepresentation of certain subgroups. For these targeted therapies, the complementary nature between real-world evidence (RWE) and RCT may expand the totality of evidence available, to better inform treatment decision-making. In particular, treatments for rare oncogenic drivers can benefit from RWE that provides additional, generalizable clinical insights for subgroups underrepresented or ineligible for RCT, or confirms outcomes observed in RCT. As a discipline, RWE has seen significant advances in methodology and healthcare stakeholder acceptability, with potential for even greater innovation, and presents a valuable opportunity to support decision-making around access and use of targeted therapies for rare oncogenic drivers in mNSCLC.

BackgroundSince the publication of the original work in 2014, significant progress has been made in the characterization of genomic alterations that drive oncogenic addiction of nonsmall cell lung cancer (NSCLC) and how the immune system can leverage non-oncogenic pathways to modulate therapeutic outcomes. This update evaluates and validates the recent and emerging data for prognostic and predictive biomarkers with therapeutic targets in NSCLC.Data sourcesWe performed a literature search from January 2015 to October 2023 using the keywords non-small cell lung cancer, clinical practice guidelines, gene mutations, genomic assay, immune cancer therapy, circulating tumor DNA, predictive and prognostic biomarkers, and targeted therapies.Study selection and data extractionWe identified, reviewed, and evaluated relevant clinical trials, meta-analyses, seminal articles, and published clinical practice guidelines in the English language.Data synthesisRegulatory-approved targeted therapies include those somatic gene alterations of EGFR ("classic" mutations, exon 20 insertion, and rare EGFR mutations), ALK, ROS1, BRAF V600, RET, MET, NTRK, HER2, and KRAS G12C. Data for immunotherapy and circulating tumor DNA in next-generation sequencing are considered emerging, whereas the predictive role for PIK3CA gene mutation is insufficient.ConclusionsAdvances in sequencing and other genomic technologies have led to identifying novel oncogenic drivers, novel resistance mechanisms, and co-occurring mutations that characterize NSCLC, creating further therapeutic opportunities. The benefits associated with immunotherapy in the perioperative setting hold initial promise, with their long-term results awaiting.

Metabolic disorders have been identified as one of the causes of drug-induced liver injury; however, the direct regulatory mechanism regarding this disorder has not yet been clarified. In this study, a single regulatory mechanism of small molecule kinase inhibitors, with crizotinib as the representative drug is elucidated. First, it is discovered that crizotinib induced aberrant lipid metabolism and apoptosis in the liver. A mechanistic study revealed that crizotinib treatment promoted the accumulation of squalene epoxidase (SQLE) by inhibiting autophagosome-lysosome fusion which blocked the autophagic degradation of SQLE. A maladaptive increase in SQLE led to disturbances in cholesterol and sphingolipid metabolism via an enzymatic activity-dependent manner. Abnormal cholesterol results in both steatosis and inflammatory infiltration, and disturbances in sphingolipid metabolism promote cell apoptosis by inducing lysosomal membrane permeabilization. The restoration of the level or activity of SQLE ameliorated steatosis and hepatocyte injury. The autophagy activator known as metformin or the SQLE enzymatic inhibitor known as terbinafine has potential clinical use for alleviating crizotinib hepatotoxicity.

The ALINA trial introduced anaplastic lymphoma kinase (ALK) inhibitors in an early-stage context, generating notable interest. This study aims to investigate the characteristics and prognostic implications of ALK rearrangement in patients with resected lung adenocarcinoma (LUAD).

We retrospectively evaluated resected LUAD cases with documented ALK status from 2008 to 2020. The association between ALK positivity and clinicopathologic characteristics, molecular profiles, and outcomes was explored.

Among 4944 cases, 238 (4.8%) were ALK-positive, correlating with younger age and nonsmokers. ALK positivity was also significantly associated with pure-solid nodules, spread through air spaces, and solid-predominant adenocarcinoma. ALK-positive tumors exhibited an overall low frequency of co-mutations (eg, TP53, STK11). ALK positivity was associated with inferior recurrence-free survival (RFS) in patients with stage I who did not receive adjuvant chemotherapy whereas it was associated with prolonged RFS in patients with stage II and III who received adjuvant chemotherapy. Notably, 6 patients treated with adjuvant ALK inhibitors experienced no recurrence or metastasis during the follow-up period. In addition, the administration of ALK inhibitors significantly improved postrecurrence survival in patients positive for ALK.

ALK positivity was associated with specific aggressive pathologic features and inferior RFS in stage I LUAD. Patients positive for ALK seemed to benefit more from adjuvant chemotherapy. Active treatment with ALK inhibitors or chemotherapy should be considered for patients with ALK-positive LUAD, although further evidence is warranted to expand their utility in early-stage disease management.

Gene fusions represent important oncogenic driver mutations resulting in aberrant cellular signaling. In up to 17% of all solid tumors at least one gene fusion can be identified. Precision therapy targeting fusion gene signaling has demonstrated effective clinical benefit. Advancements in clinically relevant next-generation sequencing and bioinformatic techniques have enabled expansion of therapeutic opportunity to subpopulations of patients with fusion gene expression. Clinically, tyrosine inhibitors have shown efficacy in treating fusion gene expressing cancers. Fusion genes are also clonal mutations, meaning it is a personal cancer target involving all cancer cells of that patient, not just a subpopulation of cancer cells within the cancer mass. Thus, both fusion signal disruption and immune signal targeting are effective therapeutic directions. This review discusses fusion gene targeting, therapeutic resistance, and molecular biomarkers.

Radical local therapy is effective for oligo-recurrence of non-small cell lung cancer (NSCLC). We retrospectively assessed patients with oligo-recurrent NSCLC and detailed the clinical course after radical local therapy.

We analyzed 1028 patients who underwent complete resection for NSCLC. We defined oligo-recurrence as up to two metachronous recurrences, radical local therapy as local therapy performed with curative intent, and progressive disease as the appearance of new lesions/re-enlargement of the initial recurrence sites.

Of the 132 patients who developed oligo-recurrence, 88 received radical local therapy. Fifty-eight patients had progressive disease. Fifteen patients remained cancer free for > 5 years. Epidermal growth factor receptor (EGFR) positivity was associated with disease progression (odds ratio, 3.90; p = 0.025). Active treatment for disease progression (hazard ratio, 2.54; p = 0.012) and the absence of re-enlarged lesions at sites of radical local therapy for recurrence (hazard ratio, 2.32; p = 0.031) were associated with prolonged post-recurrence overall survival.

Patients with EGFR mutations who develop oligo-recurrence should be monitored for disease progression. Re-enlargement of lesions after radical local therapy was associated with a poor prognosis. A good prognosis can be expected with active treatment, even in the event of disease progression.

Multigene sequencing technologies provide a foundation for targeted therapy and precision oncology by identifying actionable alterations and enabling the development of treatments that substantially improve clinical outcomes. This review emphasizes the importance of having a molecular compass guiding treatment decision-making through the multitude of alterations and genetic mutations, showcasing why NGS plays a pivotal role in modern oncology.

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase belonging to the insulin receptor subfamily, involved in cellular signaling pathways associated with insulin. While ALK gene remains inactive in normal human tissues, it exhibits high expression specifically in the central nervous system. However, dysregulation of the ALK gene has been implicated in non-small cell lung cancer (NSCLC) development. Although commercially available ALK inhibitors demonstrate favorable clinical efficacy against most Ceritinib-resistant mutants, they exhibit resistance towards G1202R mutants. Therefore, developing novel ALK inhibitors is crucial for addressing drug resistance in patients. We designed and synthesized 48 novel 2,4-diarylpyrimidine-based ALK inhibitors and investigated their antitumor activities. Among them, Ld-10 showed significant inhibitory activity against ALK kinase with an IC50 value of 1135 nM and demonstrated excellent antiproliferative activity against lung cancer cells H2228 with an IC50 value of 1.35 ± 0.13 μM. To further validate the antitumor potential of Ld-10, we conducted a series of in vitro pharmacological experiments. These included a hemolysis assay to confirm its low toxicity profile, an AO assay, a JC-1 staining assay, and a Calcein-AM/PI cell double staining assay for assessing apoptosis induction. Additionally, we performed dose-dependent arrest at G0/G1 phase to evaluate inhibition of cell growth and carried out cell cycle analysis and cloning experiments to provide evidence for significant tumor growth inhibition by compound Ld-10. In vivo pharmacological experiments demonstrated effective tumor growth inhibition without any significant toxic effects on mouse organs caused by Ld-10 administration. Based on these comprehensive findings from our experimental investigations, it can be concluded that Ld-10 holds promising potential as a novel ALK inhibitor.

The aim of this study was to investigate the prognostic value of the abnormal expression of anaplastic lymphoma kinase (ALK) protein in patients with small cell lung cancer (SCLC) based on 9-year data from our center.

A retrospective cohort study was conducted to assess the clinical outcomes of patients with ALK-positive SCLC diagnosed in our hospital over the past 9 years. We used public databases to analyze the expression of ALK in pan-cancer and its prognostic value and analyzed the correlation between ALK and SCLC prognosis-related genes.

A total of 685 patients diagnosed with SCLC underwent ALK testing, and 59 patients were identified to have abnormal expression of the ALK protein, with 10 cases showing strong expression, 14 cases displaying moderate expression, and 35 cases exhibiting weak expression. The median age of the ALK-positive cohort was 64 years (range: 58-70 years), 91.5% (54/59) were male, 61.0% (36/59) were smokers, and the median overall survival (mOS) was 7.0 months (95% CI: 4.5-9.5 months). Within this cohort, the mOS for the ALK (+) subgroup was 4.0 months (95% CI: 2.9-5.1 months), the mOS for the ALK (++) subgroup was 10.0 months (95% CI: 4.9-15.1 months), and the mOS for the ALK (+++) subgroup was 12.0 months (95% CI: 7.4-16.6 months). Kaplan-Meier revealed that the mOS of the ALKLow group was significantly worse than that of the ALKHigh group [mOS: 4.0 months (95% CI: 2.9-5.1 months) versus 11.0 months (95% CI: 8.3-13.7 months), p = 0.009]. Following covariate adjustment using a Cox regression model, it was indicated that the level of abnormal expression of the ALK protein was an independent prognostic factor for patients with SCLC (HR: 0.486, 95% CI: 0.271-0.871, p = 0.015).

The prognosis for patients with SCLC with strong abnormal expression of the ALK protein was significantly better than those with weak expression.

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.

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.

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.

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.

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.

Background and Objectives: ROS1 rearrangement is a rare but targetable alteration in non-small-cell lung cancer (NSCLC), occurring in 1-2% of cases. Crizotinib, a tyrosine kinase inhibitor, has demonstrated efficacy in clinical trials, but real-world data remain limited. This study evaluates the safety and efficacy of crizotinib in ROS1-rearranged NSCLC patients in a real-world setting. Materials and Methods: This multicenter, retrospective research included 43 individuals with advanced/metastatic NSCLC and confirmed ROS1 rearrangements. Patients were treated with crizotinib in first- or second-line settings. Efficacy endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR). Safety was assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Results: The median follow-up was 45.8 months. The ORR for first-line crizotinib was 72.1%, with a DCR of 79%. The median PFS was 20.9 months (95% CI: 6.02-35.69), and the median OS was 52.7 months (95% CI: 13.08-92.31). ECOG performance status was a significant prognostic factor for ORR (p = 0.02). The most common adverse events were fatigue (16.2%), elevated transaminases (13.9%), and vision disorders (11.6%). All reported adverse events were grade 1 or 2, with no grade ≥ 3 events observed. Conclusions:Crizotinib demonstrated significant efficacy and a favorable safety profile in real-world individuals with ROS1-rearranged NSCLC. These findings align with pivotal trials, underscoring crizotinib's role as a standard treatment for this molecular subset. Further prospective studies are warranted to explore intracranial efficacy and long-term outcomes.

Lung cancer is a major cause of cancer-related deaths globally. Targeted therapies, specifically attacking cancer cells based on genetic mutations, offer promising alternatives. ALK (anaplastic lymphoma kinase) fusions result in aberrant proteins that drive cancer growth. Drugs like crizotinib and ceritinib have shown efficacy in treating ALK-positive NSCLC. Accurate detection of ALK fusions is crucial for guiding these therapies. We conducted a retrospective analysis of a Chinese cohort of 131 ALK rearrangement-positive patients detected by DNA NGS between January 2017 and December 2021. Among those 131 ALK fusions, RNA-NGS confirmed positive transcripts in 88% of canonical ALK fusions and 75% of ALK fusions with rare partners in samples sequenced by both DNA NGS and RNA NGS. The secondary classification approach increased transcript prediction accuracy to 95.4% when combining common breakpoints and inframe fusion analysis in canonical ALK fusions. Combining rare breakpoints and inframe fusion could increase transcript prediction accuracy to 100%. For ALK fusions with rare partners, combining common breakpoints and frameshift improved transcript prediction accuracy to 100%. Additionally, combining rare breakpoints with inframe or frameshift could enhance the prediction accuracy to 100%. Combining DNA NGS and RNA NGS with a secondary classification approach significantly enhances the transcript prediction accuracy at the RNA level. This method optimizes clinical diagnostic and therapeutic strategies for ALK-positive NSCLC, highlighting the importance of advanced sequencing techniques in precision oncology.

Neuroblastoma is a pediatric cancer that originates from neural crest cells and is the most common extracranial solid tumor in children under five years of age. While low-risk neuroblastoma often regresses spontaneously, high-risk neuroblastoma poses a significant clinical challenge. Recent advances in understanding neuroblastoma's molecular mechanisms have led to the development of targeted therapies that aim to selectively inhibit specific pathways involved in tumor growth and progression, improving patient outcomes while minimizing side effects. This review provides a comprehensive review of neuroblastoma biology and emerging therapeutic strategies. Key topics include (a) immunotherapies and immunotargets, (b) non-coding RNAs (long non-coding RNA, microRNA, and circular RNA), (c) molecular biomarkers and pathways, and (d) limitations and future directions.

Lung cancer treatment has changed in the last twenty years since the discovery of EGFR mutations. In this article, we will review the current state of the art for non-small cell lung cancer (NSCLC) actionable genomic alterations (AGA). AGAs are mostly found in lung adenocarcinomas, a subtype of non-small cell lung cancers. We will focus on the current treatment for EGFR mutations, ALK fusions, ROS1 fusions, BRAF V600E mutations, MET exon 14-skipping mutations, RET fusions, KRAS G12C mutations, ERBB2 mutations (also called HER2 mutations), and NTRK fusions. We will also touch on the key toxicities associated with these medications. Treatments are mostly available for the metastatic stage, but we will also discuss adjuvant therapy for EGFR mutations and ALK fusions, as well as stage III post-chemoradiotherapy treatment for EGFR lung cancer.

The discovery of ALK gene rearrangement in 3 to 5% of non-small cell lung carcinomas has revolutionized our understanding and therapeutic approach of these cancers. This oncogenic driver is associated with specific clinical and biological features is associated with specific clinical and biological features, mainly affecting young and never-smoker patients, with a particular tropism for brain metastases. The development of ALK tyrosine kinase inhibitors has transformed patient outcomes, with remarkable efficacy of latest-generation molecules, particularly in controlling brain metastases. However, the emergence of complex resistance mechanisms, whether ALK-dependent or ALK-independent, remains a major challenge. The comprehensive understanding of these resistance mechanisms now guides the development of next-generation inhibitors and innovative therapeutic strategies, paving the way for increasingly personalized precision medicine.

The expanding armamentarium of targeted therapies has revolutionized treatment for metastatic oncogene-addicted lung cancers. For multiple subsets, such as those harboring EGFR mutations and fusions in ALK or ROS1, successive generation of increasingly potent, selective, and brain-penetrating targeted therapies have shifted the treatment paradigm towards preferential first-line use of next-generation drugs. This evolution in clinical practice provides a lens through which to review the lessons learned from drug development in oncogene-addicted lung cancers, guided by translational insights into tumor biology and mechanisms of therapeutic resistance. For oncogenic drivers that are less sensitive to single-agent targeted therapies, rationally designed combination strategies will be needed to enable first-line use of targeted agents.

Weight gain is a known adverse event (AE) of alectinib. This study evaluates the progression of actual weight gain over time and explores its association with baseline characteristics.

A pooled analysis of individual patient data from four clinical trials (ALEX, J-ALEX, ALUR, and ML29453) was conducted. Actual weight gain was calculated as the percent change from baseline. A linear mixed model estimated weight change over time and associations between clinical characteristics and weight change.

Follow-up weights were available for three trials (J-ALEX, ALUR, and ML29453) and missing for ALEX. In total, 2,622 weights were recorded in the first year (N = 302). At baseline, 13.6% of the Japanese population were underweight and 5.0% in the Western population. Actual weight gain of any grade was substantially higher than reported AE rates (49% v 5%), with 18% experiencing ≥10% weight gain (from median 55.6 kg to 64.1 kg). Time on alectinib was positively associated with weight change (β = .37; 95% CI, 0.24 to 0.51; P < .001), corresponding to an average increase of 4.4% over 1 year. Baseline BMI was not associated with weight change in J-ALEX (β = -.090 [95% CI, -0.19 to 0.012]; P = .092) and ALUR/ML29453 (β = -.016 [95% CI, -0.077 to 0.044]; P = .59). Baseline albumin was positively associated with weight change in ALUR/ML29453 (β = .084 [95% CI, 0.027 to 0.14]; P = .0045), although not considered a clinically meaningful predictor.

Weight gain is under-reported as AE in trials. Actual weights showed ≥10% weight gain in 18% of patients. Clinicians should be aware of this AE, emphasizing the importance of timely identification and monitoring weight. Identifying predictors for weight gain remains challenging.

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are vital for treating ALK-positive cancers but have been associated with liver injury, necessitating further safety investigation. This study examines hepatic adverse event (AE) signals related to ALK TKIs using the U.S. FDA Adverse Event Reporting System (FAERS) and explores potential mechanisms of liver injury.

AE reports from FAERS (Q3 2011 to Q1 2024) related to liver injury were analyzed using the reporting odds ratio (ROR) and multi-item gamma Poisson shrinker (MGPS) methods. Pathway enrichment and drug-gene network analyses were performed to investigate underlying mechanisms.

This study identified 2,132 AE reports from the FAERS database linking hepatic AEs to ALK TKIs therapy. Significant signals were detected by ROR and MGPS methods, with common AEs including aminotransferase abnormalities, hyperbilirubinemia, and increased blood alkaline phosphatase, mainly occurring within the first 30 days of treatment. Gene analysis revealed key nodes in the protein-protein interaction (PPI) network, such as PIK3CA, SRC, and PTK2. Enriched KEGG pathways included the MAPK, PI3K-Akt, and Ras signaling.

This pharmacovigilance study identifies significant AE signals linking ALK TKIs to liver injury, highlighting potential mechanisms and providing insights for clinical management and patient outcomes.

This study aimed to compare the efficacy of the second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) alectinib and brigatinib in the treatment of advanced non-small-cell lung cancer (NSCLC) with ALK rearrangements based on real-world data.

We conducted a multicenter retrospective study using the Clinical Data Warehouse from seven university hospitals affiliated with the Catholic Medical Center. Patients diagnosed with ALK-positive advanced NSCLC and treated with alectinib or brigatinib were included. Key outcomes such as time to discontinuation (TTD), duration of response (DOR), overall survival (OS), and objective response rate (ORR) were analyzed.

A total of 143 patients were included (107 treated with alectinib, 36 with brigatinib). Alectinib was more frequently used as a first-line treatment (71% vs 44.4% for brigatinib, p = 0.008). Prior crizotinib treatment was more frequent in the brigatinib group (52.8% vs 22.4% for alectinib, p < 0.001). The best ORR was similar between the groups (84.1% for alectinib vs 83.3% for brigatinib, p = 0.518). The median TTD was 57.8 months (95% confidence interval (CI): 29.0-86.7) for alectinib and 39.6 months (95% CI: 21.7-57.4) for brigatinib (p = 0.462). No significant differences were observed in intracranial TTD, intracranial DOR, or OS between the groups. Prior crizotinib treatment significantly shortened TTD for second-generation TKIs (p = 0.025), but the overall TKI treatment duration did not show a significant difference between patients who received frontline second-generation ALK TKIs and those who received second-generation ALK TKIs sequentially after crizotinib.

Alectinib and brigatinib demonstrated comparable efficacy in ALK-positive advanced NSCLC. Undergoing crizotinib followed by a second-generation TKI was not significantly different from initiating a second-generation TKI without prior crizotinib in terms of outcomes.

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis; however, advancements in cancer genome profiling using next-generation sequencing have provided new perspectives. KRAS mutations are the most frequently observed genomic alterations in patients with PDAC. However, until recently, it was not considered a viable therapeutic target. Although KRAS G12C mutations for which targeted therapies are already available are infrequent in PDAC, treatments targeting KRAS G12D and pan-KRAS are still under development. Similarly, new treatment methods for KRAS, such as chimeric antigen receptor T-cell therapy, have been developed. Several other potential therapeutic targets have been identified for KRAS wild-type PDAC. For instance, immune checkpoint inhibitors have demonstrated efficacy in PDAC treatment with microsatellite instability-high/deficient mismatch repair and tumor mutation burden-high profiles. However, for other PDAC cases with low immunogenicity, combination therapies that enhance the effectiveness of immune checkpoint inhibitors are being considered. Additionally, homologous recombination repair deficiencies, including BRCA1/2 mutations, are prevalent in PDAC and serve as important biomarkers for therapies involving poly (adenosine diphosphate-ribose) polymerase inhibitors and platinum-based therapies. Currently, olaparib is available for maintenance therapy of BRCA1/2 mutation-positive PDAC. Further therapeutic developments are ongoing for genetic abnormalities involving BRAF V600E and the fusion genes RET, NTRK, NRG, ALK, FGFR2, and ROS1. Overcoming advanced PDAC remains a formidable challenge; however, this review outlines the latest therapeutic strategies that are expected to lead to significant advancements.

This study identified a higher incidence of ALK alterations in Hispanic patients with NSCLC (12.76%) compared with that in non-Hispanic patients (5.36%) treated at a large academic center in Los Angeles, highlighting the impact of race on molecular alteration profiles and emphasizing the need to increase access to molecular analyses for this population. The variability in mutational alterations may be influenced by biological and environmental factors.

Lung cancer is mostly a disease of aging with approximately half of newly diagnosed patients being 70 years or older. Treatment decisions in this population pose unique challenges because of their heterogeneity with regards to daily functioning, cognition, organ function, comorbidities and polypharmacy, their underrepresentation in clinical trials and the impact of treatment on patient-centered outcomes, particularly in frail patients. The advent of targeted therapies and immunotherapy has revolutionized the management of advanced non-small cell lung cancer (NSCLC). Molecular profiling has allowed for the identification of actionable genomic alterations and targeted therapies have become standard of care for oncogene-driven NSCLC, significantly improving prognosis and quality of life. However, the data on the efficacy and tolerability of these treatments in older patients remain sparse. This review, conducted by the International Society of Geriatric Oncology (SIOG) NSCLC task force, examines the available literature on the use of targeted therapies in patients aged 70 years or older with oncogene-driven NSCLC. The task force's expert recommendations aim to guide treatment decisions for older patients with oncogene driven NSCLC.

Precision in critical care nutrition is paramount, as it focuses nutrition interventions on those patients most likely to benefit, or those who might potentially be harmed. Critical care nutrition must therefore be tailored to individual metabolic needs as determined by factors that control the capacity for tissue homeostasis and anabolic responses. This ideally involves the accurate and timely assessment of macronutrient and micronutrient requirements, a careful evaluation of metabolic response mechanisms and the identification of circumstances that might interfere with the productive utilization of dietary substrates. Specific surrogate markers of metabolic response, such as blood glucose levels, urea levels, or nitrogen balance, might be used to evaluate the metabolic readiness for nutrition and to establish the timing, nature, and clinical effectiveness of nutrition interventions. Despite the pressing need to further develop more targeted approaches in critically ill patients, indices of immediate metabolic responses that correlate with favorable clinical outcomes are lacking. In addition, the development of precision approaches might address timely adjustments in protein, energy, or micronutrient supplementation based on evolving clinical conditions. Here, we review why precision tools are needed in critical care nutrition, our progress thus far, as well as promising approaches and technologies by which multidisciplinary healthcare teams can improve quality of care and clinical outcomes by individualizing nutrition interventions.

Recognizing rare molecular variants of driver mutations poses a challenge in precision oncology, particularly for treatment of non-small cell lung cancer (NSCLC). In this study, we aimed to determine whether Oncomine Dx Target Test Multi-CDx System (ODxTT), the most widely used genetic test for NSCLC in Japan, potentially overlooks druggable EGFR mutations.

Among 418 patients who underwent molecular testing using ODxTT at our hospital, 267 were diagnosed with adenocarcinoma. No mutations were reported in 82 of these cases. For these 82 cases, we searched for EGFR mutations in exons 18-21 by examining the binary alignment map file. Once a mutation was identified, its pathological significance was evaluated using the ClinVar database to determine whether ODxTT had overlooked any actionable EGFR mutations.

Mutations in EGFR exons 19 and 18 were identified in six and four cases, respectively. Three, six, and none of these variants were detectable using the Cobas EGFR Mutation Test v2, Lung Cancer Compact Panel, and Amoy Dx, respectively. Of the 10 patients, five were subsequently treated with EGFR TKI; three showed partial response, one had stable disease, and one had progressive disease.

ODxTT failed to identify 10 actionable EGFR mutations, accounting for 12.2% (10/82) of the cases initially reported as not carrying actionable mutations. Therefore, comprehensive genomic profiling should be actively performed early in cases with high clinical suspicion of EGFR mutations.

We established an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method to measure alectinib concentrations in rat plasma and use it to investigate the effect of HIV protease inhibitors on the pharmacokinetic parameters of alectinib in rats. Acetonitrile was used to precipitate the samples. We used a BEH C18 column to perform chromatographic separation on a UPLC system. The mobile phase comprised 0.1 % formic acid, water, and acetonitrile. Mass spectrometry analysis was conducted using a Xevo TQ-Striple quadrupole tandem mass spectrometer. Alectinib and lorlatinib (internal standard) were measured in MRM mode. The fragment ions were 483.2-396.1 for alectinib and m/z 407.3-228.1 for lorlatinib. The validated UPLC-MS/MS method was used to study drug interactions of atazanavir, darunavir, indinavir, and ritonavir with alectinib in rat plasma. We found atazanavir, darunavir, indinavir, and ritonavir significantly inhibited alectinib metabolism. When administered with atazanavir, darunavir, indinavir, and ritonavir, the AUC0-t of alectinib increased by 94.0 %, 175.7 %, 220.9 %, and 62.4 %, respectively; the clearance of alectinib decreased by 53.4 %, 63.6 %, 67.8 %, and 41.1 %, respectively. In short, we developed an UPLC-MS/MS approach to measure alectinib in rat plasma. Atazanavir, darunavir, indinavir, and ritonavir dramatically inhibited alectinib metabolism. The dosages should be adjusted when using atazanavir, darunavir, indinavir, and ritonavir with alectinib. Real-time monitoring should occur during treatment.

Kinase-related gene fusion and point mutations play pivotal roles as drivers in cancer, necessitating optimized, targeted therapy against these alterations. The efficacy of molecularly targeted therapeutics varies depending on the specific alteration, with great success reported for such therapeutics in the treatment of cancer with kinase fusion proteins. However, the involvement of actionable alterations in solid tumors, especially regarding kinase fusions, remains unclear. Therefore, in this study, we aimed to compare the number of actionable alterations in patients with tyrosine or serine/threonine kinase domain fusions, mutations, and copy number alterations (CNAs). We analyzed 613 patients with 40 solid cancer types who visited our division between June 2020 and April 2024. Furthermore, to detect alterations involving multiple-fusion calling, we performed comprehensive genomic sequencing using FoundationOne® companion diagnostic (F1CDx) and FoundationOne® Liquid companion diagnostic (F1LCDx). Patient characteristics and genomic profiles were analyzed to assess the frequency and distribution of actionable alterations across different cancer types. Notably, 44 of the 613 patients had fusions involving kinases, transcriptional regulators, or tumor suppressors. F1CDx and F1LCDx detected 13 cases with kinase-domain fusions. We identified 117 patients with kinase-domain mutations and 58 with kinase-domain CNAs. The number of actionable alterations in patients with kinase-domain fusion, mutation, or CNA (median [interquartile range; IQR]) was 2 (1-3), 5 (3-7), and 6 (4-8), respectively. Patients with kinase fusion had significantly fewer actionable alterations than those with kinase-domain mutations and CNAs. However, those with fusion involving tumor suppressors tended to have more actionable alterations (median [IQR]; 4 [2-9]). Cancers with kinase fusions exhibited fewer actionable alterations than those with kinase mutations and CNAs. These findings underscore the importance of detecting kinase alterations and indicate the pivotal role of kinase fusions as strong drivers of cancer development, highlighting their potential as prime targets for molecular therapeutics.

Targeted therapies have changed the treatment landscape of non-small-cell lung cancer and led to improved patient survival across all stages of lung cancer. Newer advances in common and novel oncogenic drivers continue to occur at vigorous speed, making it challenging to stay up to date with the rapidly evolving field. In this article, we review the emerging perspectives in the treatment of actionable targets in lung cancer. We focus on the development of newer KRAS-directed therapies, particularly on non-G12C mutations, pan-RAS inhibitors, and RAS-GTP inhibitors. We also describe the current standard of care for EGFR- and ALK-altered NSCLC and dive into the novel treatments expected to be in the clinic soon. A similar approach is taken toward MET, HER2, RET, ROS1, and FGFR alterations as emerging targets in non-small-cell lung cancer. Finally, we conclude this review with the current body of evidence for targeting TROP-2 as a novel target, potentially of importance in post-targeted therapy scenarios.

The treatment of Non Small Cell Lung Cancer (NSCLC) has been revolutionised by the introduction of targeted therapies. With the improvement of response and frequently of overall survival, however, a whole new set of adverse events emerged. In fact, due to the peculiar mechanism of action of each one of the tyrosine kinase inhibitors and other targeted therapies, every drug has its own specific safety profile. In addition, this safety profile could not fully emerge from clinical trials data, as patients in clinical practice usually have more comorbidities and frailties. Cardiotoxicity is a well-known and established adverse event of anti-cancer therapies. However, only recently it has become a central topic for targeted therapies in NSCLC, due to the unknown real range and frequency. Management of this toxicity begins with prevention, and must balance the need of continuing an effective anticancer treatment versus low risk of even fatal events and the preservation of long-term quality of life. The aim of this review is to summarise the current knowledge focusing on currently used targeted therapies in NSCLC.

Crizotinib, as the first-generation of anaplastic lymphoma kinase (ALK) inhibitor, effectively improves the survival time of ALK-positive non-small cell lung cancer (NSCLC) patients. However, its efficacy is severely limited by drug resistance caused by secondary mutations. G1202R and L1196M are classical mutation sites located in ALK kinase domain. They may hinder the binding of ALK inhibitors to the target kinase domain, resulting in drug resistance in patients. However, the exact mechanism of drug resistance mediated by these mutations remains unclear. In this study, we aimed to evaluate how G1202R and L1196M mutations mediate crizotinib resistance. To explore the resistance mechanism, we constructed EML4-ALK G1202R and L1196M mutant cell lines with A549 cells. The results showed that the mutant cells exhibited significant epithelial-mesenchymal transition (EMT) and metastasis compared to control (A549-vector) or wild type (A549-EML4-ALK) cells. Subsequently, it was found that the occurrence of EMT was correlated to the high expression of murine double minute 2 (MDM2) protein and the activation of mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway in mutant cells. Down-regulation of MDM2 inhibited the activation of MEK/ERK pathway, thus reversed the EMT process and markedly increased the inhibitory effect of crizotinib on the growth of mutant cells. Collectively, resistance of ALK-positive NSCLC cells to crizotinib is induced by G1202R and L1196M mutations through activation of the MDM2/MEK/ERK signalling axis, promoting EMT process and metastasis. These findings suggest that the combination of MDM2 inhibitors and crizotinib could be a potential therapeutic strategy.

Patients with advanced ALK-positive NSCLC typically have poor response to immunotherapy; the benefit of consolidation durvalumab in patients with unresectable stage III ALK-positive NSCLC remains unclear. Herein, we compare the efficacy and safety of consolidation ALK tyrosine kinase inhibitor (TKI) versus durvalumab or observation after concurrent chemoradiation.

We conducted a retrospective study using a multicenter study of 17 institutions globally. Patients with unresectable stage III ALK-positive NSCLC treated between 2015 and 2022 were included. Patients received ALK TKI, durvalumab, or observation after concurrent chemoradiation. Real-world progression-free survival (rwPFS) and overall survival (OS) were estimated using Kaplan-Meier method. Treatment-related adverse events (trAEs) were classified by Common Terminology Criteria for Adverse Events version 5.0. Outcomes were assessed by multivariable Cox regression analysis.

A total of 67 patients were included, of whom 39 (58%) were female. Median age was 57 (interquartile range: 49-67) years. Furthermore, 15 received consolidation ALK TKI, 30 received durvalumab, and 22 underwent observation. Baseline characteristics were similar across the three groups other than differences in race. After adjusting for stage, age, and nodal status, median rwPFS was significantly longer for ALK TKI (rwPFS not reached, 95% confidence interval [CI]: 22.7- not reached) versus durvalumab (11.3 mo, 95% CI: 8.9-18.5, hazard ratio [HR] = 0.12, 95% CI: 0.026-0.5, p-adjusted [p-adj] = 0.006) or observation (7.2 mo, 95% CI: 3.4-10.6, HR = 0.04, 95% CI: 0.009-0.2, p-adj < 0.0001). Durvalumab significantly improved median rwPFS compared with observation (HR = 0.37, 95% CI: 0.19-0.71, p-adj = 0.002). Median OS in the ALK TKI and durvalumab cohorts was significantly improved compared with patients on observation (ALK TKI-observation: p = 0.04; durvalumab-observation: p = 0.03). TrAE of any grade occurred in eight (53%) and 11 (37%) patients treated with ALK TKI and durvalumab, respectively. Grade greater than or equal to three trAEs occurred in 27% (n = 4) of patients treated with ALK TKI and 6.7% of patients treated with durvalumab.

Patients with ALK-positive NSCLC experience significantly improved rwPFS when treated with consolidation ALK TKI therapy, surpassing outcomes found with either durvalumab or observation. Although both ALK TKI therapy and durvalumab offer an extension in OS compared with observation alone, it seems that ALK TKI therapy is the superior choice, underscoring its pivotal role in enhancing patient survival.