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Purpose: Lorlatinib improved progression-free survival (PFS) and intracranial activity versus crizotinib in patients with previously untreated, advanced, ALK -positive non-small cell lung cancer (NSCLC) in the phase III CROWN study. Here, we report long-term outcomes from CROWN after 5 years of follow-up., Methods: Two hundred ninety-six patients with ALK -positive NSCLC were randomly assigned 1:1 to receive lorlatinib 100 mg once daily (n = 149) or crizotinib 250 mg twice daily (n = 147). This post hoc analysis presents updated investigator-assessed efficacy outcomes, safety, and biomarker analyses., Results: With a median follow-up for PFS of 60.2 and 55.1 months, respectively, median PFS was not reached (NR [95% CI, 64.3 to NR]) with lorlatinib and 9.1 months (95% CI, 7.4 to 10.9) with crizotinib (hazard ratio [HR], 0.19 [95% CI, 0.13 to 0.27]); 5-year PFS was 60% (95% CI, 51 to 68) and 8% (95% CI, 3 to 14), respectively. Median time to intracranial progression was NR (95% CI, NR to NR) with lorlatinib and 16.4 months (95% CI, 12.7 to 21.9) with crizotinib (HR, 0.06 [95% CI, 0.03 to 0.12]). Safety profile was consistent with that in prior analyses. Emerging new ALK resistance mutations were not detected in circulating tumor DNA collected at the end of lorlatinib treatment., Conclusion: After 5 years of follow-up, median PFS has yet to be reached in the lorlatinib group, corresponding to the longest PFS ever reported with any single-agent molecular targeted treatment in advanced NSCLC and across all metastatic solid tumors. These results coupled with prolonged intracranial efficacy and absence of new safety signals represent an unprecedented outcome for patients with advanced ALK -positive NSCLC and set a new benchmark for targeted therapies in cancer.

Crizotinib carries an FDA hepatotoxicity warning, yet analysis of the FAERS database suggests that the severity of its hepatotoxicity risks, including progression to hepatitis and liver failure, might be underreported. However, the underlying mechanism remains poorly understood, and effective intervention strategies are lacking. Here, mRNA-sequencing analysis, along with KEGG and GO analyses, revealed that DEGs linked to Crizotinib-induced hepatotoxicity predominantly associate with the ferroptosis pathway which was identified as the principal mechanism behind Crizotinib-induced hepatocyte death. Furthermore, we found that ferroptosis inhibitors, namely Ferrostatin-1 and Deferoxamine mesylate, significantly reduced Crizotinib-induced hepatotoxicity and ferroptosis in both in vivo and in vitro settings. We have also discovered that overexpression of AAV8-mediated Nrf2 could mitigate Crizotinib-induced hepatotoxicity and ferroptosis in vivo by restoring the imbalance in glutathione metabolism, iron homeostasis, and lipid peroxidation. Additionally, both Stat1 deficiency and the Stat1 inhibitor NSC118218 were found to reduce Crizotinib-induced ferroptosis. Mechanistically, Crizotinib induces the phosphorylation of Stat1 at Ser727 but not Tyr701, promoting the transcriptional inhibition of Nrf2 expression after its entry into the nucleus to promote ferroptosis. Meanwhile, we found that MgIG and GA protected against hepatotoxicity to counteract ferroptosis without affecting or compromising the anti-cancer activity of Crizotinib, with a mechanism potentially related to the Stat1/Nrf2 pathway. Overall, our findings identify that the phosphorylation activation of Stat1 Ser727, rather than Tyr701, promotes ferroptosis through transcriptional inhibition of Nrf2, and highlight MgIG and GA as potential therapeutic approaches to enhance the safety of Crizotinib-based cancer therapy., (© 2024. The Author(s).)

Purpose: Taletrectinib, a highly potent, CNS-active, ROS1 tyrosine kinase inhibitor (TKI), has demonstrated high and durable response rates, high intracranial objective response rate (ORR), prolonged progression-free survival (PFS), and activity against G2032R with a favorable safety profile. We report outcomes from the pivotal TRUST-I study (ClinicalTrials.gov identifier: NCT04395677) of taletrectinib for ROS1+ non-small cell lung cancer in China., Methods: TRUST-I evaluated TKI-naїve and crizotinib-pretreated patients. The primary end point was confirmed ORR (cORR) by independent review committee; key secondary end points included duration of response (DOR), PFS, and safety., Results: As of November 2023, 173 patients were enrolled (median age, 55 years; 58% female; 73% never smoked; TKI naїve: n = 106; crizotinib pretreated: n = 67). In TKI-naїve patients, cORR and intracranial cORR were 91% and 88%, respectively, and 52% and 73% in crizotinib-pretreated patients. In TKI-naїve patients, median DOR and median PFS were not reached (NR) with 22.1-month and 23.5-month follow-up, respectively. In crizotinib-pretreated patients, the median DOR was 10.6 months (95% CI, 6.3 months to NR; 8.4-month follow-up), and the median PFS was 7.6 months (95% CI, 5.5 to 12.0 months; 9.7-month follow-up). Eight of 12 patients (67%) with G2032R mutations responded. The most frequent treatment-emergent adverse events (TEAEs) were increased AST (76%), diarrhea (70%), and increased ALT (68%), most of which were grade 1-2. Incidences of neurologic TEAEs were low (dizziness: 23%; dysgeusia: 10%) and mostly grade 1. Discontinuations (5%) and dose reductions (19%) due to TEAEs were low., Conclusion: Taletrectinib continues to show high and durable overall responses, prolonged PFS, robust activity against intracranial lesions and acquired resistance mutations including G2032R, and a favorable safety profile with a low incidence of neurologic TEAEs.

Background: Crizotinib was approved to treat patients with advanced non-small cell lung cancer (aNSCLC) with ROS proto-oncogene 1 (ROS1) gene fusion in 2016. We conducted a systematic literature review to identify real-world evidence (RWE) studies and estimated the efficacy and safety of crizotinib using meta-analyses (MA) for objective response rate (ORR), real-world progression-free survival (PFS), and overall survival (OS)., Methods: We searched MEDLINE®, Embase, and Cochrane CENTRAL from January 2016 to March 2023 using Ovid® for published single-arm or comparative RWE studies evaluating patients (N ≥ 20) receiving crizotinib monotherapy for aNSCLC with ROS1 gene fusion. Pooled estimates for ORR and grade 3/4 adverse events (AEs) were derived using the metafor package in R while pooled estimates for median real-world PFS (rwPFS) and OS were derived using reconstructed individual patient data from published Kaplan-Meier curves. The primary analysis included all studies regardless of crizotinib line of therapy; a subgroup analysis (SA) was conducted using studies evaluating patients receiving first-line crizotinib., Results: Fourteen studies met the eligibility criteria and were considered feasible for MA. For the primary analysis, the pooled ORR (N = 9 studies) was 70.6 % (95 % confidence interval [CI]: 57.0, 81.3), median rwPFS was 14.5 months (N = 11 studies), and OS was 40.2 months (N = 9 studies). In the SA, the pooled ORR (N = 4 studies) was 81.1 % (95 % CI: 76.1, 85.2) and the median rwPFS (N = 4 studies) and OS (N = 2 studies) were 18.1 and 60 months, respectively. All MAs were associated with significant heterogeneity (I 2  > 25 %). Grade 3/4 AEs occurred in 18.7 % of patients (pooled estimate)., Conclusion: The results from this study are consistent with clinical trial data and, taken collectively, supports crizotinib as a safe and effective treatment across different lines of therapy in patients with ROS1 aNSCLC in the real-world setting., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Ernest Nadal is a consultant for and receives research funding from Pfizer. Nada Rifi and Hannah Le are employees of Pfizer and own Pfizer stock. Imtiaz A. Samjoo, Sarah Kane, Sokhna Mbacke, Lindsey Starkman, and Beatrice Suero are employees of EVERSANA, Canada, a paid consultant to Pfizer in connection with the development of this manuscript. EN is a consultant for and receives research funding from Pfizer. NR and HL are employees of Pfizer and own Pfizer stock. IAS, SK, SM, LS, and BS are employees of EVERSANA, Canada, a paid consultant to Pfizer in connection with the development of this manuscript., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Crizotinib, an oral first-generation tyrosine kinase inhibitor (TKI), is superior to systemic chemotherapy for the treatment of non-small cell lung cancer (NSCLC) with positive rearrangement of anaplastic lymphoma kinase (ALK). However, an increased incidence of renal and hepatic cysts has been reported in the patients on crizotinib treatment., Case Presentation: Here, we describe a case of a 71-year-old Chinese women developed multiple cystic lesions in kidney and liver during crizotinib treatment for the primary and metastatic NSCLC. The renal and hepatic cysts were noted by CT scan 3 months after crizotinib treatment, which were spontaneously and significantly regressed after stopping crizotinib., Conclusions: Based on literature review and our experience in this case report, we concluded that crizotinib-associated renal cyst (CARCs) has features of malignancy and abscess in radiographic imaging, and thus, pathological confirmation is necessary to avoid inappropriate treatment decision. In addition, to benefit the patients with progress-free survival (PFS), switching from crizotinib to alectinib is recommended for the treatment of NSCLC patients who developed CARCs., (© 2024. The Author(s).)

Crizotinib-associated renal cysts (CARC) are the development of new renal cysts or pre-existing renal cysts after the treatment with crizotinib. Most CARC disappear after crizotinib is stopped. A few CARC showed aggressive behavior that could go beyond the invasion of the renal cortex into nearby structures, including perirenal space, psoas major muscle, intestine, and abdominal wall. 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.

We herein report the first case of c-ros oncogene 1 (ROS1)-rearranged advanced non-small-cell lung cancer (NSCLC) in which lung injury was induced by crizotinib and entrectinib. Crizotinib was administered as first-line chemotherapy in a woman in her early 70s with stage IV NSCLC showing ROS1 rearrangement. This resulted in the development of drug-induced organizing pneumonia, which was alleviated by discontinuing drug administration and giving corticosteroids. Following second-line chemotherapy with entrectinib, a similar lung injury was noted. In cases of crizotinib-induced lung injury, physicians must be alert for drug-induced lung injury in subsequent treatment with entrectinib.

Background: Interstitial lung disease (ILD) is a rare but life-threatening and fatal treatment-related pneumonitis. This study investigated the association between anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) and ILD., Research Design and Methods: Cases of ILD that developed after treatment with an ALK-TKI in the Food and Drug Administration' s Adverse Event Reporting System (FAERS) data were assessed. We also described the clinical features of these cases and evaluated onset time, hospitalization, life-threatening condition, and fatality rate of ILD developed after treatment with an ALK-TKI., Results: All five ALK-TKI regimens were significantly associated with ILD. The median onset time to ILD was significantly different for brigatinib, crizotinib, alectinib, lorlatinib, and ceritinib: 4.5, 25, 35.5, 54.5, and 84 days, respectively. ALK-TKI-associated ILD resulted in hospitalization in 55.77% of patients and death or life-threatening outcomes in 43.03%. The highest and lowest proportions of ILD-related fatalities were observed after crizotinib and alectinib treatment, respectively., Conclusions: ALK-TKIs were associated with ILD; therefore, the risk of developing ILD after treatment with an ALK-TKI should be carefully considered in clinical settings.

Background: Anaplastic lymphoma kinases (ALK) tyrosine kinase inhibitors (TKIs) are effective and safe targeted therapies used in advanced ALK-positive non-small cell lung cancers (NSCLC). However, ALK-TKIs associated cardiovascular toxicities in patients with ALK-positive NSCLCremain incompletely characterized. We conducted the first meta-analysis to investigate this., Research Design and Methods: To determine the cardiovascular toxicities associated with these agents, we carried out a meta-analysis comparing ALK-TKIs with chemotherapy and a meta-analysis comparing crizotinib with other ALK-TKIs. Statistical analysis was conducted to calculate the RRs and 95% confidence intervals (CIs) by using either random effects or fixed-effect models according to the heterogeneity of the included studies., Results: A total of 11 studies (2855 patients) were included. ALK-TKIs ranked to have more severe cardiovascular toxicities than chemotherapy (RR 5.03, 95% CI 1.97-12.84, P = 0.0007) . Compared with other ALK-TKIs, increased risks of cardiac disorders and VTEs associated with crizotinib were found (cardiac disorders RR 1.75, 95% CI 1.07-2.86, P = 0.03; risk of VTEs RR 3.97, 95% CI 1.69-9.31, P = 0.002; respectively)., Conclusion: ALK-TKIs were associated with higher risks of cardiovascular toxicities. Special attention should be given to the risks of cardiac disorders and VTEs related to crizotinib therapy.

Background: Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) may provoke cardiac arrhythmias. We conducted this pharmacovigilance analysis to research cardiac arrhythmias associated with ALK-TKIs using the Food and Drug Administration Adverse Event Reporting System (FAERS)., Research Design and Methods: The first ALK-TKI, named crizotinib, was approved by the Food and Drug Administration (FDA) on 26 August 2011 for the treatment of ALK-rearranged non-small cell lung cancer (NSCLC). We evaluated ALK-TKIs-induced cardiac arrhythmias, by using the reporting odds ratio (ROR) and information component (IC) for mining the adverse event report signals in the FAERS database between January 2016 and June 2022., Results: We identified a total of 362 ALK-TKIs-related cardiac arrhythmia reports which appeared to influence more men (64.44%) than women (30.76%), with a median age of 68 (interquartile range [IQR] 7-74) years. Compared with the full database, ALK-TKIs were detected with pharmacovigilance of cardiac arrhythmias (ROR025 = 1.26, IC025 = 0.26). Crizotinib and alectinib were found to be related to higher reporting of arrhythmias. The median time to onset (TTO) among five ALK-TKI therapies was significantly different ( p  = 0.044)., Conclusion: ALK-TKIs present different frequencies of cardiac arrhythmias reporting, with only crizotinib and alectinib producing positive signals in high-level group term (HLGT) level arrhythmia. The time interval between the initial of drug treatment to the onset of arrhythmia varies greatly and cannot be predicted.

What Is This Summary About?: This summary shows the updated results of an ongoing research study called CROWN that was published in The Lancet Respiratory Medicine in December 2022. In the CROWN study, researchers looked at the effects of two study medicines called lorlatinib and crizotinib. The study included people with advanced non-small-cell lung cancer (NSCLC) that had not been treated previously. All people in the study had cancer cells with changes (known as alterations) in a gene called anaplastic lymphoma kinase , or ALK . This ALK gene is involved in cancer growth. In this updated study, researchers looked at the continued benefit in people who took lorlatinib compared with people who took crizotinib after 3 years., What Did This Study Find?: After 3 years of being observed, people who took lorlatinib were more likely to be alive without their cancer getting worse than people who took crizotinib. At 3 years, 64% of people who took lorlatinib were alive without their cancer getting worse compared with 19% of people who took crizotinib. The cancer was less likely to have spread within or to the brain in people who took lorlatinib than in people who took crizotinib. After 3 years of being observed, 61% of people were still taking lorlatinib and 8% of people were still taking crizotinib. People who took lorlatinib had more severe side effects than people who took crizotinib. However, these side effects were manageable. The most common side effects with lorlatinib were high levels of cholesterol or high levels of triglycerides (a type of fat) in the blood. Life-threatening side effects were seen in 13% of people who took lorlatinib and 8% in crizotinib. Two people who took lorlatinib died because of side effects from lorlatinib., What Do the Results of the Study Mean?: The updated results from the CROWN study showed that a larger percentage of people who took lorlatinib continued to benefit from their treatment after being observed for 3 years compared with those who took crizotinib.

Background.: Oncology clinical trials demonstrate the risk of cardiotoxicity but are not sufficient to reveal the true risk. In this article, we compared the incidence of cardiotoxicity of crizotinib and osimertinib from a real-world study to data reported by phase 3 clinical trials., Methods.: Data from an ongoing real-world lung cancer study was used as a comparator. Patients were recruited retrospectively with the criteria of being diagnosed with non-small cell lung cancer and having received at least a course of treatment of tyrosine-kinase inhibitor and/or immune check-point inhibitor. Characteristics of the patients who developed cardiotoxicity associated with osimertinib and crizotinib in the real-world lung cancer study were analysed against the inclusion criteria of the corresponding phase 3 clinical trials. Variations of cardiotoxicity incidence among the real-world lung cancer study and clinical trials were investigated., Results.: 18%, n = 37/206, of the patients developed cardiotoxicity. QTc prolongation was the most frequently observed cardiotoxicity (n = 12/37). Osimertinib and crizotinib were the most cardiotoxic agents, each responsible for seven cases of cardiotoxicity. FLAURA, AURA3, PROFILE 1007 and PROFILE 1014 were the included clinical trials for analysis. None of the patients who developed cardiotoxicity in the real-world study would have been eligible to participate in FLAURA and PROFILE 1014 study whereas n = 4/7 and n = 5/7 patients were eligible to participate in AURA3 and PROFILE 1007 trials, respectively., Conclusion.: Although phase 3 clinical trials play an important role in understanding the effectiveness and give insights on side-effect profiles, real-world studies can show the real risk of cardiotoxicity more accurately and realistically.

Our study aimed to evaluate the efficacy and toxicity of alectinib compared with crizotinib and provide a reference for clinical use of ALK-TKI, systematically. We searched articles published update till October, 2021 based on the electronic databases, including PubMed, EMBASE and Cochrane Library. All trials analyzed the summary odds ratios (ORs) of the interesting outcomes. Three RCTs, including six studies were included. The pooled hazard ratio (HR) =0.33 (95%CI=0.21-0.51, P<0.00001) shown that the alectinib group achieved significant progress-free survival (PFS) superiority than crizotinib, consistent with those for the with (P=0.001) or without (P<0.00001) measurable CNS lesions at baseline. Also, the regimen of the alectinib did achieved benefit in the ORR (OR=2.07, 95% CI=1.41-3.06, P=0.0002) than crizotinib. Due to the limited data, the pool result of the difference of overall survival (OS) was without statistically significant (P=0.35). With regard to the safety, grade 3 to 5 adverse events were less frequent with alectinib than crizotinib (OR=0.53, 95% CI=0.31-0.90, P=0.02). As compared with crizotinib, alectinib demonstrated better PFS efficacy and comparable safety as a first-line treatment for advanced ALK-positive Non-Small Cell Lung Cancer (NSCLC). OS data remain immature, further trials with long-term survival rate have future to look forward to.

Crizotinib shows antitumor activity against C-ros oncogene 1-rearranged non-small-cell lung cancer (NSCLC). While corrected QT interval (QTc) prolongation and bradycardia are known as cardiac adverse effects, little is known about crizotinib-related heart failure. Our patient with C-ros oncogene 1-rearranged NSCLC on a reduced dose of crizotinib (200 mg twice daily) after initially experiencing bradycardia and QTc prolongation developed crizotinib-induced heart failure. With further dose reduction (250 mg once daily), there was no recurrence of any cardiac adverse effects, and the patient achieved a long-term response. Although crizotinib can cause heart failure, continuation of crizotinib at a low dose may be an effective treatment option.

Introduction: Lung cancer is a major global health problem because of its high incidence and mortality. Targeted therapies have transformed treatment of driver-mutated metastatic non-small cell lung cancer (NSCLC). Nevertheless, recent studies demonstrated that cardiovascular disease (CVD) was the second leading cause of mortality in cancer survivors now, management of patients' cardiovascular health during the course of anticancer therapy has become a great challenge faced by the oncologists. Anticancer related cardiovascular (CV) complications are not limited to traditional chemotherapy, but are also increasingly recognized in targeted therapy., Case Report: We present a case of pulmonary embolism (PE) and bradycardia in a 91-year-old NSCLC patient treated with crizotinib for a rare MET Y1003S mutation. To our knowledge, this is the second report to show antitumor response of crizotinib in lung cancer patients with such a rare mutation. However, the patient complained chest tightness and shortness of breath after a month of standard dose crizotinib therapy. Non-invasive examination revealed new onset bradycardia and PE., Management & Outcome: Such clinical manifestations were associated with targeted therapy-related CV toxicity, on which the emerging discipline cardio-oncology focused, and a multidisciplinary investigation and treatment was conducted., Discussion: This case highlights the CV adverse events of novel therapies and the current challenges to be tackled in cardio-oncology.

Introduction: Crizotinib is a tyrosine kinase inhibitor used in patients with non-small cell lung cancer, and there are uncertainties about its effect on kidney function. In this study, it was aimed to document the possible adverse effect of the drug on kidney functions., Materials and Methods: The estimated glomerular filtration rates (eGFRs) of the patients were calculated by creatinine-based Chronic Kidney Disease Epidemiology Collaboration and compared by months using the paired samples t-test. Kaplan-Meier survival method was used for progression-free survival and overall survival (OS) analysis., Results: Twenty-six patients who received crizotinib were included in the study, and the median progression-free survival time with crizotinib was 14.2 months and the median OS time was 27.4 months. There was a significant reduction of eGFR after the 1 st month of crizotinib treatment when compared to the rate before treatment initiation (P < 0.001). The eGFR values at the end of the 1 st month and the 2 nd month of treatment and the 2 nd and 3 rd months of treatment were statistically similar (P = 0.086, P = 0.663; respectively). This decrease in eGFR values was reversible, and there was no difference detected between pretreatment and posttreatment discontinuation (P = 0.100)., Conclusion: A reversible decrease in renal functions was detected in patients using crizotinib. When the literature data are examined, it is thought that the reason for this decrease may be related to the increase in renal inflammation or a pseudo decrease due to the decrease in creatinine excretion. When evaluating renal functions in these patients, using noncreatine-based (iothalamate, etc.) calculations can give more accurate results., Competing Interests: None

Background: Brigatinib is a next-generation anaplastic lymphoma kinase (ALK) inhibitor with demonstrated efficacy in locally advanced and metastatic non-small cell lung cancer (NSCLC) in crizotinib-refractory and ALK inhibitor-naive settings. This analysis assessed brigatinib in Asian vs. non-Asian patients from the first-line ALTA-1L trial., Patients and Methods: This was a subgroup analysis from the phase III ALTA-1L trial of brigatinib vs. crizotinib in ALK inhibitor-naive ALK+ NSCLC. The primary endpoint was progression-free survival (PFS) as assessed by blinded independent review committee (BIRC). Secondary endpoints included confirmed objective response rate (ORR) and overall survival (OS) in the overall population and BIRC-assessed intracranial ORR and PFS in patients with brain metastases., Results: Of the 275 randomized patients, 108 were Asian. Brigatinib showed consistent superiority in BIRC-assessed PFS vs. crizotinib in Asian (hazard ratio [HR]: 0.35 [95% CI: 0.20-0.59]; log-rank P = .0001; median 24.0 vs. 11.1 months) and non-Asian (HR: 0.56 [95% CI: 0.38-0.84]; log-rank P = .0041; median 24.7 vs. 9.4 months) patients. Results were consistent with investigator-assessed PFS and BIRC-assessed intracranial PFS. Brigatinib was well tolerated. Toxicity profiles and dose modification rates were similar between Asian and non-Asian patients., Conclusion: Efficacy with brigatinib was consistently better than with crizotinib in Asian and non-Asian patients with locally advanced or metastatic ALK inhibitor-naive ALK-+ NSCLC. There were no clinically notable differences in overall safety in Asian vs. non-Asian patients., (Copyright © 2022. Published by Elsevier Inc.)

Background: Conteltinib (CT-707) is a potent second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) showing promising anti-tumor activities in preclinical studies. This study aimed to assess the safety, pharmacokinetic (PK), and efficacy of conteltinib in patients with ALK-positive non-small cell lung cancer (NSCLC)., Methods: In this multicenter, single-arm, open-label, first-in-human phase 1 study, conteltinib was taken orally at doses of 50 to 800 mg quaque die (QD) in a dose-escalation phase. If the response was observed in a dose cohort of the dose-escalation phase, dose expansion was started. The primary endpoints were maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and adverse events assessed by investigators., Results: Between April 13, 2016, and February 8, 2020, 64 ALK-positive NSCLC patients were enrolled, including 41 (64.1%) patients with ALK TKI-naïve and 23 (35.9%) patients who received crizotinib previously. In the dose-escalation phase, 26 patients were treated with conteltinib at doses of 50 mg, 100 mg, 200 mg, 300 mg, 450 mg, 600 mg, and 800 mg QD. One DLT event was reported at the dose of 600 mg. MTD was not reached. Overall, 58 (90.6%) patients experienced treatment-related adverse events (TRAEs) and 9 (14.1%) patients had grade ≥ 3 TRAEs. The most common TRAEs were diarrhea (46 [71.9%]), serum creatinine elevated (29 [45.3%]), aspartate aminotransferase elevated (25 [39.1%]), and nausea (24 [37.5%]). Among 39 ALK TKI-naïve patients, the overall response rate (ORR) was 64.1% (25 of 39; 95% confidence interval [CI], 47.2-78.8), median progression-free survival (PFS) was 15.9 months (95% CI, 9.26-23.3), and median duration of response (DoR) was 15.0 months (95% CI, 9.06-25.8). Among 21 patients who received crizotinib previously, the ORR was 33.3% (7 of 21; 95% CI, 14.6-57.0), median PFS was 6.73 months (95% CI, 4.73-8.54), and median DoR was 6.60 months (95% CI, 3.77-13.3)., Conclusions: In this study, conteltinib showed manageable safety profile, favorable PK properties, and anti-tumor activity in advanced ALK-positive NSCLC patients. The recommended phase 2 dose was determined to be 600 mg QD for ALK TKI-naïve patients and 300 mg bis in die (BID) for patients who received crizotinib previously., Trial Registration: ClinicalTrials.gov, NCT02695550., (© 2022. The Author(s).)

Purpose: Lorlatinib significantly improved progression-free survival (PFS) versus crizotinib and showed robust intracranial activity in patients with previously untreated advanced ALK -positive non-small-cell lung cancer (NSCLC) in the phase III CROWN trial. Here, we report post hoc efficacy outcomes in patients with and without brain metastases at baseline, and present data on the incidence and management of CNS adverse events (AEs) in CROWN., Methods: Eligible patients were randomly assigned 1:1 to first-line lorlatinib (100 mg once daily) or crizotinib (250 mg twice a day); no crossover between treatment arms was permitted. Tumor assessments, including CNS magnetic resonance imaging, were performed at screening and then at 8-week intervals. Regular assessments of patient-reported outcomes were conducted., Results: PFS by blinded independent central review was improved with lorlatinib versus crizotinib in patients with and without brain metastases at baseline (12-month PFS rates: 78% v 22% and 78% v 45%, respectively). Lorlatinib was associated with lower 12-month cumulative incidence of CNS progression versus crizotinib in patients with (7% v 72%) and without (1% v 18%) brain metastases at baseline. In total, 35% of patients had CNS AEs with lorlatinib, most of grade 1 severity. Occurrence of CNS AEs did not result in a clinically meaningful difference in patient-reported quality of life. At analysis, 56% of CNS AEs had resolved (33% without intervention; 17% with lorlatinib dose modification), and 38% were unresolved; most required no intervention. Lorlatinib dose modification did not notably influence PFS., Conclusion: First-line lorlatinib improved PFS outcomes and reduced CNS progression versus crizotinib in patients with advanced ALK -positive non-small-cell lung cancer with or without brain metastases at baseline. Half of all CNS AEs resolved without intervention or with lorlatinib dose modification.

Anaplastic lymphoma kinase (ALK) inhibitors are commonly used for patients harboring ALK-positive non-small cell lung cancer (NSCLC). This meta-analysis was conducted to evaluate the toxicity profile of ALK inhibitors. Pubmed, Web of Science, Embase, and the Cochrane Central Register of Controlled Trials databases were systematically searched for clinical trials conducted in advanced NSCLC treated with ALK inhibitors. The incidences of pooled adverse events (AEs) were conducted using the random effects model. We included 30 studies in the meta-analysis. Almost all patients receiving ALK inhibitor monotherapy occurred at least one AE. The pooled incidences of grade ≥ 3 AEs were 71.3% for ceritinib 750 mg, 44.6% for crizotinib, 37.4% for alectinib, and 35.3% for ensartinib. Only one study each reported the incidence of grade ≥ 3 AEs for brgatinib (72.8%), lorlatinib (72.4%), and ceritinib 450 mg (64.8%), respectively. The rates of dose reduction due to AEs ranking from high to low were ceritinib 750 mg, brigatinib, ceritinib 450 mg, lorlatinib, crizotinib, ensartinib, and alectinib. The rates of treatment discontinuation due to AEs were low, ranging from 3.8% to 10.5%. Gastrointestinal AEs were most common for ceritinib 750 mg. Hepatic transaminases elevation was mostly observed in ceritinib and brigatinib. Rash frequently occurred for ensartinib. Lorlatinib had a high incidence of hypertriglyceridemia and hypercholesterolemia, which were rarely reported in other ALK inhibitors. The incidences of grade ≥ 3 AEs for individual ALK inhibitor were moderately high yet manageable. Different toxicity spectrums were found in each ALK inhibitor., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This retrospective observational study analyzed the clinical characteristics, treatment patterns and outcomes of 120 patients with advanced ALK-positive non-small-cell lung cancer (ALK+ NSCLC) according to data collected between November 2019 and October 2020 in 38 Spanish hospitals. Patients had progressed after 1-5 prior treatment lines (which included crizotinib in any prior line) and received subsequent therapy with alectinib in a local expanded access program. Median age was 58.7 years, 50% of patients were female, 64.1% had ECOG PS of 0-1, 85% presented stage IV, 95% had adenocarcinoma histology and 20.8% had brain metastases. After a median 9.6 months of alectinib treatment, objective response rate (ORR) was 54.5%, disease control rate (DCR) was 80%, median progression-free survival (PFS) was 9.4 months and median overall survival (OS) was 24.1 months. Patients with brain metastases achieved an intracranial DCR of 71.4%. Adverse events (AEs) were reported in 35.8% of patients (14.2% of AEs were grade ≥3). Over 40% of patients received some treatment after alectinib, most frequently lorlatinib (65.2%) and brigatinib (32.6%). This study provides information on real-world treatment patterns and confirms the tolerability and prolonged PFS and OS observed with alectinib in clinical trials, in unselected pretreated patients with advanced ALK+ NSCLC., Competing Interests: CONFLICTS OF INTEREST R. B.-C. reports advisory honoraria from Roche, Bristol-Myers Squibb, and AstraZeneca; speaker honoraria from Roche, Bristol-Myers Squibb, and Amgen; and grants from Roche. P. G. reports consultancy fees from Abbvie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Janssen, Lilly, Merck-Sharp-Dome, Medscape, Novartis, Pfizer, Roche, Takeda and Sanofi, and speaker honoraria from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Merck-Sharp-Dome, Novartis, Pfizer, Roche, and Takeda. R. G.-C. reports consultancy fees and speaker honoraria from Merck-Sharp-Dome, Bristol-Myers, Roche, Boehringer Ingelheim, Pfizer, Novartis, AstraZeneca, Lilly, Takeda, Bayer and Janssen. R. P. reports speaker honoraria from Guardant Health, Pfizer, Roche, Boehringer-Ingelheim, Eli-Lilly, Bristol-Myers Squibb, AstraZeneca, and Merck-Sharp-Dome; travel/meeting attendance expenses from Merck-Sharp-Dome and Roche, and membership of data safety monitoring from Boehringer-Ingelheim and Roche. A. A. reports consultancy fees from Roche, Takeda, AstraZeneca, and Bristol-Myers Squibb. C. B. reports consultancy fees from Boehringer-Ingelheim and AstraZeneca; speaker honoraria from Pfizer, Merk, Roche, Bristol-Myers Squibb, Takeda, Merck-Sharp-Dome, and Amgen; meeting and courses attendance expenses from Merck-Sharp-Dome, Roche, Merk, AstraZeneca and Boehringer-Ingelheim. D. R.-A. reports honoraria for lectures and consultancy fees from Bristol-Myers Squibb, MSD and Hoffmann-La Roche. M. L.-B. reports travel grants from Bristol-Myers Squibb, Roche, Pfizer, and Merck-Sharp-Dome; speaker honoraria, consulting fees and continuing medical education expenses from Roche, Bristol-Myers Squibb, Merck-Sharp-Dome, Pfizer, AstraZeneca, and Takeda. A. P. declares no conflicts of interests. D. V. reports speaker honoraria from Merck-Sharp-Dome, Pfizer, and AstraZeneca; and travel/accommodation expenses from Merck-Sharp-Dome, Pfizer, and AstraZeneca. J. M. S.-T. reports consultancy fees from AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Pfizer, Roche, and Takeda; and travel/accommodation expenses from Boehringer-Ingelheim, Merck-Sharp-Dome, and Roche. M. M. reports grants from Bristol-Myers Squibb, Roche, and AstraZeneca; personal fees from Bristol-Myers Squibb, AstraZeneca, Roche, Merck-Sharp-Dome, Boehringer-Ingelheim, Takeda, Sanofi-Aventis, Novartis, Vifor and Bayer. P. D. reports speaker honoraria and consultancy fees from Bristol-Myers Squibb, AstraZeneca, Boehringer-Ingelheim, Roche, Merck-Sharp-Dome, and Takeda; speaker honoraria from Pfizer and Amgen; institutional research grants from AstraZeneca and Mirati, and personal and institutional research grants from AstraZeneca and Roche. R. G. and M. G. are Roche Farma employees. J. d. C. reports educational fees from Astra Zeneca, Bristol-Myers Squibb, Merck-Sharp-Dome, and Roche; consultancy fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Janssen-Cilag, Lilly, Merck-Sharp-Dome, Novartis, Pfizer, Roche, and Takeda. All potential conflicts of interests were outside of the submitted work., (Copyright: © 2022 Bernabé-Caro et al.)

Background: Anaplastic lymphoma kinase (ALK)-rearranged nonsmall cell lung cancer (NSCLC) represents a molecular subgroup with high sensitivity to ALK inhibitors. Tyrosine kinase inhibitor crizotinib, an anticancer drug acting as an ALK inhibitor, has shown remarkable response in ALK-positive NSCLC. The aim of our study is to explore the adverse events (AEs) of patients on crizotinib therapy and analyze the predictability of AEs for better survival or response on NSCLC patients., Methods: The medical records of our ALK-positive metastatic NSCLC patients who applied between years 2013 and 2018 had been reviewed retrospectively. ALK positivity of all patients had been detected by fluorescence in situ hybridization and no other driver mutations were present. Patient demographics, performance status, smoking history, previous treatments, metastatic sites, and AEs were recorded for further analyses., Results: Thirty-six ALK-positive metastatic NSCLC patients were included in the study. Median follow-up was 30.1 months. Median progression-free survival (PFS) for patients who developed hepatic, cardiac, or endocrine toxicities was similar when compared to patients who did not develop. Although there was a numeric median PFS difference between patients who did develop visual disorders (18.4 months) and did not develop visual disorders (15.5 month), this was not regarded as statistically significant. However, median PFS of the patients who developed neutropenia upon crizotinib treatment (31.9 months) was found to be more favorable than the patients with normal neutrophil counts (12.8 months) (P = 0.026)., Conclusion: Neutropenia under crizotinib treatment was found to be associated with improved PFS suggesting that neutropenia might be an important determinant in treatment and survival strategies., Competing Interests: None

Crizotinib is a small-molecule, multitargeted tyrosine kinase inhibitor that exhibits decreased aqueous solubility at a higher pH. This open-label, randomized, phase 1 study (NCT01549574) evaluated the effect of multiple doses of the proton pump inhibitor esomeprazole on the pharmacokinetics (PK) of crizotinib and the safety of crizotinib with or without esomeprazole in healthy adults. Participants received a single 250-mg crizotinib dose after overnight fast or a single 250-mg crizotinib dose following esomeprazole 40 mg/day for 5 days. After a washout of ≥14 days, participants crossed over to the alternate treatment. Blood samples for plasma analysis were taken up to 144 hours after crizotinib dosing and relevant PK parameters estimated. Safety was assessed in all participants receiving ≥1 dose of study medication. Fifteen participants were evaluable for PK and safety for each treatment. Coadministration with esomeprazole resulted in a slight decrease (≈10%) in the crizotinib geometric mean area under the plasma concentration-time profile from time 0 to infinity (adjusted geometric mean ratio, 89.81% [90% confidence interval, 79.05-102.03]). Coadministration of esomeprazole did not affect peak crizotinib exposure. Adverse events (AEs) occurred in similar numbers between treatments; no serious or severe AEs occurred. The most common AE was diarrhea. Although esomeprazole decreased total exposure of crizotinib, it is not considered clinically meaningful, and dose modification is not required when crizotinib is coadministered with agents that affect gastric pH., (© 2021 Pfizer Inc. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Importance: Ensartinib, an oral tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK), has shown systemic and central nervous system efficacy for patients with ALK-positive non-small cell lung cancer (NSCLC)., Objective: To compare ensartinib with crizotinib among patients with advanced ALK-positive NSCLC who had not received prior treatment with an ALK inhibitor., Design, Setting, and Participants: This open-label, multicenter, randomized, phase 3 trial conducted in 120 centers in 21 countries enrolled 290 patients between July 25, 2016, and November 12, 2018. Eligible patients were 18 years of age or older and had advanced, recurrent, or metastatic ALK-positive NSCLC., Interventions: Patients were randomized (1:1) to ensartinib, 225 mg once daily, or crizotinib, 250 mg twice daily., Main Outcomes and Measures: The primary end point was blinded independent review committee-assessed progression-free survival (PFS). Secondary end points included systemic and intracranial response, time to central nervous system progression, and overall survival. Efficacy was evaluated in the intent-to-treat (ITT) population as well as a prespecified modified ITT (mITT) population consisting of patients with central laboratory-confirmed ALK-positive NSCLC., Results: A total of 290 patients (149 men [51.4%]; median age, 54 years [range, 25-90 years]) were randomized. In the ITT population, the median PFS was significantly longer with ensartinib than with crizotinib (25.8 [range, 0.03-44.0 months] vs 12.7 months [range, 0.03-38.6 months]; hazard ratio, 0.51 [95% CI, 0.35-0.72]; log-rank P < .001), with a median follow-up of 23.8 months (range, 0-44 months) for the ensartinib group and 20.2 months (range, 0-38 months) for the crizotinib group. In the mITT population, the median PFS in the ensartinib group was not reached, and the median PFS in the crizotinib group was 12.7 months (95% CI, 8.9-16.6 months; hazard ratio, 0.45; 95% CI, 0.30-0.66; log-rank P < .001). The intracranial response rate confirmed by a blinded independent review committee was 63.6% (7 of 11) with ensartinib vs 21.1% (4 of 19) with crizotinib for patients with target brain metastases at baseline. Progression-free survival for patients without brain metastases was not reached with ensartinib vs 16.6 months with crizotinib as a result of a lower central nervous system progression rate (at 12 months: 4.2% with ensartinib vs 23.9% with crizotinib; cause-specific hazard ratio, 0.32; 95% CI, 0.16-0.63; P = .001). Frequencies of treatment-related serious adverse events (ensartinib: 11 [7.7%] vs crizotinib: 9 [6.1%]), dose reductions (ensartinib: 34 of 143 [23.8%] vs crizotinib: 29 of 146 [19.9%]), or drug discontinuations (ensartinib: 13 of 143 [9.1%] vs crizotinib: 10 of 146 [6.8%]) were similar, without any new safety signals., Conclusions and Relevance: In this randomized clinical trial, ensartinib showed superior efficacy to crizotinib in both systemic and intracranial disease. Ensartinib represents a new first-line option for patients with ALK-positive NSCLC., Trial Registration: ClinicalTrials.gov Identifier: NCT02767804.

Purpose: European Organisation for Research and Treatment of Cancer (EORTC) 90101 (CREATE) was a prospective, multicentric, non-randomised, open-label phase II basket trial to assess the efficacy and safety of crizotinib in patients with different types of cancers, including advanced inflammatory myofibroblastic tumour (IMT) with or without anaplastic lymphoma kinase (ALK) rearrangements. Here, we report updated results with long-term follow-up., Patients/methods: After central reference pathology, eligible ALK-positive and ALK-negative patients with advanced/metastatic IMT deemed incurable with surgery, radiotherapy or systemic therapy received oral crizotinib 250 mg twice daily. The ALK status was assessed centrally using immunohistochemistry and fluorescence in situ hybridisation. The primary end-point was the proportion of patients who achieved an objective response (i.e. complete or partial response). If ≥6 ALK-positive patients achieved a confirmed response, the trial would be deemed successful., Results: At data cut-off on 28th January 2021, we performed the final analysis of this trial. Of the 20 eligible and treated patients (19 of whom were evaluable for efficacy), with a median follow-up of 50 months, five were still on crizotinib treatment (4/12 ALK-positive and 1/8 ALK-negative patients). The updated objective response rate (ORR) was 66.7% (95% confidence interval [CI] 34.9-90.1%) in ALK-positive patients and 14.3% (95% CI 0.0-57.9%) in ALK-negative patients. In the ALK-positive and ALK-negative patients, the median progression-free survival was 18.0 months (95% CI 4.0-NE) and 14.3 months (95% CI 1.2-31.1), respectively; 3-year overall survival rates were 83.3% (95% CI 48.2-95.6) and 34.3% (95% CI 4.8-68.5). Safety results were consistent with previously reported data., Conclusion: These updated results confirm previous findings that crizotinib is effective, with durable responses, in patients with locally advanced or metastatic ALK-positive IMT. With further follow-up after the original primary analysis, the ORR increased, as patients derived long-term benefit and some responses converted from stable disease to partial responses., Clinical Trial Number: EORTC 90101, NCT01524926., Competing Interests: Conflict of interest statement P.S. reports no competing interest related to crizotinib, Pfizer or EORTC, received research support to the institution outside of the scope of this study and reports an advisory or consulting role outside of the scope of this study. M.K., T.S. and A.W. report no competing interest. J-Y.B. reports research support and honoraria from Pfizer outside the scope of this study. S.J.S. received honoraria from Lilly for educational activities. Si.S. reports no competing interest, research support, honoraria and advisory or consulting role outside the scope of this study. P.R. received honoraria from Pfizer outside the scope of this study. V.B., M.G.L., A.I., N.I., M.D-R., R.S., F.S., Ax.N. and An.N. report no competing interest. B.K. reports no competing interest related to crizotinib, Pfizer or EORTC, received research support to the institution outside of the scope of this study and reports an advisory or consulting role outside of the scope of this study., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Rationale: Besides the T790 M mutation, it may coexist with bypass pathway activation in real clinical cases for patients with EGFR mutations who resisted to the first- and second-generation tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). There are limited clinical trial data describing the efficacy of osimertinib combined with MET inhibition in EGFR T790M-mutant NSCLC patients with Met amplification., Patient Concerns: A non-smoking 53-year-old male patient with lung adenocarcinoma underwent gefitinib, afatinib, and osimertinib combined with crizotinib treatment and developed different EGFR resistance mutations., Diagnoses: The patient was diagnosed with lung adenocarcinoma (stage cT4N2M0, IIIB). After resistance to the therapy targeting EGFR exon 21 L858R point mutation, T790 M mutation was detected in liquid biopsy and Met amplification was detected via tissue biopsy by next-generation sequencing (NGS)., Interventions: The patient received systemic treatments, including chemotherapy, gefitinib, afatinib, and osimertinib combined with crizotinib., Outcomes: The patient died of multisystem organ failure and had an overall survival of 24 months., Lessons: Although osimertinib combined with crizotinib therapy showed dramatic tumor shrinkage in both the primary tumor and bone metastasis to an EGFR T790M-mutant NSCLC patient with MET amplification, the progression-free survival (PFS) was only two months., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: We examined safety outcomes of interest (SOI) and overall survival (OS) among lung cancer patients initiating crizotinib and erlotinib in routine clinical practice., Methods: This descriptive cohort study used routinely collected health data in Denmark, Finland, Sweden, the Netherlands, and the United States (US) during 2011-2017, following crizotinib commercial availability in each country. Among crizotinib or erlotinib initiators, we reported baseline characteristics and incidence rates and cumulative incidences of the SOI - hepatotoxicity, pneumonitis/interstitial lung disease, QT interval prolongation-related events, bradycardia, vision disorders, renal cysts, edema, leukopenia, neuropathy, photosensitivity, malignant melanoma, gastrointestinal perforation, cardiac failure and OS. Results from the European Union (EU) countries were combined using meta-analysis; results from the US were reported separately., Results: There were 456 patients in the crizotinib cohort and 2957 patients in the erlotinib cohort. Rates of the SOI per 1000 person-years in the crizotinib cohort ranged from 0 to 65 in the EU and from 0 to 374 in the US. Rates of the SOI per 1000 person-years in the erlotinib cohort ranged from 0 to 91 in the EU and from 3 to 394 in the US. In the crizotinib cohort, 2-year OS was ~50% in both EU and US. In the erlotinib cohort, 2-year OS was 21% in the EU and 35% in the US., Conclusions: This study describes clinical outcomes among lung cancer patients initiating crizotinib or erlotinib in routine clinical practice. Differences between SOI rates in EU and US may be partially attributable to differences in the underlying databases., (© 2021 John Wiley & Sons Ltd.)

Crizotinib is the first-line drug for non-small cell lung cancer (NSCLC) patients who display anaplastic lymphoma kinase (ALK) rearrangement. With 60% overall response rate, crizotinib significantly prolongs median progression-free survival (ranged 8-10 months) of ALK rearrangement NSCLC patients. However, there are some adverse events from crizotinib, including diarrhea, weakness and nausea. Here, we describe a 47 years old woman with ALK-rearranged NSCLC who developed interstitial pneumonia (IP) induced by crizotinib. A female patient was diagnosed as the left lower lobe adenocarcinoma stage IV (T4N2M1, pleural metastasis) via lung biopsy and was detected wild-type EGFR and 18% ALK gene rearrangement from paraffin section. However, after going through 7 cycles of chemotherapy, she rejected chemotherapy because side effect and still experienced progression of the disease. Subsequently, crizotinib was prescribed as a targeted therapy. After 32 days, visible reduction in size was observed on the pulmonary mass and metastases found in brain and liver, but the patient presented drug-induced level 4 interstitial pneumonia. In a nutshell, the curative effect of crizotinib is worthy of note, but clinicians should also weigh the advantages and disadvantages, prior its usage.

Background: Crizotinib is the approved treatment for advanced non-small cell lung cancers (NSCLCs) of anaplastic lymphoma kinase (ALK) fusion. Failure of crizotinib treatment frequently involves drug intolerance or resistance. Comparison of using second-generation ALK inhibitors in this setting remains lacking., Methods: Sixty-five ALK-positive advanced NSCLC patients receiving second-generation ALK inhibitors following treatment failure of crizotinib were retrospectively analyzed for the therapeutic efficacy., Results: Forty-three (66.2%) and 22 (33.8%) patients received alectinib and ceritinib, respectively. Comparing alectinib to ceritinib treatment: the 12-month progression-free survival (PFS) rate (61.0% [95% confidence interval, 47.1 to 78.9%] vs. 54.5% [95% CI, 37.3 to 79.9%]); the hazard ratio (HR) for disease progression or death, 0.61 (95% CI, 0.31-1.17; p = 0.135). Multivariate Cox regression showed ECOG PS (0-1 vs. 2-3 HR 0.09 [95% CI, 0.02-0.33]; p < 0.001) and cause of crizotinib treatment failure (resistance vs. intolerance HR 2.75 [95% CI, 1.26-5.99]; p = 0.011) were the independent predictors for the PFS of second-generation ALK inhibitors. Treatment of alectinib, compared to ceritinib, was associated with a lower incidence of CNS progression (cause-specific HR, 0.10; 95% CI 0.01-0.78; p = 0.029) and a higher efficacy in patients whose cause of crizotinib treatment failure was intolerance (HR 0.29 [95% CI, 0.08-1.06]; p = 0.050). The most commonly noted adverse events were elevated AST/ALT in 10 (23.3%) patients treated with alectinib and diarrhea in 8 (36.4%) patients treated with ceritinib., Conclusion: Second-generation ALK inhibitors in crizotinib-treated patients showed a satifactory efficacy. Alectinib treatment demonstrated a CNS protection activity and a higher PFS in selected patients failing crizotinib treatment.

Background: Crizotinib is a first-generation tyrosine kinase inhibitor used for anaplastic lymphoma kinase (ALK) positive cancers. Simple and complex renal cyst formation is a rare complication of crizotinib use that has been reported previously in the adult population., Case: We report a case of a right renal mass in a 17-year-old with ALK-positive epithelioid inflammatory myofibroblastic sarcoma treated with Crizotinib. After cessation of Crizotinib and initiating Alectenib, a second generation ALK inhibitor, the mass decreased in size and the patient remained asymptomatic without evidence of recurrence at three months of follow-up., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The data of sequential therapy of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) in clinical practice have been limited., Methods: We reviewed the clinical data of patients with ALK-rearranged non-small cell lung cancer who received crizotinib (CRZ) or alectinib (ALEC) between May 2012 and December 2016. Patients were divided into two groups based on the first-administered ALK-TKI, the CRZ or ALEC group. The combined time-to-treatment failure (TTF) was defined as the sum of the 'TTF of CRZ' plus the 'TTF of ALEC' if patients were treated with CRZ followed by ALEC in the CRZ group. The primary end-point is the comparison between the combined TTF and the TTF of ALEC in the ALEC group., Results: Of 864 patients enrolled from 61 institutions, 840 patients were analysed. There were 535 of 305 patients in the CRZ/ALEC groups. The combined TTF in the CRZ group was significantly longer than TTF in the ALEC group (median, 34.4 versus 27.2 months; hazard ratio [HR], 0.709; P = 0.0044). However, there was no significant difference in overall survival (OS) between the patients who received ALEC after CRZ in the CRZ group and the patients in the ALEC group (median, 88.4 months versus. not reached; HR, 1.048; P = 0.7770). In the whole population, the CRZ group had a significantly shorter OS than the ALEC group (median, 53.6 months versus not reached; HR, 1.821, P < 0.0001)., Conclusion: The combined TTF in the CRZ group was significantly longer than the TTF in the ALEC group; however, OS benefit of sequential therapy against ALEC as the first ALK-TKI was not shown., Competing Interests: Conflict of interest statement K.I. reported receiving personal fees from Boehringer Ingelheim, AstraZeneca, Pfizer, Eli Lilly, Chugai Pharmaceutical, Merck Sharp & Dohme (MSD), Ono Pharmaceutical and Taiho Pharmaceutical. T.Y. reported receiving grants from Takeda Pharmaceutical, Chugai Pharmaceutical, Boehringer Ingelheim, Taiho Pharmaceutical, Daiichi Sankyo, Ono Pharmaceutical, Bayer, Astellas and Eli Lilly and receiving personal fees from Takeda Pharmaceutical, Chugai Pharmaceutical, Boehringer Ingelheim, Taiho Pharmaceutical, Daiichi Sankyo, Bayer, Merck Serono, Pfizer, Huya Bioscience, Gilead Sciences and EP-CRSU. H.H. reported receiving grants from MSD, A2 Healthcare Corp., inVentiv Health Japan, Astellas, Daiichi Sankyo, Novartis, AbbVie, Quintiles/IQVIA Services, ICON Japan, Chugai Pharmaceutical, Takeda Pharmaceutical, EP-CRSU CO., GRITSTONE ONCOLOGY, Linical Co., Eli Lilly, Eisai Co., Bristol Myers Squibb company, Boehringer Ingelheim, Taiho Pharmaceutical, Pfizer, PAREXEL International Corp., SymBio Pharmaceuticals Limited, Ono Pharmaceutical, Merck Serono Co./Merck Biopharma, AstraZeneca, CMIC Shift Zero, Kissei Pharmaceutical, Kyowa Hakko Kirin, EPS Corporation, Bayer Yakuhin, Syneos Health, EPS International, Pfizer R&D Japan G.K and Otsuka Pharmaceutical and receiving personal fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Kyorin Pharmaceutical, MSD, Ono Pharmaceutical, Novartis, Pfizer, Shanghai Haihe Biopharm and Taiho Pharmaceutical. Y.H. reported receiving grants from Janssen Pharmaceutical, MSD and Ono Pharmaceutical and receiving personal fees from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, Eli Lilly, MSD, Novartis, Ono Pharmaceutical and Taiho Pharmaceutical. K.N. reported receiving grants from Boehringer Ingelheim and receiving personal fees from Chugai Pharmaceutical, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novartis, Pfizer, Ono Pharmaceutical and Roche Diagnostics. H.K. reported receiving personal fees from Eli Lilly and Taiho Pharmaceutical. Y.O. reported no relevant conflicts of interests. T.Y. reported receiving personal fees from Boehringer Ingelheim, AstraZeneca, Taiho Pharmaceutical, Ono Pharmaceutical, Eli Lilly, Bristol Myers Squibb, Chugai Pharmaceutical, Novartis, Pfizer and MSD. T.S. reported receiving grants from AstraZeneca, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, MSD, Boehringer Ingelheim, Novartis, Pfizer, Takeda Pharmaceutical, AbbVie, Bayer Yakuhin, Kissei Pharmaceutical, LOXO Oncology and Merck Serono and receiving personal fees from AstraZeneca, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, MSD, Boehringer Ingelheim, Novartis, Pfizer, Takeda Pharmaceutical, Astellas, Bristol Myers Squibb, Kyowa Hakko Kirin, Ono Pharmaceutical, Taiho Pharmaceutical, Thermo Fisher Scientific and Precision Medicine Asia Co. Ltd. K.A. reported receiving personal fees from Chugai Pharmaceutical, AstraZeneca, MSD, Bristol Myers Squibb and Ono Pharmaceutical. T.F. reported receiving personal fees from AstraZeneca, Boehringer Ingelheim, Chugai Pharmaceutical, MSD, Novartis, Ono Pharmaceutical, Pfizer and Taiho Pharmaceutical. T.K. reported receiving grants from Chugai Pharmaceutical, AstraZeneca, Eli Lilly, Taiho Pharmaceutical, Bristol Meyers Squibb and Merck Biopharma and receiving personal fees from Chugai Pharmaceutical, AstraZeneca, Eli Lilly, Taiho Pharmaceutical, Bristol Meyers Squibb, Ono Pharmaceutical, MSD, Pfizer, Kyowa Hakko Kirin, Boehringer Ingelheim, Nippon Kayaku and Novartis. A.N. reported receiving personal fees from MSD, Chugai Pharmaceutical, AstraZeneca, Eli Lilly, Taiho Pharmaceutical, Boehringer Ingelheim and Kyowa Kirin. K.T. reported receiving grants from Boehringer Ingelheim, Chugai Pharmaceutical and Ono Pharmaceutical and receiving personal fees from Eli Lilly, Boehringer Ingelheim, Chugai Pharmaceutical, Ono Pharmaceutical, Taiho Pharmaceutical, AbbVie, Pfizer, SRL, MSD, Novartis and Kyowa Kirin. K.H. reported receiving personal fees from AstraZeneca, Eli Lilly, Boehringer Ingelheim, Ono Pharmaceutical, Chugai Pharmaceutical, Pfizer and Taiho Pharmaceutical. T.Y. reported receiving grants from Ono Pharmaceutical and receiving personal fees from AstraZeneca, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol Myers Squibb, MSD and Boehringer Ingelheim. H.D. reported receiving grants from Chugai Pharmaceutical, Pfizer and Eli Lilly and receiving personal fees from Chugai Pharmaceutical and Boehringer Ingelheim. S.S. reported no relevant conflicts of interests. D.F. reported receiving grants from AstraZeneca and Chugai Pharmaceutical and receiving personal fees from AstraZeneca, Ono Pharmaceutical, Bristol Myers Squibb, Taiho Pharmaceutical, Chugai Pharmaceutical, MSD, Boehringer Ingelheim, Eli Lilly and Novartis. M.M. reported receiving personal fees from AstraZeneca, MSD, Ono Pharmaceutical, Eli Lilly, Boehringer Ingelheim, Chugai Pharmaceutical, Shionogi, Taiho Pharmaceutical and Novartis. K.M. reported receiving grants from Boehringer Ingelheim and Eli Lilly and receiving personal fees from Chugai Pharmaceutical and Novartis. T.A. reported no relevant conflicts of interests. A.T. reported no relevant conflicts of interests. S.M. reported receiving personal fees from Chugai Pharmaceutical, Boehringer Ingelheim, MSD, Eli Lilly, AstraZeneca, Ono Pharmaceutical, Taiho Pharmaceutical, Novartis, Bristol Myers Squibb and Kyowa Hakko Kirin. S.W. reported receiving grants from Boehringer Ingelheim and receiving personal fees from Eli Lilly, Pfizer, Novartis Pharma, AstraZeneca, Chugai Pharma, Bristol Meyers Squibb, Boehringer Ingelheim, MSD, Ono Pharmaceutical, Daiichi Sankyo and Taiho Pharmaceutical. H.A. reported receiving grants from Chugai Pharmaceutical and receiving personal fees from Chugai Pharmaceutical, Pfizer and Novartis. O.H. reported receiving grants from GlaxoSmithKline, AstraZeneca, Novartis, Kyorin, Bayer Yakuhin, Boehringer Ingelheim and Daiichi Sankyo and receiving personal fees from GlaxoSmithKline, AstraZeneca, Novartis, Bayer Yakuhin and Boehringer Ingelheim. K.S. reported no relevant conflict of interests. S.H. reported no relevant conflict of interests. K.A. reported no relevant conflict of interests. A.B. reported receiving personal fees from Chugai Pharmaceutical, Pfizer and Novartis. A.K. reported receiving grants from the Japan Society for the Promotion of Science, Boehringer Ingelheim, Chugai Pharmaceutical, Lilly and Ono Pharmaceutical and receiving personal fees from Boehringer Ingelheim, Chugai Pharmaceutical, Lilly, Ono Pharmaceutical, Novartis, Taiho Pharmaceutical and Pfizer. M.O. reported no relevant conflict of interests. K.N. reported receiving grants from MSD, A2 Healthcare Corp., inVentiv Health Japan, Astellas, Daiichi Sankyo, Novartis, AbbVie, Quintiles/IQVIA Services, ICON Japan, Chugai Pharmaceutical, Takeda Pharmaceutical, EP-CRSU CO., GRITSTONE ONCOLOGY, Linical Co., Eli Lilly, Eisai Co., Bristol Myers Squibb company, Boehringer Ingelheim, Taiho Pharmaceutical, Pfizer, PAREXEL International Corp., SymBio Pharmaceuticals Limited, Ono Pharmaceutical, Merck Serono Co./Merck Biopharma, AstraZeneca, CMIC Shift Zero, Kissei Pharmaceutical, Kyowa Hakko Kirin, EPS Corporation, Bayer Yakuhin, Syneos Health, EPS International, Pfizer R&D Japan G.K and Otsuka Pharmaceutical; receiving personal fees from AstraZeneca, Nichi-Iko Pharmaceutical, Astellas, Takeda Pharmaceutical, MSD, Taiho Pharmaceutical, Ono Pharmaceutical, Bristol Myers Squibb company, Boehringer Ingelheim, Eli Lilly, Novartis, SymBio Pharmaceuticals Limited, Pfizer, Chugai Pharmaceutical, Clinical Trials Co., NANZANDO Co., MEDICUS SHUPPAN, Publishers Co., YODOSHA CO., Care Net, Nikkei Business Publications, Reno. Medical, Daiichi Sankyo, KYORIN Pharmaceutical, Thermo Fisher Scientific, Medical Review Co., YOMIURI TELECASTING CORPORATION, Roche Diagnostics, Nippon Kayaku Co., Bayer Yakuhin, Merck Biopharma Co., Medical Mobile Communications Co., AbbVie and 3H Clinical Trial Inc. and receiving consulting and advisor fees from Takeda Pharmaceutical, KYORIN Pharmaceutical, Ono Pharmaceutical, Pfizer and Eli Lilly. N.Y. reported receiving grants from Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Boehringer Ingelheim, Daiichi Sankyo, Ono Pharmaceutical, Astellas, MSD, Pfizer, Takeda, AstraZeneca, Terumo and Toppan and receiving personal fees from Chugai Pharmaceutical, Eli Lilly, MSD, AstraZeneca, Ono Pharmaceutical, Novartis, Pfizer and Boehringer Ingelheim., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: Crizotinib is the first-line small molecule tyrosine kinase inhibitor for ALK-positive non-small cell lung cancer. In this study, a retrospective pharmacogenomics investigation was conducted to explore the relationship between genes related to RTK downstream signaling pathways and crizotinib-induced hepatic toxicity in ALK-positive NSCLC patients., Methods: The variable importance analysis of random forest algorithm was applied to identify the significant features which contribute to the crizotinib sensitivity in Cancer Cell Line Encyclopedia (CCLE) database. The KEGG and reactome pathway enrichment analysis were conducted with EnrichR. The differential expression genes were identified with R package DESeq2 in CCLE liver derived cell lines between crizotinib sensitive and resistant groups. From 2012 to 2015, 42 NSCLC patients were enrolled in this study. 90 polymorphisms were genotyped using the Sequenom Massarray system. Sequencing of HGFR (c-Met) genes was carried out on the Ion Torrent Proton., Results: In total, 66.7% NSCLC patients suffered from crizotinib-induced liver toxicity and 11.9% progressed to severe hepatic toxicity. The features with the top importance from classification and regression random forest model were enriched in RTK downstream signaling pathways (JAK/STAT, RAS/RAF/MAPK, PI3K/AKT pathways) and immune system-related pathways. Collagen family genes (COL1A1, COL1A2, COL6A1, COL5A1) and other extracellular matrix protein (TNC, TAGLN, TENM2, EDIL3, VCAN, CNN1, SH3BP4, TAGLN), which were closely related to MAPK-ERK signaling pathways, were significantly enriched in crizotinib resistant cell lines. In multiple logistic regression, STAT1 rs10208033 (T > C) was significantly associated with crizotinib-induced liver toxicity (OR = 6.733, 95% CI 1.406-32.24, P = 0.017). Compared with non-CC, OR is 5.5 (95% CI 1.219-24.81, P = 0.027) for STAT1 rs10208033 CC genotype to develop crizotinib-induced liver toxicity. Further cell viability test in human fetal hepatocyte line, L-02, reveals that the STAT1 inhibitor might protect hepatocyte cells from the toxicity caused by crizotinib., Conclusion: Polymorphism of rs10208033 is a potential biomarker for predicting crizotinib-induced hepatotoxicity. These results suggest that STAT1 plays an important role in crizotinib-induced hepatotoxicity. Further studies are needed to confirm our finding and understand the underlying mechanisms.

Background: MET (also known as hepatocyte growth factor receptor) signalling is a key driver of papillary renal cell carcinoma (PRCC). Given that no optimal therapy for metastatic PRCC exists, we aimed to compare an existing standard of care, sunitinib, with the MET kinase inhibitors cabozantinib, crizotinib, and savolitinib for treatment of patients with PRCC., Methods: We did a randomised, open-label, phase 2 trial done in 65 centres in the USA and Canada. Eligible patients were aged 18 years or older with metastatic PRCC who had received up to one previous therapy (excluding vascular endothelial growth factor-directed and MET-directed agents). Patients were randomly assigned to receive sunitinib, cabozantinib, crizotinib, or savolitinib, with stratification by receipt of previous therapy and PRCC subtype. All drug doses were administered orally: sunitinib 50 mg, 4 weeks on and 2 weeks off (dose reductions to 37·5 mg and 25 mg allowed); cabozantinib 60 mg daily (reductions to 40 mg and 20 mg allowed); crizotinib 250 mg twice daily (reductions to 200 mg twice daily and 250 mg once daily allowed); and savolitinib 600 mg daily (reductions to 400 mg and 200 mg allowed). Progression-free survival (PFS) was the primary endpoint. Analyses were done in an intention-to-treat population, with patients who did not receive protocol therapy excluded from safety analyses. This trial is registered with ClinicalTrials.gov, NCT02761057., Findings: Between April 5, 2016, and Dec 15, 2019, 152 patients were randomly assigned to one of four study groups. Five patients were identified as ineligible post-randomisation and were excluded from these analyses, resulting in 147 eligible patients. Assignment to the savolitinib (29 patients) and crizotinib (28 patients) groups was halted after a prespecified futility analysis; planned accrual was completed for both sunitinib (46 patients) and cabozantinib (44 patients) groups. PFS was longer in patients in the cabozantinib group (median 9·0 months, 95% CI 6-12) than in the sunitinib group (5·6 months, 3-7; hazard ratio for progression or death 0·60, 0·37-0·97, one-sided p=0·019). Response rate for cabozantinib was 23% versus 4% for sunitinib (two-sided p=0·010). Savolitinib and crizotinib did not improve PFS compared with sunitinib. Grade 3 or 4 adverse events occurred in 31 (69%) of 45 patients receiving sunitinib, 32 (74%) of 43 receiving cabozantinib, ten (37%) of 27 receiving crizotinib, and 11 (39%) of 28 receiving savolitinib; one grade 5 thromboembolic event was recorded in the cabozantinib group., Interpretation: Cabozantinib treatment resulted in significantly longer PFS compared with sunitinib in patients with metastatic PRCC., Funding: National Institutes of Health and National Cancer Institute., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: BRAF inhibitors are effective in melanoma and other cancers with BRAF mutations; however, patients ultimately develop therapeutic resistance through the activation of alternative signaling pathways such as RAF/RAS or MET. The authors hypothesized that combining the BRAF inhibitor vemurafenib with either the multikinase inhibitor sorafenib or the MET inhibitor crizotinib could overcome therapeutic resistance., Methods: Patients with advanced cancers and BRAF mutations were enrolled in a dose-escalation study (3 + 3 design) to determine the maximum tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of vemurafenib with sorafenib (VS) or vemurafenib with crizotinib (VC)., Results: In total, 38 patients (VS, n = 24; VC, n = 14) were enrolled, and melanoma was the most represented tumor type (VS, 38%; VC, 64%). In the VS arm, vemurafenib 720 mg twice daily and sorafenib 400 mg am/200 mg pm were identified as the MTDs, DLTs included grade 3 rash (n = 2) and grade 3 hypertension, and partial responses were reported in 5 patients (21%), including 2 with ovarian cancer who had received previous treatment with BRAF, MEK, or ERK inhibitors. In the VC arm, vemurafenib 720 mg twice daily and crizotinib 250 mg daily were identified as the MTDs, DLTs included grade 3 rash (n = 2), and partial responses were reported in 4 patients (29%; melanoma, n = 3; lung adenocarcinoma, n = 1) who had received previous treatment with BRAF, MEK, and/or ERK inhibitors. Optional longitudinal collection of plasma to assess dynamic changes in circulating tumor DNA demonstrated the elimination of BRAF-mutant DNA from plasma during therapy (P = .005)., Conclusions: Vemurafenib combined with sorafenib or crizotinib was well tolerated with encouraging activity, including among patients who previously received treatment with BRAF, MEK, or ERK inhibitors., (© 2020 American Cancer Society.)

Background: Besides the clinical benefit of crizotinib in ALK-rearranged metastatic non-small cell lung cancer (NSCLC), concerns about its hepatotoxicity have arisen. It is not clear whether this is a drug class side effect or if the use of other selective ALKs inhibitors is safe after this serious adverse event. While evidence from clinical trials is scarce, reports of treatment after crizotinib-induces hepatitis may add to clinical decision., Case Presentation: Herein, we report a case of acute hepatitis induced by crizotinib in a 32-years-old female diagnosed with metastatic NSCLC, harboring the ALK-rearrangement. After 60 days of crizotinib therapy, the patient presented with acute hepatitis, diagnosed after investigation of non-specific symptoms, such as nausea and fatigue. Serum aspartate aminotransferase and alanine aminotransferase levels had increased from baseline to 3010 IU/L and 9145 IU/L, respectively. Total bilirubin increased up to 7.91 mg/dL, but she did not develop liver failure. After crizotinib discontinuation, a gradual hepatic function recovery occurred. Unfortunately, during the period without specific oncology treatment, her disease showed an unequivocal progression. Therefore, she started on alectinib with great response, and no liver function alteration recurred., Conclusions: This case suggests that alectinib, even belonging to the same drug class, could be used as an alternative agent when crizotinib is the etiology of liver damage, but more robust evidence has awaited.

The oral small-molecule tyrosine kinase inhibitor (TKI), crizotinib has been approved as a first-generation anaplastic lymphoma kinase (ALK) inhibitor in treatment of advanced ALK-positive non-small cell lung cancer (NSCLC). Recently, development of complex renal cysts has been reported with crizotinib usage, highlighting the importance of accurate differentiation between complex renal cysts and new metastasis in NSCLC. Here we describe a case study with confirmed EGFR wild-type and ALK-rearranged lung adenocarcinoma who developed complex renal cysts combined with hemorrhage during crizotinib treatment, with no abnormal clinical symptoms or kidney functions observed. Interestingly, without crizotinib treatment termination or reduction, the complex hemorrhagic renal cysts regressed with self-limiting and healing. The combined usage of ultrasound, CT and MRI techniques in the presented case allowed proper monitoring of the internal changes within complex renal cysts. The patient provided written informed consent authorizing publication of clinical case. Thus, better understanding of the imaging features of crizotinib-related renal cysts combined with hemorrhage would avoid misdiagnoses as a new metastatic renal mass or the aggravation of the primary disease, therefore avoiding further invasive investigation., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Crizotinib, a targeted molecular therapy drug which inhibits tyrosine kinase, is approved for treatment of non-small cell lung carcinoma which has some ocular side effects like photopsia and delayed dark adaptation.This report documents a unique case of persistent conjunctival chemosis likely due to side effects of crizotinib therapy. A 64-year-old gentleman on crizotinib for metastatic adenocarcinoma of the lung presented with conjunctival chemosis in right eye which appeared 1 month after uneventful clear corneal phacoemulsification surgery. The patient was on crizotinib 250 mg twice a day started 2 months before cataract surgery. Clinical examination revealed marked inferior bulbar conjunctival edema of the right eye. Anterior segment optical coherence tomography, slit-lamp photographs, and magnetic resonance imaging orbit and systemic investigation were done to rule out other causes of conjunctival edema. Magnetic resonance imaging shows conjunctival and preseptal edema around both eye and thinning of the optic nerve in the right eye. Anterior segment optical coherence tomography revealed elevated hyper-reflective thickened conjunctival layer with dilated empty thin wall dark spaces of varying caliber. Chemosis was persisted for the next 3 months and not responded to oral acetazolamide, topical steroid and decongestive eyedrops. After 3 months, crizotinib was discontinued by oncologist due to drug intolerance and surprisingly within 1 week, the conjunctival edema was disappeared totally. To the best of the authors' knowledge, this is the first reported case of persistent unilateral non-inflammatory conjunctival chemosis caused by crizotinib. The physicians should be vigilant about these complications., Competing Interests: The authors have no financial or conflicts of interest to disclose., (Copyright © 2020 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.)

We present here a case of ALK-positive lung adenocarcinoma that has been started on Alectinib. Treatment has been initiated at the recommended initial dose, but it subsequently required a dose adjustment following adverse drug events. Alectinib is a second-generation, CNS-active, tyrosine kinase inhibitor used in the treatment of ALK-positive non-small cell lung cancer. Its efficacy as a first-line treatment and as a second-line agent after Crizotinib has been proven across several trials both in terms of overall response rate and progression-free survival. The use of Alectinib is associated with side effects that occasionally lead to treatment discontinuation, interruption, or dose adjustment. Several studies have used two starting doses - 300 mg and 600 mg twice daily - across different populations and have consistently shown efficacy of Alectinib for both treatment doses. Results of these studies have also revealed that body weight, rather than race, affect the pharmacokinetics of Alectinib. Randomized trials have shown that the 600 mg dose is associated with more grade ≥3 adverse events and more changes in treatment in contrast to the 300 mg dose. A lower dose of Alectinib may limit treatment disruptions and dose reductions particularly for specific patient populations-particularly those with a lower body weight., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Brigatinib is a kinase inhibitor indicated for patients with advanced anaplastic lymphoma kinase-positive non-small cell lung cancer who progressed on or are intolerant to crizotinib. Approval was based on results from a randomized, dose-ranging phase II study (ALK in Lung Cancer Trial of AP26113 (ALTA)). Despite an apparent dose-response relationship for efficacy in ALTA, an exposure-response relationship was not discernable using static models driven by time-averaged exposure. However, exposure-response modeling using daily time-varying area under the concentration curve as the predictor in time-to-event models predicted that increasing the dose of brigatinib (range, 30 mg once daily (q.d.) to 240 mg q.d.) would result in clinically meaningful improvements in progression-free survival (PFS), intracranial PFS, and overall survival. Grade ≥ 2 rash and amylase elevation were predicted to significantly increase with brigatinib exposure. These results provided support for a favorable benefit-risk profile with the approved dosing regimen (180 mg q.d. with 7-day lead-in at 90 mg) versus 90 mg q.d., (© 2020 Takeda Pharmaceuticals. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Background: Lorlatinib, a third-generation inhibitor of anaplastic lymphoma kinase (ALK), has antitumor activity in previously treated patients with ALK -positive non-small-cell lung cancer (NSCLC). The efficacy of lorlatinib, as compared with that of crizotinib, as first-line treatment for advanced ALK -positive NSCLC is unclear., Methods: We conducted a global, randomized, phase 3 trial comparing lorlatinib with crizotinib in 296 patients with advanced ALK -positive NSCLC who had received no previous systemic treatment for metastatic disease. The primary end point was progression-free survival as assessed by blinded independent central review. Secondary end points included independently assessed objective response and intracranial response. An interim analysis of efficacy was planned after approximately 133 of 177 (75%) expected events of disease progression or death had occurred., Results: The percentage of patients who were alive without disease progression at 12 months was 78% (95% confidence interval [CI], 70 to 84) in the lorlatinib group and 39% (95% CI, 30 to 48) in the crizotinib group (hazard ratio for disease progression or death, 0.28; 95% CI, 0.19 to 0.41; P<0.001). An objective response occurred in 76% (95% CI, 68 to 83) of the patients in the lorlatinib group and 58% (95% CI, 49 to 66) of those in the crizotinib group; among those with measurable brain metastases, 82% (95% CI, 57 to 96) and 23% (95% CI, 5 to 54), respectively, had an intracranial response, and 71% of the patients who received lorlatinib had an intracranial complete response. The most common adverse events with lorlatinib were hyperlipidemia, edema, increased weight, peripheral neuropathy, and cognitive effects. Lorlatinib was associated with more grade 3 or 4 adverse events (mainly altered lipid levels) than crizotinib (in 72% vs. 56%). Discontinuation of treatment because of adverse events occurred in 7% and 9% of the patients, respectively., Conclusions: In an interim analysis of results among patients with previously untreated advanced ALK -positive NSCLC, those who received lorlatinib had significantly longer progression-free survival and a higher frequency of intracranial response than those who received crizotinib. The incidence of grade 3 or 4 adverse events was higher with lorlatinib than with crizotinib because of the frequent occurrence of altered lipid levels. (Funded by Pfizer; CROWN ClinicalTrials.gov number, NCT03052608.)., (Copyright © 2020 Massachusetts Medical Society.)

Purpose: Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, demonstrated superior progression-free survival (PFS) and improved health-related quality of life (QoL) versus crizotinib in advanced ALK inhibitor-naive ALK-positive non-small cell lung cancer (NSCLC) at first interim analysis (99 events; median brigatinib follow-up, 11.0 months) in the open-label, phase III ALTA-1L trial (ClinicalTrials.gov identifier: NCT02737501). We report results of the second prespecified interim analysis (150 events)., Methods: Patients with ALK inhibitor-naive advanced ALK-positive NSCLC were randomly assigned 1:1 to brigatinib 180 mg once daily (7-day lead-in at 90 mg once daily) or crizotinib 250 mg twice daily. The primary end point was PFS as assessed by blinded independent review committee (BIRC). Investigator-assessed efficacy, blood samples for pharmacokinetic assessments, and patient-reported outcomes were also collected., Results: Two hundred seventy-five patients were randomly assigned (brigatinib, n = 137; crizotinib, n = 138). With median follow-up of 24.9 months for brigatinib (150 PFS events), brigatinib showed consistent superiority in BIRC-assessed PFS versus crizotinib (hazard ratio [HR], 0.49 [95% CI, 0.35 to 0.68]; log-rank P < .0001; median, 24.0 v 11.0 months). Investigator-assessed PFS HR was 0.43 (95% CI, 0.31 to 0.61; median, 29.4 v 9.2 months). No new safety concerns emerged. Brigatinib delayed median time to worsening of global health status/QoL scores compared with crizotinib (HR, 0.70 [95% CI, 0.49 to 1.00]; log-rank P = .049). Brigatinib daily area under the plasma concentration-time curve was not a predictor of PFS (HR, 1.005 [95% CI, 0.98 to 1.031]; P = .69)., Conclusion: Brigatinib represents a once-daily ALK inhibitor with superior efficacy, tolerability, and QoL over crizotinib, making it a promising first-line treatment of ALK-positive NSCLC.

Background/aim: MET exon 14 skipping occurs in 3-4% of patients with lung adenocarcinomas. In this study, we performed a comprehensive analysis of clinical data from Korean non-small cell lung cancer (NSCLC) patients with MET exon 14 skipping., Patients and Methods: Overall, 1,020 patients diagnosed with NSCLC between January 2015 and July 2017 were analyzed by next-generation sequencing., Results: MET exon 14 skipping was identified in 20 NSCLC patients (1.9%). The median age was 69 years (range=39-86 years), 60.0% were male, and most (55.0%) were ever-smokers. For first-line chemotherapy, the median overall survival was 9.5 months and progression-free survival was 4.0 months, respectively. Twelve patients received pemetrexed-based chemotherapy and the overall response rate was 33.3% (4/12). Among four crizotinib-treated patients, one continued therapy for 8 months with the best response being disease stability., Conclusion: Given the poor clinical outcome and response to therapy for NSCLC, and the availability of promising anti-tumor MET inhibitors, screening for the MET exon 14 skip mutation should be incorporated into clinical practice., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)