Showing papers on "Ceritinib published in 2023"

Comparative Efficacy of ALK Inhibitors for Treatment-Naïve ALK-Positive Advanced Non-Small Cell Lung Cancer with Central Nervous System Metastasis: A Network Meta-Analysis

Abstract: Central nervous system (CNS) metastases and acquired resistance complicate the treatment of anaplastic lymphoma kinase (ALK) rearrangement-positive (ALK-p) advanced non-small cell lung cancer (NSCLC). Thus, this review aimed to provide a comprehensive overview of brain metastasis, acquired resistance, and prospects for overcoming these challenges. A network meta-analysis of relevant phase III randomized controlled trials was performed to compare the efficacies of multiple ALK inhibitors by drug and generation in overall patients with ALK-p untreated advanced NSCLC and a subgroup of patients with CNS metastases. The primary endpoint was progression-free survival (PFS). Generation-specific comparison results showed that third-generation ALK inhibitors were significantly more effective than second-generation ALK inhibitors in prolonging the PFS of the subgroup of patients with CNS metastases. Drug-specific comparison results demonstrated that lorlatinib was the most effective in prolonging PFS, followed by brigatinib, alectinib, ensartinib, ceritinib, crizotinib, and chemotherapy. While lorlatinib was superior to brigatinib for PFS in the overall patient population, no significant difference between the two was found in the subgroup of patients with CNS metastases. These results can serve as a foundation for basic, clinical, and translational research and guide clinical oncologists in developing individualized treatment strategies for patients with ALK-p, ALK inhibitor-naive advanced NSCLC.

Optimal first-line treatment for metastatic ALK+ non-small cell lung cancer—a narrative review

Abstract: Background and Objective First-line treatment options for patients with advanced non-small cell lung cancer (aNSCLC) whose tumors harbour anaplastic lymphoma kinase (ALK) gene rearrangements have rapidly evolved from chemotherapy, to the first in class ALK-targeted tyrosine kinase inhibitor (TKI) crizotinib in 2011, and now include no fewer than five Food and Drug Administration (FDA)-approved ALK inhibitors. However, while superiority to crizotinib has been established, head-to-head clinical trials comparing newer generation ALK inhibitors are lacking, and decisions on optimal first-line treatment must be based on analysis of the relevant trials, with attention to systemic and intracranial efficacy, toxicity profile as well as consideration of patient factors and preferences. Here we aim to synthesise findings from review of these trials and to describe options for optimal first-line treatment for ALK+ NSCLC. Methods A literature review of relevant randomised clinical trials was undertaken using Embase database. There were no limitations to time frame or language applied. Key Content and Findings Crizotinib was established as the standard of care first-line treatment for patients with ALK+ aNSCLC in 2011. Since this time, alectinib, brigatinib, ensartinib and lorlatinib have all demonstrated superiority as first-line treatments compared to crizotinib, based on progression free survival, intra-cranial efficacy, and side-effect profiles. Conclusions Options for optimal first-line treatment for ALK+ aNSCLC include alectinib, brigatinib and lorlatinib. This review serves as a resource summarizing data from key clinical trials with ALK inhibitors to aid in decision making when tailoring treatment for patients. Future research in the field includes real world analysis of efficacy and toxicity of next-generation ALK-inhibitors, identification of mechanisms of tumor persistence and acquired resistance, development of novel ALK inhibitors, and use of ALK-TKIs in earlier stage disease.

Efficacy and safety of anaplastic lymphoma kinase inhibitors for non–small cell lung cancer: A systematic review and network meta‐analysis

Abstract: To assess the efficacy and safety of anaplastic lymphoma kinase inhibitors (ALKIs) for the treatment of advanced‐stage ALK rearrangement‐positive non–small cell lung cancer (NSCLC).

Efficacy and safety of first‐line treatments for patients with advanced anaplastic lymphoma kinase mutated, non–small cell cancer: A systematic review and network meta‐analysis

Abstract: Background This study compares the safety and efficacy of first-line treatments for anaplastic lymphoma kinase (ALK)-mutated non–small cell lung cancer (NSCLC). Methods A comprehensive literature search was conducted in PubMed, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases. Abstracts related to lung cancer presented at important international conferences were also reviewed. Randomized clinical trials that qualified the inclusion criteria were subjected to Bayesian network meta-analysis and systematically reviewed. Results The authors included a total of nine studies including 2441 patients and seven first-line treatments (ensartinib, brigatinib, crizotinib, lorlatinib, alectinib, ceritinib, and pemetrexed-based chemotherapy). Overall, lorlatinib appeared to confer the best progression-free survival (PFS) (probability of being the best [Prbest], 90%; surface under the cumulative ranking curve [SUCRA], 98%), and the same conclusion was obtained on paired comparisons (lorlatinib vs. ceritinib [hazard ratio (HR), 0.31; 95% confidence interval (CI), 0.20–0.47); lorlatinib vs. chemotherapy [HR, 0.17; 95% CI, 0.12–0.23]; crizotinib vs. lorlatinib [HR, 3.6; 95% CI, 2.4–5.2]; and brigatinib vs. lorlatinib [HR, 1.7; 95% CI, 1.0–2.8]). Alectinib conferred the best overall survival (OS) and safety profile. In the Asian population, ensartinib conferred the best PFS (Prbest 50%, SUCRA 87%), and for patients with brain metastases at baseline, lorlatinib showed the best PFS (Prbest 70%, SUCRA 93%). Conclusions For first-line treatment of patients with ALK-positive NSCLC, lorlatinib was associated with the best PFS and objective response rate, but poorer safety profile, whereas alectinib demonstrated the best OS and safety profile. In Asians, ensartinib conferred the best PFS benefit, and in the brain baseline metastasis population, lorlatinib conferred the best PFS benefit. Plain Language Summary Among the many molecularly targeted drugs currently used to treat anaplastic lymphoma kinase mutation-positive non–small cell lung cancer, lorlatinib may be one of the most effective targeted drugs. Lung cancer has long been at the top of cancer rankings in terms of incidence and mortality. Today, the treatment of lung cancer has moved into the era of precision therapy. In this article, we use a statistical approach to compare the efficacy and safety of targeted drugs that have been used in the first-line treatment of anaplastic lymphoma kinase mutations to improve the reference for clinicians to make treatment decisions in the real world.

Effectiveness of ALK inhibitors in treatment of CNS metastases in NSCLC patients.

Abstract: Metastases to the central nervous system (CNS) in patients with non-small cell lung cancer constitute an extremely difficult clinical problem, and their occurrence is associated with a poor prognosis. Due to the existence of the blood-brain barrier (BBB) and the action of proteins responsible for the transport of drugs, e.g. P-glycoprotein (P-gp), the penetration of drugs into the CNS is insufficient. Until recently, the only method of CNS metastases treatment was radiotherapy and neurosurgery. The advancement of molecular biology allowed discover targets for molecularly targeted therapies. One of targets is abnormal anaplastic lymphoma kinase, which results from the rearrangement of the ALK gene in patients with non-small cell lung cancer (NSCLC). ALK rearrangement occurs in only about 4.5% of NSCLC patients, but its presence favors brain metastases. The ALK inhibitors (ALKi) were modified to obtain molecules with high ability to penetrate into the CNS. This was achieved by modifying the structure of individual molecules, which became, inter alia, less substrates for P-gp. These modifications caused that less than 10% of patients experience progression in CNS during new ALK inhibitors treatment. This review summarizes the knowledge about the action of BBB, the pharmacodynamics and pharmacokinetics of ALKi, with particular emphasis on their ability to penetrate the CNS and the intracranial activity of individual drugs from different generations of ALK inhibitors.

Real-World Treatment and Outcomes of ALK-Positive Metastatic Non–Small Cell Lung Cancer in a Southeast Asian Country

Abstract: Anaplastic lymphoma kinase (ALK) inhibitors are associated with good overall survival (OS) for ALK-positive metastatic non-small cell lung cancer (NSCLC). However, these treatments can be unavailable or limited by financial constraints in developing countries. Using data from a nationwide lung cancer registry, the present study aimed to identify treatment patterns and clinical outcomes of ALK-positive NSCLC in Malaysia.This retrospective study examined data of patients with ALK-positive NSCLC from 18 major hospitals (public, private, or university teaching hospitals) throughout Malaysia between January 1, 2015 and December 31, 2020 from the National Cardiovascular and Thoracic Surgical Database (NCTSD). Data on baseline characteristics, treatments, radiological findings, and pathological findings were collected. Overall survival (OS) and time on treatment (TOT) were calculated using the Kaplan-Meier method.There were 1581 NSCLC patients in the NCTSD. Based on ALK gene-rearrangement test results, only 65 patients (4.1%) had ALK-positive advanced NSCLC. Of these 65 patients, 59 received standard-of-care treatment and were included in the analysis. Crizotinib was the most commonly prescribed ALK inhibitor, followed by alectinib and ceritinib. Patients on ALK inhibitors had better median OS (62 months for first-generation inhibitors, not reached at time of analysis for second-generation inhibitors) compared to chemotherapy (27 months), but this was not statistically significant (P=0.835) due to sample-size limitations. Patients who received ALK inhibitors as first-line therapy had significantly longer TOT (median of 11 months for first-generation inhibitors, not reached for second-generation inhibitors at the time of analysis) compared to chemotherapy (median of 2 months; P<0.01).Patients on ALK inhibitors had longer median OS and significantly longer TOT compared to chemotherapy, suggesting long-term benefit.

Supplementary Figure 1 from Progression-Free and Overall Survival in ALK-Positive NSCLC Patients Treated with Sequential Crizotinib and Ceritinib

Abstract: <p>Supplementary Figure 1. Individual swimmer plots for each patient who underwent a post-crizotinib/pre-ceritinib biopsy</p>

A Novel ALK Gene Mutation and Its Response to Second-Generation TKIs: a Case Report and Literature Review

Abstract: Abstract Background Adenocarcinoma with positive echinoderm microtubule-associated protein-like 4 gene and anaplastic lymphoma kinase (EML4-ALK) gene fusion accounts for 3–7% of lung cancer cases and can be targeted with ALK tyrosine kinase inhibitors (TKIs). Second-generation TKIs are the standard of care for targeted populations, especially those with central nervous system (CNS) metastasis. However, most patients eventually experience disease progression because of drug resistance caused by multiple mechanisms, predominantly secondary mutations. Case description : We present a female advanced non-small cell lung cancer (NSCLC) case with positive EML4-ALK gene fusion, in which disease progression occurred in only 3 months after first-line treatment with alectinib. Two secondary mutations were detected by next-generation sequencing; one was V1180l located in exon 23, and the other was E803Q located in exon 14, which was a novel mutation that had never been reported. Ensartinib and ceritinib were administered as second-line and third-line treatments. However, the response to these TKIs was poor, and her overall survival was only 7 months. Conclusion The secondary mutation E803Q located in exon 14 seems resistant to most second-generation ALK-TKIs. If there is an opportunity, the efficacy of the third-generation ALK-TKI loratinib should be tested.

Supplementary Data from ASCEND-7: Efficacy and Safety of Ceritinib Treatment in Patients with &lt;i&gt;ALK&lt;/i&gt;-Positive Non–Small Cell Lung Cancer Metastatic to the Brain and/or Leptomeninges

Abstract: Supplementary Data from ASCEND-7: Efficacy and Safety of Ceritinib Treatment in Patients with <i>ALK</i>-Positive Non–Small Cell Lung Cancer Metastatic to the Brain and/or Leptomeninges

Data from Two Novel ALK Mutations Mediate Acquired Resistance to the Next-Generation ALK Inhibitor Alectinib

Abstract: <div>Abstract<p><b>Purpose:</b> The first-generation ALK tyrosine kinase inhibitor (TKI) crizotinib is a standard therapy for patients with <i>ALK</i>-rearranged non–small cell lung cancer (NSCLC). Several next-generation ALK-TKIs have entered the clinic and have shown promising activity in crizotinib-resistant patients. As patients still relapse even on these next-generation ALK-TKIs, we examined mechanisms of resistance to the next-generation ALK-TKI alectinib and potential strategies to overcome this resistance.</p><p><b>Experimental Design:</b> We established a cell line model of alectinib resistance, and analyzed a resistant tumor specimen from a patient who had relapsed on alectinib. We developed Ba/F3 models harboring alectinib-resistant ALK mutations and evaluated the potency of other next-generation ALK-TKIs in these models. We tested the antitumor activity of the next-generation ALK-TKI ceritinib in the patient with acquired resistance to alectinib. To elucidate structure–activity relationships of ALK mutations, we performed computational thermodynamic simulation with MP-CAFEE.</p><p><b>Results:</b> We identified a novel V1180L gatekeeper mutation from the cell line model and a second novel I1171T mutation from the patient who developed resistance to alectinib. Both ALK mutations conferred resistance to alectinib as well as to crizotinib, but were sensitive to ceritinib and other next-generation ALK-TKIs. Treatment of the patient with ceritinib led to a marked response. Thermodynamics simulation suggests that both mutations lead to distinct structural alterations that decrease the binding affinity with alectinib.</p><p><b>Conclusions:</b> We have identified two novel ALK mutations arising after alectinib exposure that are sensitive to other next-generation ALK-TKIs. The ability of ceritinib to overcome alectinib-resistance mutations suggests a potential role for sequential therapy with multiple next-generation ALK-TKIs. <i>Clin Cancer Res; 20(22); 5686–96. ©2014 AACR</i>.</p></div>

Supplementary Figure 3 from &lt;i&gt;ALK&lt;/i&gt; Amplification and Rearrangements Are Recurrent Targetable Events in Congenital and Adult Glioblastoma

Abstract: <p>Supplementary Figure 3: PPP1CB-ALK fusion is oncogenic and sensitive to targeted therapy. A. Immunoblot analysis of ALK downstream signaling proteins in cortical mNSC (CTX#6) and brainstem mNSC (BS#3) expressing PPP1CB-ALK. Cells were treated for 4 hours with ceritinib and lorlatinib at the indicated concentrations.B. Left panel: Soft agar colony-forming assay using stable mNSC PPP1CB-ALK demonstrated colony formation with dose-dependent inhibition by ceritinib. mNSC KRAS did not respond to ceritinib validating the drug specificity. Right panel: Quantification of colony formation under targeted drug inhibition using CellProfiler. Values represent colony counts relative to the untreated group ± s.d. The mean of three independent replicates is shown. Significance between treatments determined by the Mann-Whitney test. *P < 0.05, **P < 0.01.C. Cell viability of ceritinib-treated PPP1CB-ALK NIH-3T3 relative to eGFP-positive cells by CellTiterGlo.D. Relative viability of the ALK wild-type GBM line (BT164) and BT1857 lorlatinib-treated cells versus DMSO control.E. Relative viability of BT164 and BT1857 ceritinib-treated cells versus DMSO control.F. Relative viability of BT164 and BT1857 cells treated with an EGFR tyrosine kinase inhibitor neratinib.G. Pharmacodynamic analysis of NIH 3T3-PPP1CB-ALK s.c. tumors treated with vehicle or ceritinib at 30mg/kg for 5 days. Representative H&E stain, ALK, pSTAT3, pAKT S473 and Ki-67 IHC.H. Quantification of Ki-67-positive cells in vehicle and ceritinib-treated tumors using CellProfiler software. Error bars show standard error of the mean. *P < 0.05.I. Quantification of pSTAT3-positive cells in vehicle and ceritinib-treated tumors using CellProfiler software. Error bars show standard error of the mean. *P < 0.05.J. Tumor growth following subcutaneous implantation of PPP1CB-ALK and eGFP-expressing fibroblasts.K. Kaplan-Meier survival curves of SCID mice injected subcutaneously with mNSC CTX-PPP1CB-ALK (red, n = 5) or mNSC CTX-eGFP (black, n = 4) and treated with ceritinib at 30mg/kg/d for 15 days. Mice were euthanized at endpoint (tumor volume of 2000mm3). The grey area represents the treatment period.L. Vehicle or ceritinib-treated mouse weights at start and end of treatment.</p>

Supplementary Figure Legend from The ALK Inhibitor Ceritinib Overcomes Crizotinib Resistance in Non–Small Cell Lung Cancer

Abstract: <p>PDF file 100K, Legends for the supplementary figures</p>

Supplemental figure S1, S2, S3, S4, S5, S6 from Enhancer Remodeling and MicroRNA Alterations Are Associated with Acquired Resistance to ALK Inhibitors

Abstract: <p>Supplementary Figure S1. Viability of H3122-LR and H2228-LR cells Supplementary Figure S2. Gene set enrichment analysis and western blot Supplementary Figure S3. Effects of AXL inhibition on EMT gene expression in LR cells, related to Fig. 1E. Supplementary Figure S4. Mice with established H3122-derived tumors were treated with four doses (50, 75, 87.5, or 100 mg/kg) of ceritinib to derive ceritinib-resistant tumors Supplementary Figure S5. Enhancer remodeling during ceritinib resistance, related to Fig. 2. Supplementary Figure S6. Genes with H3K27ac loss or gain in their promoters during ceritinib resistance, related to Fig.2.</p>

Data from Repotrectinib Exhibits Potent Antitumor Activity in Treatment-Naïve and Solvent-Front–Mutant ROS1-Rearranged Non–Small Cell Lung Cancer

Abstract: <div>AbstractPurpose:<p>Although first-line crizotinib treatment leads to clinical benefit in <i>ROS1⁺</i> lung cancer, high prevalence of crizotinib-resistant ROS1-G2032R (ROS1^G2032R) mutation and progression in the central nervous system (CNS) represents a therapeutic challenge. Here, we investigated the antitumor activity of repotrectinib, a novel next-generation ROS1/TRK/ALK-tyrosine kinase inhibitor (TKI) in <i>ROS1⁺</i> patient-derived preclinical models.</p>Experimental Design:<p>Antitumor activity of repotrectinib was evaluated in <i>ROS1⁺</i> patient-derived preclinical models including treatment-naïve and ROS1^G2032R models and was further demonstrated in patients enrolled in an on-going phase I/II clinical trial (NCT03093116). Intracranial antitumor activity of repotrectinib was evaluated in a brain-metastasis mouse model.</p>Results:<p>Repotrectinib potently inhibited <i>in vitro</i> and <i>in vivo</i> tumor growth and ROS1 downstream signal in treatment-naïve YU1078 compared with clinically available crizotinib, ceritinib, and entrectinib. Despite comparable tumor regression between repotrectinib and lorlatinib in YU1078-derived xenograft model, repotrectinib markedly delayed the onset of tumor recurrence following drug withdrawal. Moreover, repotrectinib induced profound antitumor activity in the CNS with efficient blood–brain barrier penetrating properties. Notably, repotrectinib showed selective and potent <i>in vitro</i> and <i>in vivo</i> activity against ROS1^G2032R. These findings were supported by systemic and intracranial activity of repotrectinib observed in patients enrolled in the on-going clinical trial.</p>Conclusions:<p>Repotrectinib is a novel next-generation ROS1-TKI with improved potency and selectivity against treatment-naïve and ROS1^G2032R with efficient CNS penetration. Our findings suggest that repotrectinib can be effective both as first-line and after progression to prior ROS1-TKI.</p></div>

Supplementary Figure 2 from Progression-Free and Overall Survival in ALK-Positive NSCLC Patients Treated with Sequential Crizotinib and Ceritinib

Abstract: <p>Supplementary Figure 2. Overall survival (OS) for anaplastic lymphoma kinase (ALK)-positive patients with brain metastases</p>

Supplementary Fig. S3 from Proteasome Inhibition Overcomes ALK-TKI Resistance in &lt;i&gt;ALK&lt;/i&gt;-Rearranged/&lt;i&gt;TP53&lt;/i&gt;-Mutant NSCLC via Noxa Expression

Abstract: <p>Kaplan-Meier curves for PFS according to with and without loss-of-function mutations of TP53 in patients who received alectinib (A) or either of ALK-TKIs (alectinib, crizotinib, brigatinib, lorlatinib, ceritinib) (B) as the first TKI treatment.</p>

Brigatinib in patients with ALK‐positive anaplastic large cell lymphoma who have failed brentuximab vedotin

Abstract: ALK-positive anaplastic large cell lymphoma (ALK+ ALCL) patients (pts) who have failed brentuximab vedotin (BV) have a poor prognosis with a median OS after BV failure of 2.9 months and 2-year OS of 27.1% (Chihara D, 2019). ALK-inhibitors have shown interesting results in relapsed ALK+ ALCL, but in these studies, most pts had not received prior BV, which does not correspond to current standards of treatment in adults. Furthermore, there are currently several ALK-inhibitors, but too few pts available to test them in this rare and difficult-to-treat population. It is therefore important to evaluate these ALK-inhibitors in preclinical studies, before selecting one for a clinical study. We carried out a preclinical study and then a real-life clinical study. We generated a patient-derived xenograft (PDX) model from a fresh lymph node biopsy of a 41-year-old man newly diagnosed with ALK+ ALCL. Our PDX closely mimicked the patient’s primary tumor, as assessed by pathology, FISH, TCR gene rearrangement, WES and RNA-seq. We used this model to assess 8 ALK-inhibitors (alectinib, brigatinib, ceritinib, crizotinib, ensartinib, entrectinib, lorlatinib, gilteritinib). We selected and recommended brigatinib for clinical off-label use based on our preclinical results and the safety profile in pts with ALK-positive non-small cell lung cancer (NSCLC). Between Jan 2020 and Oct 2022, 15 French adults who have failed BV started brigatinib. At brigatinib initiation, the median age was 35 y (19–73; 2 pts > 60 y), 8/15 were male, the median number of prior treatment lines was 2 (1–8), 4/15 (27%) had received prior crizotinib, including 3 crizotinib-resistant (crizo-R) and 1 crizotinib-sensitive (crizo-S) who relapsed after discontinuation of the drug. 4 pts had previously undergone stem cell transplantation (3 autoSCT, 1 alloSCT). ALCL was refractory to the last treatment in 10/15 pts. 10/11 pts had detectable ALK transcript in blood by RT-PCR. Pts received brigatinib at a dose of 180 mg once daily (with a 7-day lead-in period at 90 mg), as recommended in ALK-positive NSCLC. The best ORR was 93% (14/15) with 73% (11/15) CR according to Lugano response criteria. 2 crizo-R and the crizo-S pts achieved CR, and 1 crizo-R pt reached PR. Time to achieve CR ranged from 8 to 325 days. 9 pts were monitored for ALK transcript in blood over time and kinetics correlated with response. 5 CR pts were bridged to alloSCT. There were 4 progressions/relapses after brigatinib initiation, all occurring within the first 6 months. After a median follow-up of 1.3 years, 1-year PFS and OS were 72% and 85%, respectively. There was no permanent discontinuation of brigatinib related to adverse event (AE), and 3 pts had dose reduction for moderate AE (1 dyspnea and 2 cramps), with complete resolution. Keywords: Aggressive T-cell non-Hodgkin lymphoma, Molecular Targeted Therapies Conflicts of interests pertinent to the abstract. D. Sibon Consultant or advisory role: Takeda, AbbVie, Janssen, Roche

Alk抑制剂在治疗nsclc脑转移中的疗效及安全性研究进展

Abstract: 肺癌是全球死亡率最高的恶性肿瘤之一，其中非小细胞肺癌（non-small cell lung cancer, NSCLC）占所有肺癌病理类型的80%-85%。NSCLC中有30%-55%的患者发生脑转移。据估计，5%-6%的脑转移患者存在间变性淋巴瘤激酶（anaplastic lymphoma kinase, ALK）融合。ALK融合阳性NSCLC患者在接受ALK抑制剂后获得了非常显著的疗效。经过十余年的迅速发展，ALK抑制剂已经形成三代同堂的局面：即第一代——克唑替尼（Crizotinib）；第二代——阿来替尼（Alectinib）、布格替尼（Brigatinib）、塞瑞替尼（Ceritinib）、恩沙替尼（Ensartinib）；第三代——洛拉替尼（Lorlatinib）。这些药物在ALK融合阳性NSCLC脑转移患者中显示出不同的疗效。由于此类药物众多，ALK抑制剂的选择给临床医生带来了困扰。因此，本文旨在对ALK抑制剂在NSCLC脑转移中的治疗效果和安全性进行综述，以期为临床医生提供治疗选择的依据。

Supplementary Data from ASCEND-7: Efficacy and Safety of Ceritinib Treatment in Patients with &lt;i&gt;ALK&lt;/i&gt;-Positive Non–Small Cell Lung Cancer Metastatic to the Brain and/or Leptomeninges

Abstract: Supplementary Data from ASCEND-7: Efficacy and Safety of Ceritinib Treatment in Patients with <i>ALK</i>-Positive Non–Small Cell Lung Cancer Metastatic to the Brain and/or Leptomeninges

Supplementary Data from Acquired Resistance to Alectinib in ALK-Rearranged Lung Cancer due to ABCC11/MRP8 Overexpression in a Clinically Paired Resistance Model

Abstract: <p>Figure S1. Schematic representation of the ABCC11 expression vector. Figure S2. Sequence analysis of the tyrosine kinase coding region of anaplastic lymphoma kinase (ALK). Figure S3. Cell viability assay of alectinib in H2228 and H2228-AR1S cells under low-attachment conditions. Figure S4. Gene expression of the ABC transporters in the five cell types. Figure S5. Intracellular concentration of alectinib. Figure S6. Tumor images on day 11 of treatment. The tumor volume at 10 days after alectinib administration. Figure S7. ALK phosphorylation in KTOR1 and KOR1-RE cell exposed to alectinib for 3 hours as determined using immunoblotting. Figure S8. IC50 values of H2228 and H2228-AR1S cell lines in the presence of crizotinib, ceritinib, lorlatinib, and brigatinib. Table S1. Immunoblotting antibodies. Table S2. Primers used for ABC transporters purchased from Thermo Fisher Scientific. Table S3. siRNA oligonucleotides purchased from Thermo Fisher Scientific. Table S4. Primer sequences for direct sequencing of ALK exons. Table S5. IC50 for alectinib in H2228-AR1S cells transfected with negative control or ABCC11 siRNA. Table S6. IC50 for alectinib in KTOR1-RE cells transfected with negative control or ABCC11 siRNA.</p>

Supplemental figure S1, S2, S3, S4, S5, S6 from Enhancer Remodeling and MicroRNA Alterations Are Associated with Acquired Resistance to ALK Inhibitors

Abstract: <p>Supplementary Figure S1. Viability of H3122-LR and H2228-LR cells Supplementary Figure S2. Gene set enrichment analysis and western blot Supplementary Figure S3. Effects of AXL inhibition on EMT gene expression in LR cells, related to Fig. 1E. Supplementary Figure S4. Mice with established H3122-derived tumors were treated with four doses (50, 75, 87.5, or 100 mg/kg) of ceritinib to derive ceritinib-resistant tumors Supplementary Figure S5. Enhancer remodeling during ceritinib resistance, related to Fig. 2. Supplementary Figure S6. Genes with H3K27ac loss or gain in their promoters during ceritinib resistance, related to Fig.2.</p>

From ASCEND-5 to ALUR to ALTA-3, an Anti-Climactic End to the Era of Randomized Phase 3 Trials of Next-Generation ALK TKIs in the Crizotinib-Refractory Setting

Abstract: The competing roles of various next-generation ALK TKIs in the first and second line treatment setting of advanced ALK+ NSCLC were based on many phase 3 clinical trials in both the first-line and crizotinib-refractory settings. The approval of all next-generation ALK TKIs was first in the crizotinib-refractory setting, based on a large-scale Phase 2 trial, and was then followed by at least one global randomized phase 3 trial comparing to platinum-based chemotherapy (ASCEND-4) or to crizotinib (ALEX, ALTA-1L, eXalt3, CROWN). In addition, three randomized phase 3 trials in the crizotinib-refractory setting were also conducted by next-generation ALK TKIs that were developed earlier before the superiority of next-generation ALK TKIs was demonstrated in order to secure the approval of these ALK TKIs in the crizotinib-refractory setting. These three crizotinib-refractory randomized trials were: ASCEND-5 (ceritinib), ALUR (alectinib), and ALTA-3 (brigatinib). The outcome of the ATLA-3 trial was recently presented closing out the chapter where next-generation ALK TKIs were investigated in the crizotinib-refractory setting as they have replaced crizotinib as the standard of care first-line treatment of advanced ALK+ NSCLC. This editorial summarizes the results of next-generation ALK TKIs in randomized crizotinib-refractory trials and provides a perspective on how natural history of ALK+ NSCLC may potentially be altered with sequential treatment. ALTA-3 compared brigatinib to alectinib, showing that both achieved near identical blinded independent review committee (BIRC)-assessed progression-free survival (PFS) (19.2-19.3 months). Importantly, 4.8% of brigatinib-treated patients developed interstitial lung disease (ILD) while no alectinib-treated patients developed ILD. Dose reduction and discontinuation due to treatment-related adverse events were 21% and 5%, respectively, for brigatinib-treated patients compared to 11% and 2%, respectively, for alectinib-treated patients. Upon analysis of these findings, we speculate that brigatinib may have a diminishing role in the treatment of advanced ALK+ NSCLC.

Alectinib for treating patients with metastatic ALK-positive NSCLC: systematic review and network metanalysis

Abstract: Aim To compare the efficacy and safety of alectinib with other ALK inhibitors in treating patients with metastatic or locally advanced ALK-positive NSCLC. Methods A systematic literature review was conducted up to November 2021. Network meta-analyses were performed using the frequentist method (random effects). GRADE evidence profile was conducted. Results 13 RCTs were selected. For overall survival, alectinib was found to reduce the risk of death compared with crizotinib. In progression-free survival, alectinib reduced the risk of death or progression compared with crizotinib and ceritinib. Subgroup analysis by brain metastasis at baseline showed the superiority of alectinib over crizotinib and a similar effect compared with second-and third-generation inhibitors. Alectinib showed a good safety profile compared with the other ALK inhibitors.

Figure Legends - Supplementary Data from Progression-Free and Overall Survival in ALK-Positive NSCLC Patients Treated with Sequential Crizotinib and Ceritinib

Abstract: <p>Figure Legends - Supplementary Data</p>

Data from Crizotinib-Resistant &lt;i&gt;ROS1&lt;/i&gt; Mutations Reveal a Predictive Kinase Inhibitor Sensitivity Model for &lt;i&gt;ROS1&lt;/i&gt;- and &lt;i&gt;ALK&lt;/i&gt;-Rearranged Lung Cancers

Abstract: <div>Abstract<p><b>Background:</b> The identification of molecular mechanisms conferring resistance to tyrosine kinase inhibitor (TKI) is a key step to improve therapeutic results for patients with oncogene addiction. Several alterations leading to EGFR and anaplastic lymphoma kinase (ALK) resistance to TKI therapy have been described in non–small cell lung cancer (NSCLC). Only two mutations in the ROS1 kinase domain responsible for crizotinib resistance have been described in patients thus far.</p><p><b>Methods:</b> A patient suffering from a metastatic NSCLC harboring an <i>ezrin</i> (<i>EZR</i>)<i>–ROS1</i> fusion gene developed acquired resistance to the ALK/ROS1 inhibitor crizotinib. Molecular analysis (whole-exome sequencing, CGH) and functional studies were undertaken to elucidate the mechanism of resistance. Based on this case, we took advantage of the structural homology of ROS1 and ALK to build a predictive model for drug sensitivity regarding future ROS1 mutations.</p><p><b>Results:</b> Sequencing revealed a dual mutation, S1986Y and S1986F, in the ROS1 kinase domain. Functional <i>in vitro</i> studies demonstrated that ROS1 harboring either the S1986Y or the S1986F mutation, while conferring resistance to crizotinib and ceritinib, was inhibited by lorlatinib (PF-06463922). The patient's clinical response confirmed the potency of lorlatinib against S1986Y/F mutations. The ROS1 S1986Y/F and ALK C1156Y mutations are homologous and displayed similar sensitivity patterns to ALK/ROS1 TKIs. We extended this analogy to build a model predicting TKI efficacy against potential ROS1 mutations.</p><p><b>Conclusions:</b> Clinical evidence, <i>in vitro</i> validation, and homology-based prediction provide guidance for treatment decision making for patients with <i>ROS1</i>-rearranged NSCLC who progressed on crizotinib. <i>Clin Cancer Res; 22(24); 5983–91. ©2016 AACR</i>.</p></div>

Data from Two Novel ALK Mutations Mediate Acquired Resistance to the Next-Generation ALK Inhibitor Alectinib

Abstract: <div>Abstract<p><b>Purpose:</b> The first-generation ALK tyrosine kinase inhibitor (TKI) crizotinib is a standard therapy for patients with <i>ALK</i>-rearranged non–small cell lung cancer (NSCLC). Several next-generation ALK-TKIs have entered the clinic and have shown promising activity in crizotinib-resistant patients. As patients still relapse even on these next-generation ALK-TKIs, we examined mechanisms of resistance to the next-generation ALK-TKI alectinib and potential strategies to overcome this resistance.</p><p><b>Experimental Design:</b> We established a cell line model of alectinib resistance, and analyzed a resistant tumor specimen from a patient who had relapsed on alectinib. We developed Ba/F3 models harboring alectinib-resistant ALK mutations and evaluated the potency of other next-generation ALK-TKIs in these models. We tested the antitumor activity of the next-generation ALK-TKI ceritinib in the patient with acquired resistance to alectinib. To elucidate structure–activity relationships of ALK mutations, we performed computational thermodynamic simulation with MP-CAFEE.</p><p><b>Results:</b> We identified a novel V1180L gatekeeper mutation from the cell line model and a second novel I1171T mutation from the patient who developed resistance to alectinib. Both ALK mutations conferred resistance to alectinib as well as to crizotinib, but were sensitive to ceritinib and other next-generation ALK-TKIs. Treatment of the patient with ceritinib led to a marked response. Thermodynamics simulation suggests that both mutations lead to distinct structural alterations that decrease the binding affinity with alectinib.</p><p><b>Conclusions:</b> We have identified two novel ALK mutations arising after alectinib exposure that are sensitive to other next-generation ALK-TKIs. The ability of ceritinib to overcome alectinib-resistance mutations suggests a potential role for sequential therapy with multiple next-generation ALK-TKIs. <i>Clin Cancer Res; 20(22); 5686–96. ©2014 AACR</i>.</p></div>