Metastatic ALK-positive Non-small Cell Lung Cancer Research Articles

Alectinib: A Review in Advanced, ALK-Positive NSCLC.

Alectinib (Alecensa®) is a potent and highly selective anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor. Oral alectinib monotherapy is approved in the EU as first-line treatment for adults with advanced ALK-positive non-small cell lung cancer (NSCLC) and for the treatment of adults with advanced ALK-positive NSCLC previously treated with crizotinib. In the USA, alectinib is indicated for the treatment of adults with ALK-positive metastatic NSCLC. The recommended dosage for alectinib in the EU and USA is 600mg twice daily. Well-designed phase III studies in patients with ALK-positive NSCLC showed that during up to ≈ 19months' follow-up, progression-free survival (PFS) was significantly improved with alectinib relative to crizotinib as first-line therapy (ALEX study), and relative to chemotherapy in patients previously treated with crizotinib and platinum-doublet chemotherapy (ALUR study). Central nervous system (CNS)-related outcomes were significantly improved with alectinib in both these settings. Two phase II registrational studies (NP28673 and NP28761) in patients previously treated with crizotinib also demonstrated the efficacy of alectinib, as assessed by objective response rates (ORRs), during up to 21months' follow-up. Overall, alectinib had a manageable tolerability profile in these settings, with most adverse events (AEs) of mild or moderate severity. Current evidence indicates that alectinib is an important treatment option for patients with advanced ALK-positive NSCLC who are previously untreated or those previously treated with crizotinib. Given its efficacy and tolerability, current guidelines include alectinib as a treatment option in these settings, with the NCCN guidelines recommending it as a preferred option for first-line therapy.

Alectinib for advanced ALK-positive non-small-cell lung cancer.

The pharmacology, pharmacokinetics, clinical efficacy, safety and tolerability, dosage and administration, and place in therapy of alectinib for treatment of patients with non-small-cell lung cancer (NSCLC) are reviewed. In patients with NSCLC driven by mutations of ALK, the gene coding for anaplastic lymphoma kinase (ALK), treatment with the ALK inhibitor crizotinib has been found to provide median progression-free survival (PFS) of 10.9 months; however, therapeutic failures and tumor progression to brain metastases are common with crizotinib use, prompting research to find more potent and tolerable ALK inhibitors that target major oncogenic drivers of NSCLC. Alectinib is a next-generation ALK inhibitor initially approved by the Food and Drug Administration for use in patients with metastatic ALK-positive NSCLC who are intolerant of or have disease progression during crizotinib therapy. In clinical trials, alectinib was found effective for delaying disease progression and, more importantly, reducing brain metastases in patients with NSCLC who developed resistance or intolerance to previous crizotinib therapy. Published data from clinical trials indicate that the most common grade 1 and 2 adverse effects associated with alectinib use are fatigue, constipation, peripheral edema, and myalgia; the most common grade 3 or 4 reactions include increases in creatine phosphokinase, alanine aminotransferase, and aspartate aminotransferase levels. Alectinib appears to be effective and safe for use in patients with metastatic ALK-positive NSCLC, with demonstrated superiority over crizotinib in terms of PFS rates. Research to better define ALK inhibitor resistance mechanisms and alectinib's place in therapy is ongoing.

Brigatinib: First Global Approval

Brigatinib (ALUNBRIG™) is a small molecule antineoplastic anaplastic lymphoma kinase (ALK) inhibitor being developed by ARIAD Pharmaceuticals (a wholly-owned subsidiary of Takeda Pharmaceutical Company). In April 2017 brigatinib received accelerated approval in the USA for the treatment of patients with ALK-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. The development of resistance to crizotinib is a therapeutic challenge that has led to the development of second-generation ALK-inhibitors such as brigatinib, which have activity against treatment-resistant ALK mutants. This article summarizes the milestones in the development of brigatinib leading to this first global approval for the treatment of patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib.

Monitoring for and Characterizing Crizotinib Progression: A Chart Review of ALK-Positive Non-Small Cell Lung Cancer Patients.

Crizotinib is recommended as first-line therapy for ALK-positive non-small cell lung cancer (NSCLC), but within a year of treatment initiation many patients develop resistance. With the recent approval of second-generation ALK inhibitors, this study assessed how physicians monitor for and diagnose progression and how they alter treatment following progression on crizotinib. A panel of oncologists from the United States were surveyed regarding their monitoring practices and criteria for diagnosing progression on crizotinib. The physicians also retrospectively provided data (March-June 2016) from the medical charts of their adult patients with locally advanced or metastatic ALK-positive NSCLC who progressed on crizotinib after the approval (April 2014) of the first second-generation ALK inhibitor, ceritinib. A total of 28 physicians responded to the survey. Data was abstracted on 74 patients. In the physician survey, most physicians (71%) reported monitoring for radiographic progression every 3-4months. When new lesions were detected, physician response varied. Following a symptomatic isolated lesion, most physicians (75%) would add local therapy and resume crizotinib. Following multiple symptomatic lesions, 96% and 64% of physicians would switch to a new therapy depending on whether the lesions were extracranial or isolated to the brain, respectively. For the patient cohort, physician-defined progression on crizotinib was diagnosed after a median of 10months, and within 30days of diagnosis, 86% of patients discontinued crizotinib. Among all patients who discontinued crizotinib, 77% switched to ceritinib, 14% to chemotherapy, and 1% to alectinib. The remaining 7% did not receive additional systemic antineoplastic therapy. The findings from this physician survey and retrospective chart review study suggest that physician response to the development of new lesions in crizotinib-treated ALK-positive NSCLC patients varies with location and extent of the lesions. Once patients were considered to have progressed, most of them were immediately switched to ceritinib. Novartis Pharmaceuticals Corporation.

Treatment Patterns and Early Outcomes of ALK-Positive Non-Small Cell Lung Cancer Patients Receiving Ceritinib: A Chart Review Study.

This study aimed to provide the first real-world description of the characteristics, treatments, dosing patterns, and early outcomes of patients with ALK-positive non-small cell lung cancer (NSCLC) who received ceritinib in US clinical practice. US oncologists provided data from medical charts of adult patients diagnosed with locally advanced or metastatic ALK-positive NSCLC who received ceritinib following crizotinib. Patient characteristics, treatment patterns, ceritinib dosing, early outcomes, and occurrence of gastrointestinal adverse events (AEs) by dose and instructions on food intake were assessed, and Kaplan-Meier analysis was used to describe clinician-defined progression-free survival (PFS) on ceritinib. Medical charts of 58 ALK-positive NSCLC patients treated with ceritinib were reviewed (median age 63years; 41% male; 21% with prior chemotherapy experience). At ceritinib initiation, 44 patients had multiple distant metastases, most commonly in the liver (60%), bone (53%), and brain (38%). Initial ceritinib dose varied: 71% received 750mg, 19% 600mg, and 10% 450mg. Although median follow-up after ceritinib initiation was short (3.8months), most patients achieved either a complete or partial response (69%) on ceritinib, regardless of metastatic sites present at initiation or initial dose. Median PFS on ceritinib was 12.9months. 17% of patients had a gastrointestinal AE reported during follow-up. The majority of events occurred in patients instructed to fast; no patients instructed to take a lower dose of ceritinib with food reported gastrointestinal AEs. These early findings of ceritinib use in clinical practice suggest that ceritinib is effective at treating crizotinib-experienced ALK-positive NSCLC patients, regardless of metastatic sites or initial dose, and dosing ceritinib with food may lead to fewer gastrointestinal AEs. Future studies with larger sample size and longer follow-up are warranted, including an ongoing randomized trial to assess the gastrointestinal tolerability of ceritinib 450 and 600mg with low-fat meals. Novartis Pharmaceutical Corporation.

Brigatinib for the treatment of ALK-positive advanced non-small cell lung cancer patients.

Brigatinib (AP-26113, Alunbrig) is a second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) that is highly active in non-small cell lung cancer (NSCLC) harboring ALK translocation. Brigatinib was found to be very active against different ALK resistance mutations that mediate acquired resistance biology processes, particularly G1269A ALK C1156Y, I1171S/T, V1180L and others. Different clinical trials evaluated the activity of brigatinib in crizotinib-resistant patients, confirming high activity with durable response not only in parenchymal disease, but also in intracranial disease. Nowadays, brigatinib is under evaluation in different clinical trials exploring TKI-naive patients in the first-line setting. On the basis of its significant activity results, brigatinib received approval by the FDA for the treatment of patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib.

Is there a benefit of first- or second-line crizotinib in locally advanced or metastatic anaplastic lymphoma kinase-positive non-small cell lung cancer? a meta-analysis.

BackgroundCrizotinib show a promising efficacy in patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). However, differences in efficacy for first- and second-line crizotinib are unclear.ResultsThe pooled overall response rate and progression-free survival were 65% and 9.38 months, respectively. In the subgroup analysis, first-line crizotinib showed a higher trend of overall response rate and longer trend of progression-free survival although there was no statistical difference between first-line and second-line crizotinib (74%, 11.28 months vs. 65%, 8.12 months, respectively; fixed effects model). Moreover, overall response rate between Asians and Caucasians were similar (67% and 66%, respectively; fixed effects model).Materials and MethodsA comprehensive search of MEDLINE, EMBASE, WEB OF SCIENCE and the COCHRANE databases from their inception to February 2016 was performed to identify clinical trials in English-language journals. Pooled overall response rate, progression-free survival and differences between first- and second-line crizotinib were estimated. Moreover, overall response rate between Asians and Caucasians were also estimated.ConclusionsFirst-line crizotinib may more effective than second-line crizotinib for patients with locally advanced or metastatic ALK-positive NSCLC.

New treatment options for ALK+ advanced non-small-cell lung cancer: critical appraisal of ceritinib.

Rearrangements in ALK gene and EML4 gene were first described in 2007. This genomic aberration is found in about 2%–8% of non-small-cell lung cancer (NSCLC) patients. Crizotinib was the first ALK tyrosine kinase inhibitor licensed for the treatment of metastatic ALK-positive NSCLC based on a randomized Phase III trial. Despite the initial treatment response of crizotinib, disease progression inevitably develops after approximately 10 months of therapy. Different resistance mechanisms have recently been described. One relevant mechanism of resistance is the development of mutations in ALK. Novel ALK tyrosine kinase inhibitors have been developed to overcome these mutations. Ceritinib is an oral second-generation ALK inhibitor showing clinical activity not only in crizotinib-resistant ALK-positive NSCLC but also in treatment-naïve ALK-positive disease. In this paper, preclinical and clinical data of ceritinib are reviewed, and its role in the clinical setting is put into perspective.

Proactive management strategies for potential gastrointestinal adverse reactions with ceritinib in patients with advanced ALK-positive non-small-cell lung cancer.

Anaplastic lymphoma kinase (ALK) gene fusions occur in 3%–7% of non-small-cell lung cancer (NSCLC) cases. Ceritinib, a once-daily, oral ALK inhibitor, has activity against crizotinib-resistant and crizotinib-naïve NSCLC, including brain metastases. Ceritinib (Zykadia™) was granted accelerated approval by the US Food and Drug Administration in 2014 for treating crizotinib-resistant ALK-positive NSCLC. Adverse events (AEs), particularly gastrointestinal (GI) AEs, are commonly experienced at the recommended dose of 750 mg/d and ∼38% of patients require dose interruption or reduction for GI AEs. This case study details our experience with the use of proactive GI AE management regimens in patients treated with ceritinib (750 mg/d) across two study sites. Proactive Regimens A and B were implemented in patients with metastatic ALK-positive NSCLC treated with ceritinib to manage drug-related GI AEs. Regimen A comprised ondansetron and diphenoxylate/atropine or loperamide, taken 30 minutes prior to ceritinib dose. Regimen B included dicyclomine (taken with the first ceritinib dose), ondansetron (taken 30 minutes prior to ceritinib dose for the first seven doses), and loperamide (taken as needed with the onset of diarrhea). The proactive medications were tapered off depending on patient tolerability to ceritinib. Nine patient cases are presented. Starting Regimens A or B before the first dose of ceritinib, or as soon as GI symptoms were encountered, prevented the need for dose reduction due to GI toxicity in eight of the nine patients. Using these regimens, 78% of patients were able to remain on 750 mg/d fasting. Two patients received 23 months and 16 months of therapy and remain on ceritinib 750 mg/d and 600 mg/d, respectively. Although not currently recommended or implemented in clinical studies, based on the patients evaluated here, upfront or proactive treatment plans that address AEs early on can allow the majority of patients to remain on the approved 750 mg/d ceritinib dose.

Personalized treatment options for ALK-positive metastatic non-small-cell lung cancer: potential role for Ceritinib.

The fusion of echinoderm microtubule-associated protein-like 4 with the anaplastic lymphoma kinase (EML4-ALK) is found in 3%–7% of non-small-cell lung cancer (NSCLC) cases and confers sensitivity to crizotinib, the first United States Food and Drug Administration (FDA)-approved ALK inhibitor drug. Although crizotinib has an excellent initial therapeutic effect, acquired resistance to this drug invariably develops within the first year of treatment. Resistance may involve secondary gatekeeper mutations within the ALK gene interfering with crizotinib–ALK interactions, or compensatory activation of aberrant bypass signaling pathways. New therapeutic strategies to overcome crizotinib resistance are needed. Ceritinib, a second-generation ALK inhibitor, overcomes several crizotinib-resistant ALK mutations and has demonstrated efficacy against tumor growth in several in vitro and in vivo preclinical models of crizotinib resistance. Notably, the dose-escalation Phase I ASCEND-1 trial has shown a marked activity of ceritinib in both crizotinib-naïve and crizotinib-resistant ALK-rearranged lung cancer. The overall response rate was 58% in a subgroup of patients with ALK-rearranged late-stage NSCLC. Drug discontinuation rate due to toxicity was 10%. The standard dose was established at 750 mg daily. This paper outlines the pathogenesis and treatment of ALK-positive lung cancer, focuses on the preclinical and clinical results surrounding the accelerated FDA approval of ceritinib for the treatment of ALK-positive metastatic NSCLC patients who have progressed on/or are crizotinib intolerant, and discusses the potential efforts seeking to maximize ceritinib efficacy and expand its usage to other indications in cancer therapy.

Ceritinib: a new tyrosine kinase inhibitor for non-small-cell lung cancer.

To review ceritinib for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small-cell lung cancer (NSCLC). Literature searches were conducted in PubMed, EMBASE (1974 to July week 5, 2014), and Google Scholar using the terms ceritinib, LDK378, and non-small-cell lung cancer. One phase 1 trial and 2 abstracts were identified. Ceritinib is approved for the treatment of ALK-positive metastatic NSCLC in patients who are intolerant to or have progressed despite therapy with crizotinib. In the phase 1 clinical trial, the maximum tolerated dose was determined to be 750 mg once daily. The overall response rate (ORR) was 58% (95% CI = 48-67) in patients who received ≥400 mg daily (n = 114). In this group, the ORR was 56% (95% CI = 41-67) and 62% (95% CI = 44-78) among crizotinib-exposed and -naïve patients, respectively. The ORR was 59% (95% CI = 47-70) in patients who received 750 mg daily (n = 78). The ORR was 56% (95% CI = 41-70) in crizotinib-treated patients and 64% (95% CI = 44-81) in crizotinib-naïve patients, respectively, in this subset. The median duration of response was 8.2 months. Median progression-free survival was 7.0 months. The most common adverse reactions included diarrhea, nausea, vomiting, abdominal pain, anorexia, constipation, fatigue, and elevated transaminases. Ceritinib has activity in crizotinib-resistant and crizotinib-naïve patients and appears to be a viable alternative for ALK-positive NSCLC. Long-term data are needed to further define the role of ceritinib in the treatment of NSCLC.

The efficacy and safety of crizotinib in the treatment of anaplastic lymphoma kinase-positive non-small cell lung cancer: a meta-analysis of clinical trials.

BackgroundCrizotinib was granted accelerated approval by the Food and Drug Administration in 2011 for the treatment of anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). To evaluate the efficacy and safety of crizotinib, we performed a meta-analysis of published clinical trials using the random effect model.MethodsThe efficacy and safety of crizotinib was evaluated based on 1-year overall survival (OS), progression-free survival (PFS), overall response rate (ORR), partial response, complete response, stable disease, and dose reduction or cessation because of crizotinib toxicity.ResultsSix clinical trials were included in the meta-analysis. Crizotinib treatment demonstrated a 1-year OS of 66.8% (95% CI, 52.2–78.8%) and a PFS of 8.6 months (95% CI, 7.3–9.9 months). The aggregate ORR, partial response and complete response rates were 61.2%, 59.8% and 1.5%, respectively. The proportion of patients achieving stable disease was 42.6% (95% CI, 17.3–72.5%). The most frequently reported adverse effects of crizotinib were mild visual disturbances, nausea, vomiting, diarrhea, constipation, edema, reduction in glomerular filtration rate, and generally reversible but sometimes severe elevations in aspartate aminotransferase and alanine aminotransferase. The proportion of patients who required dose reduction or cessation because of crizotinib toxicity was 6.5% (95% CI, 4.1–10.1%).ConclusionsThis meta-analysis revealed extended survival and improved response rates in patients treated with crizotinib. As a novel, targeted anticancer agent, crizotinib appears to be a favorable treatment option for patients with locally advanced or metastatic ALK-positive NSCLC.

Ceritinib: First Global Approval

Ceritinib is an oral anaplastic lymphoma kinase (ALK) inhibitor developed by Novartis for the treatment of tumours characterised by genetic abnormalities in ALK. ALK is a member of the insulin receptor family of tyrosine kinases that can become oncogenic when fused to other proteins. Ceritinib has been approved in the US under 'Breakthrough Therapy' designation for the second-line treatment of ALK-positive non-small cell lung cancer (NSCLC). Regulatory submissions have also been made in the EU and other countries. Phase III development is ongoing worldwide to evaluate ceritinib both as a first- and second-line therapy for ALK-positive NSCLC. This article summarizes the milestones in the development of ceritinib leading to this first approval for the treatment of patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib.

U.S. Food and Drug Administration Approval: Crizotinib for Treatment of Advanced or Metastatic Non–Small Cell Lung Cancer That Is Anaplastic Lymphoma Kinase Positive

On August 26, 2011, the U.S. Food and Drug Administration (FDA) approved crizotinib (XALKORI Capsules, Pfizer Inc.) for treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK) positive as detected by an FDA-approved test. The Vysis ALK Break-Apart FISH Probe Kit (Abbott Molecular, Inc.) was approved concurrently. In two multicenter, single-arm trials, patients with locally advanced or metastatic ALK-positive NSCLC previously treated with one or more systemic therapies received crizotinib orally at a dose of 250 mg twice daily. In 119 patients with ALK-positive NSCLC by local trial assay, the objective response rate (ORR) was 61% [95% confidence intervals (CI), 52%-70%] with a median response duration of 48 weeks. In 136 patients with ALK-positive NSCLC by the to-be-marketed test, the ORR was 50% (95% CI, 42%-59%) with a median response duration of 42 weeks. The most common adverse reactions (≥25%) were vision disorder, nausea, diarrhea, vomiting, edema, and constipation. Accelerated approval was granted on the basis of the high ORRs and durable responses. On November 20, 2013, crizotinib received full approval based on an improvement in progression-free survival in patients with metastatic ALK-positive NSCLC previously treated with one platinum-based chemotherapy regimen.

Targeted therapies for the treatment of non-small cell lung cancer: Bull’s eye or missed target?

3074 Background: Targeted drugs approved for advanced non-small cell lung cancer (NSCLC) include bevacizumab [(monoclonal antibody directed against vascular endothelial growth factor-A (VEGF-A)], erlotinib [(an epidermal growth factor receptor kinase (EGFR) inhibitor)] and crizotinib [(an anaplastic lymphoma kinase (ALK) inhibitor)]. The development programs for erlotinib and bevacizumab did not prospectively employ in vitro diagnostic tests to select patients (pts). Post-hoc exploratory analyses for bevacizumab based on VEGF-A levels have not identified subgroups with differential treatment effects: however for erlotinib, pts with activating EGFR mutations had greater improvement in overall response rates (ORR) and progression-free survival. Crizotinib is the first targeted therapy for NSCLC in which pts were selected using an analytically validated investigational test for ALK translocations. Crizotinib received accelerated approval on August 26, 2011 for the treatment of pts with locally advanced or metastatic ALK-positive NSCLC as detected by an FDA-approved test (Vysis ALK Break Apart FISH Probe Kit) that was approved by FDA on the same day. Methods: NDA file for crizotinib was examined. Results: Two single arm trials assessing efficacy of crizotinib monotherapy in ALK positive pts showed ORR of 61% and 50%. At FDA’s request, a cohort of 23 pts that tested negative for the ALK translocation evaluated showed ORR of 26%. Two additional pts had a single assessment and, if confirmed, the response rate would be 37% in this “marker negative” subgroup. Further exploration of this subgroup is a postmarketing commitment. Conclusions: Evaluation of target status (positive or negative) in all pts provides optimal information to guide clinical practice. As observed with crizotinib, responses may be observed in the “marker negative” subgroup. This unexpected finding may reflect the drug’s activity via alternate pathways, selection of a suboptimal biomarker for assessing ALK activation, or selection of a suboptimal cut-point for positive/negative. Accurate diagnostic tests will facilitate drug development with possible greater observed treatment effect and potentially smaller clinical trials.