Crizotinib: a novel and first-in-class multitargeted tyrosine kinase inhibitor for the treatment of anaplastic lymphoma kinase rearranged non-small cell lung cancer and beyond

Epidermal growth factor receptor (EGFR) tyrosine inhibitors were first approved for the treatment of non-small cell lung cancer (NSCLC) in 2003 in the US. Activating EGFR mutations were subsequently discovered in 2004, and heralded the era of molecular targeted therapy in NSCLC. The discovery of anaplastic lymphoma kinase (ALK) rearrangement in NSCLC in 2007 by two independent groups not only represents the first time ALK rearrangement has been discovered in common solid tumors but also represents another important milestone in the era of molecular targeted therapy in NSCLC. Crizotinib, a mesenchymal-epithelial transition (MET)/ALK multi-targeted receptor tyrosine kinase inhibitor went into early Phase I clinical development in 2007. Using the knowledge that NSCLC patients with activating EGFR mutations benefited from EGFR tyrosine kinase inhibitors, crizotinib was rapidly and successfully developed as an inhibitor in ALK-rearranged NSCLC, based on a break apart fluorescence in situ hybridization assay, developed by two of the crizotinib Phase I sites. It cumulated in the conditional approval of crizotinib by the US Food and Drug Administration on August 26, 2011 for the treatment of ALK-rearranged NSCLC. The conditional approval was based on response rates of 50% and 61% from 255 ALK-rearranged NSCLC patients enrolled in two single-arm trials. Common adverse events of crizotinib include mild transient visual disorders, mild gastrointestinal toxicities, fatigue, rare alanine transaminase elevations, and even rarer pneumonitis (1.6%). Confirmatory trials comparing crizotinib with standard chemotherapy are ongoing. It took an unprecedented four years from the discovery of ALK rearrangement in NSCLC to the approval of crizotinib, the first ever ALK inhibitor, for the treatment of ALK-rearranged NSCLC

ROS1 (ROS proto-oncogene 1 , receptor tyrosine kinase)

ROS1 is proto-oncogene encoding a type I integral membrane protein with receptor tyrosine kinase (RTK) activity. ROS1 is a member of the insulin receptor family and is involved in downstream signalling processes involved in cell growth and differentiation

Asymptomatic Profound Sinus Bradycardia (Heart Rate ≤45) in Non-small Cell Lung Cancer Patients Treated with Crizotinib

Abstract:Crizotinib, a dual MET/ALK inhibitor, is now in advanced clinical development for the treatment of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). We have observed several patients who developed profound but asymptomatic sinus bradycardia (HR ≤45) during the course of crizotinib treatment. Herein, we describe the clinical characteristics of three separate patients enrolled in the A8081001 trial (NCT00585195) who developed asymptomatic profound sinus bradycardia with their accompanying electrocardiogram tracings

Symptomatic CNS Radiation Necrosis Requiring Neurosurgical Resection During Treatment with Lorlatinib in ALK-Rearranged NSCLC: A Report of Two Cases.

Central nervous system (CNS) metastasis carries a significant morbidity and mortality in anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). Next-generation ALK tyrosine kinase inhibitors (TKIs) are highly CNS-penetrant and have demonstrated remarkable intracranial activity across clinical studies, and yet radiation remains the mainstay of treatment modality against CNS metastasis. We have previously reported alectinib can induce CNS radiation necrosis even after a remote history of radiation (7 years post-radiation). Lorlatinib is another potent next-generation ALK TKI that can overcome many ALK resistance mutations and has been shown to have excellent activity in patients with baseline CNS metastasis. Here we report two ALK-rearranged NSCLC patients who developed radiation necrosis shortly after initiating lorlatinib following progression on the sequential treatment of crizotinib, alectinib, and brigatinib. In both cases, radiation necrosis is evidenced by serial MRI images and histological examination of the resected CNS metastasis that had previously been radiated. Our cases highlight the importance of recognizing CNS radiation necrosis that may mimic disease progression in ALK-rearranged NSCLC treated with and potentially precipated by next-generation ALK TKIs

Treatment of Choroidal Metastasis from Epidermal Growth Factor Mutant Non-Small Cell Lung Cancer with First-line Osimertinib Therapy

Purpose: To illustrate the regression of a metastatic lesion through ophthalmic imaging and correlating findings with standard chest imaging and treatment with osimertinib, an oral chemotherapy agent specific to Epidermal Growth Factor Receptor + Non-small Cell Lung Cancer (EGFR+ NSCLC). Case Report: A 63-year-old Asian male presented to ophthalmology with a complaint of left blurry vision. Initial ophthalmic exam revealed a choroidal lesion and imaging results highlighted a spiculated lung mass with brain and bony metastases. Osimertinib was chosen for its specificity and ability to cross the blood–brain barrier. Follow-up ophthalmic and radiographic imaging were repeated over the course of treatment. Conclusion: After the initiation of osimertinib, ophthalmic and computed tomography imaging highlighted the regression of the ocular metastatic disease and primary malignancy, respectively. Osimertinib is an effective first-line treatment of EGFR+ NSCLC and corresponding metastatic sites. Additionally, ophthalmic imaging can be used to monitor general response to chemotherapy agents when ocular metastasis is identified

Efficacy of Brigatinib in Patients With Advanced ALK-Positive NSCLC Who Progressed on Alectinib or Ceritinib: ALK in Lung Cancer Trial of brigAtinib-2 (ALTA-2)

Circulating tumor DNA; Non–small cell lung cancer; Tumor biomarkerADN tumoral circulante; Cáncer de pulmón de células no pequeñas; Biomarcador tumoralADN tumoral circulant; Càncer de pulmó de cèl·lules no petites; Biomarcador tumoralIntroduction Brigatinib is a potent next-generation ALK tyrosine kinase inhibitor approved for treatment-naive and crizotinib-refractory advanced ALK-positive (ALK+) NSCLC. We evaluated brigatinib after other next-generation ALK tyrosine kinase inhibitors. Methods In this single-arm, phase 2, ALK in Lung Cancer Trial of brigAtinib-2 (NCT03535740), patients with advanced ALK+ NSCLC whose disease progressed on alectinib or ceritinib received brigatinib 180 mg once daily (after 7-d 90-mg lead-in). Primary end point was independent review committee (IRC)-assessed overall response rate (ORR). Circulating tumor DNA (ctDNA) was analyzed. Results Among 103 patients (data cutoff: September 30, 2020; median follow-up [range]: 10.8 [0.5–17.7] mo), confirmed IRC-ORR was 26.2% (95% confidence interval [CI]: 18.0–35.8), median duration of response, 6.3 months (95% CI: 5.6–not reached), and median progression-free survival (mPFS), 3.8 months (95% CI: 3.5–5.8). mPFS was 1.9 months (95% CI: 1.8–3.7) in patients with ctDNA-detectable baseline ALK fusion (n = 64). Among 86 patients who progressed on alectinib, IRC-ORR was 29.1% (95% CI: 19.8–39.9); mPFS was 3.8 months (95% CI: 1.9–5.4). Resistance mutations were present in 33.3% (26 of 78) of baseline ctDNA; 54% (14 of 26) of mutations were G1202R; 52% (33 of 64) of patients with detectable ALK fusion had EML4-ALK variant 3. Most common all-grade treatment-related adverse events were increased creatine phosphokinase (32%) and diarrhea (27%). The mean dose intensity of brigatinib (180 mg once daily) was 85.9%. Conclusions In ALK in Lung Cancer Trial of brigAtinib-2, brigatinib was found to have a limited activity in patients with ALK+ NSCLC post-ceritinib or post-alectinib therapy. mPFS was longer with brigatinib in patients without baseline detectable plasma ALK fusion

First-in-human, open-label dose-escalation and dose-expansion study of the safety, pharmacokinetics, and antitumor effects of an oral ALK inhibitor ASP3026 in patients with advanced solid tumors

Abstract Background ASP3026 is a second-generation anaplastic lymphoma kinase (ALK) inhibitor that has potent in vitro activity against crizotinib-resistant ALK-positive tumors. This open-label, multicenter, first-in-human phase I study ( NCT01284192 ) assessed the safety, pharmacokinetic profile, and antitumor activity of ASP3026. Methods Advanced solid tumor patients received oral ASP3026 in 3 + 3 dose-escalation cohorts at doses of 25–800 mg once daily in 28-day cycles. The endpoints were to identify the maximum tolerated dose (MTD), the recommended phase II dose (RP2D), and the pharmacokinetic profile of ASP3026. A phase Ib expansion cohort enrolled patients with metastatic, crizotinib-resistant ALK-positive solid tumors at the RP2D, and response was evaluated by RECIST 1.1. Results The dose-escalation cohort enrolled 33 patients, including three crizotinib-resistant, ALK-positive patients, and the dose-expansion cohort enrolled another 13 crizotinib-resistant, ALK-positive non-small cell lung cancer (NSCLC) patients. ASP3026 demonstrated both linear pharmacokinetics and dose-proportional exposure for area under the plasma concentration–time curve and maximum concentration observed with a median terminal half-life of 35 h, supporting the daily dosing. Grade 3 rash and elevated transaminase concentrations were dose-limiting toxicities observed at 800 mg; hence, 525 mg daily was the MTD and RP2D. The most common treatment-related adverse events were nausea (38 %), fatigue (35 %), and vomiting (35 %). Among the 16 patients with crizotinib-resistant ALK-positive tumors (15 NSCLC, 1 neuroblastoma), eight patients achieved partial response (overall response rate 50 %; 95 % confidence interval 25–75 %) and seven patients (44 %) achieved stable disease. Conclusions ASP3026 was well tolerated and had therapeutic activity in patients with crizotinib-resistant ALK-positive advanced tumors. Trial registration ClinTrials.gov: NCT0128419

Amivantamab compared with real-world therapies in patients with advanced non-small cell lung cancer harboring EGFR exon 20 insertion mutations who progressed after platinum-based chemotherapy

BACKGROUND: In the single-arm CHRYSALIS study, amivantamab showed durable responses and manageable safety in patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) exon 20 insertion mutations (ex20ins) who progressed on prior platinum-based chemotherapy. External controls can provide context for interpreting amivantamab efficacy. METHODS: External controls were selected from three US-based databases (ConcertAI, COTA, and Flatiron). Key inclusion criteria were diagnosis of EGFR ex20ins advanced NSCLC, prior platinum-based chemotherapy, and performance status score ≤ 1. Duplicate external controls were identified using a tokenization procedure and removed, and adjustment for differences in baseline characteristics between amivantamab-treated and external control cohorts was achieved using propensity score weighting. RESULTS: Amivantamab-treated and pooled external control cohorts included 81 and 125 patients, respectively. Baseline characteristics were generally similar across cohorts, except more amivantamab-treated patients were Asian (56% vs 13%). Most common therapies received by external controls were non-platinum-based chemotherapy (25.1%), immuno-oncology therapies (24.2%), EGFR tyrosine kinase inhibitors (16.3%), and platinum-based chemotherapy (16.3%). Overall response rate was 40% among amivantamab-treated patients and 16% among external controls. Amivantamab-treated patients had longer progression-free survival (median 8.3 vs 2.9 months; hazard ratio [HR; 95% CI]: 0.47 [0.34-0.65]), time to next therapy (median 14.8 vs 4.8 months; HR [95% CI]: 0.40 [0.28-0.57]), and overall survival (median 22.8 vs 12.8 months; HR [95% CI]: 0.49 [0.31-0.77]) than external controls. Results were consistent in sensitivity analyses comparing each external control dataset against the amivantamab-treated group separately. CONCLUSION: Among post-platinum patients with EGFR ex20ins advanced NSCLC, those treated with amivantamab had improved outcomes, including 10-month longer overall survival, versus external controls

Brief Report: Safety and Antitumor Activity of Alectinib Plus Atezolizumab From a Phase 1b Study in Advanced ALK-Positive NSCLC

INTRODUCTION: Alectinib is a preferred first-line treatment option for advanced ALK-positive NSCLC. Combination regimens of alectinib with immune checkpoint inhibitors are being evaluated for synergistic effects. METHODS: Adults with treatment-naive, stage IIIB/IV, or recurrent ALK-positive NSCLC were enrolled into a two-stage phase 1b study. Patients received alectinib 600 mg (twice daily during cycle 1 and throughout each 21-d cycle thereafter) plus atezolizumab 1200 mg (d8 of cycle 1 and then d1 of each 21-d cycle). Primary objectives were to evaluate safety and tolerability of alectinib plus atezolizumab. Secondary objectives included assessments of antitumor activity. RESULTS: In total, 21 patients received more than or equal to 1 dose of alectinib or atezolizumab. As no dose-limiting toxicities were observed in stage 1 (n = 7), the starting dose and schedule were continued into stage 2 (n = 14). Median duration of follow-up was 29 months (range: 1-39). Grade 3 treatment-related adverse events occurred in 57% of the patients, most often rash (19%). No grade 4 or 5 treatment-related adverse events were reported. Confirmed objective response rate was 86% (18 of 21; 95% confidence interval [CI]: 64-97). Median progression-free survival was not estimable (NE) (95% CI: 13 mo-NE), neither was median overall survival (95% CI: 33 mo-NE). CONCLUSIONS: The combination of alectinib and atezolizumab is feasible, but increased toxicity was found compared with the individual agents. With small sample sizes and relatively short follow-up, definitive conclusions regarding antitumor activity cannot be made