scholarly journals Alectinib in the treatment of ALK-positive metastatic non-small cell lung cancer: clinical trial evidence and experience with a focus on brain metastases

2019 ◽  
Vol 13 ◽  
pp. 175346661983190 ◽  
Author(s):  
Pascale Tomasini ◽  
Julie Egea ◽  
Maxime Souquet-Bressand ◽  
Laurent Greillier ◽  
Fabrice Barlesi
Keyword(s):  
Lung Cancer ◽  
Clinical Trial ◽  
Brain Metastases ◽  
Small Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
Alk Inhibitor ◽  
Clinical Trial Evidence ◽  
Alk Positive ◽  
Trial Evidence

Molecular profiling of metastatic nonsquamous non-small cell lung cancer (NSCLC) is required to guide the treatment strategy. Anaplastic lymphoma kinase ( ALK) gene rearrangements are found in approximately 5% of lung adenocarcinomas and are associated with specific clinical features including a high risk of brain metastases. Crizotinib was the first ALK inhibitor developed and it demonstrated improved outcomes in patients with ALK-positive advanced NSCLC in comparison with chemotherapy. However, despite an initial response, all ALK-positive NSCLC patients develop acquired resistance to crizotinib. Because the most frequent mechanism of resistance is the development of a secondary ALK mutation, second (ceritinib, alectinib, brigatinib) and third-generation (lorlatinib) ALK inhibitors were developed. Alectinib is a second-generation ALK inhibitor and was shown to be effective for a broad spectrum of ALK rearrangements and ALK mutations. It was also shown to have high intracranial efficacy. In this article, we review clinical trial evidence of alectinib efficacy as well as publications reporting the experience of alectinib in daily practice, with a focus on brain metastases.

scholarly journals ALK-Brain Prognostic Index—Preliminary Study of a Prognostic Tool for Patients with ALK-Rearranged, Non-small Cell Lung Cancer and Brain Metastases

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1804
Author(s):  
Georgios Tsakonas ◽  
Caroline Kamali ◽  
Luigi De Petris ◽  
Signe Friesland ◽  
Rolf Lewensohn ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Brain Metastases ◽  
Small Cell Lung Cancer ◽  
Prognostic Index ◽  
Small Cell ◽  
Prognostic Scores ◽  
Small Cell Lung ◽  
Prognostic Tool ◽  
Prognostic Group ◽  
Alk Positive

Background: Disease-specific Graded Prognostic Assessment (DS-GPA) is the most validated prognostic tool for patients with brain metastasized lung cancer. The Lung-molGPA scoring system was recently introduced for oncogenic-driven brain metastasized lung cancer, but has not yet been validated in cohorts including only ALK-translocated tumors. Methods: We designed a retrospective cohort study consisting of 44 patients with brain metastasized ALK-positive, non-small cell lung cancer (NSCLC) who were treated between January 2009 and November 2019 at Karolinska University Hospital in Stockholm, Sweden. Information about demographics and clinicopathological parameters were collected. Predictors of overall survival (OS) were identified by Cox regression analyses. A bootstrap validation with 1000 samples was performed in order to compare the different prognostic scores. Results: The variables found to independently influence OS in the multivariate analysis, i.e., PS, sex and brain metastases at diagnosis, were used as prognostic variables in our new prognostic index (ALK-BPI). Patients were divided into two prognostic groups. The median OS was 65.7 months for the good prognostic group and 22.7 months for the poor prognostic group (p = 0.0068). In the univariate analysis of the different prognostic scores, ALK-BPI performed better than the others (HR = 3.6; 95% CI: 1.3–9.9). The mean C-statistics of the different prognostic scores were compared to each other, and no significant difference was observed. Conclusion: We propose the ALK-BPI score as a new prognostic tool that can easily be applied for ALK-positive lung cancer patients with brain metastases in daily clinical practice, as it has at least the same prognostic value as Lung-molGPA.

scholarly journals Brigatinib Versus Crizotinib in Advanced ALK Inhibitor–Naive ALK-Positive Non–Small Cell Lung Cancer: Second Interim Analysis of the Phase III ALTA-1L Trial

2020 ◽  
Vol 38 (31) ◽  
pp. 3592-3603 ◽  
Author(s):  
D. Ross Camidge ◽  
Hye Ryun Kim ◽  
Myung-Ju Ahn ◽  
James C. H. Yang ◽  
Ji-Youn Han ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Interim Analysis ◽  
Small Cell ◽  
Phase Iii ◽  
Small Cell Lung ◽  
Once Daily ◽  
Alk Inhibitor ◽  
Alk Positive

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.

Long-term clinical outcomes of ALK inhibitors in patients with ALK-positive advanced non-small cell lung cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20542-e20542
Author(s):  
Haruyasu Murakami ◽  
Akira Ono ◽  
Kazuhisa Nakashima ◽  
Shota Omori ◽  
Kazushige Wakuda ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Clinical Outcomes ◽  
Advanced Nsclc ◽  
Small Cell ◽  
Small Cell Lung ◽  
Alk Inhibitors ◽  
Alk Inhibitor ◽  
Alk Positive

e20542 Background: Anaplastic lymphoma kinase (ALK) inhibitors show high clinical efficacy in patients with ALK-positive advanced non-small cell lung cancer (NSCLC). However, the long-term clinical outcomes remain unknown. Methods: We retrospectively reviewed medical records of patients with ALK inhibitor-naïve ALK-positive advanced NSCLC who initiated alectinib or crizotinib therapy at the Shizuoka Cancer Center between June 2010 and December 2011. Results: This retrospective study included 14 patients (male/female, 5/9; PS 0/1, 6/8; adenocarcinoma/adenosquamous carcinoma, 13/1; smoker/never smoker, 8/6; brain metastasis presence/absence, 5/9; number of prior chemotherapy regimens 0/1/≥2, 1/7/6; alectinib/crizotinib, 4/10) with a median age of 55 years (range, 28-71). At the data cut-off (January 16, 2017), three patients were still receiving first ALK inhibitors (alectinib in two patients and crizotinib in one). One patient requested the discontinuation of alectinib therapy after five years. One patient discontinued crizotinib therapy due to unacceptable toxicity. Nine patients discontinued first ALK inhibitors due to disease progression. The overall response rate was 78.6% with complete response in two patients (14.3%), partial response in nine (64.3%), stable disease in one (7.1%), and progressive disease in two (14.3%). The median progression-free survival (PFS) for all 14 patients was 15.3 months, and the five-year PFS rate was 35.7%. The five-year PFS rates in patients treated with alectinib and crizotinib were 75.0% and 20.0%, respectively. The median overall survival (OS) for all 14 patients was 36.8 months, and the five-year OS rate was 42.9%. The five-year OS rates in patients treated with alectinib and crizotinib were 75.0% and 30.0%, respectively. Conclusions: ALK inhibitors showed favorable long-term clinical outcomes in patients with ALK inhibitor-naïve ALK-positive advanced NSCLC, especially in patients treated with alectinib.

scholarly journals Economic impact of preventing brain metastases with alectinib in ALK-positive non-small cell lung cancer

Lung Cancer ◽  
2018 ◽  
Vol 119 ◽  
pp. 103-111 ◽  
Author(s):  
C. Burudpakdee ◽  
W. Wong ◽  
A. Seetasith ◽  
F.A. Corvino ◽  
W. Yeh ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Brain Metastases ◽  
Small Cell Lung Cancer ◽  
Economic Impact ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
Alk Positive

scholarly journals Three-Year Follow-Up of an Alectinib Phase I/II Study in ALK-Positive Non–Small-Cell Lung Cancer: AF-001JP

2017 ◽  
Vol 35 (14) ◽  
pp. 1515-1521 ◽  
Author(s):  
Tomohide Tamura ◽  
Katsuyuki Kiura ◽  
Takashi Seto ◽  
Kazuhiko Nakagawa ◽  
Makoto Maemondo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Phase Ii ◽  
Small Cell ◽  
Tumor Shrinkage ◽  
Small Cell Lung ◽  
Cancer Symptoms ◽  
Alk Inhibitor ◽  
Alk Positive

Purpose Alectinib is an anaplastic lymphoma kinase (ALK) –specific kinase inhibitor that seems to be effective against non–small-cell lung cancer (NSCLC) with a variety of ALK mutations. The primary analysis of AF-001JP reported a promising overall response rate. To assess progression-free survival (PFS) and overall survival (OS), patients from the phase II part of AF-001JP were followed up for approximately 3 years. Patients and Methods Oral alectinib 300 mg was administered twice per day to patients with ALK inhibitor–naïve, ALK-positive NSCLC who had progressed after one or more regimens of previous chemotherapy. In this long-term follow-up, efficacy (PFS, OS), correlation between tumor shrinkage and PFS, safety of alectinib, and relief of cancer symptoms were evaluated. Results At the updated data cutoff (September 10, 2015; first patient in August 30, 2011, last patient in April 18, 2012), 25 of 46 phase II patients were still receiving alectinib. Disease progression was confirmed in 18 patients (39%); median PFS was not reached (3-year PFS rate, 62%; 95% CI, 45 to 75). Fourteen patients had brain metastases at baseline; of these, 6 remained in the study without CNS and systemic progression. Tumor shrinkage and PFS showed no correlation. The 3-year OS rate was 78% (13 events). The most common treatment-related adverse event (all grades) was increased blood bilirubin (36.2%). Most cancer symptoms were relieved early, and medication for symptoms was dramatically decreased during alectinib therapy. Conclusion Alectinib was effective in this 3-year follow-up with a favorable safety profile over a long administration period in ALK-positive NSCLC without previous ALK inhibitor treatment.

SAF-189s in previously treated patients with advanced ALK-rearranged non-small cell lung cancer (NSCLC): Results from the dose-finding portion in a single-arm, first-in-human phase I/II study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21689-e21689 ◽  
Author(s):  
Jin-Ji Yang ◽  
Jianying Zhou ◽  
Nong Yang ◽  
Zhuli Wu ◽  
Juan Sun ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Systemic Therapy ◽  
Small Cell ◽  
Small Cell Lung ◽  
Cns Metastases ◽  
Alk Inhibitor ◽  
Alk Positive ◽  
Prior Systemic Therapy

e21689 Background: Patients(pts) with ALK-rearranged non-small cell lung cancer (NSCLC) are sensitive but progress in 8–11 months with treatment of ALK inhibitor crizotinib, with leading progression in brain metastasis. SAF-189s is a novel and selective ALK inhibitor, can penetrate through blood brain barrier, and overcome multiple resistance mutation. This study aimed to explore the safety, efficacy, and pharmacokinetic properties of SAF-189s in patients with advanced ALK-rearranged NSCLC. Methods: In this multicenter I/II study, SAF-189s was orally administered under fasting condition at doses ranging from 20–210 mg once daily in a 21-day cycle to 36 pts with advanced ALK-positive NSCLC who had failed to prior systemic therapy. In this analysis report, anti-tumor activity of SAF-189s was evaluated in 34 pts received 40(n = 6), 80(n = 8), 120(n = 8), 160(n = 9) and 210(n = 3) mg doses daily. Safety was evaluated in all 36 pts who received ≥1 treatment. This study is registered with clinicaltrials.gov, NCT04237805. Results: 36 pts were enrolled in total, 22 pts had CNS metastases at baseline and 26 pts had progressed to prior TKIs therapy. There was no treatment-related SAE among the 36 pts. The most common drug-related events were nausea (14 [38.9%] of 36 pts), vomiting (10[27.8%] of 36 pts), QT prolongation (9 [25.0%] of 36 pts), sinus bradycardia (7 [19.4%] of 36 pts), ALT increase (10 [27.8%] of 36 pts), diarrhea (6 [16.7%] of 36 pts). Only one DLT of grade 3 blood glucose increase occurred at 210 mg out of the first 3 pts, so another 3 pts will be enrolled to determine RP2D/MTD. SAF-189s had shown response in the starting dose of 20mg, with 1of 2 pts achieving partial response (PR) over 43 cycles until clinical data cut off. All 34 pts in efficacy analysis set had achieved tumor shrinkage, with 17 confirmed PR (50%) (95% CI, 32.4–67.6%) and 4 unconfirmed PR (11.7%). 11 (45.8%) pts had confirmed PR among 24 pts who had failed to Crizotinib or Ceritinib and 10 (47.6%) pts had confirmed PR among 21pts who had CNS metastases. PFS data is pre-mature, with only median PFS of the 80 mg cohort being inferred as 19.42 months. Conclusions: In the dose-escalation portion of this study, SAF-189s was safe, very tolerable, and demonstrated both systemic and intracranial activity in pts with advanced ALK-positive NSCLC who had failed to at least 1 prior systemic therapy. Therefore, this study warrants further investigation to prove SAF-189s as an effective therapeutic option for pts who have ALK+ NSCLC. Clinical trial information: NCT04237805.

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