Generation Anaplastic Lymphoma Kinase Research Articles

Lorlatinib as a first-line treatment of adult patients with anaplastic lymphoma kinase-positive advanced non-small cell lung cancer: Α cost-effectiveness analysis in Greece

ABSTRACT Objectives To evaluate the cost-effectiveness of lorlatinib compared to 1st generation anaplastic lymphoma kinase (ALK) TKI crizotinib, and 2nd generation TKIs alectinib and brigatinib, for previously untreated patients with ALK+ advanced Non-Small Cell Lung Cancer (aNSCLC). Methods A partitioned survival model was locally adapted from a Greek payer perspective over a lifetime horizon. Clinical, safety and utility data were extracted from literature. Direct medical costs reflecting the year 2023 were included in the analysis (€). Model outcomes were patients’ life years (LYs), quality-adjusted life years (QALYs), total costs and incremental cost-effectiveness ratios (ICERs). Results Total cost per patient with lorlatinib, alectinib, crizotinib, and brigatinib was estimated to be €188,205, €183,343, €75,028, and €145,454 respectively. Lorlatinib appeared to yield more LYs and QALYs gained versus alectinib, crizotinib, and brigatinib. Hence, lorlatinib resulted in ICERs of €4,315 per LY gained and €4,422 per QALY gained compared to alectinib, €34,032 per LY gained and €48,256 per QALY gained versus crizotinib and €16,587 per LY gained and €26,271 per QALY gained compared to brigatinib. Conclusion Lorlatinib provides substantial clinical benefit and appears to be a cost – effective treatment option compared to 1st and 2nd generation TKIs for previously untreated patients with ALK+ aNCSLC in Greece.

979P Long-term intracranial safety and efficacy analyses from the phase III CROWN study

Updated results from the ongoing phase III CROWN study (NCT03052608) confirmed the durable systemic and intracranial (IC) benefit of lorlatinib (LOR), a 3rd generation anaplastic lymphoma kinase (ALK) inhibitor, vs crizotinib (CRIZ) in patients (pts) with treatment-naive ALK-positive non-small cell lung cancer. The 3-year follow up evaluated long-term IC safety and efficacy of LOR (data cutoff 20 September 2021).

MO100: Alectinib-Induced Reversible Acute Kidney Injury

Abstract BACKGROUND AND AIMS Alectinib is a second generation anaplastic lymphoma kinase (ALK) tyrosine inhibitor approved for ALK-positive lung adenocarcinoma. This drug may be associated with acute kidney injury, mainly causing acute tubular necrosis. Usually inducing a reversible chronic increase of serum creatinine that improves after dose reduction or suspension. Severe renal impairment is a very rare adverse effect. METHOD We report a case of 85-year-old male patient diagnosed with ALK-positive lung adenocarcinoma for which alectinib was started with a good neoplasm response. He was admitted to our hospital due to acute kidney injury, presenting with anasarca, anuria, hyperkalemia and metabolic acidosis which required emergency dialysis support. RESULTS Alectinib was discontinued, and the patient recovered from kidney function. However, subsequent re-administration of alectinib (1 month thereafter) caused a new episode of acute kidney injury, requiring new transitory dialysis therapy with new recovering kidney function after drug suspension. CONCLUSION This case is unusual due to its severe renal presentation. Thus far, there have only been two similar cases reported. Our case report shows an uncommon and severe adverse effect of alectinib, where it is found that there exists a temporal relation between alectinib exposure and acute kidney injury. Furthermore, the patient recovered from kidney function after drug discontinuation. Frequent monitoring of renal functions is important, as it allows for drug dosage adjustment, which can prevent severe AKI and reduce the morbidity of these frail patients.

Short communication: The activity of brigatinib in patients with disease progression after next generation anaplastic lymphoma tyrosine kinase inhibitors and an exploratory analysis of circulating tumor DNA

BackgroundBrigatinib, a second generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), is central nervous system (CNS) penetrant and active against anaplastic lymphoma kinase (ALK) resistance mutations. We prospectively studied the activity of brigatinib in patients with disease progression after second generation ALK TKIs. MethodsPatients with stage IIIB/IV ALK + non-small cell lung cancer (NSCLC), and progressive disease after second ALK TKIs were eligible. Cohort A enrolled patients with disease progression on any second ALK TKI, cohort B enrolled patients with disease progression after first-line therapy with alectinib, and cohort C enrolled patients who experienced disease progression on standard dose brigatinib. Brigatinib treatment was 90 mg daily for seven days and then escalated to 180 mg daily in cohorts A and B, and 240 mg daily in cohort C. The primary endpoint was objective response rate (ORR), and a 2-stage design was used. The intended enrollment was 20 patients in stage 1, and 20 patients in stage 2. ResultsThe study was closed due to slow accrual. Between March 2017 and June 2020, 32 patients received study therapy; three patients in cohort A moved to cohort C after initial progression for a total of 35 study subjects. Of the 32 patients, 16 (50%) were male, the median age was 55 years (range 32–76), and patients received a median number of 2 prior ALK TKI’s (range 1–3). Cohort A enrolled 27 patients, cohort B enrolled four patients, and cohort C enrolled four patients. The ORR in cohorts A, B, and C was 33% (95% confidence interval (CI: 16% to 54%), 25% (95% CI: 0.63% to 81%), and 0%, respectively. ConclusionBrigatinib has activity in ALK positive NSCLC patients with disease progression after second generation ALK TKIs.

Acute kidney Injury due to Alectinib, an Anaplastic Lymphoma Kinase inhibitor

Introduction: The array of unintended effects of targeted oncological treatments is still being elucidated. Cognizance of these effects is important since they allow early identification and intervention. Methods: We report a case of progressive reduction in kidney function following the introduction of the oral second generation Anaplastic Lymphoma Kinase (ALK) Inhibitor: Alectinib for the treatment of metastatic non-small cell carcinoma of the lung (NSCLC). Kidney biopsy findings suggested that the predominant manifestation was acute tubular injury, which resolved with cessation of Alectinib therapy and did not recur with the introduction of the third generation ALK inhibitor Lorlatinib. Conclusions: This case report adds to the Onco-Nephrology literature in relation to the potential nephrotoxic effects of ALK inhibitors.

I.17 ALK Genomic Aberrations in NSCLC and Clinical Implications

Anaplastic Lymphoma Kinase (ALK) genomic aberrations in NSCLC was one of the first genomic aberrations, which was successfully targeted with specific drug, e.g. crizotinib, and led to rapid development of personalized therapy in NSCLC. Crizotinib as single agent showed remarkable response (70-80%) in patients with advanced NSCLC, who had the EML-4/ALK- translocation, which occurs in 2-5% of the patients. The genomic abnormality was originally diagnosed by FISH using a defined criterion (split- apart FISH pattern in at least 15% of the cells). However, later the US FDA also approved ALK-IHC for diagnosis using the Ventana ALK-specific antibody, D5F3). Today, this genomic abnormality is mostly detected by NGS. Not only was crizotinib associated to high response rate, but also to long-term outcomes (Solomon BJ et al). However, most of the ALK-positive patients progressed, particularly in the brain. During the studies with crizotinib resistance mutations were seen Second generation ALK- targeted therapies were developed, e. g. alectinib, ceritinib and brigatinib, primarily studied after progression of crizotinib. The new generation ALK-inhibitors showed significant better effect compared to standard chemotherapy and had particularly a good penetration and effect in the CNS. Alectinib was clinically compared to crizotinib as first line therapy in two large randomized studies (J-ALEX and ALEX), and both demonstrated significantly better outcome with alectinib (updated results from ALEX-study showed HR(DFS)= 0.43 with a median disease-free survival of 27.8 months versus 22.8 months for crizotinib), which was approved based on these studies for first line therapy in ALK-positive NSCLC ( Hida T et al, Shaw A et al). Brigatinib was also developed as a second-generation agent and was compared to crizotinib in the ALTA-1 study as first line therapy (HR for PFS=0.49) (Camidge DR et al), but has never been compared to alectinib. Brigatinib was demonstrated to be clearly superior to crizotinib, both with regard to outcome as well as for CNS effect. A question is, however, whether brigatinib is equal or better than alectinib as first line therapy in ALK-positive patients. The third generation ALK-inhibitors have been developed represented by lorlatinib. Ongoing randomized studies have to demonstrate the relative role of lorlatinib compared to other generation ALK-inhibitors. The most important question on this stage is how to sequence the different generations ALK-inhibitors. At most places alectinib is adapted as first line therapy, but there is no clear consensus on what comes after alectinib when the patient is progressing. In the future guidance based on resistant mutation pattern might direct subsequent therapy, but mutation guided therapy for ALK-positive patients has still to be fully developed. The sequencing of different ALK-inhibitors are currently studied in the US national Cancer Institute launched ALK Masterprotocol. 1.Solomon BJ et al: N Engl J Med 2014; 371: 2167-2177 (Crizotinib) 2. Hida T et al: Lancet 2017 (Alectinib) 3. Peters S et al: N Engl J Med 2017: 377(9): 829-838 (Alectinib) 4. Camidge DR et al. J Thorac Oncol 2019: (7): 1233-1243 (Alectinib) 4. Soria JC et al: Lancet 2017; 389: 917-929 (Ceritinib) 5. Camidge DR et al. N Engl J Med 2018; (21): 2027-2039 (Brigatinib) 5. Shaw A et al: J Clin Oncol 2019: 37(16): 1370-1379 (Lorlatinib) Crizotinib, Ceritinib, Alectinib, Brigatinib, Lorlatinib

New generation anaplastic lymphoma kinase inhibitors.

Anaplastic lymphoma kinase (ALK) gene translocations are pro-tumoral driver alterations that encompass 3-7% of non-squamous non-small cell lung cancer (NSCLC) with specific, clinic and histologic features. The therapeutic strategy depends on anti-ALK tyrosine kinase inhibitors (TKIs) of which crizotinib was the first approved for clinical use. Despite its use improved significantly progression-free survival, overall response rate and duration of response of this illness, after a median period of 10.9 months all patients progress due to the development of acquired resistance mutations in the ALK tyrosine kinase domain in approximately one third of patients. Moreover, 60-90% of patients treated with crizotinib has a progression in the central nervous system (CNS) in absence of extracranial worsening of the disease. This is primarily attributed to poor CNS penetration by crizotinib as many pre-clinical and clinical models suggest. For instance, in order to overtake acquired resistance to crizotinib, prolong the control of the disease and manage CNS localizations, several II and III generation TKIs have been developed. Some of them were approved after the failure of crizotinib (ceritinib, alectinib, brigatinib and lorlatinib) and in first line setting (ceritinib, alectinib and brigatinib) while others are still under evaluation for TKI-naive patients such as lorlatinib, ensartinib and entrectinib. In this review we will discuss the most recent results of new TKIs in order to describe a fast growing therapeutic landscape in this setting.

<p>Brigatinib for <em>ALK</em>-positive metastatic non-small-cell lung cancer: design, development and place in therapy</p>

Despite the benefits of first and second generation anaplastic lymphoma kinase (ALK) inhibitors in the management of ALK-rearranged advanced non-small-cell lung cancer (NSCLC), the development of acquired resistance poses an ongoing dilemma. Brigatinib has demonstrated a wider spectrum of preclinical activity against crizotinib-resistant ALK mutant advanced NSCLC. The current review narrates a brief history of tyrosine kinases, the development and clinical background of brigatinib (including its pharmacology and molecular structure) and its use in ALK-positive NSCLC.

MA26.02 Upfront or Sequential Strategy for New Generation Anaplastic Lymphoma Kinase (ALK) Inhibitors: An Italian Retrospective Study.

MA26.02 Upfront or Sequential Strategy for New Generation Anaplastic Lymphoma Kinase (ALK) Inhibitors: An Italian Retrospective Study.

Progressive renal insufficiency related to ALK inhibitor, alectinib

Alectinib is a second generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor and is generally effective and tolerated in patients who have demonstrated disease progression or adverse effects while on the first generation inhibitor, crizotinib. ALK inhibitors can cause a reversible chronic increase of serum creatinine concentration; however, they rarely induce progressive renal insufficiency. We herein report a case of a 68-year-old woman diagnosed with ALK-positive advanced non-small cell lung cancer and who received ALK inhibitors. Due to dysgeusia and transaminitis, her medication was switched from crizotinib to alectinib. Rapid progressive glomerulonephritis developed 1 year after the initiation of alectinib treatment. A renal biopsy revealed unique kidney lesions in both tubules and glomeruli. Glucocorticoid therapy partially reversed kidney impairment. However, re-administration of alectinib caused kidney dysfunction, which was improved by the cessation of alectinib. Our case suggests that much attention should be paid to kidney function when using ALK inhibitors.

OA03.08 Activity of Ensartinib after Second Generation Anaplastic Lymphoma Kinase (ALK) Tyrosine Kinase Inhibitors (TKI): Topic: Medical Oncology

OA03.08 Activity of Ensartinib after Second Generation Anaplastic Lymphoma Kinase (ALK) Tyrosine Kinase Inhibitors (TKI): Topic: Medical Oncology

ALKG1269A mutation as a potential mechanism of acquired resistance to crizotinib in an ALK-rearranged inflammatory myofibroblastic tumor

Inflammatory myofibroblastic tumors are rare mesenchymal neoplasms frequently harboring oncogenic chromosomal rearrangements, most commonly, involving the ALK (anaplastic lymphoma kinase) gene. Treatment of this molecularly defined subgroup with the anaplastic lymphoma kinase inhibitor crizotinib has shown to be effective. However, comparable to lung adenocarcinoma, resistance inevitably develops. Second generation anaplastic lymphoma kinase inhibitors such as ceritinib are able to overcome acquired resistance to crizotinib. Here, we report the case of a patient with an inflammatory myofibroblastic tumors harboring a DCTN1-ALK fusion who developed resistance to crizotinib treatment. Next-generation sequencing of a rebiopsy sample revealed the acquisition of the ALKG1269A mutation as a mechanism of resistance. Therapy with ceritinib resulted in a short but profound clinical, metabolic and morphologic response. This case illustrates that (i) different tumor entities may share similar oncogenic driver mechanisms, rendering them vulnerable for the same therapeutic substances and (ii) likewise, the same mode of resistance may occur under targeted therapy among different tumor entities.

Abstract 3721: ALK inactivation induced acquired resistance to alectinib in lung cancer harboring EML4-ALK fusion gene

Abstract Dramatic clinical responses to a first generation anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (TKI) crizotinib have been observed in patients with advanced non-small cell lung cancer (NSCLC) haboring ALK fusion gene. Alectinib (CH5424802) (Chugai Pharmaceutical Co., Ltd.) is a second generation ALK-TKI could partially overcome acquired resistance to crizotinib in vitro (Cancer Cell 19, 2011: 679-90), and showed promising result in phase I/II clinical trials with high response rate (93.5 %) and less toxicity than crizotinib. However, even this promising ALK-TKI, the problem of acquired resistance is inevitable. To elucidate resistant mechanisms, we established an alectinib-resistant cell line H2228/CHR from H2228 that have echinoderm microtubule associated protein like 4 (EML4)-ALK fusion gene, by continuous exposure to this agent. ALK fusion gene disappeared in H2228/CHR, which was confirmed Western blotting, IHC, qRT-PCR and FISH. H2228/CHR cells presented higher phosphorylated levels of epidermal growth factor receptor (EGFR) than the parental H2228 cells and became more sensitive to EGFR-TKI erlotinib. Next, we established alectinib-resistant ABC-11/CHR cells from ABC-11, a cell line established from pleural effusion of EML4-ALK positive ALK-TKI naïve patient. In ABC-11/CHR cells, phosphorylated levels of ALK was markedly decreased and phosphorylated levels of MET was increased.In addition, autocrine of HGF was increased in ABC-11/CHR cells. ABC-11/CHR showed sensitivity to ALK/MET tyrosine kinase inhibitor, crizotinib in vitro and in vivo model. In conclusion, inactivation of ALK signaling induced acquired resistance to alectinib in NSCLC harboring ALK fusion gene. Signaling switch from ALK to EGFR or MET was observed in the alectinib-resistant cells. We revealed to overcome such acquired resistance using erlotinib or crizotinib. Citation Format: Hideko Isozaki, Eiki Ichihara, Masayuki Yasugi, Ochi Nobuaki, Katsuyuki Hotta, Nagio Takigawa, Toshiaki Sendo, Mitsune Tanimoto, Katsuyuki Kiura. ALK inactivation induced acquired resistance to alectinib in lung cancer harboring EML4-ALK fusion gene. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3721. doi:10.1158/1538-7445.AM2014-3721

Acquired Resistance to a New Alk Inhibitor, Alectinib in Lung Cancer

ABSTRACT Aim: Alectinib (CH/RO5424802) is a second generation anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (TKI). It has been reported to overcome acquired resistance to the first generation ALK-TKI, crizotinib, in a preclinical study (Cancer Cell 19, 2011: 679-90). A phase I/II clinical trial of alectinib for ALK positive non-small cell lung cancer (NSCLC) showed an unprecedented response rate (93.5 % in phase II portion) and the drug seemed to lead to less toxicities than crizotinib (Lancet Oncol 14, 2013: 590-98). However, subsequent resistance to alectinib is expected after its approval. Thus, we need to consider the therapeutic strategy to overcome the resistance to alectinib in advance. Methods: Two alectinib-resistant H2228/CHR and ABC-11/CHR NSCLC cell lines from H2228 and ABC-11, respectively, harboring EML4-ALK fusion genes were established by continuous exposure to alectinib. We characterized the resistant cell lines using MTT assay, western blotting, immunohistochemistry, polymerase chain reaction, fluorescent in situ hybridization, phospho-receptor tyrosine kinase array, comparative genomic hybridization, RNA array, ELISA and xenograft models. Results: H2228/CHR and ABC-11/CHR cells showed 130-fold and 17-fold higher resistance to alectinib than their respective parent cells in vitro. H2228/CHR cells had lost EML4-ALK fusion gene and ALK protein expression. In addition, the resistant cells overexpressed IGF1R, and were sensitive to IGF1R-TKI (TAE684) as a result. While ABC-11/CHR cells reduced phospho-ALK in spite of preservation of total ALK protein, they activated MET with increment of its ligand (hepatocyte growth factor) as an autocrine action. Because crizotinib originally functions as MET-TKI along with ALK-TKI, ABC-11/CHR was sensitive to the drug both in vitro and in vivo. Conclusions: Loss or inactivation of ALK leads to the acquired resistance to alectinib in the two cell lines we established. In addition, signaling switch from ALK to IGF1R or MET was observed. IGF1R inhibitor or MET inhibitor was effective on such cases. Thus, ALK positive NSCLC patients refractory to alectinib might benefit from IGF1R or MET inhibitors. Disclosure: K. Hotta: Honoraria from speaker's bureau from Chugai pharmaceutical CO., LTD.; N. Takigawa: Honoraria from speaker's bureau from Pfizer Inc. Japan; K. Kiura: Honoraria from speaker's bureau from Chugai pharmaceutical CO., LTD., Pfizer Inc. Japan and Novartis Pharma K.K. All other authors have declared no conflicts of interest.