Generation Anaplastic Lymphoma Kinase Inhibitor Research Articles

Sequential analysis of cfDNA reveals clonal evolution in neuroblastoma patients receiving ALK targeted therapy.

The study of cell free DNA (cfDNA) enables sequential analysis of tumor cell-specific genetic alterations in neuroblastoma patients. Eighteen patients with relapsing neuroblastoma having received Lorlatinib, a 3rd generation ALK inhibitor, were identified (SACHA national registry and/or in the institution). cfDNA was analyzed at relapse for 9 patients, and sequentially for 5 patients (blood/bone marrow plasma) by performing WGS library construction followed by ALK-targeted ddPCR of the hotspot mutations (F1174L, R1275Q, I1170N) (variant allele fraction (VAF) detection limit 0.1%) and WES to evaluate disease burden and clonal evolution, following comparison with tumor/germline WES. Overall response rate to Lorlatinib was 33% (CI 13-59%), with response observed in 6/10 cases without versus 0/8 cases with MYCN amplification (MNA). ALK VAFs correlated with the overall clinical disease status, with a VAF<0.1% in clinical remission, versus higher VAFs (>30%) at progression. Importantly, sequential ALK ddPCR detected relapse earlier than clinical imaging. cfDNA WES revealed new SNVs, not seen in the primary tumor, in all instances of disease progression after Lorlatinib treatment, indicating clonal evolution, including alterations in genes linked to tumor aggressivity (TP53) or novel targets (EGFR). Gene pathway analysis revealed an enrichment for genes targeting cell differentiation in emerging clones, and cell adhesion in persistent clones. Evidence of clonal hematopoiesis could be observed in follow-up samples. We demonstrate the clinical utility of combining ALK cfDNA ddPCR for disease monitoring and cfDNA WES for the study of clonal evolution and resistance mechanisms in neuroblastoma patients receiving ALK targeted therapy.

Abstract 3357: Identifying mechanisms of acquired resistance to lorlatinib utilizing a genome-wide CRISPR-Cas9 screen

Abstract Survival rates for neuroblastoma (NB), a predominantly pediatric solid tumor arising from the sympathoadrenal neural crest, have improved incrementally from 25% to 50% over three decades with dramatic escalation in therapy intensity. Gain-of-function mutations in anaplastic lymphoma kinase (ALK), of which 85% occur at residues F1174, F1245, and R1275, confer inferior survival compared to patients with wild-type ALK. Lorlatinib, a third generation ALK inhibitor, has completed Phase 1 testing in the NANT Consortium and has moved to frontline therapy in the Children’s Oncology Group. The robust and sustained activity observed with minimal toxicity is transient in relapse patients harboring MYCN amplification and ALK activation. We aim to elucidate and target mechanisms of acquired resistance that emerge from lorlatinib treatment. We utilized the Brunello library, a genome-wide CRISPR-CAS9 loss of function screen targeting 19,114 genes (4 sgRNA per gene), which allows for a high confidence of detection of hits. We screened four clinically representative cell lines: Kelly (ALKF1174L, MYCN-amplified, p53P117T), SMS-SAN (ALKF1174L, MYCN-amplified), LAN5 (ALKR1275Q, MYCN-amplified), and SY5Y (ALKF1174L, MYCN-nonamplified). sgRNAs were ranked according to the degree of depletion or enrichment. We validated top depleted targets through cell-based assays and immunoblotting. We identified several actionable targets across multiple NB cell lines that, when depleted, increase the efficacy of lorlatinib, including FGFR2, BCL2L1, SOX11, SMARCA2, and SMARCD2. Genetic knockout of FGFR2 led to a 40% reduction (p&amp;lt;0.05) in KO cells upon lorlatinib treatment compared to control. PROTAC degradation of the anti-apoptotic BCL-xL (BCL2L1) revealed the combination of lorlatinib and the PROTAC led to a decrease in IC50 in vitro. Additionally, we identified conserved core components of the SWI/SNF complex, a subfamily of ATP-dependent chromatin remodelers, as well as SOX11, a regulator of the SWI/SNF complex and transcription factor of the core regulatory circuitry in adrenergic high-risk NB. In conclusion, we identified actionable targets across four NB cell lines that, when depleted, increase the efficacy of lorlatinib. Depletion of FGFR2 led to increased sensitivity to lorlatinib, however enzymatic inhibition showed minimal effect. Future investigation into dual targeting of ALK and FGFR2 through novel alternative methods is warranted. Furthermore, we observed a synergistic relationship between lorlatinib and a BCL-xL PROTAC in vitro. Ongoing in vivo studies will test the combinatorial efficacy in lorlatinib-naïve and resistant models. Finally, we are investigating epigenetic remodeling by the SWI/SNF complex and its regulators in NB cells during lorlatinib treatment through targeted genetic manipulation of SOX11 to understand its role as a master transcriptional regulator of MYCN and FGFR2. Citation Format: Joshua Renn Kalna, Smita Matkar, Emily O'Drisoll, Skye Balyasny, Matteo Calafatti, Mark Gerelus, Dave Groff, Tina Acholla, Colleen E. Casey, Paul Kamitsuka, Grant Li, Steven J. Pastor, Gabriela Witek, Kateryna Krytska, Jarrett Lindsay, Ophir Shalem, Yael P. Mossé. Identifying mechanisms of acquired resistance to lorlatinib utilizing a genome-wide CRISPR-Cas9 screen [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3357.

Insight into systematic development of ALK (anaplastic lymphoma kinase) inhibitors towards NSCLC treatment

Among cancer-related disorders, lung carcinoma is one of the leading causes of mortality. Anaplastic lymphoma kinase (ALK) belongs to tyrosine kinase receptor family and exhibits similar characteristics to insulin type receptors. The treatment of advanced non-small cell lung cancer (NSCLC) associates with ALK gene rearrangement has significantly improved since the approval of Crizotinib in 2011 as the first generation ALK inhibitor. In continuation, the second-generation drugs like ceritinib, alectinib, and brigatinib were developed to address and counteract resistance that was associated with the first-generation agents. However, resistance can develop over time, necessitating ongoing research to enhance their effectiveness. Therefore, the third-generation drug lorlatinib, which has demonstrated broad-spectrum potency against the majority of known resistance mutations and better lipophilicity, has been developed. According to current reports, the USFDA has approved five ALK-TKIs crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib for ALK-associated lung cancer. Currently, several clinical trials are underway in search of better ALK inhibitors. Trials such as TPX-0131 and NVL-655 are considered fourth-generation ALK inhibitors for the treatment of patients with advanced ALK-positive or metastatic NSCLC. This review aims to provide specifics information on research works involving various ALK tyrosine kinase inhibitors, clinical studies, and the development of ALK TKIs. Additionally, we suggest potential future strategies involving sequential therapy and combination techniques for managing non-small cell carcinoma.

1509TiP The 1825-EORTC, ALKALINE: Activity of lorlatinib based on ALK resistance mutations on blood in ALK positive NSCLC patients previously treated with second generation ALK inhibitor

1509TiP The 1825-EORTC, ALKALINE: Activity of lorlatinib based on ALK resistance mutations on blood in ALK positive NSCLC patients previously treated with second generation ALK inhibitor

Sustained Improvement in the Management of Patients with Non-Small-Cell Lung Cancer (NSCLC) Harboring ALK Translocation: Where Are We Running?

ALK translocation amounts to around 3-7% of all NSCLCs. The clinical features of ALK+ NSCLC are an adenocarcinoma histology, younger age, limited smoking history, and brain metastases. The activity of chemotherapy and immunotherapy is modest in ALK+ disease. Several randomized trials have proven that ALK inhibitors (ALK-Is) have greater efficacy with respect to platinum-based chemotherapy and that second/third generation ALK-Is are better than crizotinib in terms of improvements in median progression-free survival and brain metastases management. Unfortunately, most patients develop acquired resistance to ALK-Is that is mediated by on- and off-target mechanisms. Translational and clinical research are continuing to develop new drugs and/or combinations in order to raise the bar and further improve the results attained up to now. This review summarizes first-line randomized clinical trials of several ALK-Is and the management of brain metastases with a focus on ALK-I resistance mechanisms. The last section addresses future developments and challenges.

Third Generation ALK Inhibitors - The Development of Lorlatinib and the Problems that Exist

The malignant tumor with the greatest morbidity and fatality rates in the world today is lung cancer, from which Non-Small Cell Lung Cancer (NSCLC) accounts for 85%. To treat NSCLC, a variety of targeted therapeutics been developed in medicine. ALK inhibitors are one of them, and they're frequently used to treat NSCLC.The 3rd Generation of ALK inhibitors are now in use, starting with the initial 1st generation ALK inhibitors. Because the development of 1st and 2nd generation ALK inhibitors medicines has been motivated by a number of unfavorable factors. These medications include the 3rd generation ALK inhibitor lorlatinib as well as the 2nd and 3rd generation ALK inhibitors ceritinib and alectinib. Current study discusses the clinical features, effectiveness, and side effects of lorlatinib as well as its pharmacological effects.

ZYY-B-2, a novel ALK inhibitor, overcomes resistance to ceritinib by inhibiting P-gp function and induces apoptosis through mitochondrial pathway in ceritinib-resistant H2228 cells

Targeting the Echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase (EML4-ALK) fusion gene is a promising therapeutic strategy for non–small-cell lung cancer (NSCLC) patients. With the advent of the first- and second-generation ALK inhibitors, the mortality rate of lung cancer has shown a downward trend, but almost inevitably, patients will eventually develop resistance, which severely limits the clinical application. Hence, developing new ALK inhibitors which can overcome resistance is essential.Here, we synthesized a novel ALK inhibitor 1-[4-[[5-Chloro-4-[[2-[(1-methylethyl)sulfonyl]phenyl]amino]-2-pyrimidinyl]amino]-3-methoxyphenyl]-3-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]-2-imidazolidinone (ZYY-B-2) based on the structure of the second-generation ALK inhibitor ceritinib. ZYY-B-2 exhibited impressive anti-proliferative effect in the EML4-ALK positive H2228 cells and ceritinib-resistant H2228 (H2228/Cer) cells. Meanwhile, ZYY-B-2 inhibited the activation of p-ALK in a concentration-dependent manner, and inactivated its downstream target proteins p-AKT and p-ERK to inhibit cell proliferation. Subsequently, we found that ZYY-B-2 blocked H2228 cells and H2228/Cer cells in G0/G1 phase and induced cells to undergo apoptosis through the mitochondrial pathway. The ability of its anti-proliferation and pro-apoptosis was significantly stronger than the second generation ALK inhibitor ceritinib. In addition, high expression of P-gp was found in H2228/Cer cells compared with H2228 cells. ZYY-B-2 could inhibit the expression of P-gp in a dose-dependent manner to overcome ceritinib resistance, and the suppression effect of ZYY-B-2 on P-gp might be related to its inhibition of PI3K/AKT signaling pathway.In summary, ZYY-B-2, a promising ALK inhibitor, shows potent activity against ceritinib-resistant cells, which provides experimental and theoretical basis for the further development of new ALK inhibitors.

Treatment of lorlatinib induced hypercholesterolemia with PCSK9 inhibitors; A new solution to an emerging need in non-small cell lung cancer therapy

Lorlatinib is a third generation ALK inhibitor used in the treatment of non-small cell lung cancer. Lorlatinib invariably causes hypercholesteremia, though most patients respond to statin therapy.

Catalytic Degraders Effectively Address Kinase Site Mutations in EML4-ALK Oncogenic Fusions.

Heterobifunctional degraders, known as proteolysis targeting chimeras (PROTACs), theoretically possess a catalytic mode-of-action, yet few studies have either confirmed or exploited this potential advantage of event-driven pharmacology. Degraders of oncogenic EML4-ALK fusions were developed by conjugating ALK inhibitors to cereblon ligands. Simultaneous optimization of pharmacology and compound properties using ternary complex modeling and physicochemical considerations yielded multiple catalytic degraders that were more resilient to clinically relevant ATP-binding site mutations than kinase inhibitor drugs. Our strategy culminated in the design of the orally bioavailable derivative CPD-1224 that avoided hemolysis (a feature of detergent-like PROTACs), degraded the otherwise recalcitrant mutant L1196M/G1202R in vivo, and commensurately slowed tumor growth, while the third generation ALK inhibitor drug lorlatinib had no effect. These results validate our original therapeutic hypothesis by exemplifying opportunities for catalytic degraders to proactively address binding site resistant mutations in cancer.

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

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. A literature review of relevant randomised clinical trials was undertaken using Embase database. There were no limitations to time frame or language applied. 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. 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.

The Landscape of ALK-Rearranged Non-Small Cell Lung Cancer: A Comprehensive Review of Clinicopathologic, Genomic Characteristics, and Therapeutic Perspectives.

Simple SummaryIn recent years, prognosis of non-small cell lung cancer (NSCLC) patients significantly improved thanks to the introduction of tyrosine kinase inhibitors (TKIs) in clinical practice. ALK-rearranged NSCLC patients benefit from treatment with ALK inhibitors (ALK-i), which have shown a greater efficacy and a better intracranial activity than chemotherapy. Comparative studies between next-generation ALK-i are still lacking and clinicians are looking for reliable tools to determine which drug suits best for each patient. The aim of this review is to deepen the role of clinical and pathological characteristics influencing patients’ prognosis during treatment with ALK-i and to provide an overview of molecular mechanisms of ALK-i resistance. In this setting, liquid biopsy may play an important role in predicting tumor response and monitoring resistance mutations. We will summarize ongoing trials developing new ALK-i or combinations between ALK-i and other agents, which may represent future scenarios in the field of NSCLC research.During the last decade, the identification of oncogenic driver mutations and the introduction of tyrosine kinase inhibitors (TKIs) in daily clinical practice have substantially revamped the therapeutic approach of oncogene-addicted, non-small cell lung cancer (NSCLC). Rearrangements in the anaplastic lymphoma kinase (ALK) gene are detected in around 3–5% of all NSCLC patients. Following the promising results of Crizotinib, a first-generation ALK inhibitor (ALK-i), other second-generation and more recently third-generation TKIs have been developed and are currently a landmark in NSCLC treatment, leading to a significant improvement in patients prognosis. As clinical trials have already demonstrated high efficacy of each ALK-i, both in terms of systemic and intracranial disease control, comparative studies between second and third generation ALK-i are still lacking, and primary or secondary ALK-i resistance inevitably limit their efficacy. Resistance to ALK-i can be due to ALK-dependent or ALK-independent mechanisms, including the activation of bypass signaling pathways and histological transformation: these findings may play an important role in the future to select patients’ subsequent therapy. This review aims to provide an overview of underlying molecular alterations of ALK-i resistance and point out promising role of liquid biopsy in predicting tumor response and monitoring resistance mutations. The purpose of this review is also to summarize current approval for ALK-rearranged NSCLC patients, to help clinicians in making decisions on therapeutic sequence, and to deepen the role of clinicopathological and genomic characteristics influencing patients’ prognosis during treatment with ALK-i.

Alectinib for the treatment of pretreated RET-rearranged advanced NSCLC: Results of the ETOP ALERT-lung trial

BackgroundAlectinib, a highly selective next generation ALK-inhibitor, has exhibited potent anti-tumour activity in RET-rearranged NSCLC in the preclinical stage. MethodsALERT-lung is a single-arm, phase II trial evaluating the activity of alectinib for the treatment of pretreated RET-rearranged advanced NSCLC. Alectinib was administered orally, 600 mg, twice per day until progression, refusal or unacceptable toxicity (treatment could continue beyond progression, if patient was deriving clinical benefit). Patient recruitment closed prematurely due to discouraging results for alectinib in a phase I/II study in the same indication. ResultsAll 14 patients who enrolled until the premature accrual closure, received at lease one dose of alectinib. Among them, median age was 61 years, majority (71 %) was female, never smokers, of ECOG PS 1.No objective response (complete or partial response) was recorded. Of the 13 evaluable patients, three (23 %) achieved and maintained disease stabilisation for 24 weeks. Up to 31 March 2021 (median follow-up 15.9 months), 12 PFS-events (92 %) were observed, with median PFS of 3.7 months (95 % C.I.: 1.8 – 7.3 months). Overall, three deaths (23 %) were reported.Seven patients (50 %) experienced grade ≥ 3 adverse events, while three discontinued treatment due to erythema multiforme of grade 3, related to alectinib. No treatment-related serious adverse event was reported. ConclusionsAccrual into our trial was terminated early in response to other reports of limited activity of alectinib in patients with RET-fusion NSCLC and the emergence of more potent selective RET-inhibitors. Also in our trial, alectinib did not show the expected potential for anti-tumour activity in NSCLC.

Discovery and preclinical evaluations of WX-0593, a novel ALK inhibitor targeting crizotinib-resistant mutations

ALK gene rearrangements are oncogenic drivers in approximately 5% of NSCLC. Crizotinib, a first generation ALK inhibitor, is widely prescribed for ALK-positive NSCLC in clinic. Resistance to crizotinib and other ALK inhibitors has been problematic. Addressing resistance, here we describe discovery and development of a novel, proprietary spirocyclic diamine-substituted aryl phosphine oxide series of inhibitors, which led to the identification of WX-0593 (16a) as a potent ALK inhibitor. WX-0593 inhibited the activity of both wild type and resistant mutants of ALK in vitro, showed strong antitumor activity in a crizotinib-resistant mouse PDX model. WX-0593 is currently under development in phase II/III clinical trials.

Recommendations from Experts in the Management of Adverse Reactions to ALK Inhibitors (2021 Version)

间变性淋巴瘤激酶（anaplastic lymphoma kinase, ALK）融合基因作为肿瘤驱动基因，对非小细胞肺癌（non-small cell lung cancer, NSCLC）的发生和发展至关重要，而靶向ALK融合基因已成为ALK阳性NSCLC患者的主要治疗手段。第一、二代ALK抑制剂（ALK inhibitor, ALKi）克唑替尼、塞瑞替尼、阿来替尼、恩沙替尼已在中国上市并广泛应用。然而，针对ALKi不良反应尚无统一的管理指导规范，在一定程度上降低甚至限制了ALKi的临床使用及患者获益。本文由四川省肿瘤学会肺癌专业委员会及四川省肿瘤性疾病医疗质量控制中心牵头，针对国内已经获批上市的ALKi，参考国内外临床研究和相关文献，并结合专家实践经验，总结出《ALKi不良反应管理专家建议（2021年版）》，以期为临床提供切实可行的ALKi不良反应的管理策略。

P24.02 Unique Efficacy of Ensartinib on Different ALK Fusion Subtypes Evaluated by Plasma ctDNA

FDA has approved second generation ALK inhibitors such as alectinib, ceritinib, brigatinib for ALK-positive metastatic non-small cell lung cancer (NSCLC). Ensartinib, a next generation ALK TKI approved by NMPA in China, showed comparable efficacy to other ALK TKIs in the post-crizotinib setting. Precision therapy and clinical management need to know resistance mechanisms of TKIs and their efficacy on different ALK fusion subtypes and ALK secondary mutations. In this analysis, we investigated the unique efficacy of ensartinib on different mutations via ctDNA analysis.

The value of innovation: association between improvements in survival of advanced and metastatic non-small cell lung cancer and targeted and immunotherapy

BackgroundSignificant improvements in mortality among patients with non-small cell lung cancer (NSCLC) in the USA over the past two decades have been reported based on Surveillance, Epidemiology, and End Results (SEER) data. The timing of these improvements led to suggestions that they result from the introduction of new treatments; however, few studies have directly investigated this. The aim of this study was to investigate the extent to which population level improvements in survival of advanced and/or metastatic NSCLC (admNSCLC) patients were associated with changes in treatment patterns.MethodsWe utilized a de-identified database to select three cohorts of patients with admNSCLC: (1) patients with non-oncogene (EGFR/ALK/ROS1/BRAF) positive tumors, (2) patients with ALK-positive (ALK+) tumors, and (3) patients with EGFR-positive (EGFR+) tumors. All patients were diagnosed with admNSCLC between 2012 and 2019. Multivariable Cox models adjusting for baseline characteristics and receipt of targeted and immunotherapy were utilized to explore the relationship between these variables and changes in the hazard of death by calendar year in each cohort.ResultsWe included 28,154 admNSCLC patients with non-oncogene positive tumors, 598 with ALK+ tumors, and 2464 with EGFR+ tumors eligible for analysis. After adjustment for differences in baseline characteristics, the hazard of death in patients who had non-oncogene positive tumors diagnosed in 2015, 2016, 2017, 2018 ,and 2019 was observed to be 12%, 11%, 17%, 20%, and 21% lower respectively than that for those diagnosed in 2012. Upon additionally adjusting for receipt of first line or second line immunotherapy, the decrease in the hazard of death by calendar year was no longer observed, suggesting improvements in survival observed over time may be explained by the introduction of these treatments. Similarly, decreases in the hazard of death were only observed in patients with ALK+ tumors diagnosed between 2017 and 2019 relative to 2012 but were no longer observed following adjustment for the use of 1st and later generation ALK inhibitors. Among patients with EGFR+ tumors, the hazard of death did not improve significantly over time.ConclusionOur findings expand on the SEER data and provide additional evidence suggesting improvements in survival of patients with advanced and metastatic NSCLC over the past decade could be explained by the change in treatment patterns over this period.

Brigatinib as a treatment of ALK-positive non-small cell lung cancer

ABSTRACT Introduction Anaplastic lymphoma kinase (ALK) gene rearrangements and resulting fusion proteins occur in 3%-7% of patients with non-small-cell lung cancer (NSCLC), conferring sensitivity to treatment with ALK Tyrosine-Kinase Inhibitors. After the first-generation ALK inhibitor crizotinib, newer generation ALK inhibitors have been developed and showed greater potency and brain penetration in both crizotinib-naïve and crizotinib-refractory advanced NSCLC patients. Areas covered Brigatinib is a potent and highly selective second generation ALK inhibitor. Brigatinib is approved by Food and Drug Administration and European Medicines Agency for ALK-positive advanced NSCLC patients previously treated with crizotinib and more recently as first-line treatment in naïve patients. In the current review we present an up-to-date overview of the current and evolving clinical data regarding the biology of the disease, the emerging clinical decision-making and the targeted therapy options in advanced NSCLC harboring ALK translocation, especially focusing on the activity of brigatinib. Expert opinion Brigatinib shows a deep systemic and intracranial efficacy in both naïve and refractory metastatic ALK-positive NSCLC patients in the clinical studies, which marked its clinical development. Given its efficacy and tolerability brigatinib could be an excellent therapeutic option for the treatment of advanced ALK-positive NSCLC patients.

Abstract 1469: TPX-0131, a potent inhibitor of wild type ALK and a broad spectrum of both single and compound ALK resistance mutations

Abstract Three generations of ALK inhibitors are approved for the treatment of ALK+ NSCLC but their efficacy is often limited by ALK resistance mutations. The solvent front mutation G1202R and gatekeeper mutation L1196M are major resistance mechanisms to the first two generations of inhibitors. Patients treated with second generation inhibitors are reported to progress with multiple mutations on separate alleles (mutations in trans). In contrast, 35 - 48% of patients treated with lorlatinib progress with multiple mutations on the same allele (compound mutations, mutations in cis). TPX-0131 is an ALK inhibitor with a compact macrocyclic structure designed to bind completely within the ATP binding boundary and overcome a spectrum of single and compound ALK resistant mutations. TPX-0131 was profiled against previous generations of ALK inhibitors both in vitro and in vivo. In biochemical assays, TPX-0131 potently inhibits (IC50 &amp;lt;10 nM) wild type (WT) ALK and 26 ALK mutations (single and compound). Cell proliferation assays of WT, single mutations, and compound mutations were used to evaluate TPX-0131 relative to previous generations of ALK inhibitions (crizotinib, alectinib, brigatinib, ceritinib, lorlatinib). TPX-0131 is more potent against WT EML4-ALK (IC50 = 0.4 nM) than previous generations of ALK inhibitors (2-fold, lorlatinib; 10 - 30-fold, second generation inhibitors; &amp;gt;100-fold, crizotinib). TPX-0131 potently inhibits EML4-ALK harboring a G1202R solvent front mutation (IC50 = 0.2 nM) which is &amp;gt;100-fold more potent than previous generations of ALK inhibitors. TPX-0131 potently inhibits ALK harboring a gatekeeper mutation (IC50 = 0.5 nM) and is &amp;gt;10-fold more potent than previous generations of ALK inhibitors. TPX-0131 potently inhibits ALK with a L1198F hinge area mutation (IC50 = 0.2 nM) which is 87 - 3000-fold more potent than previous generations of ALK inhibitors. TPX-0131 is the most potent inhibitor against nine EML4-ALK double and triple compound mutations (6 with IC50 &amp;lt; 1 nM, 3 with IC50 1.6 - 14.9 nM). Evaluation of ALK phosphorylation as a pharmacodynamic marker in tumors showed potent ALK inhibition by TPX-0131 that correlated with TPX-0131 exposure. In Ba/F3 cell-derived xenograft tumor models with EML4-ALK mutations, TPX-0131 (2, 5, 10 mg/kg BID) demonstrated robust anti-tumor activity in the G1202R model (64%, 120%, 200% TGI), G1202R/L1198F model (complete regression, all doses), and G1202R/L1196M model (44%, 83% and 200% TGI). In contrast, lorlatinib (5 mg/kg BID) caused 31% TGI in the G1202R/L1198F model and did not have statistically significant TGI in the G1202R/L1196M model. Taken together, TPX-0131 is a next generation ALK inhibitor that has preclinical potency against WT ALK as well as a broad spectrum of acquired resistance mutations, especially compound mutations, which currently lack any effective ALK inhibitor therapy. Citation Format: Brion W. Murray, Dayong Zhai, Wei Deng, Evan Rogers, Xin Zhang, Jane Ung, Vivian Nguyen, Han Zhang, Maria Barrera, Ana Parra, Jessica Cowell, Dong Lee, Herve Aloysius. TPX-0131, a potent inhibitor of wild type ALK and a broad spectrum of both single and compound ALK resistance mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1469.

Selected Articles from This Issue

Mutations in ALK are common in neuroblastoma, rendering ALK an attractive therapeutic target. Foster and colleagues conducted a phase I/II clinical trial of the ALK inhibitor crizotinib in children with neuroblastoma. Crizotinib was well tolerated in this population. The objective response rate was 15%, with two patients showing a partial response and one patient showing a complete response. Interestingly, all three responders' tumors harbored the same somatic ALK R1275Q mutation. Two additional patients with this mutation had prolonged stable disease, although patients with other hotspot mutations or amplification of ALK did not respond to crizotinib. Further study will elucidate whether third generation ALK inhibitors will prove more effective against a broader spectrum of ALK mutations in neuroblastoma.Although immunotherap. has emerged as an important treatment strategy for many cancers, many patients either do not respond or progress on treatment, indicating that additional strategies for immunotherapy are needed. Curigliano and colleagues performed a phase I clinical trial of sabatolimab, an anti-TIM-3 antibody, with or without spartalizumab, an anti-PD-1 antibody, in patients with solid tumors. A maximum tolerated dose was not reached. Although no responses were observed for sabatolimab alone, combination treatment led to partial responses in 5 patients and prolonged stable responses in 9 patients. Further trials are underway to further determine the therapeutic relevance of TIM-3 in solid and hematologic malignancies.Pepinemab is a first-in-class monoclonal antibody that blocks the activity of SEMA4D, a potent regulator of immune cell migration and of the maturation and activity of myeloid suppressor cells. Shafique and colleagues performed a phase Ib/II clinical trial assessing the combination of pepinemab and avelumab, a PD-L1 inhibitor, in patients with lung cancer (the CLASSICAL-Lung trial). This combination was well tolerated and demonstrated antitumor activity in some patients who failed prior therapy with single-agent checkpoint inhibitors as well as in immunotherapy naïve patients with challenging PD-L1 negative or low tumors. These results show promise and warrant additional trials of pepinemab in combination with checkpoint inhibitors in other cancer indications.PSMA-targeted PET imaging has been considered a promising strategy for detecting prostate cancer that evades standard imaging techniques. Morris and colleagues performed a prospective clinical trial (CONDOR) designed to definitively establish the diagnostic performance of 18F-DCFPyL-PET/CT in patients with biochemical recurrence of prostate cancer and uninformative standard imaging. The trial demonstrated that the radiotracer correctly localized disease in approximately 85% of men, leading to a changed disease management plan in 64% of cases. This study adds greatly to the evidence base in support of the value of PSMA-PET/CT in the management of prostate cancer.

PCN68 Brigatinib Compared with Crizotinib and Alectinib in Patients with ALK-Positive Non-Small Cell Lung Cancer (NSCLC) with Brain Metastases at Diagnosis: A Cost-Effectiveness Analysis from the Perspective of the Brazilian Private Health Care System

Second generation ALK-inhibitors have shown improvement in brain disease control compared with Crizotinib in patients with metastatic ALK+ NSCLC. However, Crizotinib is the only treatment covered by the Brazilian private health care system (BHCS) so far. The objective of this study was to evaluate the cost-effectiveness of first-line Brigatinib in patients with ALK+ NSCLC and brain metastases at diagnosis, in comparison with Crizotinib and Alectinib, according to BHCS perspective.