Treatment Of ALK-positive Non-small Cell Lung Cancer Research Articles

Three-Year Overall Survival of Advanced Stage ALK-Positive NSCLC at a Single Clinical Setting in Indonesia

Background: ALK-positive Non-Small Cell Lung Cancer (NSCLC) is a rare condition predominantly observed in much younger non-smokers with adenocarcinoma histology, often accompanied by brain metastases. Despite its unique features, there is a lack of data concerning the treatment of ALK-positive NSCLC in Indonesia. Therefore, this study represented the first attempt to document the treatment landscape for ALK-positive NSCLC in the country. The available ALK inhibitors included crizotinib, alectinib, brigatinib, and lorlatinib, and none of these were listed under the Indonesian Universal Health Coverage as of September 2022. This study aimed to characterize survival outcomes of ALK-positive NSCLC patients treated within a specialized thoracic oncology practice in Indonesia.Methods: The retrospective observational cohort study drew secondary data from medical records of ALK-positive NSCLC patients treated at a private thoracic oncology clinic. Data were collected retrospectively, spanning from December 2019 to December 31, 2022. Exclusion criteria included incomplete data, untreated ALK-positive NSCLC, cases at stage I-III, or diagnoses made after August 2021. The observation period extended up to 36 months, although several patients exceeded 48 months, with one individual currently boasting a 96-month survival.Results: A total of 15 patients with ALK-positive NSCLC were selected as the respondents in this study. The median age stood at 50.8 years, predominantly female, and diagnosed with adenocarcinoma. Predominant sites of metastasis included pleural effusion and brain metastases, and preliminary 36-month survival rates reached 73.3%. The 1-year survival rate was recorded at 100%, while the 2-year overall survival (OS) stood at 80%, aligning closely with global ALK inhibitors clinical trial data.Conclusions: This study provided the first-ever dataset indicating an ALK-positive profile within a singular thoracic oncology clinic in Indonesia. Despite the accessibility constraints of treatments, ALK-positive patients showed comparable total survival to pivotal clinical trial data. This preliminary dataset shed light on the profile and treatment of ALK-positive NSCLC in the country.

Precision medicine-based platform to guide the treatment of EML4-ALK fusion lung cancers and other non-small cell lung cancers.

146 Background: Lung cancer remains the number one cause of cancer-associated mortality worldwide, with a 10-year survival rate of only 5%. While most lung cancers are smoking related, 25% of non-small cell lung cancer (NSCLC) are diagnosed in patients with little or no smoking history. Fusions involving anaplastic lymphoma kinase (ALK) are the oncogenic driver in ~3–7% of NSCLC. While inhibitors targeting the kinase domain of ALK have proven extremely effective in the treatment of ALK-positive NSCLC, inevitably, resistance develops with limited effective treatment options. Methods: We developed a precision medicine-based platform to screen patient-derived material (PDM) directly from the operating room with curated panels of approved and IND drugs. PDM collected during clinically indicated procedures is dissociated into single cells, plated in culture to generate patient-derived organoids (PDOs), and screened with drugs that are curated to each tumor based on treatment history and clinically relevant sequencing. PDOs are screened at therapeutically relevant levels, drawing from pharmacokinetic data for each drug, when available. We have optimized an assay to rapidly screen for EML4-ALK fusions and can perform next-generation DNA and RNA sequencing in real time (~7 days) to integrate with drug screening results. Results: To date, we have screened 51NSCLC cases, including 7 ALK-positive NSCLC. Screening in highly progressed EML4-ALK patients demonstrates sensitivity to earlier generation ALK TKIs, a known phenomenon in the literature. Our screening results recapitulate known clinical resistance/progression in samples previously exposed to therapy, demonstrating a strong negative predictive value. Longitudinal assessment will be required to robustly assess the positive predictive value (PPV). In one EML4-ALK NSCLC (JTI026) we were able to collect PDM from two distinct regions (pleural effusion and thoracentesis) and screen them with the same panel of drugs, with identical results. These data highlight the reproducibility of our assay. Conclusions: Our precision medicine-based platform captures robust and reproducible results that are consistent with known clinical pathogenesis. Moving forward, we are collecting longitudinal data from enrolled patients in parallel with clinical trials to demonstrate PPV of our platform. We additionally strive to demonstrate reproducibility to obtain Clinical Laboratory Improvement Amendments (CLIA) approval and to deliver results to patients and physicians to help guide clinical care. [Table: see text]

Efficacy and safety of anaplastic lymphoma kinase inhibitors for non-small cell lung cancer: A systematic review and network meta-analysis.

To assess the efficacy and safety of anaplastic lymphoma kinase inhibitors (ALKIs) for the treatment of advanced-stage ALK rearrangement-positive non-small cell lung cancer (NSCLC). We searched PubMed, EMBASE, and the Cochrane Library for randomized controlled trials (RCTs) that included patients with ALK-positive NSCLC receiving ALKIs. The outcomes of the study included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and treatment-related adverse events (TRAEs) of grade ≥3. A total of 12 RCTs consisting of 3169 patients with eight treatment options were included in this study. Our results showed that ALKIs have superior efficacy in OS, PFS, and ORR than chemotherapy or crizotinib (first-generation ALKI). Our study showed that only alectinib has a significant improvement in OS compared to chemotherapy (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.40-0.94). Alectinib appeared to have better OS than crizotinib (HR, 0.66; 95% CI, 0.45-0.95). Ensartinib has a significant PFS advantage over alectinib (HR, 0.62; 95% CI, 0.40-0.96). The surface under the ranking curve indicated that ensartinib (99.0%) was the highest rank regarding PFS. Moreover, both ensartinib and ceritinib showed significantly higher TRAEs of grade ≥3 compared with chemotherapy (risk ratios [RR], 2.74; 95% CI, 1.45-5.18; RR, 1.80; 95% CI, 1.26-2.57, respectively). These results indicated that alectinib could be associated with the best therapeutic efficacy and well-tolerance AEs in the treatment of ALK-positive NSCLC.

Cost–effectiveness of ensartinib for patients with anaplastic lymphoma kinase-positive non-small-cell lung cancer in China

Background: Crizotinib and ensartinib improved survival in patients with ALK arrangement non-small-cell lung cancer (NSCLC); however, the economic outcomes of using ensartinib versus crizotinib are still unclear. Aim: The objective of this study was to assess the cost-effectiveness of ensartinib versus crizotinib for ALK-positive NSCLCpatients from the perspective of China's healthcare system. Methods: A partitioned survival model with threehealth states (stable, progressiveand death) was developed. Survival data were obtained from published eXalt3 clinical trials of ensartinib versescrizotinib for patients with anaplastic lymphoma kinase-positive non-small-celllung cancer. Parametric models were used to extrapolate outcomes beyond the trial period. The drug cost comes from the local drug procurement platform. Other costs and utility values were obtained from published literature, and one-way and probabilistic sensitivity analyses were carried out to determine the robustness of the model outcomes. Results: In the whole life cycle, the average annual cost of ensatinib was US$77,636.63, and utility value was 5.5 quality adjusted life years (QALYs). Patients receiving crizotinib had 3.315QALYsand US$32,935.88 costs over the same time horizon. The incremental cost utility ratio is US$19,810.55/QALYs. In 2021, the per capita GDP of China is US$12,721.33, and the incremental cost utility is lower than the threshold of willingness to payUS$38,163.99. Conclusion: Compared with crizotinib, ensatinib is economical in the treatment of ALK-positiveNSCLCand should be promoted.

Abstract 503: Longitudinal minimally invasive monitoring of resistance mutations in ALK rearranged lung cancer patients

Abstract Background: ALK is a proto-oncogene encoding the receptor tyrosine kinase ALK, which can be aberrantly activated by gene rearrangements or point mutations to promote tumor cell growth, survival, and metastasis. ALK rearrangements are detected in approximately 4% of patients with advanced non-small cell lung cancer (NSCLC), and the tyrosine kinase inhibitors (TKIs) crizotinib, alectinib, brigatinib, ceritinib, and lorlatinib have been approved by the FDA for the treatment of ALK-positive NSCLC. The durability of response to these therapies has been limited, in many cases, by the emergence of mutations that confer resistance to ALK. The major resistance mutation to alectinib, brigatinib, and ceritinib is the ALK G1202R solvent front mutation. The detection of resistance mutations has been improved with the evolution of biotechnology, making it possible to search for tumor-derived plasma free DNA as a liquid biopsy in cases where tissue biopsies are difficult to obtain. Digital PCR (dPCR) is an improved method of the conventional PCR method, which is more accurate and allows absolute quantification than the RT-PCR method. Materials and Methods: For a total of 9 patients, 2 patients newly diagnosed with ALK+ NSCLC by tissue biopsy and about to receive ALK-TKI and 7 patients already diagnosed with ALK+ NSCLC and receiving ALK-TKI, 10 ml of plasma was collected in addition to the blood collection at each 3-monthly visit. cfDNA was extracted and digital PCR was used to simultaneously detect 10 ALK mutations (T1151ins, C1156Y, L1196M, G1269A, F1174L, L1152R, V1180L, I1171T, G1202R, S1206Y). This Study was supported by an Investigator Initiated Research (IIR) from Pfizer. Results: The total number of samples analyzed in 9 cases was 65, and the median number of samples collected in each case was 7 (minimum 2 - maximum 12). cfDNA concentration was a median of 9.9 ng/ml of plasma (4.0-35.8 ng/ml). The number of samples detected for each mutation was 32 for G1202R, 16 for C1156Y, 5 for G1269A, 4 for F1174L, 1 for T1151ins, and 1 for I1171T. G1202R was detected in 19 of 37 samples during treatment with alectinib. The median time from detection of G1202R to clinical disease progression was 388 days (123-2004 days), with repeated emergence and disappearance in some cases. Conclusions: The dPCR method was highly sensitive in detecting gene mutations with low allele frequency. It was also found to be able to monitor variable resistance mutations over time during ALK-TKI treatment. In addition, we found that the appearance of G1202R did not always indicate clinical acquisition of resistance that required drug modification. A limitation of this study is that the mutations detected are not distinguishable between the same allele or Cis/trans. In particular, EML4-ALK forms a trimeric protein, suggesting that single mutations such as G1202R and drug susceptibility do not always match in clinical specimens. Citation Format: Takaaki Sasaki, Noriko Hirai, Yoshinori Minami, Shunsuke Okumura, Shin-ichi Chiba, Ryohei Yoshida. Longitudinal minimally invasive monitoring of resistance mutations in ALK rearranged lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 503.

Lorlatinib (Lorbrena)


 CADTH recommends that Lorbrena should be reimbursed by public drug plans for the treatment of adult patients with ALK-positive locally advanced or metastatic non–small cell lung cancer (NSCLC) if certain conditions are met.
 Lorbrena should only be covered to treat adult patients with ALK-positive NSCLC who are diagnosed when their cancer has spread to lymph nodes (locally advanced disease) or other parts of the body (metastatic disease) and who have had no prior systemic treatment for advanced or metastatic NSCLC.
 Lorbrena should only be reimbursed by public drug plans when used as a single drug. It should be prescribed by an oncologist with experience in the treatment of ALK-positive NSCLC although thereafter it can be given in an outpatient clinic by the patient’s health care team. The cost of Lorbrena should not be higher than the cost of treatment with alectinib or brigatinib for these patients.

An overview of alectinib hydrochloride as a treatment option for ALK positive non-small cell lung cancer

ABSTRACT Introduction: Alectinib is a second-generation inhibitor of anaplastic lymphoma kinase (ALK) and RET. Phase III clinical trials have established its superiority to crizotinib in the first-line ALK inhibitor-naïve setting. Studies also support its use over chemotherapy in the post-crizotinib setting. It is currently one of several FDA- and EMA-approved ALK inhibitors, and it is listed as a preferred initial therapy for treatment-naïve ALK-positive non-small cell lung cancer (NSCLC). Areas covered: Herein, the authors provide the reader with details of the chemical structure, pharmacologic properties, resistance mutations, phase I, II, and III clinical trials, and safety profile of alectinib. Furthermore, the authors provide the reader with the expert opinion and future perspectives on the drug. Expert opinion: Alectinib compares favorably to other second-generation ALK inhibitors with regards to safety, tolerability, and efficacy. Based on currently available data, it is an appropriate first-line option. Ongoing studies will better resolve the ideal sequencing of ALK inhibitors in the treatment of ALK-positive NSCLC.

Efficacy of Crizotinib, Ceritinib, and Alectinib in ALK-Positive Non-Small Cell Lung Cancer Treatment: A Meta-Analysis of Clinical Trials.

This study aimed to evaluate the efficacy of anaplastic lymphoma kinase (ALK)-inhibitors in the treatment of ALK-positive non-small cell lung cancer (NSCLC) by using a meta-analysis of clinical trials. We searched PubMed, EMBASE, Cochrane Library, and Clinicaltrials.gov by using keywords related to the topic in August 2018. The pooled effect sizes were calculated based on a random-effects model. We also performed subgroup meta-analysis by types of ALK inhibitors (crizotinib, ceritinib, and alectinib). A total of 20 clinical trials with 10 single-arm trials and 10 double-arm trials were included in the final meta-analysis. The median overall survival (OS), progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR), 1 year survival rate, and 2 year survival rate were 19.14 months, 8.47 months, 62%, 78%, 74%, and 62%, respectively. ALK inhibitors showed a significantly superior efficacy compared with chemotherapy (hazard ratio (HR) for OS, 0.83; HR for PFS, 0.43; rate difference (RD) for ORR, 0.23; and RD for DCR, 0.10). The current meta-analysis of clinical trials showed the significant efficacy of ALK inhibitors in the treatment of ALK-positive NSCLC. Further head-to-head trials are needed to compare their efficacy with other types of NSCLC treatment regimens. PROSPERO registration: CRD42018085987.

Comparative efficacy of first-line ceritinib and crizotinib in advanced or metastatic anaplastic lymphoma kinase-positive non-small cell lung cancer: an adjusted indirect comparison with external controls

Objective: In the absence of head-to-head trials, this study indirectly compared progression free survival (PFS) and overall survival (OS) between ceritinib and crizotinib among patients with previously untreated advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC).Methods: A matching-adjusted indirect comparison method was implemented to adjust for cross-trial differences in patient characteristics between ASCEND-4 and PROFILE 1014 trials. Patient-level data from ASCEND-4 and published summary data from PROFILE 1014 were used. Patients in ASCEND-4 were reweighted to match average baseline characteristics (i.e. age, sex, race, tumor histology, ECOG score, smoking status, extent of disease, and presence of brain metastases) reported for PROFILE 1014 patients using propensity score weighting. PFS and OS were then compared between balanced populations.Results: ASCEND-4 included more current smokers (8.0% vs 4.4%) and fewer patients under the age of 65 years (78.5% vs 84.0%) compared to PROFILE 1014. After matching, these and all other patient characteristics were balanced between the two trial populations. Compared to crizotinib, ceritinib was associated with a significantly longer PFS (hazard ratio [95% confidence interval] (HR [CI]) = 0.64 [0.47–0.87]; median PFS: 25.2 vs 10.8 months, log-rank p-value = 0.003). OS did not differ significantly, with a HR of 0.82 [0.54–1.27] for ceritinib compared to crizotinib.Conclusions: In the adjusted indirect comparison with external controls, the second generation ALK inhibitor, ceritinib, was associated with a significantly prolonged PFS compared to crizotinib as first-line treatment for ALK-positive NSCLC.

Progress of ALK gene inhibitors in the treatment of brain metastases from non-small cell lung cancer

Anaplastic lymphoma kinase (ALK) rearrangement is one of the most potent carcinogenic genes in non-small cell lung cancer (NSCLC). The first-generation ALK inhibitor such as crizotinib is superior to chemotherapy for NSCLC patients with ALK rearrangement. At the same time, more and more studies have reported ALK inhibitors in brain metastases of NSCLC patients with intracranial efficiency. However, despite the initial clinical data of first-generation ALK inhibitors in the treatment of ALK-positive NSCLC with brain metastases, different degrees of recurrence of tumors after acquired resistance have posed new challenges for follow-up treatment of cancer patients. A new generation of ALK inhibitors, such as alectinib, ceritinib, AP26113 and PF-06463922 have emerged to solve this problem. Key words: Carcinoma, non-small-cell lung; Neoplasm metastasis; Anaplastic lymphoma kinase fusion gene inhibitors

Upregulation of PD-L1 by EML4-ALK fusion protein mediates the immune escape in ALK positive NSCLC: Implication for optional anti-PD-1/PD-L1 immune therapy for ALK-TKIs sensitive and resistant NSCLC patients

ABSTRACTDriver mutations were reported to upregulate programmed death-ligand 1 (PD-L1) expression. However, how PD-L1 expression and immune function was affected by ALK-TKIs and anti-PD-1/PD-L1 treatment in ALK positive non-small-cell lung cancer (NSCLC) remains poorly understood. In the present study, western-blot, real-time PCR, flow cytometry and immunofluorescence were employed to explore how PD-L1 was regulated by ALK fusion protein. ALK-TKIs and relevant inhibitors were used to identify the downstream signaling pathways involved in PD-L1 regulation. Cell apoptosis, viability and Elisa test were used to study the immune suppression by ALK activation and immune reactivation by ALK-TKIs and/or PD-1 blocking in tumor cells and DC-CIK cells co-culture system. We found that PD-L1 expression was associated with EGFR mutations and ALK fusion genes in NSCLC cell lines. Over-expression of ALK fusion protein increased PD-L1 expression. PD-L1 mediated by ALK fusion protein increased the apoptosis of T cells in tumor cells and DC-CIK cells co-culture system. Inhibiting ALK by sensitive TKIs could enhance the production of IFNγ. Anti-PD-1 antibody was effective in both crizotinib sensitive and resistant NSCLC cells. Synergistic tumor killing effects were not observed with ALK-TKIs and anti-PD-1 antibody combination in co-culture system. ALK-TKIs not only directly inhibited tumor viability but also indirectly enhanced the antitumor immunity via the downregulation of PD-L1. Anti-PD-1/PD-L1 antibodies could be an optional therapy for crizotinib sensitive, especially crizotinib resistant NSCLC patients with ALK fusion gene. Combination of ALK-TKIs and anti-PD-1/PD-L1 antibodies treatment for ALK positive NSCLC warrants more data before moving into clinical practice.

First-line treatment of advanced ALK-positive non-small-cell lung cancer.

Non-small-cell lung cancer (NSCLC) is one of the leading causes of cancer deaths, both within the US and worldwide. There have been major treatment advances in NSCLC over the past decade with the discovery of molecular drivers of NSCLC, which has ushered in an era of personalized medicine. There are several actionable genetic aberrations in NSCLC, such as epidermal growth factor receptor and anaplastic lymphoma kinase (ALK). In 3%–7% of NSCLC, a chromosomal inversion event in chromosome 2 leads to fusion of a portion of the ALK gene with the echinoderm microtubule–associated protein-like 4 (EML4) gene. The constitutive activation of the ALK fusion oncogene renders it vulnerable to therapeutic intervention. This review focuses on the first-line treatment of advanced ALK-positive NSCLC using ALK inhibitors. Crizotinib was the first agent proven to be efficacious as first-line treatment for ALK-positive NSCLC. However, acquired resistance inevitably develops. The central nervous system is a sanctuary site that represents a common site for disease progression as well. Hence, more potent, selective next-generation ALK inhibitors that are able to cross the blood–brain barrier have been developed for treatment against crizotinib-resistant ALK-positive NSCLC and are also currently being evaluated for first-line therapy as well. In this review, we provide summary of the clinical experience with these drugs in the treatment of ALK-positive NSCLC.

C-Met: A Potential Target for Current Non-Small-Cell Lung Cancer Therapeutics

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. In early stages of NSCLC tumor development (stage I/II), surgical resection is often performed; however, when the cancer becomes metastatic, chemotherapy is most commonly implemented. Due to the fact that traditional chemotherapies result in adverse and cytotoxic effects on healthy cells in addition to NSCLC cells, targeted therapeutics have been extensively developed over recent years to combat the disease. These targeted therapies include small molecule inhibitors and monoclonal antibodies (MAbs), some of which are used as first-line treatments for NSCLC patients. Several inhibitors against the mesenchymal-epithelial transition factor (c-Met), and its ligand hepatocyte growth factor (HGF), have shown promising results in NSCLC clinical trials. For example, crizotinib, a multi-kinase inhibitor has been approved by the FDA for the treatment of ALK positive NSCLC. c-Met is known to be overexpressed, mutated and gene amplified, specifically in NSCLC, and has also been implicated in the development of resistance against other small-molecule inhibitors (e.g. EGFR). Thus, this review will discuss the current developments and usages of c-Met inhibitors in NSCLC, and their potential for future therapeutic advancement.

Targeted inhibition in tumors with ALK dependency.

The oncogenic function of gene translocations involving the anaplastic lymphoma kinase (ALK) was first reported in rare subtypes of non-Hodgkin's lymphoma almost two decades ago. More recently, aberrant ALK signaling was found to be an oncogenic driver in subsets of non-small cell lung cancer (NSCLC), particularly in patients with little or no tobacco smoking history. The advent of molecularly targeted therapies that inhibit ALK has allowed the pairing of ALK inhibitors such as crizotinib as treatment for ALK-positive NSCLC, yielding dramatic responses and long-term disease control. The clinicopathologic features of ALK-driven NSCLC, the clinical development of ALK inhibitors, and the genetic determinants of acquired resistance to ALK inhibition are among the topics covered in this review.

ALK and NSCLC: Targeted therapy with ALK inhibitors

For many years treatment for advanced or metastatic non-small cell lung cancer (NSCLC) has employed chemotherapy regimens for patient care, with limited effect. Five-year survival rates for these patients are not encouraging. However, for a subgroup of these patients, there have been radical changes over recent years. Our understanding of the basic pathology behind NSCLC at the molecular level has offered up a host of new molecularly targeted therapies, which are revolutionizing this area of cancer care. Results from recent clinical trials provide hope for NSCLC patients harboring oncogenic translocations involving the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase. Just as inhibition of the breakpoint cluster region–ABL complex has changed the face of chronic myeloid leukemia diagnosis, oncogenic ALK fusions offer a step forward in the diagnosis and treatment of ALK-positive NSCLC. This article discusses the current knowledge and potential implications concerning ALK inhibitors and NSCLC.