ALK-positive Patients Research Articles

Anaplastic lymphoma kinase fusion protein expression is associated with a favorable prognosis in resected invasive mucinous lung adenocarcinoma: A retrospective study from two Chinese tertiary hospitals.

Invasive mucinous adenocarcinoma (IMA) is a distinct variant of lung adenocarcinoma, which typically has a worse survival. However, its pathogenesis is potentially associated with a high degree of molecular heterogeneity, which might determine its different prognosis. We retrospectively analyzed 2207 consecutive lung adenocarcinoma patients who underwent radical resection at Qilu Hospital of Shandong University and Shandong Provincial Hospital from 2013 to 2019. Anaplastic lymphoma kinase (ALK) fusion protein expression was routinely detected by immunohistochemistry. The clinicopathological characteristics and treatment outcomes of IMA patients were retrieved, and compared between ALK-positive and ALK-negative IMA patients as well as between pure IMA and mixed IMA patients. The last follow-up was on December 31, 2020, and the median follow-up was 42 months. A total of 98 patients (4.4%) were diagnosed with IMA. ALK protein expression was positive in 24.5% of IMAs, which was significantly higher than that of non-IMA lung adenocarcinomas (4.7%, P < 0.001). ALK-positive and ALK-negative IMA, as well as pure IMA and mixed IMA, showed similar distribution in terms of patients' age, gender and smoking history, stage, and primary tumor location, except for a higher rate of lymph node metastasis in mixed IMA (22.0% vs. 46.2%, P = 0.012). Five cases (20.8%) of ALK-positive IMAs and 28 cases (40.6%) of ALK-negative IMAs experienced recurrence. Multivariable-adjusted Cox regression analysis demonstrated that ALK expression was a favorable prognostic factor for both disease-free survival (hazard ratio [HR]: 0.354; 95% confidence interval [CI]: 0.131-0.960; P = 0.041) and overall survival (HR: 0.138; 95% CI: 0.029-0.658; P = 0.013) in resected IMA. No difference in disease-free survival (HR: 0.524; 95% CI: 0.237-1.157; P = 0.110) and OS (HR: 0.553; 95% CI: 0.199-1.537; P = 0.256) was observed between pure IMA and mixed IMA. Invasive mucinous lung adenocarcinoma showed higher ALK protein expression, which was a favorable prognostic factor for survival in early resected patients.

ALK-Fusion Transcripts Can Be Detected in Extracellular Vesicles (EVs) from Nonsmall Cell Lung Cancer Cell Lines and Patient Plasma: Toward EV-Based Noninvasive Testing.

ALK rearrangements are present in 5% of nonsmall cell lung cancer (NSCLC) tumors and identify patients who can benefit from ALK inhibitors. ALK fusions testing using liquid biopsies, although challenging, can expand the therapeutic options for ALK-positive NSCLC patients considerably. RNA inside extracellular vesicles (EVs) is protected from RNases and other environmental factors, constituting a promising source for noninvasive fusion transcript detection. EVs from H3122 and H2228 cell lines, harboring EML4-ALK variant 1 (E13; A20) and variant 3 (E6a/b; A20), respectively, were successfully isolated by sequential centrifugation of cell culture supernatants. EVs were also isolated from plasma samples of 16 ALK-positive NSCLC patients collected before treatment initiation. Purified EVs from cell cultures were characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and flow cytometry. Western blot and confocal microscopy confirmed the expression of EV-specific markers as well as the expression of EML4-ALK-fusion proteins in EV fractions from H3122 and H2228 cell lines. In addition, RNA from EV fractions derived from cell culture was analyzed by digital PCR (dPCR) and ALK-fusion transcripts were clearly detected. Similarly, plasma-derived EVs were characterized by NTA, flow cytometry, and the ExoView platform, the last showing that EV-specific markers captured EV populations containing ALK-fusion protein. Finally, ALK fusions were identified in 50% (8/16) of plasma EV-enriched fractions by dPCR, confirming the presence of fusion transcripts in EV fractions. ALK-fusion transcripts can be detected in EV-enriched fractions. These results set the stage for the development of EV-based noninvasive ALK testing.

Chemotherapy versus alectinib for the treatment of crizotinib-pretreated ALK-positive patients with non small cell lung cancer: A protocol for systematic review and meta-analysis.

There are no evidence-based data in the literature to demonstrate that alectinib shows a clinically relevant advantage over chemotherapy in anaplastic lymphoma kinase-positive non-small cell lung cancer pretreated with crizotinib. Therefore, we designed this systematic review and meta-analysis protocol to reveal whether the safety and efficacy of alectinib are indeed superior to chemotherapy alone in this special group of patients. This protocol will be written following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols statement guidelines. We will search databases from Web of Science, Embase, PubMed, Wanfang Data, Scopus, Science Direct, Cochrane Library from their inception to June 2022, restricting them to human subjects and clinical trials. Outcomes include progression-free survival, central nervous system progression, and incidence of adverse events. Pooled analyses will be calculated using fixed-effect models, whereas random-effect models will be applied in case of significant heterogeneity across studies. Any disagreements will be discussed and resolved in discussions with the third reviewer. We hypothesized that alectinib would be superior to chemotherapy in patients with anaplastic lymphoma kinase-positive non-small cell lung cancer pretreated with crizotinib. The review will add to the existing literature by showing compelling evidence and improved guidance in clinic settings. 10.17605/OSF.IO/PQF53.

EML4-ALK Variant 3 Promotes Mitotic Errors and Spindle Assembly Checkpoint Deficiency Leading to Increased Microtubule Poison Sensitivity.

This study suggests that combining the microtubule poison, paclitaxel, with targeted ALK inhibitors may provide an effective new treatment option for patients with NSCLC with tumors that express the EML4-ALK V3 oncogenic fusion.

A Polytherapy Strategy Using Vincristine and ALK Inhibitors to Sensitise EML4-ALK-Positive NSCLC.

Simple SummaryLung cancer is the third most common cancer worldwide with poor survival after initial diagnosis. A large proportion, approximately 85%, of patients with lung cancer are classified as non-small cell lung cancer (NSCLC). The most common genetic alterations in NSCLCs are KRAS, EGFR and ALK mutations. Patients carrying the EML4-ALK mutation are treated with potent ALK drugs. Up to date, there are 15 different EML4-ALK mutations found in NSCLC patients. Of note, patients carrying the EML4-ALK V3 mutation respond poorly to ALK chemotherapeutic regime and acquire resistance. The aim of the present study was to assess the potential of a combination chemotherapy using vincristine, a traditional chemotherapeutic drug, and potent ALK drugs. We demonstrated that vincristine sensitises cells carrying EML4-ALK V1 mutation but not V3. Cells carrying the EML4-ALK V3 mutation confer low response to drug combination due to high levels of tubulin acetylation and active proliferation pathways compared to V1 cells.The oncogenic fusion of EML4-ALK is present in about 4–6% of non-small cell lung cancer (NSCLC). A targeted approach with ALK tyrosine kinase inhibitors (TKIs) has been proven highly effective in ALK-positive NSCLC patients. However, despite the initial responses, the outcome of the treatment is variable. Previous studies have shown that the differential response depends in part on the type of EML4-ALK variant. Here, we examined the combination of ALK inhibitors and microtubule poison, vincristine, in cells expressing EML4-ALK V1 and V3, the two most common variants in NSCLC. We showed that combination therapy of ALK-TKIs with vincristine had anti-proliferative effects and blocked RAS/MAPK, PI3K/AKT and JAK/STAT3 signalling pathways in EML4-ALK V1 but not V3 cells. Our results demonstrate that high levels of tubulin acetylation are associated with poor response to vincristine in EML4-ALK V3 cells. Additionally, we demonstrated differences in microtubule stability between the two EML4-ALK fusions. EML4-ALK V3 cells exhibited dynamic microtubules that confer poor response to vincristine compared to V1 cells. Hence, we suggested that the portion of EML4 in the fusion has an important role for the outcome of the combination treatment.

ALK Inhibitors or Chemotherapy for Third Line in ALK-positive NSCLC? Real-world Data.

ObjectivesALK inhibitors (ALKi) are the standard-of-care treatment for metastatic ALK-rearranged non-small cell lung cancer (NSCLC) in the first- and second-line setting. We conducted a real-world multi-institutional analysis, aiming to compare the efficacy of third-line ALKi versus chemotherapy in these patients.MethodsConsecutive ALK-positive metastatic NSCLC patients treated with at least one ALKi were identified in the working databases of 7 Israeli oncology centers (the full cohort). Demographic and clinical data were collected. Patients receiving any systemic treatment beyond 2 ALKi comprised the third-line cohort, whether a third ALKi (group A) or chemotherapy (group B). Groups A and B were compared in terms of overall survival (OS) and time-to-next-treatment line (TNT).ResultsAt a median follow-up of 41 months (95% confidence interval [CI]: 32-55), 80 (47.1%) have died. Median OS (mOS) in the full cohort (n = 170) was 52 months (95% CI: 32-65). Number of ALKi (hazard ratio [HR] 0.765; 95% CI: 0.61-0.95; P = .024) and age (HR 1.02, 95% CI: 1.01-1.04, P = .009) significantly associated with OS in the full cohort. The third-line cohort included 40 patients, of which 27 were treated with third ALKi (group A) and 13 treated with chemotherapy (group B). mOS from third-line initiation was 27 months in group A (95% CI: 13-NR) and 13 months for group B (95% CI: 3-NR); the difference was not significant (NS; P = .12). Chemotherapy as first line (HR 0.17, 95% CI: 0.05-0.52, P = .002) and a higher number of ALKi (HR 0.38, 95% CI: 0.20-0.86, P = .011) associated significantly with longer OS of the third-line cohort. TNT was 10 months for group A (95% CI: 5-19) and 3 months for group B (95% CI: 0-NR); the difference was NS (P = .079).ConclusionWe report mature real-world data of more than 4-year mOS in ALK-positive patients. The number of ALKi given was associated with a better outcome. OS and TNT demonstrated a statistically nonsignificant trend for a better outcome in patients receiving a third-line ALKi.

Intracranial efficacy of alectinib in ALK-positive NSCLC patients with CNS metastases\u2014a multicenter retrospective study

BackgroundCentral nervous system (CNS) metastases in patients with ALK-positive non-small cell lung cancer (NSCLC) are a cause of substantial morbidity and mortality. Although alectinib had demonstrated promising intracranial efficacy in several clinical trials, data were limited on its CNS activity in real-world settings.MethodsIn this retrospective study, ALK-positive NSCLC patients with brain metastases (BM) or leptomeningeal metastases (LM) from six hospitals in China were divided into three cohorts based on the treatment history before the administration of alectinib. ALK-TKI-naive patients were enrolled in cohort 1, cohort 2 included patients who experienced intracranial progression with or without extracranial progression after treatment with crizotinib, and cohort 3 included patients who developed progression only in CNS following treatment with other second-generation ALK-TKIs. The definition and evaluation of intracranial and extracranial lesions were based on Response Evaluation Criteria in Solid Tumors version 1.1.ResultsSixty-five patients were eligible and included in our study (cohort 1: 20, cohort 2: 32, cohort 3: 13). For the overall population and patients with uncontrolled CNS metastases, similar intracranial response in CNS target lesions was observed: cohort 1: 81.8% and 80%; cohort 2: 76.5% and 86.7%; cohort 3: 42.8% and 33.3%. For patients in these three cohorts, 75% (6/8), 78.6% (11/14), and 83.3% (5/6) were reported to have significant improvement in CNS-related symptoms respectively. The number of patients who were in need of mannitol or corticosteroids decreased remarkably after the treatment of alectinib (p < 0.001), and there was also a steep fall-over in the number of patients with ECOG ≥2 points before and after the administration of alectinib (p = 0.003). All patients (8/8) diagnosed with LM ± BM experienced substantial alleviation in CNS-related symptoms. In cohort 1 and cohort 2, no significant difference in CNS-time to progression was found between patients with symptomatic or asymptomatic BM when treated with alectinib alone.ConclusionsOur study substantiated the potent CNS activity of alectinib in real-world settings. Patients with symptomatic and asymptomatic BM could benefit from alectinib comparatively, which indicated that alectinib alone might defer the timing of local treatment. However, our results should be treated cautiously owing to limited sample size.

Predictive role of neutropenia under crizotinib treatment in ALK-rearranged nonsmall cell lung cancer patients: A single-institution retrospective analysis.

Anaplastic lymphoma kinase (ALK)-rearranged nonsmall cell lung cancer (NSCLC) represents a molecular subgroup with high sensitivity to ALK inhibitors. Tyrosine kinase inhibitor crizotinib, an anticancer drug acting as an ALK inhibitor, has shown remarkable response in ALK-positive NSCLC. The aim of our study is to explore the adverse events (AEs) of patients on crizotinib therapy and analyze the predictability of AEs for better survival or response on NSCLC patients. The medical records of our ALK-positive metastatic NSCLC patients who applied between years 2013 and 2018 had been reviewed retrospectively. ALK positivity of all patients had been detected by fluorescence in situ hybridization and no other driver mutations were present. Patient demographics, performance status, smoking history, previous treatments, metastatic sites, and AEs were recorded for further analyses. Thirty-six ALK-positive metastatic NSCLC patients were included in the study. Median follow-up was 30.1 months. Median progression-free survival (PFS) for patients who developed hepatic, cardiac, or endocrine toxicities was similar when compared to patients who did not develop. Although there was a numeric median PFS difference between patients who did develop visual disorders (18.4 months) and did not develop visual disorders (15.5 month), this was not regarded as statistically significant. However, median PFS of the patients who developed neutropenia upon crizotinib treatment (31.9 months) was found to be more favorable than the patients with normal neutrophil counts (12.8 months) (P = 0.026). Neutropenia under crizotinib treatment was found to be associated with improved PFS suggesting that neutropenia might be an important determinant in treatment and survival strategies.

Current Insights on the Treatment of Anaplastic Lymphoma Kinase-Positive Metastatic Non-Small Cell Lung Cancer: Focus on Brigatinib.

Rearrangement of anaplastic lymphoma kinase (ALK) gene is detected in approximately 5% of non-small cell lung cancer (NSCLC) patients. Tyrosine kinase inhibitors targeting ALK have significantly improved the prognosis of these patients. However, most patients experienced disease progression within a few years due to acquired resistance. Brigatinib is a second-generation ALK inhibitor effective in presence of several ALK mutations with demonstrated activity against central nervous system metastases. Currently, brigatinib is approved to treat ALK-positive metastatic NSCLC patients not previously treated with ALK inhibitors and patients who have progressed on or are intolerant to crizotinib. In this review, we provide a summary of results from clinical trials involving brigatinib, and we discuss its possible role in the management of ALK-positive NSCLC in the following years.

The Need for a National Guideline for the Management of NSCLC ALK-Positive Lung Cancer in the UK: Results of Patient-Driven Surveys

Introduction: There are currently no national guidelines specifically for the management of NSCLC ALK-positive lung cancer in the UK. National guidelines exist for lung cancer in general and reference is made to ALK-positive lung cancer. However, the generic nature of these guidelines is not sufficient for the optimal management of this specific type of lung cancer, with its unique disease management requirements. Method: In 2021, members of the charity ALK POSITIVE LUNG CANCER (UK) completed anonymised surveys to gather real-world data about their treatment. Results: Data were gathered on the prescribing of blood thinners (n = 127); frequency of brain MRI scans (n = 123); prescribing bone strengthening medication (n = 127); frequency of CT scans (n = 123); mental health (n = 132). There was significant variation in each of these five aspects of treatment. Conclusions: The findings, from a representative population of ALK-positive patients, provide new information on the significant disparities in the treatment that patients receive. This health inequality is likely to have a detrimental effect on the survival outcomes for some of these patients. It would improve patient outcomes and overall survival if ALK-positive lung cancer disease management national guidelines were established and utilised across the NHS in the UK. The evidence presented.

The Extent of Expression of Thyroid Transcription Factor 1, Cytokeratin 7, and Anaplastic Lymphoma Kinase in Lung Adenocarcinoma.

Background:New forms of genetic alteration were developed giving a new era of lung adenocarcinoma (AdC) with diverse clinical and pathological features.Aim and Objectives:The aim is to investigate the ALK-rearranged gene as one of these genetic alterations in AdC. The role of TTF-1 and CK7 is to exclude the metastases.Material and Methods:Paraffin-embedded 50 AdC specimens were cut into 4-mm thick sections and stained with the primary antibody, using an anti-TTF-1 antibody, (all at a 1:200 dilution, mouse monoclonal antibody; Dako, Denmark), anti-CK 7 antibody (DAKO, Carpentaria, CA), and the rabbit monoclonal anti- ALK antibody (D5F3) (Ventana, USA). Positive reactivity was considered as brown nuclear immunostaining for TTF-1 and cytoplasmic for CK 7and both cytoplasmic and nuclear for ALK.Results:The median age was 56±2, with male to female ratio 7:3. Forty-four cases revealed a mixed pattern (88%), with focal intraluminal mucin. Forty-one cases (82%) were positive for TTF-1, of these; weak (13; %), moderate (16; %) and strong (12; %). Regarding CK7; 48 cases (96%) were positive; weak (7 cases; 14.5; %), moderate (18 cases; 37.5%) and strong (23 case; 47.9 %) of the positive cases. Regarding D5F3; five cases (10%) were positive; weak (1 case; 20 %), moderate (2 cases; 40 %) and strong (2 cases; 40%) out of the positive cases. Four ALK-positive cases were male and ALK-positive patients ranged from 42-55 years with median 48.Conclusion:Despite the incidence of ALk-AdC is uncommon, it might be suspected in lesions of lower age group especially with mucinous foci.

Outcomes of Gamma Knife Radiosurgery for Brain Metastases From Anaplastic Lymphoma Kinase Rearrangement-Positive and EGFR Mutation-Positive Non-Small Cell Lung Cancer.

IntroductionThe outcomes after gamma knife radiosurgery (GKRS) were retrospectively analysed in patients with brain metastases from anaplastic lymphoma kinase (ALK) rearrangement-positive and epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) to evaluate the efficacy, safety and difference for overall survival and local tumor control.MethodsThe medical records were retrospectively reviewed of 607 patients (25 ALK-positive, 171 EGFR-positive, and 411 wild type) with 2959 tumors who had undergone GKRS.ResultsThe median overall survival time after initial GKRS was 14 months. Driver gene mutation-positive patients had significantly longer overall survival than wild type patients (p < 0.0001), and ALK-positive patients survived significantly longer than EGFR-positive patients (p = 0.04). Multivariate analysis showed the unfavorable factors significantly affecting overall survival outcomes were older age, lower Karnofsky Performance Status score, multiple intracranial metastases, uncontrolled primary cancer, uncontrolled extracranial metastases, no administration of immune checkpoint inhibitors, and driver gene mutation-negative cases. Seventy-three patients died of uncontrolled brain metastases at a median of 12 months. Driver gene mutations had no influence (p = 0.33), and ALK-positive and EGFR-positive patients showed no significant difference in neurological survival (p = 0.83). A total of 174 patients demonstrated distant brain control failure at a median of 15 months. ALK-positive type was significant compared with EGFR-positive type (p = 0.047), but driver gene mutation-positive and -negative types showed no significant difference in the development of new brain metastases (p = 0.2). The median tumor volume was 1.06 cm3 in the driver gene mutation-positive type and 1.85 cm3 in wild type. The median marginal dose was 20 Gy in both types. The 6-, 12-, and 24-month local tumor control rates were 97.3%, 96.1%, and 95.9%, respectively. Driver gene mutations had a significantly positive impact on local tumor control (p = 0.001), and ALK-positive and EGFR-positive types showed no significant difference (p = 0.95). A total of 193 tumors had radiation injury at a median of 12 months after GKRS. The 6-, 12-, and 24-month GKRS-related complication rates were 3.3%, 8.1%, and 8.7%, respectively. Driver gene mutations significantly induced radiation damage (p = 0.021), and the ALK-positive type was affected more than the EGFR-positive type (p = 0.02).ConclusionsALK rearrangement-positive NSCLC patients tended to have significantly longer survival, but had higher incidence of new intracranial metastases due to long-term survival after GKRS, compared with EGFR mutation-negative and driver gene mutation-negative NSCLC patients. GKRS induced significantly satisfactory local tumor control in driver gene mutation-positive tumors but GKRS-related complication frequency was higher, especially in ALK-positive NSCLC patients. Therefore, more careful imaging follow-up is necessary after GKRS for patients with driver gene mutation-positive NSCLC.

Efficacy of lorlatinib in the treatment of ALK-positive non-small cell lung cancer patients with progression on crizotinib: personal experience

Introduction. Lorlatinib is a third generation ALK tyrosine kinase inhibitor. Back in 2018, the drug underwent accelerated FDA approval and was recommended for the treatment of patients with ALK-positive non-small cell lung cancer after progression on crizotinib and another ALK inhibitor. For a long time, the use of the drug in Russia was possible only in clinical trials or expanded access program. However, now this drug is becoming available in our country.Purpose. To analyze the overall and intracranial response during lorlatinib therapy, as well as the tolerability of lorlatinib therapy in patients with ALK-positive non-small cell lung cancer who previously received crizotinib and one or more lines of cytostatic therapy.Materials and methods. The study included 39 patients aged 28 to 76 years, diagnosed with non-small cell lung cancer. In 36 cases, a translocation in the ALK gene was detected, in three, a ROS1 translocation. All patients received targeted therapy with crizotinib and one or more lines of chemotherapy before starting lorlatinib therapy. All patients received 100 mg lorlatinib therapy until disease progression or intolerable toxicity.Results. During the observation period for the moment of September 2021, an objective response was achieved in 28 patients (71.7%), in 10 patients (25.6%) – stabilization of the disease, in one patient (2.6%) – progression. The median duration of the drug was just over 40 months. The drug intake was characterized by a predictable and manageable toxicity profile.Conclusions. These data indicate a high direct efficacy of lorlatinib in patients with ALK/ROS1 translocations. The data obtained do not contradict the results obtained in the course of clinical trials. The drug lorlatinib has currently received registration in Russia for the treatment of non-small cell lung cancer in cases of the development of progression while taking secondgeneration ALK inhibitors or several lines of therapy with ALK inhibitors.

Alectinib Together with Intracranial Therapies Improved Survival Outcomes in Untreated ALK-Positive Patients with Non-Small-Cell Lung Cancer and Symptomatic and Synchronic Brain Metastases: A Retrospective Study.

PurposeThe performance of alectinib and crizotinib in untreated anaplastic lymphoma kinase (ALK)-positive patients with non-small-cell lung cancer (NSCLC) and symptomatic and synchronic brain metastases is largely unknown. This retrospective study assessed the effectiveness of alectinib and crizotinib, together with intracranial therapies in a cohort of these patients.Patients and MethodsThis study included 34 previously untreated ALK-positive NSCLC patients with three or fewer intracranial metastases. Of these patients, 13 received oral alectinib 600 mg twice daily, and 21 received oral crizotinib 250 mg twice daily, until progressive disease, unacceptable toxicity, or death. All intracranial metastases were treated with craniotomy, CyberKnife, or both.ResultsMedian overall progression-free survival (PFS) was 32.8 months (95% CI 24.4–41.2 months) in patients treated with alectinib and 8.0 months (95% CI 7.3–8.7 months) in patients treated with crizotinib. Median PFS of brain lesions was not yet reached with alectinib (95% CI 30.1 months–not estimated) and was 8.5 months (95% CI 7.2–12.3 months) with crizotinib. Median PFS of lung lesions was 38.5 months (95% CI 27.5–49.5 months) with alectinib and 9.2 months (95% CI 7.4–11.0 months) with crizotinib. Median overall survival was not yet reached with alectinib (95% CI 31.0 months–not estimated) and 30.3 months (95% CI 27.3–37.1 months) with crizotinib.ConclusionCompared with crizotinib, alectinib showed superior efficacy and lower toxicity in the treatment of ALK-positive patients with NSCLC and symptomatic and synchronic brain metastases. The inclusion of intracranial therapies such as craniotomy or CyberKnife further improved the brain PFS and overall survival of these patients.

Clinical value of serum albumin level in patients with non-small cell lung cancer and anaplastic lymphoma kinase (ALK) rearrangement.

There are few data on the clinical value of serum albumin (Alb) level as a prognostic indicator in advanced non-small cell lung cancer (NSCLC) patients with positive anaplastic lymphoma kinase (ALK) rearrangement. Thus, we retrospectively analyzed the clinicopathological features of advanced, ALK-positive NSCLC patients diagnosed and treated at our institution to investigate the effects of pretreatment serum Alb on outcome in this patient setting. We selected 261 consecutive patients with newly diagnosed pathologically or cytologically confirmed NSCLC harboring ALK rearrangement between May 2016 and February 2018. The target-independent and dependent variables were Serum albumin level measured in patients before anticancer treatment and progression-free survival (PFS). Pre-treatment serum Alb levels and demographic, clinical, and histological characteristics, as well as outcome variables were recorded and analyzed. Serum albumin level was estimated before treatment and at every visit. The pretreatment and the lowest serum albumin level during treatment were recorded. The mean pretreatment Alb level was 42.185 g/L. Before the treatment initiation, low Alb level (<40 g/L) was measured in 74 (28.4%) patients and normal Alb (≥40 g/L) was measured in 187 (71.6%) participants. Low pretreatment Alb (<40 g/L) was more highly prevalent in those with pleural effusion (P=0.013). Pretreatment hypoalbuminemia was significantly associated with shorter progression-free survival (PFS) [8.0 months, 95% confidence interval (CI): 4.56-11.44 vs. 12.0 months, 95% CI: 9.85-14.15; P=0.046]. Crizotinib-treated participants had a significantly prolonged PFS compared to those treated with chemotherapy, regardless of Alb level [normal Alb level: 19.0 (95% CI: 12.72-25.28) vs. 8.0 (95% CI: 6.22-9.78), P<0.001; low Alb level: 12.0 months (95% CI: 10.13-13.87) vs. 6.0 months (95% CI: 2.95-9.05), P=0.006]. Multivariate analyses indicated that poor Eastern Cooperative Oncology Group performance status (ECOG PS) [hazard ratio (HR) =1.66; 95% CI: 1.16-2.38; P=0.005] and presence of pleural effusion (HR =2.43; 95% CI: 1.55-3.82; P<0.001) were significantly independent predictive factors for PFS in ALK-positive NSCLC. Pretreatment hypoalbuminemia is associated with poor outcome of NSCLC patients harboring ALK rearrangement. However, the role of the pretreatment serum Alb level as predictive biomarker requires further investigation.

The impact of theALK fusion variant on clinical outcomes in EML4-ALK patients with NSCLC: a systematic review and meta-analysis.

Background: Recent studies showed that ALK-fusion variants are associated with heterogeneous clinical outcomes. However, contradictory conclusions have beendrawn inother studies showing no correlation between ALK variants and prognoses. Methods: A systematic review and meta-analysis wasperformed to evaluate the prognostic value of EML4-ALK fusion variants for patientoutcomes. Results: 28 studies were included in the analysis. According to the pooled results, patients harboring variant 1 showed equivalent progression-free survival(PFS)and overall survival (OS) with non-v1 patients(hazard ratio [HR] for PFS: 0.91 [0.68-1.21];p=0.499; OS: 1.12 [0.73-1.72];p=0.610). Similarly, patients with v3 showed the same disease progress as non-v3 patients (pooled HR for PFS=1.07 [0.72-1.58];p=0.741). However, pooled results for OS suggested that patients with v3 had worse survival than non-v3 patients(HR=3.44 [1.42-8.35];p=0.006). Conclusion: Results suggestthat patients with v1 exhibited no significant difference from non-v1 in terms of OS and PFS, while v3 was associated with shorter OS in ALK-positive patients withnon-small cell lung cancer.

CD30-Directed Chimeric Antigen Receptor (CAR)-T Cells for Treatment of Hodgkin Lymphoma and Non-Hodgkin Lymphoma in Pediatric Patients

Background:Chimeric antigen receptor (CAR)-T cell therapy targeting the CD19 antigen has been effective in treating B-cell acute lymphoblastic leukemia. As CAR-T cells targeting new antigens are being explored for the treatment of other cancers in adults, parallel studies are warranted for pediatric cohorts. We have previously shown the safety and efficacy in adults of CAR-T cells targeting CD30, which is expressed in classical Hodgkin Lymphoma (HL) and in some Non-Hodgkin Lymphoma (NHL). We have therefore sought to study the feasibility and the safety of CD30.CAR-T cells in pediatric patients with relapsed/refractory CD30-expressing HL and Anaplastic Large Cell Lymphoma (ALCL).Design/Methods:Six pediatric patients (ages 9 to 17 years) with CD30+ HL (4) and NHL (2) were enrolled on two trials at the University of North Carolina. One NHL patient with ALK+ ALCL was enrolled on both trials. Two patients, one HL and one NHL, were enrolled on a phase I study and received 2x10 7 CD30.CAR-T cells/m 2 as consolidation for high-risk of relapse after autologous stem cell transplant (ASCT, NCT02663297). Five patients, 3 HL and 2 NHL, were enrolled on a phase Ib/II study and received 1x10 8 CD30.CAR-T cells/m 2, as treatment for relapsed disease, after lymphodepletion with bendamustine and fludarabine (NCT02690545). HL patients had failed multiple lines of therapies (5-6), including 2 with prior pembrolizumab, 2 with prior ASCT, and all 3 with prior brentuximab vedotin (BV) and radiation therapy. The two NHL patients both had ALCL, one was ALK positive and one was ALK negative. Both had been treated with prior BV. The ALK negative patient had been treated with 3 prior lines of therapy and the ALK positive patient had been treated with 6 lines of prior therapy including ASCT and two ALK inhibitors, crizotinib and brigatinib. The brigatinib was stopped 3 weeks prior to starting lymphodepletion.Results:CD30.CAR-T cells were successfully manufactured for all 7 patients and no differences were observed as compared to products manufactured for adults, based on cell number, transduction, potency or immunophenotype. For all patients, infusions were well-tolerated and no neurotoxicity experienced.On the post-ASCT study, 1 patient with HL and 1 with ALCL were treated. All adverse events (AE) were less than grade 4. The patient with HL remains in complete remission (CR) 41 months following therapy, while the patient with ALCL progressed.Five patients with relapsed/refractory disease (3 HL and 2 ALCL) were treated on the post-lymphodepletion study. Most grade 3 or higher AEs were anticipated hematologic toxicity secondary to lymphodepletion. The youngest HL patient on the study developed symptoms consistent with grade 2 cytokine release syndrome (CRS) and a concomitant pneumonia based on imaging, accompanied by a marked inflammatory response based on labs with maximum ferritin 9,920 ng/mL and CRP 150.7 mg/L. He responded to antibacterial agents and two doses of tocilizumab, as well as brief supplemental oxygen by nasal cannula. He did not require vasopressors. One patient with ALK+ ALCL had symptoms compatible with CRS and macrophage activation syndrome (maximum ferritin >100,000 ng/mL and CRP 39.7 mg/L), which were ultimately determined to be secondary to progressive disease, confirmed at autopsy 5 weeks post therapy. The other four patients (3 HL and 1 ALCL) achieved CR and remain in CR 4 to 27 months post CAR-T cell infusion. Of note, 2 of the HL patients chose to come off study while in CR to receive treatment with checkpoint inhibitor therapy.Conclusion:Our studies show that CD30.CAR-T cells are well tolerated in pediatric patients. CRs were observed in all heavily pre-treated and refractory HL patients, highlighting the potential of this strategy. All patients treated on both studies had previously received BV, which suggests CD30.CAR-T cells are effective even post BV progression. We continue to investigate how to better tailor CD30.CAR-T cells in NHL given the need for better therapies in ALCL, which is often aggressive at relapse. One patient with ALK negative ALCL remains in CR while the patient with ALK+ ALCL had rapid relapse.After study initiation, UNC entered into a research collaboration with Tessa Therapeutics. DisclosuresSavoldo: Tessa: Patents & Royalties: Approach for CD30.CAR-T Cells for Hodgkin Lymphoma. Dotti: Tessa: Patents & Royalties: Approach for CD30.CAR-T Cells for Hodgkin Lymphoma. Grover: Tessa: Consultancy; Kite: Other: Advisory Board; Novartis: Consultancy; Genentech: Research Funding; ADC: Other: Advisory Board. Morrison: Vesselon: Consultancy. Riches: Jazz Pharmaceuticals: Other: Payment; ATARA Biotherapeutics: Other: Payment; BioIntelect: Membership on an entity's Board of Directors or advisory committees. Serody: Tessa: Patents & Royalties: Approach for CD30.CAR-T Cells for Hodgkin Lymphoma.

Anaplastic lymphoma kinase rearrangements in non-small cell lung cancer in Jordan

Abstract Introduction/Objective ALK rearrangement is an important oncogenic driver in a substantial portion of non-small cell lung cancer (NSCLC) patients ranging from 2-7%. Treatment options such as ALK tyrosine kinase inhibitors (TKI) improve progression-free survival and overall survival. Candidates for such treatment are selected based on the identification of the ALK rearrangement. While fluorescence in situ hybridization (FISH) was considered the gold standard method, the availability of a robust FDA-approved companion diagnostic immunohistochemistry (IHC) assay has led to a paradigm shift in ALK testing. The purpose of this study is to determine the prevalence of ALK rearrangement in Jordanian NSCLC patients along with their clinicopathological characteristics and to compare the results of IHC and FISH methods for detecting ALK rearrangements. Methods/Case Report A retrospective study was conducted on 449 Jordanian King Hussein Cancer Center patients with NSCLC whose biopsy samples were tested for ALK rearrangement using FISH and or IHC (clone D5F3) in the period between 2018 and 2020. Results (if a Case Study enter NA) During the study period, the rate of ALK positivity by either IHC or FISH method was 4 percent (18 ALK positive cases out of 449 cases of non-small cell lung cancer). Seven cases were positive for both IHC and FISH, and nine cases were positive for IHC with no confirmation by FISH method; one case was ALK positive by IHC and negative by FISH with a significant response to ALK TKI; one case was IHC negative but FISH positive, with no ALK TKI therapy. The calculated sensitivity of ALK D5F3 immunostain compared to FISH results in the current study is 87.5% while the specificity is 96%. ALK positive patients were significantly younger than those with negative results (p-value=0.051), and women were three times more likely than men to have the rearrangement (p-value=0.013). Rearrangement was more likely to be found in nonsmokers/light or ex-smokers (p-value= 0.013). All patients had clinical stage IV or III disease at presentation with stage IV found in tow thirds of the patients. Conclusion ALK rearrangement is found in 4% of all NSCLC in Jordan. Patients are more likely to be younger, females and light or nonsmokers with an advanced stage disease at presentation. IHC is an acceptable alternative to FISH for ALK testing with reasonable sensitivity and specificity in addition to its advantages in terms of robustness, turnaround time and cost savings

Assessment of Alectinib vs Ceritinib in ALK-Positive Non–Small Cell Lung Cancer in Phase 2 Trials and in Real-world Data

Quantitative assessment of bias from unmeasured confounding and missing data can help evaluate uncertainty in findings from indirect comparisons using real-world data (RWD). To compare the effectiveness of alectinib vs ceritinib in terms of overall survival (OS) in patients with ALK-positive, crizotinib-refractory, non-small cell lung cancer (NSCLC) and to assess the sensitivity of these findings to unmeasured confounding and missing data assumptions. This comparative effectiveness research study compared patients from 2 phase 2 alectinib trials and real-world patients. Patients were monitored from June 2013 to March 2020. Comparisons of interest were between alectinib trial data vs ceritinib RWD and alectinib RWD vs ceritinib RWD. RWD treatment groups were selected from nationally representative cancer data from US cancer clinics, the majority from community centers. Participants were ALK-positive patients aged 18 years or older with advanced NSCLC, prior exposure to crizotinib, and Eastern Cooperative Oncology Group Performance Status (PS) of 0 to 2. Data analysis was performed from October 2020 to March 2021. Initiation of alectinib or ceritinib therapy. The main outcome was OS. In total, there were 355 patients: 183 (85 men [46.4%]) in the alectinib trial, 91 (43 men [47.3%]) in the ceritinib RWD group, and 81 (38 men [46.9%]) in the alectinib RWD group. Patients in the alectinib trial were younger (mean [SD] age, 52.53 [11.18] vs 57.97 [11.71] years), more heavily pretreated (mean [SD] number of prior therapy lines, 1.95 [0.72] vs 1.47 [0.81]), and had more favorable baseline ECOG PS (ECOG PS of 0 or 1, 165 patients [90.2%] vs 37 patients [77.1%]) than those in the ceritinib RWD group. The alectinib RWD group (mean [SD] age, 58.69 [11.26] years) had more patients with favorable ECOG PS (ECOG PS of 0 or 1, 49 patients [92.4%] vs 37 patients [77.1%]) and more White patients (56 patients [72.7%] vs 53 patients [62.4%]) compared with the ceritinib group. Compared with ceritinib RWD, alectinib-exposed patients had significantly longer OS in alectinib trials (adjusted hazard ratio [HR], 0.59; 95% CI, 0.44-0.75; P < .001) and alectinib RWD (HR, 0.46; 95% CI, 0.29-0.63; P < .001) after adjustment for baseline confounders. For the worst-case HR estimate of 0.59, residual confounding by a hypothetical confounder associated with mortality and treatment by a risk ratio greater than 2.24 was required to reverse the findings. Conclusions were robust to plausible deviations from random missingness for missing ECOG PS and underrecorded comorbidities and central nervous system metastases in RWD. Alectinib exposure was associated with longer OS compared with ceritinib in patients with ALK-positive NSCLC, and only substantial levels of bias examined reversed the findings. These findings suggest that quantitative bias analysis can be a useful tool to address uncertainty of findings for decision-makers considering RWD.

MA08.02 Outcomes of Early Stage ALK-positive NSCLC patients in a Real-World Cohort

While there has been a series of real-world studies on ALK-positive non-small cell lung cancer (NSCLC) in the advanced/metastatic setting, there are far fewer reports about the outcome of early stage ALK-positive cancer. The aim of this analysis was to study treatment patterns and outcomes in a real-world cohort of patients with ALK+ NSCLC diagnosed in stages I-III.