ALK-positive Non-small Cell Lung Cancer Patients Research Articles

Chinese expert consensus on iruplinalkib for the treatment of locally advanced or metastatic ALK-positive non-small cell lung cancer (2024 edition)

Anaplastic lymphoma kinase (ALK) fusion gene is one of the most common driver gene in non-small cell lung cancer (NSCLC). Epidemiological data showed that ALK gene fusion is detected in 9.06% of Chinese advanced NSCLC patients. ALK-tyrosine kinase inhibitors (TKIs) have become the standard treatment for advanced NSCLC patients with ALK gene fusion. Seven different ALK-TKIs have been approved by the National Medical Products Administration (NMPA) of China, including crizotinib, ceritinib, alectinib, ensartinib, brigatinib, lorlatinib, and iruplinalkib. Iruplinalkib is a novel new-generation ALK-TKI independently developed in China. On June 27, 2023, the NMPA approved iruplinalkib for the treatment of locally advanced or metastatic ALK-positive NSCLC patients whose disease has progressed after previous treatment with crizotinib or who are intolerant to crizotinib. On January 16, 2024, the NMPA approved iruplinalkib for the first-line treatment of locally advanced or metastatic ALK-positive NSCLC patients. In order to better understand the efficacy and safety of iruplinalkib, and facilitate more rationally clinical application of iruplinalkib, the Medical Oncology Branch of China International Exchange and Promotive Association for Medical and Health Care and the Chinese Association for Clinical Oncologists co-organized experts to compile the "Chinese expert consensus on iruplinalkib for the treatment of locally advanced or metastatic ALK-positive non-small cell lung cancer (2024 edition)".

China expert recommendations on anaplastic lymphoma kinase-tyrosine kinase inhibitors treatment for advanced non-small cell lung cancer (2024 edition)

Anaplastic lymphoma kinase (ALK) fusion represents one of pivotal driver genes within the realm of non-small cell lung cancer (NSCLC). ALK-tyrosine kinase inhibitors (ALK-TKI) have demonstrated remarkable therapeutic efficacy for patients afflicted with ALK-positive NSCLC. As of June 27, 2023, seven ALK-TKI, including crizotinib, ceritinib, alectinib, ensartinib, brigatinib, lorlatinib, and iruplinalkib, have garnered approval from the China National Medical Products Administration (NMPA)(ranking according to the approval time for marketing by NMPA), providing individualized treatment modalities for ALK-positive NSCLC patients. To standardize the application of ALK-TKI, the Chinese Association for Clinical Oncologists and the Medical Oncology Branch of China International Exchange and Promotive Association for Medical and Health Care has organized experts to compile the " China expert recommendations on anaplastic lymphoma kinase-tyrosine kinase inhibitors treatment for advanced non-small cell lung cancer (2024 edition)". This treatment expert recommendation provides recommendations in four aspects, encompassing ALK fusion testing, ALK-TKI targeted therapy, ALK-TKI adverse events management, and patient post-treatment follow-up, thus serving as a valuable reference for the standardized treatment of Chinese advanced ALK fusion-positive NSCLC.

Real-world evidence of lorlatinib therapy in taiwanese patients with advanced anaplastic lymphoma kinase-positive non-small cell lung cancer

BackgroundLorlatinib is a brain-penetrant, third-generation anaplastic lymphoma kinase (ALK) inhibitor indicated for ALK-positive metastatic non-small cell lung cancer (NSCLC). In a global phase II study, patients who experience disease progression despite prior treatment with ALK tyrosine kinase inhibitors (TKIs) was assessed. Herein, we report real-world clinical outcomes of lorlatinib-treated patients with ALK-positive advanced NSCLC who were heavily pretreated and progressed on first- and second-generation ALK-TKIs, in a Taiwanese population under the lorlatinib expanded access program (EAP). MethodsThis multicenter observational study examined the effectiveness and safety of ALK-positive advanced NSCLC patients that progressed from previous second-generation ALK-TKI therapy and received lorlatinib treatment subsequently. Patients who received lorlatinib treatment under EAP between Jul 2017 and Sep 2019 were eligible. Patients were followed for at least one year from the first lorlatinib treatment until study completion. ResultsSixty-three patients were eligible for safety analysis (male: 46.0 %; median age: 52.8 [27.5–78.3] years; brain metastases: 81.0 %). Fifty-four patients with more than one-month lorlatinib treatment were included in the effectiveness analysis. Prior to lorlatinib treatment, 10 patients (18.5 %) received one ALK-TKI, 27 (50.0 %) received two ALK-TKIs, and 17 (31.5 %) received three or more ALK-TKIs. The overall median rwPFS was 9.2 months (95 % confidence interval: 5.3–21.1). The best overall response rate (n = 51) was 13.7 %, with a disease control rate of 80.4 %. ConclusionLorlatinib exhibits substantial activity and tolerability when used clinically in a later-line setting in a Taiwanese population with ALK-positive advanced NSCLC.

Real-World Data on Treatment Outcome of ALK-Positive Non-Small Cell Lung Cancer from an Indian Multicentric Cancer Registry

The Anaplastic lymphoma kinase inhibitors (ALKi) represent the standard of care for metastatic non-small cell lung cancer (NSCLC) patients with EML4-ALK rearrangements. Various ALKi agents are available; however, not all eligible patients receive treatment with them due to various reasons. Given the limited real-world data available in our country, we aimed to assess treatment outcomes through a multicenter collaboration. This retrospective, multi-institutional study was conducted under the Network of Oncology Clinical Trials India and included a total of 67 ALK-positive metastatic lung cancer patients from 10 institutes across India, with a median follow-up of 23 months. In the first line setting, the objective response rate (ORR) with ALKi was 63.6% (crizotinib: 60.7%, ceritinib: 70%, alectinib: 66.6%, p = 0.508), while with chemotherapy, it was 26.1%. The median progression-free survival (mPFS) for the first line ALKi group was significantly higher than that for chemotherapy (19 vs. 9 months, p = 0.00, hazard ratio [HR] = 0.30, 95% confidence interval [CI]: 0.17–0.54). The mPFS for crizotinib, alectinib, and ceritinib was 17, 22, and 19 months, respectively (p = 0.48). Patients who received ALKi upfront or after 1 to 3 cycles of chemotherapy or after 4 or more cycles of chemotherapy had mPFS of 16, 22, and 23 months, respectively (p = 0.47). ALKi showed superior mPFS compared to chemotherapy in the second line (14 vs. 5 months; p = 0.002) and the third line (20 vs. 4 months; p = 0.009). The median overall survival (OS) was significantly better in patients who received ALKi in any line of therapy (44 vs. 14 months, p < 0.001, HR = 0.10, 95% CI: 0.04–0.23). Brain progression was higher among those who did not receive ALKi (69.2 vs. 31.5%). In conclusion, the use of ALKi as first line treatment for ALK-positive metastatic NSCLC patients resulted in improved PFS. PFS and ORR did not significantly differ between patients who received ALKi upfront or after initiating chemotherapy. Notably, patients who received ALKi in second or later lines demonstrated significantly better outcomes compared to those receiving chemotherapy. The use of ALKi in any line of therapy was associated with significantly prolonged OS.

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.

Safety of lorlatinib in ALK-positivenon-small-cell lung cancer and management of central nervous system adverse events.

The use of tyrosine kinase inhibitors has made a breakthrough in the treatment of non-small-cell lung cancer (NSCLC). Recently, lorlatinib, a third-generation tyrosine kinase inhibitor, has demonstrated significant systemic and intracranial activity in both first-line and subsequent-line therapy in ALK-positive NSCLC patients. In this review, general characteristics of lorlatinib, its efficacy in the treatment of ALK-positive NSCLC patients and the safety of lorlatinib, particularly addressing central nervous system adverse events, are discussed. Management of central nervous system adverse events, which seem to be specific to lorlatinib therapy, is outlined.

Distinct metastatic spread and progression patterns in patients treated with crizotinib for ROS1- and ALK-rearranged non-small cell lung cancer: a single-center retrospective study.

Crizotinib has been approved for C-ros oncogene 1 (ROS1)- and anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) patients. Few studies have examined the differences in crizotinib treatment outcomes between these patients and the progression sites during treatment. We investigated the metastatic spread, crizotinib efficacy, and progression patterns during crizotinib treatment in ROS1- and ALK-rearranged NSCLC patients. We retrospectively reviewed crizotinib-treated ROS1- and ALK-rearranged NSCLC patients between January 2011 and March 2021. Patient characteristics, clinical outcomes, and progression patterns during treatment were collected from medical records. The metastasis extent, crizotinib response, and progression patterns between the groups were compared. We identified 26 patients with ROS1- and 42 with ALK-positive NSCLC. The baseline proportion of central nervous system (CNS) metastases did not differ between the groups (12% vs. 29%, P=0.10), but the proportion of extrathoracic metastases, including CNS metastases, was significantly higher in ALK-positive than in ROS1-positive NSCLC patients (35% vs. 71%, P=0.003). Regarding the response to crizotinib, the objective response rate (ORR), progression-free survival (PFS), or overall survival (OS) did not significantly differ between the groups (ROS1 vs. ALK, ORR: 69% vs. 69%, P=0.987; PFS: median 10.9 vs. 10.7 months, P=0.232; median OS: not reached vs. 67.7 months, P=0.495). The CNS was the most common metastasis site in both groups [ROS1 vs. ALK, 69% (11/16) vs. 46% (17/37), P=0.127], and the cumulative incidence of CNS metastasis did not differ between the groups (P=0.914). Crizotinib treatment outcomes, including progression patterns, were similar between ROS1- and ALK-positive NSCLC patients.

Efficacy and safety of SY-3505, a third-generation ALK TKI, in ALK-positive advanced non-small cell lung cancer: Results from a phase I/II, multi-center study.

9110 Background: SY-3505 is a potent, brain-penetrant, 3rd-generation (gen) anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) with preclinical activity against both wild-type and most known resistance mutations of ALK occurring in 1st and 2nd-gen ALK TKI-resistant patients. Here we report the efficacy and safety results from the ongoing phase I/II study of SY-3505. Methods: Patients aged ≥18 years with histologically/cytologically confirmed, advanced, ALK-positive non-small cell lung cancer (NSCLC) and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2 were recruited from 13 hospitals in China. In phase I study, patients received SY-3505 from 25-800mg once daily in dose-escalation phase, followed by dose-expansion at 500/600mg. Patients received alectinib only or ≥2 prior ALK TKIs were recruited in phase II study and treated with SY-3505 at 600mg once daily. The primary endpoint was investigator (INV)-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. Results: At data cut-off date of Feb.03, 2023, 92 ALK-positive NSCLC patients were enrolled in phase I/II, 82 were evaluable for efficacy, the ORR was 34.2% (95% confidence interval [CI] 24.0-45.5%), DCR was 74.4% (95% CI 63.6-83.4%). Herein the ORR and DCR of 59 patients in phase I for dose-escalation and dose-expansion was 32.3% (95% CI 20.6-45.6%) and 69.5% (95% CI 56.1-80.8%), respectively; median DoR and PFS was 11.1 (95% CI 5.28-not reached [NR]) and 6.20 (95% CI 3.08-10.3) months, respectively. Fifty-six patients received SY-3505 at 600mg once daily (two patients received non-alectinib 2nd-gen ALK TKI only, 22 received alectinib only and 32 received ≥2 prior ALK TKIs). Thirty-two (57.1%) patients experienced treatment-related adverse events (TRAEs) and two (3.6%) had grade ≥3 TRAEs. The most common TRAEs were diarrhea (42.9%), nausea (28.6%) and vomiting (26.8%), consistent with previous reported in phase I. Forty-seven patients were evaluable for efficacy, the ORR and DCR was 38.3% (95% CI 24.5-53.6%) and 83.0% (95% CI 69.2-92.4%), respectively. Median DoR and PFS were NR. Twenty-two patients had baseline central nervous system metastases, the ORR and DCR was 50.0% and 86.4%, respectively. Conclusions: SY-3505 was well-tolerated and showed significant and durable clinical activity in ALK-positive NSCLC patients who received at least one prior 2nd-gen ALK TKI, demonstrating a potential new treatment option for these patient population. Pivotal clinical study will be performed in future. Clinical trial information: NCT05257512 .

Association of PD-L1 expression with efficacy of alectinib in advanced NSCLC patients with ALK fusion

BackgroundProgrammed cell death–ligand 1 (PD-L1) expression was found to be a biomarker of inferior efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutated non-small cell lung cancer (NSCLC). However, whether PD-L1 expression could also serve as a similar biomarker in anaplastic lymphoma kinase (ALK)-positive patients, especially for those treated with front-line alectinib, remains unclear. The aim of the study is to investigate the association of PD-L1 expression and efficacy of alectinib in this setting. MethodsFrom January 2018 to March 2020, 225 patients with ALK-rearranged lung cancer were consecutively collected at Shanghai Pulmonary Hospital, Tongji University. Baseline PD-L1 expression was detected using immunohistochemistry (IHC) in 56 patients of advanced ALK-rearranged lung cancer who received front-line alectinib. ResultsAmong the 56 eligible patients, 30 (53.6%) were PD-L1 expression negative, 19 (33.9%) patients had TPS 1%–49% and 7 (12.5%) had TPS ≥ 50%.We found no statistically significant associations between PD-L1 positivity and objective response rate (ORR, 90.0% vs. 80.8%, p = 0.274) or progression-free survival (PFS, not reached vs. not reached, HR: 0.98, 95 %CI: 0.37–2.61, p = 0.97) in patients treated with alectinib. Meanwhile, patients with PD-L1 high expression (TPS ≥ 50%) had a trend of longer PFS (not reached vs. not reached, p = 0.61). ConclusionsPD-L1 expression might not serve as a predict biomarker for the efficacy of front-line alectinib in ALK-positive NSCLC patients.

Pretherapy investigations using highly robust visualized biomarkers from CT imaging by multiple machine-learning techniques toward its prognosis prediction for ALK-inhibitor therapy in NSCLC: a feasibility study.

Molecularly targeted therapy has revolutionized the therapeutic landscape and is emerging as the first-line treatment option for ALK-rearranged non-small-cell lung cancer (NSCLC). In this study, the highly informative and robust biomarkers based on pre-treatment CT images and clinicopathologic features will be developed and validated to predict the prognosis for ALK-inhibitor therapy in NSCLC patients. A total of 161 ALK-positive NSCLC patients treated with ALK inhibitors were retrospectively collected as training, validation and test sets from multi-center institutions. Cox proportional hazard regression (CPH) penalized by LASSO and random survival forest (RSF) coupled with recursive feature elimination (RFE) were used for radiomics and clinical features identification and model construction. An overlapping post-processing method was extra added to training process to investigate the stronger biomarker on the whole set. 123 of the collected cases progressed after a median follow-up of 15.5months (IQR, 8.3-25.3). The T and M staging, pericardial effusion, age and ALK inhibitor-alectinib were determined as significant predictors in the survival analysis. Furthermore, we visualized the finally retained 4 radiomics feature. The RSF models built from overlapping-processed clinical and radiomics features respectively reached the maximum C-index of 0.68 and 0.75,but the combination of them,radioclinical signature, improved the score to 0.78. The model on the validation and external test datasets yielded the C-index of 0.73 and 0.79, with the iAUC of 0.76 and 0.83, the IBS of 0.119 and 0.112. With respect to a simple selection strategy of overlapping optimal radiomics and clinical features from different survival models may promote better progression-free survival(PFS) prediction than conventional survival analysis, which provides a potential method for guiding personalized pre-treatment options of NSCLC.

Early-stage anaplastic lymphoma kinase (ALK)-positive lung cancer: a narrative review.

While anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are standard of care treatment for metastatic ALK-positive non-small cell lung cancer (NSCLC), the benefit of moving ALK inhibitors to earlier disease stages is unclear. The objective of this review is to summarize the literature regarding the prevalence and prognosis of early-stage ALK-positive NSCLC and the utility of targeted therapies, immunotherapy, and chemotherapy in the neoadjuvant and adjuvant settings. We identified the references for this narrative review through a literature search of papers about early stage ALK-positive NSCLC using PubMed and clinicaltrials.gov. Last search was run on July 3, 2022. There were no language or time frame restrictions. The incidence of oncogenic ALK alterations in early-stage NSCLC ranges from 2-7%, and ALK-positive NSCLC patients are more likely to be younger and never or light smokers. Studies on the prognostic impact of ALK in early-stage disease have had conflicting results. ALK TKIs are not approved in the neoadjuvant or adjuvant setting and there is a lack of large, randomized trial results. Several trials are currently accruing but results are not expected for several years. Attempts at large, randomized trials to evaluate the benefit of ALK TKIs in the adjuvant and neoadjuvant has been hampered by slow recruitment given the rarity of ALK alterations, lack of universal genetic testing, and the rapid pace of drug development. Expanded lung cancer screening recommendations, liberalization of surrogate endpoints (i.e., pathological complete response and major pathological response), growth of multicenter national clinical trials, and new diagnostic technologies (i.e., cell-free DNA liquid biopsies) provide hope of generating much needed data to definitively answer the question of the utility of ALK-directed therapies in the early-stage setting.

An update on lorlatinib: a novel first line treatment for ALK-positive advanced lung cancer

ABSTRACT Introduction Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of ALK-rearranged non-small cell lung cancer (NSCLC), but these patients will eventually develop resistance and progression of disease after 10 months of first-generation and more than 30 months after second-generation TKIs. Lorlatinib is a third-generation highly selective ALK-TKI capable of inducing significant and durable CNS responses and overcoming known ALK resistance mutations. Areas covered This review summarizes the mechanism of action, efficacy, and safety of lorlatinib in ALK-positive NSCLC. The authors provide their expert opinions on the use of this drug, including its future prospects. Expert opinion Lorlatinib has shown good efficacy and safety in ALK-positive NSCLC patients progressing to first- and second-generation ALK-TKIs. The phase III trial CROWN evaluating lorlatinib as first-line therapy has provided promising results; however, the comparing arm was crizotinib, supplanted now by second-generation agents. Whether lorlatinib can replace them as upfront strategy is a relevant question that still remains open. In our opinion, longer follow-up and face-to-face studies are required to determine which is the best treatment sequence strategy. The advent of liquid biopsy will contribute to treatment tailoring according to the genomic profile at progression.

Phase II Trial of the Combination of Alectinib with Bevacizumab in Alectinib Refractory ALK-Positive Nonsquamous Non-Small-Cell Lung Cancer (NLCTG1501)

Anaplastic lymphoma kinase (ALK)-positive lung cancer is a rare cancer that occurs in approximately 5% of non-small-cell lung cancer (NSCLCs) patients. Despite the excellent efficacy of ALK-tyrosine kinase inhibitor in ALK-positive NSCLCs, most patients experience resistance. We conducted a phase II study to investigate the combination of alectinib with bevacizumab in ALK-positive NSCLC patients after failure of alectinib. In this study, ALK-positive nonsquamous NSCLC patients previously treated with alectinib received bevacizumab 15 mg/kg on day 1 every 3 weeks and alectinib 600 mg/day until disease progression. The primary endpoints were progression-free survival (PFS) and the safety of alectinib and bevacizumab. The secondary endpoints included overall survival (OS) and correlation of circulating tumor DNA and plasma proteins with PFS. Of the 12 patients treated, the median PFS was 3.1 months (95% CI 1.2-16.1), and the median OS was 24.1 months (95% CI 8.3-not estimable). The EML4-ALK fusion gene in circulating tumor DNA was significantly correlated with shorter PFS (1.2 months vs. 11.4 months, HR 5.2, p = 0.0153). Two patients experienced grade 3 adverse events; however, none of the patients required dose reduction. Although the primary endpoint was not met, alectinib combined with bevacizumab showed clinical efficacy in ALK-positive patients.

Longitudinal monitoring of cell-free DNA methylation in ALK-positive non-small cell lung cancer patients

BackgroundDNA methylation (5-mC) signals in cell-free DNA (cfDNA) of cancer patients represent promising biomarkers for minimally invasive tumor detection. The high abundance of cancer-associated 5-mC alterations permits parallel and highly sensitive assessment of multiple 5-mC biomarkers. Here, we performed genome-wide 5-mC profiling in the plasma of metastatic ALK-rearranged non-small cell lung cancer (NSCLC) patients receiving tyrosine kinase inhibitor therapy. We established a strategy to identify ALK-specific 5-mC changes from cfDNA and demonstrated the suitability of the identified markers for cancer detection, prognosis, and therapy monitoring.MethodsLongitudinal plasma samples (n = 79) of 21 ALK-positive NSCLC patients and 13 healthy donors were collected alongside 15 ALK-positive tumor tissue and 10 healthy lung tissue specimens. All plasma and tissue samples were analyzed by cell-free DNA methylation immunoprecipitation sequencing to generate genome-wide 5-mC profiles. Information on genomic alterations (i.e., somatic mutations/fusions and copy number alterations) determined in matched plasma samples was available from previous studies.ResultsWe devised a strategy that identified tumor-specific 5-mC biomarkers by reducing 5-mC background signals derived from hematopoietic cells. This was followed by differential methylation analysis (cases vs. controls) and biomarker validation using 5-mC profiles of ALK-positive tumor tissues. The resulting 245 differentially methylated regions were enriched for lung adenocarcinoma-specific 5-mC patterns in TCGA data and indicated transcriptional repression of several genes described to be silenced in NSCLC (e.g., PCDH10, TBX2, CDO1, and HOXA9). Additionally, 5-mC-based tumor DNA (5-mC score) was highly correlated with other genomic alterations in cell-free DNA (Spearman, ρ > 0.6), while samples with high 5-mC scores showed significantly shorter overall survival (log-rank p = 0.025). Longitudinal 5-mC scores reflected radiologic disease assessments and were significantly elevated at disease progression compared to the therapy start (p = 0.0023). In 7 out of 8 instances, rising 5-mC scores preceded imaging-based evaluation of disease progression.ConclusionWe demonstrated a strategy to identify 5-mC biomarkers from the plasma of cancer patients and integrated them into a quantitative measure of cancer-associated 5-mC alterations. Using longitudinal plasma samples of ALK-positive NSCLC patients, we highlighted the suitability of cfDNA methylation for prognosis and therapy monitoring.

Conteltinib (CT-707) in patients with advanced ALK-positive non-small cell lung cancer: a multicenter, open-label, first-in-human phase 1 study

BackgroundConteltinib (CT-707) is a potent second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) showing promising anti-tumor activities in preclinical studies. This study aimed to assess the safety, pharmacokinetic (PK), and efficacy of conteltinib in patients with ALK-positive non-small cell lung cancer (NSCLC).MethodsIn this multicenter, single-arm, open-label, first-in-human phase 1 study, conteltinib was taken orally at doses of 50 to 800 mg quaque die (QD) in a dose-escalation phase. If the response was observed in a dose cohort of the dose-escalation phase, dose expansion was started. The primary endpoints were maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and adverse events assessed by investigators.ResultsBetween April 13, 2016, and February 8, 2020, 64 ALK-positive NSCLC patients were enrolled, including 41 (64.1%) patients with ALK TKI-naïve and 23 (35.9%) patients who received crizotinib previously. In the dose-escalation phase, 26 patients were treated with conteltinib at doses of 50 mg, 100 mg, 200 mg, 300 mg, 450 mg, 600 mg, and 800 mg QD. One DLT event was reported at the dose of 600 mg. MTD was not reached. Overall, 58 (90.6%) patients experienced treatment-related adverse events (TRAEs) and 9 (14.1%) patients had grade ≥ 3 TRAEs. The most common TRAEs were diarrhea (46 [71.9%]), serum creatinine elevated (29 [45.3%]), aspartate aminotransferase elevated (25 [39.1%]), and nausea (24 [37.5%]). Among 39 ALK TKI-naïve patients, the overall response rate (ORR) was 64.1% (25 of 39; 95% confidence interval [CI], 47.2–78.8), median progression-free survival (PFS) was 15.9 months (95% CI, 9.26–23.3), and median duration of response (DoR) was 15.0 months (95% CI, 9.06–25.8). Among 21 patients who received crizotinib previously, the ORR was 33.3% (7 of 21; 95% CI, 14.6–57.0), median PFS was 6.73 months (95% CI, 4.73–8.54), and median DoR was 6.60 months (95% CI, 3.77–13.3).ConclusionsIn this study, conteltinib showed manageable safety profile, favorable PK properties, and anti-tumor activity in advanced ALK-positive NSCLC patients. The recommended phase 2 dose was determined to be 600 mg QD for ALK TKI-naïve patients and 300 mg bis in die (BID) for patients who received crizotinib previously.Trial registrationClinicalTrials.gov, NCT02695550.

EP02.04-001 Alectinib as Neoadjuvant Treatment in Surgically Resectable Stage III ALK-Positive NSCLC: ALNEO Phase II Trial (GOIRC-01-2020)

Stage III Non-Small Cell Lung Cancer (NSCLC) is a heterogeneous group of tumors with a wide spectrum of clinical presentations and no single definitive therapeutic approach. The role of neoadjuvant anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors in stage III ALK-positive non-small cell lung cancer (NSCLC) is still unclear and poorly explored. We designed a phase II, open-label, single-arm, multicenter study aimed at investigating alectinib in potentially resectable locally advanced stage III ALK-positive NSCLC patients (ALNEO trial, EUDRACT number 2020-003432-25).

Abstract 4120: Acquired TPM3-NTRK1 fusion resistant to larotrectinib in a non-small cell lung cancer with EML4-ALK fusion progressed on lorlatinib

Abstract Background: As oncogenic driver genes have been detected, targeted therapy plays a crucial role in non-small cell lung cancer (NSCLC) with targeted mutation. Lorlatinib, a selective third-generation inhibitor of anaplastic lymphoma kinase (ALK), is a treatment option for ALK-positive NSCLC patients who previously failed on ALK tyrosine kinase inhibitors (TKIs). Larotrectinib, a highly selective tropomyosin receptor kinase (TRK) inhibitor, is a treatment option for NSCLC with neurotrophic tyrosine receptor kinase (NTRK) mutation. Herein, we present an acquired TPM3-NTRK1 fusion resistant to larotrectinib in lung adenocarcinoma with EML4-ALK fusion progressed on lorlatinib. Case Presentation: A 48-year-old male with stage IV adenocarcinoma of lung with metastatic disease of bone was initially treated with carboplatin, pemetrexed, and pembrolizumab. Follow up CT in 4 months showed numerous hepatic lesions and liver biopsy demonstrated large cell neuroendocrine carcinoma. Upon progression of disease (PD), systemic therapy regimen was switched to combination of carboplatin, paclitaxel, and bevacizumab. After two months since starting the new regimen, a second PD was observed. Follow-up MRI brain demonstrated multiple small metastatic lesions. Subsequently, he was started on alectinib 600 mg twice a day given EML 4-ALK fusion mutation [4.8% of variant allele frequency (VAF)] in circulating tumor DNA (ctDNA) NGS assay. Follow-up CT chest in 5 months showed 5 mm left lower lobe nodule which remained unchanged in size. He maintained SD for 9 months before repeat MRI brain demonstrated PD with new leptomeningeal carcinomatosis. Subsequently, he received whole brain radiotherapy and the treatment regimen was switched to lorlatinib 100 mg daily. In 7-week follow-up CT, the 5 mm nodule in the left lower lobe was stable. Follow-up MRI brain in 16 weeks showed decrease in size and number of numerous enhancing parenchymal and leptomeningeal lesions. Overall SD was maintained for 8 months before follow-up MRI brain showed new punctate lesions. Repeat ctDNA NGS assay revealed new TPM3-NTRK1 fusion (VAF 0.2%) and ALK L1196M (VAF 2.8%), and a decision was made to add larotrectinib 100 mg daily. The 6-week follow-up MRI brain showed new parenchymal brain metastases. Discussion: It has been reported that the development of ALK resistance mutations may be associated with specific EML4-ALK variants. However, the influence of the specific EML4-ALK variants in NSCLC was not fully investigated. We report the case of acquired TPM3-NTRK1 fusion resistant to larotrectinib and acquired ALK L1196M in lung adenocarcinoma with EML4-ALK fusion progressed on lorlatinib. Further investigations are warranted to explore the mechanism of resistance to ALK TKIs. Citation Format: Horyun Choi, Jinah Kim, Yeun Ho Lee, Leeseul Kim, Na Hyun Kim, Young Kwang Chae. Acquired TPM3-NTRK1 fusion resistant to larotrectinib in a non-small cell lung cancer with EML4-ALK fusion progressed on lorlatinib [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 4120.

Driver mutations and air pollution in advanced non-small cell lung cancer (NSCLC) at two reference hospitals in Mexico City.

e20545 Background: Currently, precision medicine has allowed the classification of NSCLC according to the profile of driver mutations and the development of highly effective treatments. There is evidence to support the relationship between outdoor air pollution, particularly particulate matter (PM) in outdoor air, with lung cancer incidence and mortality. Smoking is a negative predictor of EGFR mutation, but the effect of air pollution has not been stablished. Methods: We perform a retrospective study in two referral hospitals in Mexico City between 2015 to 2020 to determinate the frequency of key driver mutations in patients with advanced NSCLC and the relation with smoking habit, wood smoke exposure and pollution indexes (PM2.5, PM10, SO2, O3, NO2) according to their place of residence. We used WHO air quality thresholds for air pollutants to classify cases with high or low exposure. Results: A total of 1277 cases were analyzed. The median age at diagnosis was 66 years (range 18-97 years), 53% were females and 49.6% had history of smoking habit. According to histology, 61.6% of cases corresponded to adenocarcinoma, 11.7% were squamous, 1.3% large cell, and 25.4% indeterminate. Wood smoke was assessed in 83.1% of cases and 28.5% had exposure history. Air pollutants were measured in half of cases, high level of exposure for PM2.5, PM10, NO2 and SO2 occurred in 63.2%, 30.8%, 15.6%, 53.4%, respectively. EGFR, ALK and KRAS mutations were evaluated in 85%, 16.7% and 8.6% of patients, respectively. The presence of these mutations was: EGFR 17.1%, ALK 11.1%, and KRAS 16.5%. Patients with EGFR-positive NSCLC were more frequently female (65.1% vs 34.9%, OR 1.8 95%CI 1.4-2.5, p < 0.001) and had no history of tobacco use (35% vs 65%, OR 0.49 95%CI 0.36-0.67, p < 0.001). Wood smoke was not statistically significant. High exposure to PM2.5 was most common in patients with non-mutated EGFR NSCLC (65.3% vs 34.7%, OR 1.7 95%CI 1.2-2.5, p = 0.006). Relationship with other air pollutants were not statistically significant. ALK-positive NSCLC patients tend to be females (68% vs 32%, p = 0.07) and had no history of smoking habit (20.8% vs 79.2% OR 0.28 95%CI 0.1-0.78, p = 0.01). High exposure to SO2 was common (78.6% vs 21.4% p = 0.05). Association in KRAS-positive NSCLS patients were not found. Conclusions: A low rate of key driver mutations assessment was found in this Mexican cohort. Clinical profile of NSCLC EGFR positive is according with previous reports in the literature. Exposure to PM2.5 and SO2 were found associated with EGFR and ALK status in this retrospective study and are hypothesis generating information.

Role of chemokine-mediated angiogenesis in resistance towards crizotinib and its reversal by anlotinib in EML4-ALK positive NSCLC

BackgroundThe identification of early plasma biomarkers for clinical outcomes and drug resistance has key importance for risk stratification in anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) patients. Moreover, it remains unclear whether the anti-angiogenic drug anlotinib can reverse the resistance of ALK-tyrosine kinase inhibitor (ALK-TKI) crizotinib, and no research has explored the effect of anlotinib combined with crizotinib on ALK-positive patients.MethodsIn this study, 76 baseline and longitudinal plasma samples from 61 ALK-positive NSCLC patients receiving crizotinib treatment were analyzed by Luminex liquid suspension chip for 40 chemokines. RNA sequence (RNA-seq) was used to identify differentially expressed genes (DEGs) between H3122 and H3122-crizotinib resistant (H3122CR) cells. Tube formation assay was performed to investigate the effect of chemokines on angiogenesis. And H3122CR-derived xenograft model was constructed to validate the efficacy and safety of anlotinib combined with crizotinib in vivo.ResultsBaseline and progression plasma samples detection suggested that CCL20 played a crucial role in monitoring and predicting the clinical response of crizotinib (hazard ratio for progression-free survival: 2.27 (1.13–4.58); for overall survival: 2.7 (1.23–5.8)). RNA-seq results for H3122 and H3122CR cells showed that high expression of chemokines and angiogenesis pathways were involved in crizotinib resistance. Subsequently, in vitro experiments indicated that CCL20 may induce crizotinib resistance by activation of angiogenesis via JAK2/STAT3-CCL20-VEGFA/IL6 axis. We further found that anti-angiogenic TKI anlotinib could reverse crizotinib resistance by inhibiting chemokines-induced angiogenesis, and anlotinib combined with crizotinib has a better antitumor effect than monotherapy in vitro & in vivo.ConclusionsOverall, CCL20-mediated angiogenesis is involved in crizotinib resistance and could be overcome by using anlotinib in EML4-ALK positive NSCLC. The combination of anlotinib and crizotinib is a promising strategy for patients resistant to ALK-TKIs.

The regulation of CD73 in non-small cell lung cancer

BackgroundLung cancer is the leading cause of global cancer-related mortality. Although immune checkpoint therapy has achieved remarkable results in lung cancer, EGFR-mutant or ALK-positive non-smallcell lung cancer patients show limited benefit. Besides the low tumor mutational burden, PD-L1 expression and CD8+ tumor-infiltrating T cells, upregulation of CD73/adenosine pathway also contributes to the immune-inert microenvironment of EGFR-mutant NSCLC. However, the detailed mechanism underlying the regulation of CD73 is unclear. MethodsTCGA data was used to analyze the CD73 expression in cancer patients. Western blotting, qPCR, and ChIP-PCR were performed in multiple NSCLC cancer cell lines and patient derived organoids were used to explore the regulation of CD73 expression using western blotting. ResultsCD73 expression was highly expressed in multiple cancer types. Pharmacological or genetic inhibition of EGFR, MEK, KRAS, or ALK dramatically reduced the CD73 mRNA and protein expression in NSCLC cancer cells and patient-derived organoids with EGFR mutation, KRAS mutation or ALK-rearrangement. C-Jun overexpression-induced CD73 mRNA and protein expression. ChIP assay showed that c-Jun bind to CD73 genomic regions. ConclusionsHigher CD73 expression in NSCLC cancer cells and patient-derived organoids with EGFR mutation, KRAS mutation or ALK-rearrangement. Mechanistically, CD73 is regulated by ERK-Jun pathway, wherein c-Jun regulates CD73 expression via binding to CD73 genomic regions.