Advanced ALK-positive Non-small Cell Lung Research Articles

Lorlatinib Versus Crizotinib in Patients With Advanced ALK-Positive Non-Small Cell Lung Cancer: 5-Year Outcomes From the Phase III CROWN Study.

Lorlatinib improved progression-free survival (PFS) and intracranial activity versus crizotinib in patients with previously untreated, advanced, ALK-positive non-small cell lung cancer (NSCLC) in the phase III CROWN study. Here, we report long-term outcomes from CROWN after 5 years of follow-up. Two hundred ninety-six patients with ALK-positive NSCLC were randomly assigned 1:1 to receive lorlatinib 100 mg once daily (n = 149) or crizotinib 250 mg twice daily (n = 147). This post hoc analysis presents updated investigator-assessed efficacy outcomes, safety, and biomarker analyses. With a median follow-up for PFS of 60.2 and 55.1 months, respectively, median PFS was not reached (NR [95% CI, 64.3 to NR]) with lorlatinib and 9.1 months (95% CI, 7.4 to 10.9) with crizotinib (hazard ratio [HR], 0.19 [95% CI, 0.13 to 0.27]); 5-year PFS was 60% (95% CI, 51 to 68) and 8% (95% CI, 3 to 14), respectively. Median time to intracranial progression was NR (95% CI, NR to NR) with lorlatinib and 16.4 months (95% CI, 12.7 to 21.9) with crizotinib (HR, 0.06 [95% CI, 0.03 to 0.12]). Safety profile was consistent with that in prior analyses. Emerging new ALK resistance mutations were not detected in circulating tumor DNA collected at the end of lorlatinib treatment. After 5 years of follow-up, median PFS has yet to be reached in the lorlatinib group, corresponding to the longest PFS ever reported with any single-agent molecular targeted treatment in advanced NSCLC and across all metastatic solid tumors. These results coupled with prolonged intracranial efficacy and absence of new safety signals represent an unprecedented outcome for patients with advanced ALK-positive NSCLC and set a new benchmark for targeted therapies in cancer.

Rutin attenuates ensartinib-induced hepatotoxicity by non-transcriptional regulation of TXNIP

Ensartinib, an approved ALK inhibitor, is used as a first-line therapy for advanced ALK-positive non-small cell lung cancer in China. However, the hepatotoxicity of ensartinib seriously limits its clinical application and the regulatory mechanism is still elusive. Here, through transcriptome analysis we found that transcriptional activation of TXNIP was the main cause of ensartinib-induced liver dysfunction. A high TXNIP level and abnormal TXNIP translocation severely impaired hepatic function via mitochondrial dysfunction and hepatocyte apoptosis, and TXNIP deficiency attenuated hepatocyte apoptosis under ensartinib treatment. The increase in TXNIP induced by ensartinib is related to AKT inhibition and is mediated by MondoA. Through screening potential TXNIP inhibitors, we found that the natural polyphenolic flavonoid rutin, unlike most reported TXNIP inhibitors can inhibit TXNIP by binding to TXNIP and partially promoting its proteasomal degradation. Further studies showed rutin can attenuate the hepatotoxicity of ensartinib without antagonizing its antitumor effects. Accordingly, we suggest that TXNIP is the key cause of ensartinib-induced hepatotoxicity and rutin is a potential clinically safe and feasible therapeutic strategy for TXNIP intervention.Graphical

Clinical difference on the variants and co-mutation in a Chinese cohort with ALK-positive advanced non-small cell lung cancer.

Despite the generally favourable prognoses observed in patients with ALK-positive non-small cell lung cancer (NSCLC), there remains significant variability in clinical outcomes. The objective of this study is to enhance patient stratification by examining both the specific sites of gene fusion and the presence of co-occurring mutations. We collected retrospective clinical and pathological data on ALK-positive patients with locally advanced or metastatic disease. ALK fusion variants and concomitant mutations were identified through next-generation sequencing technology. We then assessed treatment efficacy via tumor response and survival metrics. This study included a total of 59 patients, with 49 harboring echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusions and 10 presenting with rare fusions. The median follow-up period was 33 months. Clinical outcomes between non-EML4-ALK and EML4-ALK patients were comparable. Among the EML4-ALK cohort, patients with longer variants (v1, v2, v8) demonstrated superior progression-free survival (PFS) (median PFS: 34 months vs. 11 months; hazard ratio [HR]: 2.28; P = 0.05) compared to those with shorter variants (v3, v5). Furthermore, patients treated with second-generation ALK inhibitors (ALKi) displayed a progression-free survival advantage (median PFS: not reached [NR] vs. 9 months; HR: 5.37; P = 0.013). Baseline TP53 co-mutation were linked with a substantially shorter OS (median OS,37 months vs. NR; HR 2.74; P = 0.047). In ALK+ NSCLC, longer EML4-ALK variants correlate with improved prognosis and enhanced response to second-generation ALKi, while TP53 co-mutations indicate a negative prognosis.

Symptomatic androgen deficiency and sexual dysfunctions in male patients receiving alectinib for ALK-positive advanced non-small cell lung cancer.

It is reported that treatment with anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) induces hypogonadism both in male patients with ALK-positive cancer and in murine models. In this study, three groups, including an experimental group of male patients with ALK-positive, advanced non-small cell lung cancer (ANSCLC) who were receiving alectinib (cohort A), a control group of female patients with ALK-positive ANSCLC who were receiving alectinib (cohort B), and a control group of male patients with ALK-negative ANSCLC (cohort C), prospectively underwent a full hormone assessment for androgen deficiency at 8 weeks after the start of treatment and in case of reported suspected symptoms. Patients with major sexual dysfunctions were referred to an endocrinologist. Ninety-five patients were consecutively enrolled onto the study. Among sixty-eight male patients, both median total testosterone levels (2.93 vs. 4.92 ng/ml; p=.0001) and free testosterone levels (0.11 vs. 0.17 pg/ml; p=.0002) were significantly lower in ALK-positive ANSCLC patients in cohort A compared with ALK-negative patients in cohort C; conversely, median FSH (10.32 vs. 17.52 mUI/ml; p=.0059) and LH levels (4.72 vs. 7.49 mUI/ml; p=.0131) were significantly higher in cohort C compared to cohort A. Median inhibin B levels were higher in ALK-positive male patients (74.3 vs. 44.24 pg/ml; p=.0038), but all patients had inhibin B values within the normal range. The percentage of male patients who had positive scores on the Androgen Deficiency in Aging Males (ADAM) questionnaire was 62% in cohort A and 26.8% in cohort C, including eight patients who reported at least one major symptom and were referred to Andrology Unit. No significant differences in the endocrine assessment were reported between cohorts A and B. Symptoms of androgen deficiency should be tracked in male patients with ALK-positive ANSCLC who are receiving alectinib, and testosterone replacement should be considered, as appropriate.

Formation and characterization of charge transfer complex between alectinib and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone: Application to development of microwell spectrophotometric method

Alectinib (ALC) is a novel highly selective anaplastic lymphoma kinase (ALK) inhibitor that is effective in the treatment of patients with advanced ALK-positive non-small cell lung cancer and lymphomas. This study, describes, for the first time, the formation of a charge transfer complex (CTC) between ALC with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). The CTC was characterized using different spectrophotometric and computational techniques. UV–visible spectrophotometry ascertained the formation of the CTC in methanol via the formation of a new broad absorption band with a maximum absorption peak (λmax) at 505 nm. The molar absorptivity (ε) of the complex was 2.72 × 103 L mol−1 cm−1 and its band gap energy was 1.94 eV. The stoichiometric ratio of ALC:DDQ was found to be 1:1. The association constant of the complex was 9.6 × 102 L mol−1, and its standard free energy was −16.98 J mol−1. Computational calculations were conducted using different calculation tools. The computed geometrical parameters, specifically bond lengths, exhibited variations in the CTC compared to the individual reactants (ALC and DDQ). The Mulliken atomic charge analysis indicated increased values for DDQ (the acceptor) and decreased values for ALC (the donor) in the CTC, confirming the formation of a CTC. The reaction was employed as a basis for a novel microwell spectrophotometric method for the quantification of ALC in its bulk form, capsule content, and uniformity testing. This greenness and high throughput of the method was documented. The method represents a valuable tool for routine use in quality control laboratories for analysis of ALC's bulk form and capsules.

HER3 overexpression: a predictive marker for poor prognosis in advanced ALK-positive non-small cell lung cancer treated with ALK inhibitors.

Anaplastic lymphoma kinase (ALK)-targeted tyrosine kinase inhibitors (TKIs) improve patient survival; however, some patients develop ALK-TKI resistance with unidentified mechanisms. We investigated ErbB family and c-MET expression in patients with ALK-positive non-small cell lung cancer (NSCLC) to understand their roles in the ALK-TKI response. We studied 72 patients with advanced ALK-positive NSCLC with EML4-ALK fusion variant subtyping and immunostaining for c-MET, EGFR, HER2, and HER3 on tissue specimens both pre- (primary) and post-treatment (secondary) with ALK-TKI. We investigated the association of their expression with survival outcomes and assessed the effectiveness of combining ALK and EGFR inhibitors in ALK-positive NSCLC cell lines stimulated with the HER3-specific ligand HRG1. High expression of c-MET, EGFR, HER2, and HER3 was observed in 4.9%, 18.0%, 1.6%, and 25.8% of primary tumors, respectively, and 18.5%, 37.0%, 10.7%, and 35.7% of secondary tumors, respectively. HER3 overexpression in primary tumors showed inferior survival (P=0.132). In the subgroup with EML4-ALK variant 1/2 (V1/V2), HER3 overexpression was significantly associated with inferior survival in both primary and secondary tumors (P=0.022 and P=0.004, respectively). Combination treatment with lorlatinib and erlotinib significantly reduced HRG1-induced activation of RTK signaling in ALK-positive NSCLC cells. HER3 overexpression has potential as a prognostic marker in ALK-positive NSCLCs, including ALK-TKI naïve and treated cases, especially those with EML4-ALK V1/V2. Assessing HER3 expression may be crucial for treatment planning and outcome prediction in these patients.

Long-Term Efficacy and Safety of Lorlatinib in Japanese Patients With ALK-Positive Advanced NSCLC—A Brief Report From the CROWN Study

IntroductionLorlatinib was found to have improved efficacy versus crizotinib in the global phase 3 CROWN study (NCT03052608). Similar results were revealed for the Japanese population as for the overall population. We present results from the unplanned 3-year follow-up from the CROWN study in Japanese patients. MethodsPatients were randomized to either lorlatinib 100 mg once daily (n = 25) or crizotinib 250 mg twice daily (n = 23). The primary end point was progression-free survival assessed by blinded independent central review. Secondary end points included objective and intracranial responses assessed by blinded independent central review and safety. ResultsAt the data cutoff of September 20, 2021, median progression-free survival was not reached with lorlatinib and 11.1 months with crizotinib (hazard ratio = 0.36). Objective response rate was 72.0% with lorlatinib and 52.2% with crizotinib. For patients with baseline brain metastases, intracranial response rate was 100.0% versus 28.6% with lorlatinib versus crizotinib. Nine patients in the lorlatinib group received more than or equal to 1 subsequent anticancer systemic therapy, with ALK tyrosine kinase inhibitor as the most common first subsequent therapy. The safety profile was consistent with that reported previously, with no new safety signals. ConclusionsThis updated analysis in the Japanese population revealed prolonged benefits of lorlatinib over crizotinib in patients with treatment-naive advanced ALK-positive NSCLC with and those without brain metastases.

PT32 Cost-Effectiveness of Lorlatinib in Second-Line Treatment of ALK-Positive Advanced Non-Small Cell Lung Cancer in China

PT32 Cost-Effectiveness of Lorlatinib in Second-Line Treatment of ALK-Positive Advanced Non-Small Cell Lung Cancer in China

Clinical Pharmacology of Brigatinib: A Next-Generation Anaplastic Lymphoma Kinase Inhibitor.

Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor designed to overcome mechanisms of resistance associated with crizotinib, is approved for the treatment of ALK-positive advanced or metastatic non-small cell lung cancer. After oral administration of single doses of brigatinib 30-240 mg, the median time to reach maximum plasma concentration ranged from 1 to 4 h. In patients with advanced malignancies, brigatinib showed dose linearity over the dose range of 60-240 mg once daily. A high-fat meal had no clinically meaningful effect on systemic exposures of brigatinib (area under the plasma concentration-time curve); thus, brigatinib can be administered with or without food. In a population pharmacokinetic analysis, a three-compartment pharmacokinetic model with transit absorption compartments was found to adequately describe brigatinib pharmacokinetics. In addition, the population pharmacokinetic analyses showed that no dose adjustment is required based on body weight, age, race, sex, total bilirubin (<1.5× upper limit of normal), and mild-to-moderate renal impairment. Data from dedicated phase I trials have indicated that no dose adjustment is required for patients with mild or moderate hepatic impairment, while a dose reduction of approximately 40% (e.g., from 180 to 120 mg) is recommended for patients with severe hepatic impairment, and a reduction of approximately 50% (e.g., from 180 to 90 mg) is recommended when administering brigatinib to patients with severe renal impairment. Brigatinib is primarily metabolized by cytochrome P450 (CYP) 3A, and results of clinical drug-drug interaction studies and physiologically based pharmacokinetic analyses have demonstrated that coadministration of strong or moderate CYP3A inhibitors or inducers with brigatinib should be avoided. If coadministration with a strong or moderate CYP3A inhibitor cannot be avoided, the dose of brigatinib should be reduced by approximately 50% (strong CYP3A inhibitor) or approximately 40% (moderate CYP3A inhibitor), respectively. Brigatinib is a weak inducer of CYP3A in vivo; data from a phase I drug-drug interaction study showed that coadministration of brigatinib 180 mg once daily reduced the oral midazolam area under the plasma concentration-time curve from time zero to infinity by approximately 26%. Brigatinib did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations in vitro. Exposure-response analyses based on data from the ALTA (ALK in Lung Cancer Trial of AP26113) and ALTA-1L pivotal trials of brigatinib confirm the favorable benefit versus risk profile of the approved titration dosing regimen of 180 mg once daily (after a 7-day lead-in at 90 mg once daily).

First-in-human, multicenter phase Ⅰ study of TGRX-326 in patients with advanced ALK-positive non-small cell lung cancer.

9113 Background: TGRX-326, a deuterated derivative of lorlatinib (LOR), is a potent 3rd generation ALK and ROS1 dual TKI with high potency against multiple ALK-resistant mutations. Deuteration of the key metabolic site of the molecule allows to achieve a higher exposure than with LOR and this may result in alleviated toxicities and better efficacy. Methods: The study comprised 3 phases: dose escalation (D-ESCAL), dose expansion (D-EXP) and cohort expansion (C-EXP). In D-ESCAL and D-EXP, ALK+ pts prior failed on 2nd gen ALK-TKIs or ROS1+ pts resistant to crizotinib (CRZ) were enrolled; in C-EXP, ALK+ pts progression after CRZ (C-EXP-A1),progression after ≥1 2nd gen TKIs (C-EXP A2), ROS1+ progression after CRZ (C-EXP-B) and pts with ALK TKI naïve (C-EXP-C) were enrolled. Results: Up to Jan 13, 2023, 185 pts (median age 53 years, 45.9% male) were enrolled; Median treatment and follow-up was 5.5 and 6.7 months, respectively. There were no DLT observed and no MTD identified in D-ESCAL (5-125mg QD, n=19). Based on the safety, efficacy and PK exposure data of 42 pts in D-ESCAL and D-EXP, 60 mg QD was selected as the RP2D for C-EXP,the average AUCtau of 60mg QD reached to 5443ng*hr/mL. Treatment-related adverse events (TRAEs) occurred in 87.5% patients (162/185), the most common TRAEs were hypercholesterolemia (74.1%), hypertriglyceridemia (68.1%), weight gain (36.2%), peripheral edema (15.7%), peripheral neuropathy (14.1%). As for R2PD, 132 of 155 (85.2%) experienced TRAEs, Grade ≥3 TRAEs occurred in 19.7%, most frequent were hypertriglyceridemia (11%) and hypercholesterolemia (8.4% ). Dose interruptions and dose reductions associated with TRAEs were reported in 10 (5.4%) and 5 (2.7%) pts respectively. Confirmed response were observed in 142 ALK+pts enrolled in C-EXP, results are shown in the Table (Efficacy of B-ROS1+ pts will be reported separately). Eleven ALK mutations were detected in 16 pts (either alone or in combination); 50.0% pts achieved PR. Out of 6 pts who were positive for G1202R, 50.0% experienced PR. Conclusions: TGRX-326 was well tolerated in pts with advanced ALK+ NSCLC and showed promising clinical antitumor activity irrespectively of ALK+ resistance to CRZ and 2nd gen TKIs, especially among those with brain metastases. Impressive activity was seen in ALK TKI naïve NSCLC. TGRX-326 demonstrated antitumor activity against multiple ALK mutations including G1202R. Clinical trial information: NCT05441956 . [Table: see text]

A comprehensive clinical evaluation of first-line drugs for ALK-positive advanced non-small cell lung cancer.

Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) are mainly used in the treatment of ALK-positive advanced non-small cell lung cancer (NSCLC), but a comprehensive clinical evaluation of ALK-TKIs is lacking. Hence, a comparison of ALK-TKIs for first-line treatment of ALK-positive advanced NSCLC is essential to provide rational drug use and a basis for improving national policies and systems. According to the Guideline for the Administration of Clinical Comprehensive Evaluation of Drugs (2021) and the Technical Guideline for the Clinical Comprehensive Evaluation of Antitumor Drugs (2022), a comprehensive clinical evaluation index system of first-line treatment drugs for ALK-positive advanced NSCLC was established by literature review and expert interviews. We conducted a systematic literature review, meta-analysis, and other relevant data analyses, combined with an indicator system, to establish a quantitative and qualitative integration analysis for each indicator and each dimension of crizotinib, ceritinib, alectinib, ensartinib, brigatinib, and lorlatinib. The comprehensive clinical evaluation results of all dimensions were as follows: in terms of safety, alectinib had a lower incidence of grade 3 and above adverse reactions; for effectiveness, alectinib, brigatinib, ensartinib, and lorlatinib showed better clinical efficacy, and alectinib and brigatinib have been recommended by several clinical guidelines; in terms of economy, second-generation ALK-TKIs have more cost-utility advantages, and both alectinib and ceritinib have been recommended by the UK and Canadian Health Technology Assessment (HTA) agencies; for suitability, accessibility, and innovation, alectinib has a higher degree of physician recommendations and patient compliance. Except for brigatinib and lorlatinib, all other ALK-TKIs have been admitted to the medical insurance directory; the accessibility of crizotinib, ceritinib, and alectinib is good, meeting the needs of patients. Second- and third-generation ALK-TKIs have higher blood-brain barrier permeability, stronger inhibition ability, and innovation than first-generation ALK-TKIs. Compared with other ALK-TKIs, alectinib performs better across six dimensions and has a higher comprehensive clinical value. The results provide better drug choice and rational use for patients with ALK-positive advanced NSCLC.

35P Drug treatment management of advanced ALK-positive non-small cell lung cancer in Spain: A real-world cross-sectional analysis

35P Drug treatment management of advanced ALK-positive non-small cell lung cancer in Spain: A real-world cross-sectional analysis

Alectinib as first-line treatment for advanced ALK-positive non-small cell lung cancer in the real-world setting: preliminary analysis in a Chinese cohort

Tyrosine kinase inhibitors (TKIs) have been a major advance in the treatment of anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) which have been substantiated in clinical trials. However, real-world data on first-line alectinib in a Chinese patient population are limited. We enrolled patients diagnosed with advanced ALK-positive NSCLC treated with first-line alectinib at 8 centers in China, including cases with symptomatic or active CNS metastases. Continuation of alectinib was permitted after local or gradual progression at the treating clinician's discretion. Time-to-treatment failure (TTF) was defined as the period from the start of alectinib to discontinuation for any cause including disease progression, death, adverse events and patient's preference. We defined longer EML4-ALK variants as containing EML4 fusions to at least exon 13 and shorter variants had EML4 fusions up to exon 6. Of the 110 patients included, 26.4% had Eastern Cooperative Oncology Group Performance Status (ECOG) ≥2 points. The objective response rate (ORR) was 88.5% [95% confidence interval (CI): 79.9-94.3%] and median tumor shrinkage rate was 60% (range, 0-100%) in patients with target lesions. For patients with measurable central nervous system (CNS) metastases, the CNS-ORR was 92.9% (95% CI: 66.1-99.8%), additionally, 80% (8/10) of patients experienced significant improvement in CNS-related symptoms following alectinib treatment. With a median follow-up of 18.3 months, the estimated 2-year progression-free survival (PFS) rate and 2-year treatment failure-free rate were 81.1% (95% CI: 71.5-87.7%) and 81.0% (95% CI: 70.6-88.0%) respectively. Grade 3-4 adverse events occurred in 6.4% and only 2 patients (1.8%) permanently discontinued alectinib due to adverse events. Multivariate analysis indicated that patients with metastases in ≥3 distant organs and a tumor reduction rate ≤50% demonstrated more unfavorable mPFS than their counterparts. Furthermore, patients carrying longer variants showed superior mPFS to those with shorter variants (not reached vs. 24.2 months, hazard ratio =0.17, 95% CI: 0.04-0.68, P=0.004). Alectinib showed substantial efficacy and an excellent safety profile in a real-world setting of Chinese patients. Clinical outcomes and long-term survival still require longer follow-up. Tumors with shorter EML4 fusion variants, more extensive metastases and less reduction in tumor lesions may require more aggressive strategies.

Ensartinib in advanced ALK-positive non-small cell lung cancer: a multicenter, open-label, two-staged, phase 1 trial.

Ensartinib, a potent second-generation tyrosine kinase inhibitor (TKI) that targets anaplastic lymphoma kinase (ALK), MET and ROS1, was evaluated in a phase I clinical trial in patients with advanced, ALK-rearranged non-small cell lung cancer (NSCLC). Patients with advanced, ALK or ROS1-positive NSCLC were recruited from 2 centers in China. This study consisted of dose escalation and expansion stages. Patients were treated with oral ensartinib [dosage of escalation stage was from 150, 200, 225 to 250 mg per day, expansion stage was recommended phase II dose (RP2D)] in continuous 28-day cycles. The primary objectives were safety, dose limited toxicity (DLT), maximum tolerated dose (MTD), and RP2D based on tolerability. Key secondary objectives included pharmacokinetic (PK) and anti-tumor activity. Forty-eight patients were enrolled, 37 (77.1%) were ALK TKI-naïve, 11 (22.9%) patients had previously received crizotinib, ceritinib or alectinib. Ensartinib was well tolerated and common treatment-related adverse events (TRAEs) included rash (87.5%), transaminase elevation (60.4%), pruritus (45.8%) and creatinine elevation (35.4%). The top 3 grade 3-5 TRAEs were rash (14.6%), elevated alanine aminotransferase (ALT) (12.5%) and aspartate transaminase (AST) (4.2%). Two DLTs were observed in 250 mg, so MTD and RP2D was 225 mg per day. Ensartinib was moderately absorbed (median Tmax: 3.00-4.00 h) and slowly eliminated (mean T1/2: 21.0-30.2 h). The area under the curve (AUC) of ensartinib reached saturation at 200 to 225 mg and no major accumulation after daily administration. For all patients, the objective response rate (ORR) and disease control rates (DCR) were 64.6 % and 81.3%, median progression-free survival (mPFS) was 16.79 months. In subgroup analysis, the ORR and mPFS was 81.3% and 45.5%, 25.73 and 4.14 months in TKI-naïve and -treated ALK+ patients, respectively. The intra-cranial ORR and mPFS for patients with measurable brain metastases were 66.7% and 22.90 months. ALK abundance may predict the efficacy of ensartinib. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed specific signaling pathways enrichment in long and short progression-free survival (PFS) groups. Ensartinib was well tolerated under 225 mg (MTD) and demonstrated promising anti-tumor activity in ALK+ NSCLC patients, including those with CNS metastases and those previously TKI-treated. ClinicalTrials.gov NCT02959619.

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.

Patient-reported outcomes from the randomized phase 3 CROWN study of first-line lorlatinib versus crizotinib in advanced ALK-positive non-small cell lung cancer

ObjectivesQuality of life (QoL) for patients with non-small cell lung cancer (NSCLC) is negatively impacted by their disease and treatment side effects. We present detailed patient-reported outcome (PRO) data from the phase 3 CROWN study, which compared lorlatinib with crizotinib in patients with previously untreated ALK-positive advanced NSCLC. Materials and methodsPROs were assessed using the European Organisation for Research and Treatment of Cancer QoL Questionnaire with Lung Cancer module. A longitudinal, random-intercept, random-slope, mixed-effect model assessed score changes from baseline up to (not including) end of treatment. Mean changes of absolute scores from baseline at each cycle were calculated and presented up to cycle 18 (≥ 10-point change considered clinically meaningful). ResultsIn both lorlatinib (n = 148) and crizotinib (n = 140) arms, there were longitudinal improvements across multiple functioning and symptom scores during treatment compared with pre-treatment. Numerical improvements for most longitudinal functioning scores (physical, role, emotional, social) favored lorlatinib; cognitive functioning favored crizotinib. Numerical improvements favored lorlatinib for several symptoms (fatigue, nausea and vomiting, insomnia, appetite loss, constipation, diarrhea [clinically meaningful improvement], and cough); peripheral neuropathy favored crizotinib. Subgroup analyses showed PROs did not differ by presence/absence of baseline brain metastases. ConclusionsPatients receiving first-line lorlatinib or crizotinib showed improvements and delayed deterioration in QoL, functioning, and several symptoms. Alongside the previously reported significantly longer progression-free survival and higher intracranial response rates for lorlatinib versus crizotinib, these data further support the use of lorlatinib over crizotinib in patients with advanced ALK-positive NSCLC with/without baseline brain metastases and provide evidence of several QoL improvements with lorlatinib when used in the first-line setting.

ALK-positive advanced non-small cell lung cancer patients with poor performance status: Outcomes in a real-world scenario.

BackgroundAnaplastic lymphoma kinase (ALK) inhibitors have shown significant efficacy in ALK -rearranged non-small cell lung cancer (NSCLC) patients with good performance status (PS) in multiple randomised studies. However, there is limited data on patients with poor performance status.Patients and methodsWe carried out a retrospective analysis of prospectively collected data of patients with ALK-rearranged NSCLC and Eastern Cooperative Oncology Group (ECOG) PS of 2–4 treated at a single academic cancer centre from January 2013 to November 2018. The outcomes, progression-free survival (PFS) and overall survival (OS) were calculated from the date of diagnosis. SPSS version 20 was used for all statistical calculations.ResultsOut of the total 441 ALK-positive patients, 97 (21.9%) had ECOG PS 2–4 (poor PS). The median PFS was 9.3 months (95% CI = 6.6–12.0) as compared to 14.9 months (95% CI = 13.4–16.4) for patients with a PS of 0–1 (HR = 1.38, 95% CI = 1.04–1.84, p = 0.027). The corresponding median OS were 17.9 months (95% CI = 12.8–23.1) and 33.5 months (95% CI = 28.6–38.4), respectively (HR = 1.89, 95% CI = 1.36–2.62, p < 0.001). Among poor PS patients, a subgroup of patients with PS 2 had median OS of 20.6 months (95% CI = 10.8–47.3) as compared to 8.6 months for PS 3–4 (95% CI = 7.8–27.8) (HR = 1.79, 95% CI = 1.01–3.20, p = 0.047). The patients treated with upfront ALK inhibitors had better survival as opposed to those treated with chemotherapy. On multivariate analysis, PS 3–4, smoking, stage 4 and not using ALK inhibitors as first-line therapy were associated significantly with poor outcomes.ConclusionThe ALK-rearranged NSCLC patients with poor PS derived significant benefits with ALK inhibitors. The outcomes were significantly poorer as compared to patients with PS 0–1; the subgroup of patients with PS 2 had better outcomes as compared to patients with PS 3–4.

Efficacy and safety of lorlatinib in Asian and non-Asian patients with ALK-positive advanced non-small cell lung cancer: Subgroup analysis of a global phase 2 trial

ObjectivesTo analyze the efficacy and safety of lorlatinib in Asian and non-Asian patients with pretreated anaplastic lymphoma kinase (ALK)-positive, advanced non-small cell lung cancer (NSCLC) from a phase 1/2 study. Materials and methodsIn this ongoing phase 2 part of the trial, patients with ALK- or ROS1-positive, advanced NSCLC enrolled into six expansion cohorts (EXP1–6), based on ALK and ROS1 status and previous therapy, and received lorlatinib 100 mg once daily. The primary endpoint was objective tumor response and intracranial response. Post hoc analyses of activity were conducted in Asian and non-Asian (based on race) ALK-positive patients who received either previous crizotinib with or without chemotherapy (EXP2–3A) or at least one second-generation ALK tyrosine kinase inhibitor with any number of chemotherapy regimens (EXP3B–5). Analysis of safety (adverse events [AEs]) was in the phase 1 and 2 study population who started lorlatinib 100 mg once daily. Results17 Asian patients were enrolled in EXP2–3A and 53 in EXP3B–5; 33 non-Asian patients were enrolled in EXP2–3A and 73 in EXP3B–5. Objective response rates in the Asian and non-Asian subgroups were 82.4% (95% confidence interval [CI]: 56.6–96.2) and 63.6% (95% CI: 45.1–79.6) in EXP2–3A, and 47.2% (95% CI: 33.3–61.4) and 30.1% (95% CI: 19.9–42.0) in EXP3B–5, and median progression-free survival was 13.6 and 12.5 months (EXP2–3A) and 6.9 and 5.5 months (EXP3B–5). Lorlatinib exhibited antitumor activity across ALK resistance mutations, while no differences according to the EML4-ALK variant could be detected. The most common treatment-related AEs were hypercholesterolemia, hypertriglyceridemia, edema, and peripheral neuropathy in both Asian and non-Asian subgroups. ConclusionLorlatinib showed substantial overall and intracranial activity in pretreated patients with ALK-positive NSCLC in both Asian and non-Asian patients. AE profiles were similar between Asian and non-Asian patients. ClinicalTrials.gov NCT01970865.

Efficacy of different sequential patterns after crizotinib progression in advanced anaplastic lymphoma kinase-positive non-small cell lung cancer.

BackgroundThe efficacy difference between the second‐ and third‐generation of anaplastic lymphoma kinase‐tyrosine kinase inhibitors (ALK‐TKIs) after crizotinib failure in advanced ALK‐positive non–small cell lung cancer (NSCLC) has not been clarified. This study evaluates the efficacy of different sequential patterns after crizotinib progression.MethodsData of patients who met the study criteria were retrospectively analyzed. The Kaplan–Meier method was used to draw survival curves, log‐rank method was used to compare the differences between groups, and Cox multivariate analysis was used to evaluate the significance of influencing factors.ResultsA total of 128 patients developed disease progression after crizotinib. The overall survival (OS) of 57 patients in the sequential second‐generation ALK‐TKIs group was significantly longer than that of 65 patients with other systemic treatment (58.5 months vs. 33.0 months, p < 0.001); The OS of the direct sequential lorlatinib group was significantly longer than the second‐generation ALK‐TKIs group (114.0 months vs. 58.5 months, p = 0.020). Similarly, of the 48 patients who developed disease progression after first‐ and second‐generation ALK‐TKIs treatment, 16 patients with sequential lorlatinib had significantly longer OS than the others (62.0 months vs. 43.0 months, p = 0.014). The progression‐free survival (PFS) of second‐line and third‐ or later‐line lorlatinib were statistically different (20.0 months vs. 5.5 months, p = 0.011).ConclusionsThe application of next‐generation ALK‐TKIs after crizotinib progression significantly prolonged survival, whereas direct sequencing lorlatinib seemed advantageous. Similarly, lorlatinib also prolonged survival in patients with first‐ and second‐generation ALK‐TKIs failure.

30P A phase I, dose-escalation and dose-expansion study of SY-3505: A third-generation ALK TKI in Chinese ALK-positive advanced non-small cell lung cancer

SY-3505 is a third-generation Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) against both wild-type and a broad range of mutations occurring in first-generation and second-generation ALK inhibitor-resistant patients. This First-in-human phase I study is to investigate the safety, pharmacokinetics (PK) and clinical efficacy of SY-3505 in Chinese ALK-positive advanced non-small cell lung cancer (NSCLC) patients. Eligible Patients in this multi-center, open-label phase I study (CTR20191702) were administered orally with SY-3505 (25,50,100,200,300,400,500,600 or 800mg) once daily. Primary endpoints included safety, tolerability, maximum tolerated dose (MTD), dose limited toxicities (DLTs) and RP2D. Secondary endpoints included preliminary efficacy and PK parameters. Between Apr.26, 2020 and Dec.31, 2021, totally 32 ALK+ NSCLC patients including 2 (6.25%) ALK TKI-naive and 30 (93.75%) previously treated with ALK inhibitors were enrolled into 9 dose escalation cohorts (n=24) and 2 dose expansion cohorts (500mg/600mg, n=8). Totally, 22 (68.7%) of 32 patients experienced treatment-related adverse events (TRAEs), and grade 3-4 TRAEs were observed in 1 (3.12%) patient. One DLT (grade 3 diarrhea) was occurred in the 800mg dose cohort. The most common TRAEs (>10% frequency) were diarrhea (all grade 25.00%; grade 3-4 3.12%), nausea (all grade 15.63%; grade 3-4 0.00%), vomiting (all grade 15.63%, grade 3-4 0.00%), aspartate aminotransferase elevation (all grade 12.50%; grade 3-4 0.00%). Tumor regression was observed in 18 (64.30%) of 28 assessable patients who had received at least one ALK TKI. PK analyses indicated the accumulation of SY-3505 in the patients with an approximately t1/2 of 26-56 hours. RP2D will be identified based on the safety, PK parameters and anti-tumor activity in dose-expansion period. SY-3505 was well tolerated in patients including those previously treated with two or more ALK TKIs, and most of the TRAEs were minor and reversible. Preliminary anti-tumor activity was also observed in patients who had received more than one first or second-generation ALK TKI. The dose-expansion phase of this study is ongoing.