Deciphering the Mechanism of Gilteritinib Overcoming Lorlatinib Resistance to the Double Mutant I1171N/F1174I in Anaplastic Lymphoma Kinase

Anaplastic lymphoma kinase (ALK) is validated as a therapeutic molecular target in multiple malignancies, such as non-small cell lung cancer (NSCLC). However, the feasibility of targeted therapies exerted by ALK inhibitors is inevitably hindered owing to drug resistance. The emergence of clinically acquired drug mutations has become a major challenge to targeted therapies and personalized medicines. Thus, elucidating the mechanism of resistance to ALK inhibitors is helpful for providing new therapeutic strategies for the design of next-generation drug. Here, we used molecular docking and multiple molecular dynamics simulations combined with correlated and energetical analyses to explore the mechanism of how gilteritinib overcomes lorlatinib resistance to the double mutant ALK I1171N/F1174I. We found that the conformational dynamics of the ALK kinase domain was reduced by the double mutations I1171N/F1174I. Moreover, energetical and structural analyses implied that the double mutations largely disturbed the conserved hydrogen bonding interactions from the hinge residues Glu1197 and Met1199 in the lorlatinib-bound state, whereas they had no discernible adverse impact on the binding affinity and stability of gilteritinib-bound state. These discrepancies created the capacity of the double mutant ALK I1171N/F1174I to confer drug resistance to lorlatinib. Our result anticipates to provide a mechanistic insight into the mechanism of drug resistance induced by ALK I1171N/F1174I that are resistant to lorlatinib treatment in 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.

ALK Inhibitor Plus Vinblasitine for Refractory/Relapsed Pediatric ALK+ Anaplastic Large Cell Lymphoma: A Prospective, One-Arm, Open-Label Real-World Study

Background: Refractory and relapsed (r/r) anaplastic lymphoma kinase (ALK)-positive anaplastic large cell Lymphoma(ALK+ALCL) have a poor prognosis. Studies had confirmed vinblastine (VBL) may be an effective treatment for relapsed ALCL and ALK inhibitors may have high efficacy and tolerability in patients carrying ALK fusions. Therefore, we put forward a hypothesis that for those r/r ALK+ALCL patients with poor chemotherapy tolerance and effect, combining ALK inhibitors with vinblastine may have a sustained anti-tumor effect and good tolerance. Aims: To assess the efficacy and safety of ALK inhibitors combined with VBL in pediatric relapsed/refractory (r/r) ALK+ ALCL. Methods: Patients aged between 0 and 18 years with r/r ALK+ ALCL were included in this trial. ALK inhibitors are given orally with a converted dosage according to body surface area and VBL was given with injection once a week at 4-6 mg/(m2.week). And no intensive chemotherapy and hematopoietic stem cell transplantation will be in our study.We may decrease the dosage of VBL or delete VBL if patients suffer severe bone marrow suppression, repeated infections, and peripheral neuritis and other VBL-related toxicities. Available ALK inhibitors included crizotinib(CZ), alectinib(AL) and ceritinib(CER). Patients without CNS involvement took CZ, and patients with CNS involvement took AL or CER. A cycle of therapy is 28 days. Evaluation for responses toxicities were monitored and recorded. Results:27 patients were enrolled in this trial between April 2018 and April 2021. The median age was 8.3 years old(ranging from 0.75 to 16), male/female ratio is19:8. By St.jude's staging, 20 cases were in stage III (74.1%), 7 cases in stage IV (25.9%) including 3 cases (11.1%) with CNS involvement at initial diagnosis. Before being enrolled in our study, 6 patient (22.2%) failed to achieve CR with prior 4-10 chemotherapy regimens, 21 patients (77.8%) relapsed after an average of 5-16 courses of standard pulse chemotherapy regimens. After 1st cycle of treatments, 62.9%(17/26) achieved comlpele remission(CR) without measurable tumors and ALK gene transcription, no progressed cases. Additional 6 case got CR after 2-10 month(23.1%). In general, 7 patients withdraw due to death, progress, ineffectiveness, economics, adverse reactions. The treatment retention rate was ,7.1%（20/7），objective response rate (ORR) was 85.2%(23/27), best complete remission rate(CRR) was 85.2%(23/27), disease control rate(DCR) was 92.5%(25/27), average duration of CR was 14.85 months(0-36months). Toxicities included nausea and vomiting, stomachache, diarrhea(81.5%,22/27, one or more above toxicities), neutropenia (27/27), pneumonia(7.4%, 2/27), sepsis(7.4%, 2/27), creatine kinase-MB elevation (81.5%,22/27,all are in crizotinib group including 2 abnormal ECG cases), liver enzyme elevation (63.%,17//27), intestinal obstruction(7.4%, 2/26). 2 cases relapsed because of the treatment discontinuation due to severe elevated liver enzymes. Summary/Conclusion: ALK inhibitors combined with VBL may rapidly induce the tumor remission of r/r ALK+ALCL and the tolerance is good. Combination therapy may induce a more lasting remission in for patients without BM involvement. Patients with BM involvement are more likely to fail treatment. Sequential use of ALK kinase inhibitors may be an efficient strategy to counter drug resistance.More data and longer follow-up time are needed to support our study. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.