Third-generation Tyrosine Kinase Inhibitors Research Articles

Benefits of Conventional Chemotherapy in Progressive Disease Patients with Tyrosine-Kinase Inhibitors: A Case Report

Background. Mutation of the epidermal growth factor receptor (EGFR) in non-small cell lung carcinoma is a favorable predictive factor for targeted EGFR tyrosine kinase inhibitor (TKI) therapy, but patients with EGFR-mutated lung cancer who are given EGFR-TKI will experience disease progression after average 10 to 14 months on average. This study aims to describe a case of progressive lung adenocarcinoma and its chemotherapy treatment.
 Case presentation: A 54 years old woman who came with stage IV left lung adenocarcinoma (exon 21 mutation) who had received EGFR TKI for 17 months progressed, so the treatment was shifted to systemic chemotherapy. Based on these diagnostic results, the patient was diagnosed with progressive disease T3N1M1c left lung adenocarcinoma (pleura, contralateral nodule, ribs, suprarenal) Stage IVb PS ECOG 0. The patient was then treated with conventional doublet-platinum-based chemotherapy with the Carboplatin-Paclitaxel combination.
 Conclusion: Systemic chemotherapy with doublet-platinum is an option in patients with progressive adenocarcinoma with EGFR-TKI who cannot obtain tissue for histopathological examination at rebiopsy or do not have access to advanced molecular biology (e.g., T790M) or follow-up therapy (third-generation TKI, osimertinib).

Non-small-cell lung cancer: how to manage ALK-, ROS1- and NTRK-rearranged disease.

Oncogene addiction in non-small-cell lung cancer (NSCLC) has profound diagnostic and therapeutic implications. ALK, ROS1 and NTRK rearrangements are found in about 2–7%, 1–2% and 0.2% of unselected NSCLC samples, respectively; however, their frequency is markedly higher in younger and never-smoker patients with adenocarcinoma histology. Moreover, ALK, ROS1 and NTRK rearrangements are often mutually exclusive with other known driver alterations in NSCLC. Due to such a low frequency, diagnostic screening with accurate and inexpensive techniques such as immunohistochemistry is useful to identify positive cases; however, confirmation with fluorescent in situ hybridization or next-generation sequencing is often required due to higher specificity. In ALK-rearranged NSCLC, sequential treatment with second-generation and third-generation tyrosine kinase inhibitors leads to long-lasting disease control with most patients surviving beyond 5 years with metastatic disease. In ROS1-rearranged NSCLC, first-line treatment with crizotinib or entrectinib and subsequent treatment with lorlatinib at disease progression leads to similar results in patients with metastatic disease. NTRK1–3 fusions are extremely rare in unselected NSCLC. However, treatment with TRK inhibitors yields high response rates and durable disease control in most patients; diagnostic screening through multigene DNA/RNA-based next-generation sequencing testing is therefore crucial to identify positive cases.This article is part of the Treatment of advanced non-small-cell lung cancer: one size does not fit all Special Issue: https://www.drugsincontext.com/special_issues/treatment-of-advanced-non-small-cell-lung-cancer-one-size-does-not-fit-all/

Adverse events and dose modifications of tyrosine kinase inhibitors in chronic myelogenous leukemia.

The prognosis of chronic myelogenous leukemia (CML-CP) in chronic phase has improved dramatically since the introduction of imatinib. In addition to imatinib, second- and third-generation tyrosine kinase inhibitors (TKIs) and a novel allosteric inhibitor, asciminib, are now available. During long-term TKI therapy, the optimal selection of TKI therapy for individual patients requires the understanding of specific patterns of toxicity profile to minimize chronic toxicity and the risk of adverse events, including pulmonary arterial hypertension, pleural effusion, and cardiovascular events. Given the high efficacy of TKI therapy, dose modifications of TKI therapy reduce the risk of toxicities and improves quality of life during therapy. In this review article, we summarize the characteristics and adverse event profile of each TKI and dose modifications in patients with CML-CP and discuss future perspectives in the treatment of CML-CP.

EGFR T790M Mutation Detection in Patients With Non-Small Cell Lung Cancer After First Line EGFR TKI Therapy: Summary of Results in a Three-Year Period and a Comparison of Commercially Available Detection Kits.

EGFR mutation in non-small cell lung cancer (NSCLC) offers a potential therapeutic target for tyrosine kinase inhibitor (TKI) therapy. The majority of these cases, however eventually develop therapy resistance, mainly by acquiring EGFR T790M mutation. Recently, third-generation TKIs have been introduced to overcome T790M mutation-related resistance. Cell free circulating tumor DNA (liquid biopsy) has emerged as a valuable alternative method for T790M mutation detection during patient follow up, when a tissue biopsy cannot be obtained for analysis. In this study, we summarized our experience with Super-ARMS EGFR Mutation Detection Kit (AmoyDx) on 401 samples of 242 NSCLC patients in a 3-year period in Hungary, comprising 364 plasma and 37 non-plasma samples. We also compared the performance of two commercially available detection kits, the cobas EGFR Mutation test v2 (Roche) and the Super-ARMS EGFR Mutation Detection Kit (AmoyDx). The same activating EGFR mutation was detected with the AmoyDx kit as in the primary tumor in 45.6% of the samples. T790M mutation was identified in 48.1% of the samples containing activating EGFR mutation. The detection rate of T790M mutation was not dependent on the DNA concentration of the plasma sample and there was no considerable improvement in mutation detection rate after a second, subsequent plasma sample. The concordance of EGFR activating mutation detection was 89% between the two methods, while this was 93% for T790M mutation detection. The AmoyDx kit, however showed an overall higher detection rate of T790M mutation compared to the cobas kit (p = 0.014). T790M mutation was detected at 29.8% of the patients if only plasma samples were available for analysis, while the detection rate was 70.2% in non-plasma samples. If the activating EGFR was detected in the plasma samples, the detection rate of T790M mutation was 42.4%. Although non-plasma samples provided a superior T790M mutation detection rate, we found that liquid biopsy can offer a valuable tool for T790M mutation detection, when a tissue biopsy is not available. Alternatively, a liquid biopsy can be used as a screening test, when re-biopsy should be considered in case of wild-type results.

ALL-049 A Phase 1/2 Study to Evaluate Ponatinib With Chemotherapy in Pediatric Patients With Relapsed/Resistant/Intolerant Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia or With T315I Mutation

Ponatinib, a potent third-generation tyrosine kinase inhibitor (TKI), is approved for adults with chronic/accelerated/blast-phase chronic myeloid leukemia or Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) whose disease is resistant/intolerant to other TKIs or has the T315I mutation. This study in pediatric patients with relapsed/resistant/intolerant Ph+ ALL or those with the T315I mutation aims to establish the recommended Phase 2 dose (RP2D) of ponatinib and assess the pharmacokinetics, safety, and efficacy of ponatinib in combination with chemotherapy. This Phase 1/2, single-arm, open-label, multicenter study is enrolling patients age ≥1-21 years with Ph+ ALL, Ph+ mixed-phenotype acute leukemia, or Ph-like ALL (United States only) who have a targetable kinase-activating lesion and whose disease has relapsed or is resistant/intolerant to ≥1 prior therapy with a second-generation BCR::ABL1-targeted TKI or has a BCR::ABL1 T315I mutation. Phase 1 uses a rolling 6 design; the first cohort will include up to 12 patients (≥30 kg and able to swallow tablets) for dose confirmation. Another cohort of 6 patients will be enrolled to assess the age-appropriate mini-tablet formulation at the RP2D. Phase 2 will enroll ≈68 patients, including those enrolled in Phase 1 at the RP2D. Patients must have an age-appropriate (Lansky or Karnofsky) Performance Scale score of ≥50%. In Phase 1, the primary endpoint is the RP2D of ponatinib in combination with chemotherapy. Secondary endpoints are complete response (CR) rate at the end of the reinduction block and characterization of BCR::ABL1 domain mutations before and after ponatinib treatment. In Phase 2, the primary endpoint is the CR rate at the end of the reinduction block. Secondary endpoints include the proportion of patients in continued CR or who achieve CR at the end of consolidation, event-free survival (EFS), progression-free survival, and overall survival. The study is currently open and enrolling patients and includes ≈70 study sites in ≈16 countries.

CML-475 Real-World Treatment Patterns Among Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Cycling Through Multiple Tyrosine Kinase Inhibitors (TKIs) in the United States (US)

While TKIs are mainstay therapy for patients with CML-CP, many are refractory/intolerant to treatment. To describe real-world treatment patterns of CML-CP patients receiving third or later lines of therapy (3L+). Retrospective chart review of data collected through online case report forms completed between 03/05/2021-06/14/2021 by physicians from a panel of US oncologists/hematologists treating ≥1 adult with CML-CP who reached 3L+ between 01/01/2013-11/30/2018. In total, 64 physicians (academic: 36%; community: 64%) compiled data for 164 patients in 3L+ (median age: 58; females: 45%; White: 65%; Sokal score: intermediate: 47%, and high: 13%). In 1L (median duration: 13 months), most patients received the first-generation TKI (1G-TKI) imatinib (82%), and 12% received a second-generation TKI (2G-TKI) among which dasatinib was most common (9%). In 2L (median duration: 12 months), 92% received 2G-TKI including dasatinib (47%), nilotinib (31%) and bosutinib (13%). In 3L (median duration: 33 months), 2% received 1G-TKI, 49% 2G-TKI, 41% the third-generation TKI (3G-TKI, ponatinib), and 7% other CML-CP treatments. At data collection, most patients were undergoing 3L (67%), 15 patients were observed with a 4L and 3 with 5L. Main reasons for treatment discontinuation in earlier lines, based on physicians' interpretation, were lack of efficacy (1L: 34%; 2L: 26%), resistance (both 27%), and intolerance (1L: 21%; 2L: 26%). Proportion of patients with last molecular response (MR; achieved and sustained) of MR2 or better was 44% in 1L and 53% in 2L, and MR3 or better was 32% in both lines. Patients mainly cycled from 1G-TKI in 1L to 2G-TKI in 2L (81%), with 46% receiving imatinib and dasatinib in 1L/2L. From 2L to 3L, 46% cycled between 2G-TKIs and 39% switched from 2G-TKI to 3G-TKI. Patients with CML-CP in 3L+ have rapidly cycled between 1G-TKI and 2G-TKI in 1L and 2L. Rates of MR3 did not improve between earlier lines, with lack of efficacy/resistance being the most important reasons for discontinuation; intolerance became more prevalent in 2L. Findings highlight the need for novel therapeutics with improved safety/efficacy to prolong treatment in earlier lines and for patients in later lines who exhaust treatment options quickly.

Amivantamab in the Treatment of Metastatic NSCLC: Patient Selection and Special Considerations.

Amivantamab is a bispecific antibody that recognizes epidermal growth factor receptor (EGFR) and MET proto-oncogene (MET). In May 2021, the Food and Drug Administration gave an accelerated approval of amivantamab for the treatment of non-small cell lung cancer (NSCLC) patients with EGFR exon 20 insertions (Exon20ins) who progressed after platinum-based chemotherapy. Amivantamab prevents ligand binding to EGFR and MET and the dimerization of the receptors suppressing the downstream signal transduction. Moreover, amivantamab determines antibody dependent cellular cytotoxicity and down regulation of cell surface proteins through internalization of the receptor and trogocytosis. Preliminary results of the Phase I/IB CHRYSALIS trial demonstrated an objective response rate of 40% with a median duration of response of 11.1 months (95% CI 9.6-not reached) in 81 patients treated with amivantamab with pretreated NSCLC with Exon20ins EGFR mutations. In a different cohort of the CHRYSALIS trial, patients with Ex19del and L858R EGFR mutations were enrolled after progression on osimertinib. 121 and 45 patients received amivantamab or a combination with lazertinib, a third-generation tyrosine kinase inhibitor, respectively. The objective response rate was 19% and 36% in patients treated with amivantamab alone or in combination with lazertinib, with a median progression-free survival of 6.9 (95% CI: 3.2–5.3) and 11.1 (95% CI: 3.7–9.5) months, respectively. All 20 patients with Ex19del and L858R EGFR mutations who received amivantamab and lazertinib as their first line treatment achieved an objective response. Amivantamab is currently under evaluation in Phase III clinical trials for the first line treatment of NSCLCs with Exon20ins EGFR mutations in combination with chemotherapy (PAPILLON), for the first line therapy of Ex19del and L858R mutated NSCLCs in combination with lazertinib (MARIPOSA) and in combination with chemotherapy and lazertinib in NSCLCs who progressed on osimertinib (MARIPOSA-2).

The Landscape of ALK-Rearranged Non-Small Cell Lung Cancer: A Comprehensive Review of Clinicopathologic, Genomic Characteristics, and Therapeutic Perspectives.

Simple SummaryIn recent years, prognosis of non-small cell lung cancer (NSCLC) patients significantly improved thanks to the introduction of tyrosine kinase inhibitors (TKIs) in clinical practice. ALK-rearranged NSCLC patients benefit from treatment with ALK inhibitors (ALK-i), which have shown a greater efficacy and a better intracranial activity than chemotherapy. Comparative studies between next-generation ALK-i are still lacking and clinicians are looking for reliable tools to determine which drug suits best for each patient. The aim of this review is to deepen the role of clinical and pathological characteristics influencing patients’ prognosis during treatment with ALK-i and to provide an overview of molecular mechanisms of ALK-i resistance. In this setting, liquid biopsy may play an important role in predicting tumor response and monitoring resistance mutations. We will summarize ongoing trials developing new ALK-i or combinations between ALK-i and other agents, which may represent future scenarios in the field of NSCLC research.During the last decade, the identification of oncogenic driver mutations and the introduction of tyrosine kinase inhibitors (TKIs) in daily clinical practice have substantially revamped the therapeutic approach of oncogene-addicted, non-small cell lung cancer (NSCLC). Rearrangements in the anaplastic lymphoma kinase (ALK) gene are detected in around 3–5% of all NSCLC patients. Following the promising results of Crizotinib, a first-generation ALK inhibitor (ALK-i), other second-generation and more recently third-generation TKIs have been developed and are currently a landmark in NSCLC treatment, leading to a significant improvement in patients prognosis. As clinical trials have already demonstrated high efficacy of each ALK-i, both in terms of systemic and intracranial disease control, comparative studies between second and third generation ALK-i are still lacking, and primary or secondary ALK-i resistance inevitably limit their efficacy. Resistance to ALK-i can be due to ALK-dependent or ALK-independent mechanisms, including the activation of bypass signaling pathways and histological transformation: these findings may play an important role in the future to select patients’ subsequent therapy. This review aims to provide an overview of underlying molecular alterations of ALK-i resistance and point out promising role of liquid biopsy in predicting tumor response and monitoring resistance mutations. The purpose of this review is also to summarize current approval for ALK-rearranged NSCLC patients, to help clinicians in making decisions on therapeutic sequence, and to deepen the role of clinicopathological and genomic characteristics influencing patients’ prognosis during treatment with ALK-i.

Survey and analysis of the concerns of patients with chronic myeloid leukemia in China in 2021

Objective: To investigate the concerns of adult patients with chronic myeloid leukemia (CML) in the chronic phase receiving tyrosine kinase inhibitor (TKI) therapy in China. Methods: A cross-sectional questionnaire including 23 issues of concern was filled by patients with CML nationwide from August to September 2021. The results were compared with those from 2015 to 2016. Results: Data from 952 questionnaires were analyzed. The five most concerned issues were "TKI-related adverse effects and management" (66%) , "stopping TKI therapy" (46%) , "CML risk assessment" (46%) , "TKI dose reduction" (42%) , and "restrictions in daily life activities" (41%) . Compared with the results from 2015 to 2016, patients paid more attention to "TKI-related adverse effects and management" , "monitoring" , and "interpretation of laboratory reports" (all P<0.01) . Concerns of "TKI reimbursement policies" , "price reduction of TKIs" , and issues related to generic TKIs decreased significantly (all P<0.01) . Multivariate analysis showed that female patients (OR=1.8, 95% CI 1.4-2.5, P<0.001) , elderly patients (OR=1.0, 95% CI 1.0-1.0, P<0.001) , or patients with bachelor's degree or higher (OR=1.8, 95% CI 1.3-2.4, P<0.001) were more concerned with "TKI dose reduction" than others. Patients with a bachelor's degree or higher (OR=1.6, 95% CI 1.2-2.2, P=0.002) paid more attention to "CML risk assessment" , whereas those currently receiving a second- or third-generation TKI therapy (OR=1.9, 95% CI 1.3-2.6, P<0.001) were more concerned about "TKI resistance" . Conclusion: Patients with CML paid the most attention to "TKI-related adverse effects and management" , "stopping TKI therapy" , "CML risk assessment" , "TKI dose reduction" , and "restrictions in daily life activities" . Patients' sociodemographic covariates and treatment status were associated with their concerns.

EP08.02-019 Phase 1/2 Study of BLU-701, a Highly Selective EGFR Inhibitor, in Patients With EGFR-Mutant Non-Small Cell Lung Cancer

Third-generation tyrosine kinase inhibitors (TKIs), such as osimertinib, are highly effective in front-line metastatic EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC), but treatment resistance can ultimately occur, including the emergence of the on-target C797X mutation for which there are no approved TKIs. BLU-701 is an investigational, reversible, central nervous system (CNS)-penetrant, wildtype-sparing oral TKI with nanomolar potency on common activating (exon 19 deletion and L858R) and C797X resistance mutations.

Involvement of Rho-Associated Coiled-Coil Containing Kinase (ROCK) in BCR-ABL1 Tyrosine Kinase Inhibitor Cardiovascular Toxicity

BackgroundSecond- and third-generation BCR-ABL1 tyrosine kinase inhibitors (TKIs) are associated with cardiovascular adverse events (CVAEs) in patients with Philadelphia chromosome–positive (Ph+) leukemia. ObjectivesWe hypothesized that second- and third-generation BCR-ABL1 TKIs may cause CVAEs through the activation of Rho-associated coiled-coil containing kinase (ROCK). MethodsPeripheral blood mononuclear cells from 53 Ph+ patients on TKIs and 15 control patients without Ph+ leukemia were assessed for ROCK activity through capillary electrophoresis (median follow-up = 26 months [Q1-Q3: 5-37 months]). We also investigated the effects of TKIs and ROCK on endothelial dysfunction in vitro, which could contribute to CVAEs. ResultsPatients receiving second- and third-generation TKIs had 1.6-fold greater ROCK activity compared with patients receiving imatinib and control patients. Elevated ROCK activity was associated with an increased incidence of CVAEs in Ph+ leukemia patients. In endothelial cells in vitro, we found that dasatinib and ponatinib treatment led to changes in actin intensity and endothelial permeability, which can be reversed by pharmacologic inhibition of ROCK. Ponatinib led to decreased cell proliferation, but this was not accompanied by senescence. Dasatinib and ponatinib treatment led to phosphor-inhibition of endothelial nitric oxide synthase and decreased nitric oxide production. ROCK inhibition reversed endothelial permeability and endothelial nitric oxide synthase–related endothelial dysfunction. Imatinib and nilotinib induce phosphorylation of p190RhoGAP. ConclusionsOur findings suggest ROCK activity may be a prognostic indicator of CVAEs in patients receiving BCR-ABL1 TKIs. With further study, ROCK inhibition may be a promising approach to reduce the incidence of CVAEs associated with second- and third-generation BCR-ABL1 TKIs.

Safety and outcomes of maintenance therapy with third-generation tyrosine kinase inhibitor after allogeneic hematopoietic cell transplantation in Philadelphia chromosome positive acute lymphoblastic leukemia patients with T315I mutation

Studies using third-generation tyrosine kinase inhibitor (TKI) as maintenance therapy after hematopoietic cell transplantation (HCT) for patients with Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) harboring the T315I mutation remain scarce. We conducted a cohort study to evaluate the safety and outcomes of ponatinib maintenance therapy after HCT in Ph+ALL patients with T315I mutation. BCR-ABL kinase domain mutations were assessed using direct sequencing. Twenty-six Ph+ALL patients with T315I mutation who received allogeneic HCT were enrolled. After HCT, ponatinib was administered as a prophylactic regimen (n = 12) or a preemptive therapy (n = 7). Seven patients did not receive maintenance therapy. Adverse events (AEs) occurred in 69.4 % of patients with ponatinib maintenance, but most presented with mild toxicities. Serious non-hematological AEs were not observed. The 5-year disease-free survival (DFS), overall survival (OS), and cumulative incidence of relapse in patients receiving prophylactic ponatinib were 81.5 %, 91.7 %, and 18.5 %, respectively, whereas they were 39.8 %, 46.0 %, and 48.4 % in the total cohort, respectively. The measurable BCR-ABL transcripts in the first three months after HCT was associated with poor DFS and OS, even with ponatinib therapy. We concluded that maintenance therapy with ponatinib is safe after HCT. Patients with T315I mutation who received prophylactic regimen showed promising results with an acceptable relapse rate and encouraging survival. However, patients with measurable BCR-ABL transcripts early post-transplant had poor outcomes.

Non-small-cell lung cancer: how to manage EGFR-mutated disease.

The treatment of non-small-cell lung cancer (NSCLC) harbouring EGFR mutations has witnessed some major breakthroughs in the last years. On the one hand, the recent advent of the third-generation tyrosine kinase inhibitor (TKI) osimertinib has reshaped the therapeutic algorithm both in the first-line and adjuvant settings for patients with common activating Ex19del and L858R EGFR mutations. On the other hand, the availability of new comprehensive next-generation sequencing panels, to be used on tumour tissue or on liquid biopsy, has revealed the existence of uncommon as well as compound mutations that partially explain the onset of resistance. Nevertheless, dissecting the biological mechanisms underlying primary and secondary resistance to EGFR-TKIs is crucial to developing alternative therapeutic strategies and further improving patient outcomes. Herein, we provide an updated and comprehensive summary of the latest advancements in the quest for compounds targeting EGFR-mutant advanced non-small-cell lung cancer, discussing the biological rationale underlying the development of a forefront combination of TKI and/or new antibody–drug conjugates. We also suggest a treatment algorithm that could be followed considering the latest published data.

Combination regimens in EGFR-mutated lung cancer: can we get ORIENT-ed?

EGFR-directed therapy has revolutionised the therapeutic landscape for patients with EGFR-mutated non-small-cell lung cancer (NSCLC). On the basis of the FLAURA trial,1 showing overall survival and progression-free survival benefits, osimertinib, a third-generation tyrosine-kinase inhibitor, was approved for patients with metastatic EGFR-mutated lung cancers as first-line therapy. However, the development of resistance to EGFR tyrosine-kinase inhibitors and subsequent disease progression is inevitable.

Simultaneous quantification of dasatinib, nilotinib, bosutinib, and ponatinib using high-performance liquid chromatography-Photodiode array detection.

BackgroundDasatinib, nilotinib, and bosutinib, second‐generation tyrosine kinase inhibitors (TKIs), and ponatinib, a third‐generation TKI, are approved pharmaceuticals used in the treatment of chronic myeloid leukemia (CML). Although liquid chromatography‐tandem mass spectrometry assays for simultaneous quantification of the four TKIs in human serum have been reported in the literature, a high‐performance liquid chromatography (HPLC) assay that simultaneously quantifies these compounds has not yet been developed. This study aims to establish and validate an efficient HPLC analytical method using a photodiode array (PDA) detector for the simultaneous quantification of the four TKIs.MethodsCalibration standards were prepared by serial dilution of serum samples containing the four TKIs, followed by solid‐phase extraction. The four TKIs were eluted in order within 10 min using a binary HPLC gradient system.ResultsThe calibration ranges were 2–500 ng/ml for dasatinib, 100–5000 ng/ml for nilotinib, and 10–500 ng/ml for bosutinib and ponatinib. Intra‐day and inter‐day precision and accuracy values were found to be in accordance with the U.S. Food and Drug Administration guidelines. The recovery rates were 92.9%–96.0%, 80.7%–86.1%, 91.6%–99.0%, and 86.4%–92.6% for dasatinib, nilotinib, bosutinib, and ponatinib, respectively.ConclusionTo the best of our knowledge, this is the first report of an HPLC‐PDA analytical method that allows efficient simultaneous quantification of the four TKIs in the serum of patients with CML. We believe that the method developed herein can improve the efficiency of therapeutic drug monitoring in patients with CML in clinical practice.

Audit of Molecular Mechanisms of Primary and Secondary Resistance to Various Generations of Tyrosine Kinase Inhibitors in Known Epidermal Growth Factor Receptor-Mutant Non-small Cell Lung Cancer Patients in a Tertiary Centre

AimsPresently, three generations of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are approved against oncogene addicted EGFR-mutant non-small cell lung cancer (NSCLC). Patients with actionable EGFR mutations invariably develop resistance. This resistance can be intrinsic (primary) or acquired (secondary). Materials and methodsThis was a retrospective study carried out between January 2016 and April 2021 analysing 486 samples of NSCLC for primary and secondary resistance to first- (erlotinib, gefitinb), second- (afatinib) and/or third-generation (osimertinib) TKIs in EGFR-mutant NSCLCs by next generation sequencing (NGS). Tissue NGS was carried out using the Thermofischer Ion Torrent™ Oncomine™ Focus 52 gene assay; liquid biopsy NGS was carried out using the Oncomine Lung Cell-Free Total Nucleic Acid assay. All cases were previously tested for a single EGFR gene with the Therascreen® EGFR RGQ PCR kit. ResultsThe results were divided into four groups: (i) group 1: primary resistance to first- and/or second-generation TKIs. This group, with 21 cases, showed EGFR exon 20 insertions, dual, complex mutations and variant of unknown significance, de novo MET gene amplification besides other mutations. (ii) Group 2: primary resistance to third-generation TKIs. This group showed two cases, with one showing dual EGFR mutation (L858R and E709A) and EGFR gene amplification. (iii) Group 3: secondary resistance to first- and second-generation TKIs. This group had 27 cases, which were previously reported negative for EGFR T790M by single gene testing. Significant findings were MET gene amplification in four cases, with one also showing MET exon 14 skipping mutation. Three cases showed small cell change and one showed loss of primary mutation. (iv) Group 4: secondary resistance to third-generation TKIs. The latter group was further subgrouped into group 4A: secondary resistance to osimertinib (third-generation TKI) when offered as second-line therapy after first- and second-generation TKIs on detection of T790M mutation. This group had 15 cases. EGFR T790M mutation was lost in 10 (10/15; 67%) cases and was retained in five cases. Patients with T790M loss experienced early resistance (6.9 months versus 12.6 months mean, P = 0.0024) compared with cases that retained T790M. Two cases gained MET amplification as the resistance mechanisms. Other mutations that were found when EGFR T790M was lost were in FGFR3, KRAS, PIK3CA, CTNNB1, BRAF genes. One case had EML4-ALK translocation. Two cases showed driver EGFR deletion 19, retained T790M and C797S mutation in Cis form. Group 4B: secondary resistance to osimertinib (when given as first-line therapy) in EGFR-mutant NSCLC. This group had three cases. The duration of osimertinib treatment ranged from 11 to 17 months. Two patients showed additional C797S mutation along with primary EGFR mutation. ConclusionThis study shows the wide spectrum of primary and secondary EGFR resistance mechanisms to first, second and third generation of TKIs and helps us to identify newer therapeutic targets that could carry forward the initial advantage offered by EGFR TKIs.

A systematic review of economic evaluations of tyrosine kinase inhibitors for non-small cell lung cancer (NSCLC)

Introduction Although tyrosine kinase inhibitors (TKIs) have improved the efficacy of treatment for non-small cell lung cancer (NSCLC), the accessibility of TKIs is limited due to high costs. Despite the critical role of the cost-effectiveness of TKIs on decision making, no systematic reviews have compared the cost-effectiveness of comparable TKIs. Therefore, we systemically reviewed the economic evaluation studies on various TKIs for NSCLC. Areas covered We searched PubMed and the Cochran Library to identify the published economic evaluation studies of TKIs in NSCLC patients that were published by January 2022. All of the included studies (n=38) evaluated the cost-effectiveness of epidermal growth factor receptor (EGFR)-TKIs (n=29) or anaplastic lymphocyte kinase (ALK)-TKIs (n=9). The cost-effectiveness results were reported as the incremental cost-effectiveness ratio per quality-adjusted life-year, except for three studies. Expert opinion We found that the economic evaluation studies of the first and second generation of EGFR-TKIs and ALK-TKIs varied by the country and study settings, such as comparator and input parameters. In 12 studies, osimertinib (EGFR-TKI) was not cost-effective compared to other first/second EGFR-TKIs, regardless of the study settings. More evidence can be provided about cost-effectiveness of the third-generation TKIs in future research.

P697: PONATINIB IN A REAL-LIFE SETTING: A RETROSPECTIVE ANALYSIS FROM THE MONITORING REGISTRIES OF THE ITALIAN MEDICINES AGENCY (AIFA)

Background: The efficacy and safety of ponatinib, a third-generation tyrosine kinase inhibitor (TKI), are mainly reported in sponsored clinical trials. Aims: The aim of this study, based on a retrospective analysis from the monitoring Registries of the Italian Medicines Agency (AIFA wMRs), is to provide real-world data on daily practice management, treatment modifications and outcome of a large cohort of chronic myeloid leukemia (CML) patients treated with ponatinib. Methods: AIFA wMRs is an administrative database whose main scope is monitoring the appropriateness of drug prescription in Italy. Information collected through the wMRS included demographic (place of birth, age, and sex) and clinical data (BCR-ABL levels, mutations and chromosomal abnormalities if evaluated), drug prescription and administration data (date of prescription and administration, dose administered, dose changes, occurrence of adverse events as yes/no dichotomic variable, reasons for treatment interruption and/or discontinuation) and response to treatment (response assessment was requested every 90 days). Subjects who had not been administered ponatinib for ≥ 120 days were adjudicated as “discontinued” even in the absence of the “end of treatment form”. Time to treatment discontinuation (TTD) was defined as the time occurring between the date of first administration and the date of treatment discontinuation for any cause, including death. Results: Overall, 666 CML subjects were eligible for analysis: 515 patients had chronic phase (CP) CML, 50 accelerated phase (AP) and 101 blast phase (BP). Median age at baseline was 58.7 years, male prevalence (57.1%). Median time from diagnosis to start of ponatinib was 2.35 years: 259 (38.9%) subjects had received 2 lines of treatment, 260 (39.0%) 3 lines and 147 (22.1%) 4 or more lines. Mutational status was available for 58.3% of patients (n=388), with a T315I mutation reported in 46 (6.9%) patients and other mutations (the most represented being E255K, F317L, Y253H and V299L) in 99 (14.9%) subjects. At baseline, 181 patients (27.2%) had arterial hypertension, 33 (5.0%) a history of arterial and/or venous thromboses, 32 (4.8%) a pre-existing ischemic heart disease, and 13 (2.0%) a history of congestive heart failure. Overall, 593 patients (89.0%) were evaluable for best response. Ten cases (1.7%, 3 AP/BP and 7 CP) did not achieve molecular response, whereas 58 patients (8.7%, 26 AP/BP patients and 32 CP) reached a BCR/ABL1 ratio between 1% and 10% IS. A MR2 (less than 1%IS) was obtained by 82 subjects (12.3%, 20 AP/BP and 62 CP patients); 128 patients (19.2%, 12 AP/BP and 116 CP patients) achieved a molecular response ranged between MR3 (0.1%) and MR4 (0.01% IS) and 266 (39.9%, 44 AP/BP and 222 CP patients) a deeper molecular response (< 0.01% IS). With a median follow-up of 14.4 months, 136 subjects (20.4%) required at least one dose reduction due to adverse events; 309 patients (46.4%) had their dose decreased in the absence of any evidence of side effects. Treatment discontinuation occurred in 144 patients (21.6%): intolerance (7.4%), primary resistance (3.5%) and acquired resistance (5.6%). Kaplan-Meier estimated TTD was 47.2 months (CI 95% 39.3 – NA) and 7.3 months (CI 95% 4.6 – 11.8) for CP and AP/BP patients, respectively. The probability of treatment discontinuation did not significantly differ for ponatinib in second, third or subsequent line of therapy (p=0.58). Summary/Conclusion: This real-life investigation shows that ponatinib dose reductions were mainly performed in the absence of reported toxicity rather than owing to the occurrence of adverse reactions.

Abstract 3324: Optimizing the therapeutic potential of tyrosine kinase inhibitors in chemo-immunotherapy of B-cell acute lymphoblastic leukemia involving rituximab

Abstract B-cell acute lymphoblastic leukemia (B-ALL) is a malignancy caused by accumulation of immature B cells. Advances in the field, especially in genomic studies and new treatment development, significantly improved the prognosis of B-ALL over the last decades. However, the B-ALL subtype harboring Philadelphia chromosome t(9;22)(q34;q11) (Ph+ B-ALL) still remains a therapeutic challenge despite available targeted treatment with tyrosine kinase inhibitors (TKIs). The novel therapeutic regimens for adult B-ALL often include rituximab (RTX) - a monoclonal anti-CD20 antibody - for patients with &amp;gt;20% CD20+ blasts. Moreover, drug combinations including approved TKIs and antibodies are being tested in clinical trials. Since some TKIs display immune effector cell inhibition, investigating their immunomodulatory effects in the context of combined chemo-immunotherapies is clinically relevant for the rational combination design. We found that blasts isolated from Ph+ B-ALL patients showed the highest CD20 expression on mRNA level among defined B-ALL genetic subtypes. As Ph+ CD20+ patients may be qualified for treatment with TKIs along with RTX, this result prompted the need of investigating the effects of TKIs on immune effectors. We therefore compared how first-, second- and third-generation TKIs (imatinib, dasatinib, nilotinib, bosutinib, ponatinib) and allosteric inhibitor asciminib recently approved for the treatment of chronic myeloid leukemia (CML) affect innate and antibody-mediated cytotoxicity. B-ALL cell lines, patient-derived lymphoblasts propagated in NSG mice (primografts) and ex vivo whole blood assays were used for testing the efficacy of effector cell-mediated mechanisms in the presence of TKIs. The TKIs were compared in NK-cell based natural cytotoxicity tests, antibody-dependent cytotoxicity (ADCC) tests and phagocytosis assays with monocyte-derived macrophages. Dasatinib was also tested using whole blood ex vivo ADCC assays before and after administration of the TKI. Out of six tested TKIs, asciminib presented the most favorable profile, causing slight or no effector cell inhibition in both innate and antibody-mediated responses. In contrast, dasatinib significantly decreased the immune cells activity in all tests, reducing natural and RTX-mediated cytotoxicity of NK cells against B-ALL blasts. Dasatinib and ponatinib significantly inhibited in vitro phagocytosis of primograft B-ALL cells. To a lesser extent, cytotoxicity and phagocytosis were suppressed by imatinib, bosutinib and nilotinib. Importantly, we confirmed that the orally administered dasatinib impairs the NK cell activity in patients’ blood. Our findings indicate that the TKIs differentially impact RTX-mediated effector mechanisms. The novel, allosteric TKI asciminib could be preferentially used in combination with RTX-based immunotherapy. This work was supported by the Polish National Science Centre grant 2019/35/B/NZ5/01428 and by the Ministry of Education and Science within “Regional Initiative of Excellence” program 013/RID/2018/19." Citation Format: Krzysztof Domka, Martyna Poprzeczko, Zuzanna Urbanska, Lukasz Komorowski, Agata Pastorczak, Klaudyna Fidyt, Agnieszka Dabkowska, Mieszko Lachota, Magdalena Winiarska, Karolina Siudakowska, Elzbieta Patkowska, Łukasz Sędek, Bartosz Perkowski, Beata Krzymieniewska, Malgorzata Firczuk. Optimizing the therapeutic potential of tyrosine kinase inhibitors in chemo-immunotherapy of B-cell acute lymphoblastic leukemia involving rituximab [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 3324.

Abstract 3328: Antitumor activity of BLU-945 and BLU-701 as single agents and in combination in EGFR L858R-driven models of NSCLC

Abstract BACKGROUND: Lung cancer is the leading cause of cancer death globally. EGFR mutations are the most common genomic drivers of non-small cell lung cancer (NSCLC), occurring in ~17% and up to 50% of Caucasian and Asian patients, respectively, with exon 19 deletions (ex19del) and L858R substitutions being the most prevalent activating EGFR mutations (EGFRm). Outcomes have improved in patients with EGFR-driven NSCLC since the introduction of EGFR tyrosine kinase inhibitors (TKIs); however, treatment resistance almost inevitably occurs. It has been reported that patients harboring the EGFR L858R mutation, who represent 3.4% of lung adenocarcinoma cases in North America and 23% in Asia, have poorer outcomes than those with EGFR ex19del, suggesting a significant unmet need in this population. BLU-945 and BLU-701 are investigational, reversible, selective, and orally available TKIs optimized for use as single-agent or combination therapy to effectively suppress activating and on-target resistance EGFR mutants while sparing WT EGFR, and have the potential to treat or prevent central nervous system metastases. In vivo studies previously demonstrated the antitumor activity of BLU-945 against EGFR L858R/T790M and EGFRm/T790M/C797S mutants, and BLU-701 against EGFR ex19del and EGFRm/C797S mutants. Because EGFR L858R-driven NSCLC constitutes a large population of patients who may not be receiving the same benefit from third-generation (3G) TKIs as those with EGFR ex19del, studies were conducted to evaluate the antitumor activity of BLU-945 and BLU-701, as single agents and in combination, in preclinical NSCLC tumor models driven by L858R in the absence of the T790M mutation. METHODS: The in vivo antitumor activities of BLU-945 and BLU-701, as single-agents or in combination, were evaluated in 2 EGFR L858R-driven patient-derived xenograft (PDX) subcutaneous tumor models and in an engineered EGFR L858R/C797S-driven Ba/F3 cell line-derived xenograft (CDX) subcutaneous tumor model. RESULTS: Oral daily administration of single-agent BLU-945 and single-agent BLU-701 resulted in sustained tumor regression in 2 PDX models of EGFR L858R NSCLC. Compared with single agents in an EGFR L858R/C797S Ba/F3 CDX tumor model, combination of BLU-945 with BLU-701 resulted in marked antitumor activity and prolonged tumor regression. CONCLUSION: The in vivo antitumor activities of BLU-945 and BLU-701 in preclinical tumor models suggest that both BLU-945 and BLU-701 have the potential to be used in patients with EGFR L858R-driven NSCLC, including those who are treatment naïve or previously treated with 3G TKI. Combining BLU-945 and BLU-701 may enable coverage of frequent on-target resistance mechanisms, including the EGFR C797S mutation, in addition to the common L858R activating mutation. Citation Format: Luz Tavera, Stefanie Schalm, John Campbell, Jian Guo, Clare Medendorp, Maxine Chen, Faris Albayya, Tom Dineen, Zhuo Zhang, Maria Iliou, Ebby Job, Nisha Perez, Yoav Timsit, Scott Wardwell, Katie McGinn, Richard Woessner, Chiara Conti. Antitumor activity of BLU-945 and BLU-701 as single agents and in combination in EGFR L858R-driven models of NSCLC [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 3328.