Third-generation Tyrosine Kinase Inhibitors Research Articles

Olverembatinib Based Therapy in Recurrent Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia with BCR/ABL Mutation

Acute lymphoblastic leukemia (ALL) accounts for approximately 20% of adult leukemias, 25% of which are Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). In the past decade, tyrosine kinase inhibitors (TKIs) based regimens greatly improved the prognosis for newly diagnosed and recurrent Ph+ ALL patients, but facing challenges of kinase mutations. In the current study, five relapsed/refractory (R/R) Ph+ ALL patients harboring BCR/ABL kinase mutations were treated with olverembatinib, a third-generation TKI based therapy. Before the treatment, all patients had bone marrow relapses, of whom one presented with central nervous system leukemia (CNSL) and one with both CNSL and extramedullary disease (pleura involvement). The patients received olverembatinib in combination with glucocorticoids or chemotherapy, and intrathecal prophylaxis was used regardless of CNS involvement. At the last follow-up, all patients responded to olverembatinib based treatment with three complete molecular remission (CMR), one complete remission (CR) and one partial remission (PR). Our results suggest that olverembatinib is effective with R/R Ph+ ALL with BCR/ABL kinase mutations and warrants broader clinical evaluation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Olverembatinib Plus Low-Intensive Regimen in Frontline Therapy for Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia： a Case Series from a Single Center

BCR::ABL1 tyrosine kinase inhibitors (TKI) have shown promising results in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). However, resistance and intolerance to TKIs remains a clinical challenge. Olverembatinib is an oral, novel third-generation TKI developed by Ascentage Pharma. Olverembatinib is effective against most ABL1 kinase domain mutants, including mutant T315I. In November 2021, olverembatinib was approved in China for the treatment of adults with BCR::ABL1T315I-mutant chronic myeloid leukemia (CML). However, data on clinical use of olverembatinib in Ph+ ALL are very limited. Herein, we report a retrospective analysis of patients with newly diagnosed Ph+ ALL who received olverembatinib plus low-intensive regimen (VP: Vindesine + dexamethasone / prednisone ) at our institution. Olverembatinib was administered at a dose of 40 mg orally QOD continuously. Vindesine was given 4 mg intravenously on day 1, 8, 15, 22 and dexamethasone /prednisone was administered from days 1 to 22 during induction. After two courses of olverembatinib plus VP, olverembatinib-based regimens was recommended for consolidation. The choice of sequentially consolidation treatment with allogeneic hematopoietic stem-cell transplantation (allo-HSCT), blinatumomab or intensive chemotherapy, was made by the investigators and patients preference. Prophylactic intrathecal chemotherapy with cytarabine and dexamethasone was administered in each cycle. Maintenance therapy was olverembatinib and low-intensive regimens. The primary endpoint was complete molecular response (CMR) rate. CMR was defined as BCR-ABL1/ABL1 ratio < 0.01% by quantitative real-time polymerase chain reaction(qPCR). Between November 2021 and June 2022, a total of 12 consecutive patients with Ph +ALL treated with the olverembatinib plus VP at our center were enrolled. The median age was 48 years (range, 18-72 years). Ten patients were male and two were female. The median white-cell counts were 77,000 per cubic millimeter (range, 1200 to 356,000). Seven patients had the p190 fusion transcript, five had the p210 transcript. All 12 patients completed induction phase with olverembatinib plus VP regimen. At the end of the 4 weeks of induction , all 12 patients (100%) achieved complete hematologic response. The primary endpoint CMR was reached in 6/12 patients (60%) at 4 weeks; in 12/12 patients (100%) at 8 weeks. For treatment-emergent adverse events, most of which were mild and manageable. No serious nonhematologic toxicities were observed. With a median follow-up of 5 months, all patients were in CMR in the last follow-up, four patients proceeded to allo-HSCT. Conclusions: Olverembatinib was well tolerated and showed high early response in newly diagnosed Ph +ALL. These promising findings warrant further investigation in future trials.

Cancer-Related Gene Mutations Drive Resistance to the Third-Generation Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukaemia

Objectives Interrogate the dynamic evolution of cancer-related gene mutations in subjects with chronic myeloid leukaemia (CML) receiving the third generation- (3G-) tyrosine kinase inhibitor (TKI) therapy, and define those mediating resistance. Methods 176 consecutive subjects with chronic or accelerated phase CML failing imatinib and/or the second generation- (2G-) TKI and receiving a 3G-TKI (ponatinib or olverembatinib) were studied. Deep targeted sequencing was used to screen cancer-related gene mutations and Sanger sequencing for ABL mutations. Results 176 subjects in chronic (n = 136) or accelerated (n = 41) phases received ponatinib (n = 147) or olverembatinib (n = 29) therapy. 19 subjects were exposed to imatinib priorly; 16, the 2G-TKI; 141, imatinib and the 2G-TKI. 142 (81%) had ABL mutations including ABLT315I (n = 87, 61%), ABLT315I+additional (n = 30, 21%) or ABLothers (n = 25, 18%) at baseline. 157 (89%) subjects had other cancer-related gene mutations including ASXL1 (n = 121, 69%), KMT2D (n = 14, 8%), RUNX1 (n = 12, 7%), PHF6 (n = 9, 5%), KMT2C (n = 8, 5%), IKZF1 (n = 8, 5%), STAT5A (n = 8, 5%), TET2 (n = 8, 5%), DNMT3A (n = 7, 4%) and KDM6A (n = 7, 4%) and so on at baseline. In multivariable analyses, ASXL1G646Wfs*12 and PHF6 mutations were significantly-associated with the poor cytogenetic and molecular responses; RUNX1 and PHF6 mutations with poor progression-free survival; IKZF1 and STAT5A mutations with poor survival. ABLT315I mutation was significantly-associated with good responses. Follow-up analyses were done in 105 subjects. According to the therapy response of 3G-TKI, 51 subjects were classified into responsive cohort; 54 subjects, resistant cohort including primary (n = 44) and secondary (n = 10) resistance. In the responsive cohort, only 1 subject retained their ABL mutation and none developed a new ABL mutation (Figure 1B). In the resistant cohort, 6 subjects developed new ABL mutations including E255K/V (n = 2), F359V/I (n = 2), G250E and T315M (Figure 1C). There was a significantly-higher proportion of subjects with ABL mutations in the resistant cohort compared with the responsive cohort (52% vs. 2%, p < 0.001) despite similar ABL mutation status at baseline. As for other cancer-related gene mutations, 92 (88%) had other cancer-related gene mutations with a median number of 2 (range, 0 - 7) at baseline. Compared with the responsive cohort, the detected frequency and the median number of mutations in the resistant cohort were significantly-higher both at the baseline (p < 0.001 - 0.027) and at the end of observation period (p < 0.001 - 0.002) (Figure 2&3). More subjects developed new mutations in the resistant cohort than those in the responsive cohort (74% vs. 39%, p < 0.001, Figure 2&3). As the most frequently detected of ASXL1 mutation, despite similar frequency of ASXL1 mutation between the responsive and resistant cohorts at baseline (p = 0.68), more subjects in the resistant cohort had ASXL1G646Wfs*12 mutation than those in the responsive cohort (p = 0.03), while similar frequency of ASXL1non-G646Wfs*12 mutations. At the end of observation, 52 (50%) subjects (including 40 in the resistant cohort and 12 in the responsive cohort) had the ASXL1 mutation. In subjects with ASXL1 mutation, 21 subjects were detected to the ASXL1G646Wfs*12 mutation, with only 1 (2%) subject in the responsive cohort, 20 (37%) in the resistant cohort (p < 0.001). Frequencies of ASXL1non-G646Wfs*12 were similar. In addition, the variant allele frequencies (VAFs) of ASXL1G646Wfs*12 and ASXL1non-G646Wfs*12 mutations were significantly-decreased during 3G-TKI therapy in the responsive cohort (p < 0.001 - 0.002, Figure 4) but not in the resistant cohort. There were no significant differences in the primary resistance cohort during the 3G-TKI therapy. However, the VAFs of ASXL1G646Wfs*12 mutation significantly-decreased when in the temporarily response (p = 0.05), while significantly-increased when the secondary resistance occurred (p = 0.015, Figure 4A) in the secondary resistant cohort. In contrast, the VAFs of ASXL1non-G646Wfs*12 mutation presented the decreased trend when in both temporarily response and secondary resistance (Figure 4B). The patterns of the dynamic evolution in RUNX1, IKZF1, SETBP1 and PHF6 mutations were similar as those in ASXL1 G646Wfs*12 mutation. ConclusionsASXL1G646Wfs*12, RUNX1, IKZF1, SETBP1 and PHF6 mutations are the key drivers of resistance to 3G-TKI therapy in CML. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical Outcomes of Patients with Epidermal Growth Factor Receptor–Mutated Non-Small-Cell Lung Cancer with Leptomeningeal Metastasis in the Modern Target Therapy Era

Leptomeningeal metastasis (LM) is a severe complication in patients with non-small-cell lung cancer (NSCLC) and the optimal treatment strategy remains a challenge. This study aimed to investigate the treatment strategies and clinical outcomes in these patients. We retrospectively reviewed the data of 44 patients with epidermal growth factor receptor (EGFR)-mutated NSCLC with LM between 2014 and 2020 at our institute. The patient characteristics, treatment approaches, LM progression-free survival (LMPFS) and overall survival (OS) after the diagnosis of LM (OSLM) were analyzed. The median OSLM was 16.0 months and the 3-year OS rate was 22.5%. The PFSLM in EGFR T790M-positive NSCLC patients with leptomeingeal disease was significantly improved by initiation of third-generation tyrosine kinase inhibitors (TKIs) compared with that of patients who were T790M negative (14.0 vs. 7.0 months; P= 0.030). A significantly higher LM disease control rate was shown in patients who received third-generation TKIs compared with previous generations of TKIs (90.1% vs. 60.0%; P= 0.024). Better Eastern Cooperative Oncology Group performance status, EGFR exon 19del, and clinical improvement of LM after therapy were independently associated with better OS. The survival of patients with NSCLC with LM has improved in the target therapy era. Our study provided real-world clinical evidence that patients with EGFR-mutated NSCLC who developed LM from previous TKIs can be benefit from third-generation EGFR-TKIs, especially for patients with EGFR T790M-positive.

Structural Basis for Inhibition of Mutant EGFR with Lazertinib (YH25448).

Lazertinib (YH25448) is a novel third-generation tyrosine kinase inhibitor (TKI) developed as a treatment for EGFR mutant non-small cell lung cancer. To better understand the nature of lazertinib inhibition, we determined crystal structures of lazertinib in complex with both WT and mutant EGFR and compared its binding mode to that of structurally related EGFR TKIs. We observe that lazertinib binds EGFR with a distinctive pyrazole moiety enabling hydrogen bonds and van der Waals interactions facilitated through hydrophilic amine and hydrophobic phenyl groups, respectively. Biochemical assays and cell studies confirm that lazertinib effectively targets EGFR(L858R/T790M) and to a lesser extent HER2. The molecular basis for lazertinib inhibition of EGFR reported here highlights previously unexplored binding interactions leading to improved medicinal chemistry properties compared to clinically approved osimertinib (AZD9291) and offers novel strategies for structure-guided design of tyrosine kinase inhibitors.

Abstract 14372: Case Series: Non-Lipid Plaque Formation as the Mechanism for Ponatinib-Induced Vascular Toxicity Using Operator-Assisted Virtual Histology Optical Coherence Tomography

Introduction: The third-generation tyrosine kinase inhibitor ponatinib approved for treating chronic myeloid leukemia (CML) rendered drug resistant with a threonine-315-isoleucine (T315I) mutation is associated with increased incidence of vascular adverse events (VAEs). This case series sought to elucidate the mechanism of these VAEs. Methods: Two patients with CML and two patients with Philadelphia chromosome positive acute lymphocytic leukemia (Ph+ ALL) on at least one year of ponatinib therapy were imaged with optical coherence tomography (OCT) after presenting with angina. An additional four patients from an institutional OCT database were matched across clinical parameters (age, sex, diabetes, prior coronary artery disease (CAD) history, prior congestive heart failure (CHF) history, hypertension, and family history of CAD) to serve as controls. Plaque composition was assessed using operator-assisted virtual histology OCT (vOCT). Results: Clinical presentations included 2 cases of NSTEMI, 1 case of unstable angina, and 1 case of stable angina pectoris among the 4 ponatinib patients. Atherosclerosis was composed primarily of calcium and fibrous tissue with minimal lipid presence (0 ± 0°) compared to the matched controls. The matched controls had a mean non-zero lipid content of 48.43 ± 18.36°, ( P &lt; 0.05) (Table 1). Three of the four patients had cardiovascular risk factors. Conclusions: Ponatinib causes VAEs through non-lipid plaque formation driving a symptomatology consistent with an oxygen supply-demand mismatch. This mechanism is distinct from traditional pathways of excess lipid and plaque instability causing coronary artery disease and merits further investigation.

Covalent Binding Mechanism of Furmonertinib and Osimertinib With Human Serum Albumin.

As third-generation tyrosine kinase inhibitors, furmonertinib and osimertinib exhibit better efficacy than first- and second-generation tyrosine kinase inhibitors in patients with advanced non-small cell lung cancer. However, radioactive pharmacokinetics studies showed that parent-related components remain in human plasma for at least 21 days after oral administration. Similar pharmacokinetic profiles were found in pyrotinib and neratinib, which have been identified to covalently bind with human serum albumin at Lys-190, leading to low extraction recovery in protein precipitation. However, the binding mechanism of furmonertinib and osimertinib in human plasma has not been confirmed. Comprehensive techniques were used to investigate the mechanism of this binding, including ultra high-performance liquid chromatography coupled with high-resolution mass spectrometry and online/offline radioactivity profiling. SDS-PAGE and further autoradiography were also used to detect drug-protein adducts. We found that most furmonertinib exists in the human plasma following ex vivo incubation in the form of protein-drug adducts. Only lysine-furmonertinb adducts were found in pronase digests. A standard reference of lysine-furmonertinib was synthesized and confirmed by NMR. Through peptide mapping analysis, we confirmed that furmonertinib almost exclusively binds with human serum albumin (HSA) in plasma following ex vivo incubation, via Michael addition at Lys-195 and Lys-199, instead of Lys-190. Two peptides found to bond with furmonertinib were ASSAKQR and LKCASLQK. Osimertinib was also found to bond with Lys-195 and Lys-199 of HSA via peptide mapping analysis. SIGNIFICANCE STATEMENT: Here we report that furmonertinib and osimertinib can covalently bind with human serum albumin at the site of Lys-195 and Lys-199 instead of Lys-190, potentially leading to the long duration of drug-protein adducts in the human body.

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.&#x0D; 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.&#x0D; 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.