Third-generation Tyrosine Kinase Inhibitors Research Articles

Osimertinib in NSCLC With Atypical EGFR-Activating Mutations: A Retrospective Multicenter Study

IntroductionEGFR mutations drive a subset of NSCLC. Patients harboring the common EGFR mutations, deletion of exon 19 and L858R, respond well to osimertinib, a third-generation tyrosine kinase inhibitor. Nevertheless, the effect of osimertinib on NSCLC with atypical EGFR mutations is not well described. This multicenter retrospective study evaluates the efficacy of osimertinib among patients with NSCLC harboring atypical EGFR mutations. MethodsPatients with metastatic NSCLC treated with osimertinib, harboring at least one atypical EGFR mutation, excluding concurrent deletion of exon 19, L858R, or T790M mutations, from six U.S. academic cancer centers were included. Baseline clinical characteristics were collected. The primary end point was the time to treatment discontinuation (TTD) of osimertinib. Objective response rate by the Response Evaluation Criteria in Solid Tumors version 1.1 was also assessed. ResultsA total of 50 patients with NSCLC with uncommon EGFR mutations were identified. The most frequent EGFR mutations were L861Q (40%, n = 18), G719X (28%, n = 14), and exon 20 insertion (14%, n = 7). The median TTD of osimertinib was 9.7 months (95% confidence interval [CI]: 6.5–12.9 mo) overall and 10.7 months (95% CI: 3.2–18.1 mo) in the first-line setting (n = 20). The objective response rate was 31.7% (95% CI: 18.1%–48.1%) overall and 41.2% (95% CI: 18.4%–67.1%) in the first-line setting. The median TTD varied among patients with L861Q (17.2 mo), G719X (7.8 mo), and exon 20 insertion (1.5 mo) mutations. ConclusionsOsimertinib has activity in patients with NSCLC harboring atypical EGFR mutations. Osimertinib activity differs by the type of atypical EGFR-activating mutation.

Treatment de-escalation in Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia: the emerging role of chemotherapy-free regimens.

The management of Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukemia (ALL) has witnessed major progress over the past two decades. Initially, the incorporation of the first-generation BCR::ABL1 tyrosine kinase inhibitor (TKI) imatinib into intensive chemotherapy regimens improved outcomes compared with chemotherapy alone. The combinations of chemotherapy with second- or third-generation TKIs further improved outcomes, with higher rates of complete molecular remission (CMR) and superior survival. The combination of ponatinib plus chemotherapy resulted in durable remissions and prolonged long-term survival, even in patients who did not receive allogeneic stem cell transplantation (SCT). The promising results seen with later-generation TKIs have caused many to re-evaluate the role of allogeneic SCT for patients who achieve CMR with potent TKI regimens. Recently, the chemotherapy-free combinations of blinatumomab plus TKIs were shown to be safe and effective in newly diagnosed Ph-positive ALL, sparing patients the toxicities associated with intensive chemotherapy. In particular, encouraging early results have been seen with the combination of blinatumomab plus ponatinib, suggesting that this regimen may represent a chemotherapy-free and SCT-sparing strategy for patients with Ph-positive ALL. Herein, we discuss the current evidence for frontline therapies of Ph-positive ALL, the treatment de-escalation strategies over time, and the role of allogeneic SCT in view of the emergence of newer chemotherapy-free regimens using potent TKIs.

Targeting BCR-ABL1-positive leukaemias: a review article.

Treatment and understanding of BCR::ABL1-positive leukaemias is a precision medicine success story. Our appreciation of the BCR::ABL1 gene and resulting BCR::ABL1 oncoprotein in chronic myeloid leukaemia (CML) and Philadelphia chromosome-positive (Ph+) acute leukaemias, has led to treatment advances associated with exceptional improvements in patient outcomes with normal life expectancy for many patients with chronic phase (CP-)CML. However, despite these major therapeutic advances, the management of Ph+ leukaemias remains complex, with development of specific resistance mutations on treatment, as well as the need for lifelong therapy in most patients due to the persistence of CML stem cells despite prolonged tyrosine kinase inhibitors (TKIs) treatment. BCR::ABL1-specific TKIs are associated with chronic toxicities affecting quality-of-life in many patients but can also result in more serious pulmonary and cardiovascular complications. Dose optimisation is increasingly being used to manage side effects and maintain molecular response in CML patients. Here, we review the development of BCR::ABL1-specific TKIs from the discovery of imatinib in 1996 to the more recent second- and third-generation TKIs and emerging specifically targeting the ABL myristoyl pocket (STAMP) inhibitors. We will also evaluate the current evidence for treatment of BCR::ABL1-positive leukaemias, including TKI discontinuation in optimally responding CP-CML patients.

Ponatinib-Associated Cutaneous Eruptions—A Case Series and Review of Clinicopathologic Findings

Ponatinib is a third-generation tyrosine kinase inhibitor used to treat chronic myeloid leukemia and Philadelphia-positive acute lymphoblastic leukemia. Cutaneous toxicities are a commonly reported side effect of ponatinib treatment with "rash" being one of the most common. Specific subtypes are infrequently reported, but include hyperkeratotic, folliculocentric, ichthyosiform, and pityriasis rubra pilaris-like eruptions. Herein, we highlight the clinicopathologic features of 2 cases of ponatinib-induced pityriasis rubra pilaris-like eruptions. We also classify the clinical and histopathologic features of all previously reported ponatinib-associated eruptions in the literature and discuss treatment and potential diagnostic pitfalls.

RETRACTED ARTICLE: Tarsoconjunctival Granulation Tissue Formation Associated with EGFR Inhibitors.

The combination of amivantamab, an epidermal growth factor receptor (EGFR)-MET bispecific antibody, with the third-generation tyrosine kinase inhibitor lazertinib is used to overcome drug resistance in the treatment of non-small cell lung carcinoma (NSCLC). We present a 58-year-old woman with NSCLC who developed tarsoconjunctival granulation tissue while she was under amivantamab-lazertinib combination therapy. After the excision of tarsoconjunctival granulation tissue, she was maintained on amivantamab-lazertinib combination therapy. Tarsoconjunctival lesions recurred and she also developed trichomegaly and paronychia, which are well-known side effects of EGFRinhibitors. This case presentation aims to raise awareness among ophthalmologists and oncologists of the association between EGFR-Is and an unusual side effect; tarsoconjunctival granulation tissue formation.

Ph+ ALL in 2022: is there an optimal approach?

Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) carried a very poor prognosis prior to the advent of tyrosine kinase inhibitors (TKIs) that block the activity of the BCR-ABL1 oncoprotein. With improvements in TKI efficacy and allogeneic hematopoietic cell transplantation (HCT), survival has improved over the past 3 decades, and the role of chemotherapy and allogeneic HCT is now changing. Better risk stratification, the application of the third-generation TKI ponatinib, and the use of immunotherapy with the CD19-CD3 bifunctional T-cell engaging antibody blinatumomab in place of chemotherapy has made therapy for Ph+ ALL more tolerable and arguably more efficacious, especially for older patients who comprise most patients with Ph+ ALL.

A review of the therapeutic role of the new third-generation TKI olverembatinib in chronic myeloid leukemia.

Several tyrosine kinase inhibitors (TKIs) have been developed as targeted therapies to inhibit the oncogenic activity of several tyrosine kinases in chronic myeloid leukemia (CML), acute lymphoid leukemia (ALL), gastrointestinal stromal tumor (GIST), and other diseases. TKIs have significantly improved the overall survival of these patients and changed the treatment strategy in the clinic. However, approximately 50% of patients develop resistance or intolerance to imatinib. For second-generation TKIs, approximately 30%-40% of patients need to change therapy by 5 years when they are used as first-line treatment. Clinical study analysis showed that the T315I mutation is highly associated with TKI resistance. Developing new drugs that target the T315I mutation will address the dilemma of treatment failure. Olverembatinib, as a third-generation TKI designed for the T315I mutation, is being researched in China. Preliminary clinical data show the safety and efficacy in treating CML patients harboring the T315I mutation or who are resistant to first- or second-line TKI treatment. Herein, we review the characteristics and clinical trials of olverembatinib. We also discuss its role in the management of CML patients.

Possible heart failure caused by osimertinib in a lung cancer patient.

Osimertinib is a third-generation tyrosine kinase inhibitor (TKI) indicated for the treatment of epidermal growth factor receptor mutated non-small cell lung cancer (NSCLC). It has demonstrated better results concerning effectiveness than other TKIs for the same indication. However, despite a good safety profile, it could produce some cardiotoxicity that does not occur with other drugs of the same group. We report the evolution and management of a female patient diagnosed with NSCLC who developed a grade 3 cardiotoxicity due to treatment with osimertinib. This patient suffered from a left bundle branch block, dyslipidemia, and hypertension as cardiovascular risk factors. After a long period of treatment with osimertinib, she developed a severe heart failure (HF) with an important decrease in left ventricular ejection fraction (LVEF), which triggered an admission to the oncology unit for eight days. Treatment with osimertinib was first suspended and then resumed after stabilization of the HF. She also developed atrial fibrillation during admission and has required narrow cardiac monitoring and management since the debut of the HF. After evaluating the benefit-risk balance, osimertinib was reintroduced and the patient continues in treatment at the moment, although the baseline LVEF is not recovered. There is scarce evidence in the literature concerning HF and important LVEF decrease due to osimertinib. However, its severity and repercussion for the patient justify the thorough screening of cardiovascular risk factors before starting the therapy.

Novel third-generation tyrosine kinase inhibitor for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia: a case study.

Although Philadelphia chromosome-positive acute leukemia (Ph + -ALL) has been revolutionized with tyrosine kinase inhibitors (TKIs), resistance and mutation are universal events during treatment with first-generation and second-generation TKIs. The present third-generation TKI has a dose-dependent, increased risk of serious cardiovascular events and the sensitivity is poor for patients with ≥2 mutations accompanied by the T315I mutation. Thus, novel and well-tolerated TKIs should be explored. This study analyzes the efficacy and advert effects of olverembatinib, a novel third TKI, in the treatment of newly diagnosed adult Ph + -ALL in induction therapy. Four adult patients with newly diagnosed Ph + -ALL were treated with olverembatinib as the first-line treatment. For induction therapy, these patients received 40 mg of oral olverembatinib quaque omni die for 28 days, 1 mg/kg/d of prednisone for 14 days, then tapered and stopped at 28 days and vindesine 4 mg/d at days 1, 8 and 15. After induction therapy, these patients received median or high-dose of cytarabine and methotrexate combined with oral olverembatinib as consolidation therapy. Then the allogeneic hematopoietic stem cell transplantation (allo-HSCT) was performed. All patients reached complete remission with a complete cytogenetic response after induction therapy. Two patients reached major molecular remission and one with complete molecular remission. Before allo-HSCT, all the patients achieved complete molecular remission. All the patients have survived disease-free for 3-6 months. No severe advert effects were observed. It is well-tolerated and effective for olverembatinib in the treatment of newly diagnosed adult patients with Ph + -ALL. A prospective study should be performed to further testify the role.

Towards chemotherapy-free treatment of Philadelphia chromosome-positive acute lymphoblastic leukaemia

The addition of tyrosine kinase inhibitors (TKIs) to conventional chemotherapy backbones for adults with newly diagnosed Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukaemia has substantially improved treatment outcomes.1,2 However, the long-term outcomes are still unsatisfactory, with treatment-related resistance and toxicity. Over the past 10 years, several clinical trials have incrementally shown improved outcomes and reduced toxicity for these patients. These steps include the upfront use of the third-generation TKI ponatinib, which is active against the gatekeeper mutation, Thr315Ile, in the ABL1 tyrosine kinase domain.

The First Report of Third-Generation TKI Olverembatinib in Adult Ph/BCR-ABL1-Positive Acute Lymphoblastic Leukemia with T315I Mutation and Relapsed Disease

Background Tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of patients(pts) with Ph/BCR-ABL1-positive (Ph/BCR-ABL1+) acute lymphoblastic leukemia (ALL). However, mutations in the ABL1 kinase domain, especially T315I, are the main mechanism of resistance to the first- or second-generation TKIs. Olverembatinib is a novel third-generation TKI developed in China and approved in Dec. 2021, which has been demonstrated great efficacy and safety in clinical trials of CML with T315I mutation. Our study is the first application of Olverembatinib in adult Ph/BCR-ABL1+ ALL with T315I mutation. Herein, we report the preliminary results. Methods In this exploratory study, adult Ph/BCR-ABL1+ ALL pts with T315I mutation or disease progression were treated with olverembatinib monotherapy (40 mg, every 2 days) or in combination with VP based low intensive chemotherapy (Vincristine/Prednisone) in our institution. Efficacy was assessed by complete remission (CR) rate, MRDneg (<0.01%) rate by multiparameter flow cytometry (MFC) and CMR (BCR-ABL1 transcript<10-5) rate by real-time quantitative polymerase chain reaction (RT-qPCR). Safety profiles were also monitored in this study. Results From December 2021 to June 2022, 10 Ph/BCR-ABL1+ ALL pts were treated with olverembatinib due to T315I mutation or disease recurrence, after prior TKIs combined with chemotherapy. Median age was 60.5 years (range, 37-65), and 6/10 were males. 5 pts had received 2 types of TKIs previously, of which 2 pts relapsed after ponatinib (Table 1). Among 10 pts, 6 were still in CR1 (pt 1-6), their T315I mutations were detected during regular follow-up. 4/6 pts were persistently molecular positive, while the other 2 had molecular relapse. Median time from diagnosis to the administration of olverembatinib was 5 months (range, 3-17). Among the 4 pts with hematologic relapse (pt 7-10), 2 (pt 7, 8) had T315I mutation. Because of the successive occurrence of G250E, Y253H, L248V mutations and L248 K274del, the 3rd one (pt 9) relapsed twice and failed to response to two kinds of TKIs and chemotherapy. As for the last pt (pt 10), although no ABL1 mutations were found, she was in 3rd relapse with CNS and BM involvement. Median time from diagnosis to the start of olverembatinib for these 4 relapsed pts was 28 months (range, 5-41). Among 6 pts with T315I mutation and persistent molecular diseases or molecular relapse, the CMR rate was 66.7%, with a median time of 3 months (range, 1-4) to achieve CMR. Then 2 pts underwent allo-HSCT (pt3, 4), who were still in CR. Among 4 hematological relapsed pts, the CR rate was 75%. 1 pt (pt8) with T315I was unresponsive, while another T315I positive patient achieved MRDneg by MFC after 1 month of treatment, with a complete disappearance of T315I mutation (pt7), though the BCR-ABL1 transcript was still positive. The remaining 2 relapsed pts without T315I mutation achieved hematologic CR after 1 month of olverembatinib monotherapy (pt9,10). Totally, overall response rate (ORR) was 70% and MRDneg rate by MFC was 71.4% (5/7), while the CMR rate by PCR was 57.1% (4/7). Notably, olverembatinib was ineffective in neither of the 2 pts who have been previously treated by ponatinib. Meanwhile, the olverembatinib-based therapy was well-tolerated, and the main adverse events of the third-generation TKIs, such as cytopenia, elevated transaminases, hypertension, and cardiovascular events, were less frequent than those reported relating to ponatinib. In addition, 4 patients developed grade 1 skin pigmentation (pt2,3,6,9). There were no drug-related death or permanent discontinuation due to toxicity. Conclusion This work suggests that Olverembatinib is a very promising 3rd-generation TKI. It is effective and safe in Chinese adult Ph/BCR-ABL1+ ALL with extremely poor prognosis, especially in T315I mutated or relapsed pts. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

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.

Olverembatinib (HQP1351) Overcomes Ponatinib Resistance in Patients with Heavily Pretreated/Refractory Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL)

Background Olverembatinib is a novel third-generation BCR-ABL1 tyrosine kinase inhibitor (TKI) with antitumor activity against CML and Ph+ ALL regardless of genotype and a preliminarily favorable human safety profile. This study is the first to report on the safety, efficacy, and pharmacokinetic (PK) profiles of olverembatinib in patients with CML (all phases) and Ph+ ALL outside China, whose disease failed ponatinib treatment and at least 2 prior TKI treatments. Methods In this multicenter, open-label, randomized trial, olverembatinib is administered orally on alternate days (QOD) in adults with chronic-phase (CP-CML), accelerated-phase (AP-CML), or blast-phase CML (BP-CML) or Ph+ ALL. Enrolled patients have had no fewer than 2 prior TKI failures, except for those whose disease harbors T315I mutation, for whom the number of previous TKIs is not limited. Study participants are randomized 3:3:2 to olverembatinib 30, 40, or 50 mg QOD in 28-day cycles. Results A total of 30 patients have been enrolled, including 23 with CP-CML, 4 with AP-CML, 2 with BP-CML, and 1 with Ph+ ALL. The median (range) treatment duration is 4.8 (0.03-21.29) months and the median (range) interval from CML/Ph+ ALL diagnosis to olverembatinib treatment onset, 7.0 (1.5-24.0) years. Half (15/30) of patients are men, and the median (range) age is 47.0 (21.0-74.0) years. In all, 1 (3.3%), 7 (23.3%), 8 (26.7%), and 9 (30.0%) patients received 2, 3, 4, and ≥ 5 prior TKIs, respectively. A total of 21 (70.0%) patients were pretreated with third-generation TKI ponatinib, including 17 (81.0%) with resistance and 4 (19.0%) with intolerance; a total of 5 (16.7%) were pretreated with asciminib; 12 (40.0%) had T315I mutations; and 13 (43.3%), hypertension. At baseline, all patient BCR-ABL1IS levels were > 1%. Olverembatinib was well tolerated. Twenty-two (73.3%) patients experienced any-grade treatment-related AEs (TRAEs; Table 1), incidences of which tended to be dose-dependent. Most nonhematologic TRAEs were grade 1/2. Common grade 3/4 hematologic TRAEs included thrombocytopenia (7/30; 23.3%), neutropenia (5/30; 16.7%), and decreased leukocyte counts (4/30; 13.3%). In all, 11 (36.7%) of 30 patients experienced serious AEs, of which 6 (20.0%) were considered olverembatinib-related and 1 (3.3%) led to treatment discontinuation. One patient with AP-CML from the 50-mg dose cohort died of progressive disease. Olverembatinib conferred potent antileukemic activity in patients with CML and Ph+ ALL (Table 2). Of 21 efficacy-evaluable patients, 17 were evaluable for cytogenetic response, of whom 10 (58.8%) had complete cytogenetic response (CCyR); 9/21 (42.9%) patients had major molecular responses (MMR). Olverembatinib was effective in patients with either T315I-mutant (62.5%, CCyR; 50%, MMR) or T315IWT (55.6%, CCyR; 38.5%, MMR), and its effectiveness was not compromised by prior use of ponatinib or asciminib. Among patients pretreated with ponatinib with available responses, 5 (55.6%) of 9 patients with ponatinib-resistant disease experienced CCyR and 6 (54.5%) of 11, MMR. Four of 5 patients pretreated with asciminib showed response. PK analyses indicated an approximately dose-proportional increase in olverembatinib plasma exposure from 30 to 50 mg QOD and comparable plasma exposure between Chinese and US CML populations. Conclusions Olverembatinib monotherapy is efficacious and well tolerated in patients with TKI-refractory CML and Ph+ ALL. Even in patients with CML who were ponatinib or asciminib resistant, or who had T315I mutations, olverembatinib showed strong efficacy. This analysis confirms that olverembatinib is a potentially viable treatment option for patients with CML and Ph+ ALL, including those with ponatinib failure or T315I mutation. Internal study identifier: HQP1351-CU101. Clinicaltrials.gov identifier: NCT04260022. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

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).