Prior Tyrosine Kinase Inhibitor Therapy Research Articles

Updated overall survival and ctDNA analysis in patients with EGFR T790M-positive advanced non-small cell lung cancer treated with lazertinib in the phase 1/2 LASER201 study.

Lazertinib is a potent, irreversible, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with significant efficacy in patients with EGFR T790M-mutated non-small cell lung cancer (NSCLC). This is the final overall survival (OS) report from the phase 1/2 LASER201 study in patients with advanced NSCLC with disease progression on or after prior EGFR TKI therapy. Eligible patients were aged ≥ 20years, with advanced EGFR-mutated NSCLC and previous therapy with EGFR TKI. Patients in this integrated analysis received oral lazertinib 240mg/day. Endpoints included efficacy and safety; exploratory analyses included associations between circulating EGFR-mutant tumor DNA (ctDNA) and efficacy parameters. This integrated analysis included 78 patients in Korea who received second- or later-line lazertinib. The median OS was 38.9months; estimated survival rates at 12, 24, and 36months were 89.5%, 73.9%, and 52.8%, respectively. The cumulative 12-month incidence of central nervous system progression was 9.4%. EGFR-mutant ctDNA was detected in 46 patients (62.2%) at baseline. The presence of ctDNA at baseline significantly predicted progression-free survival (PFS), disease control rate (DCR), and OS. PFS, response rate, and DCR were significantly associated with EGFR-mutant ctDNA clearance at cycle 3; PFS and OS were significantly associated with ctDNA clearance at cycle 5. The safety profile of lazertinib 240mg/day was consistent with previous findings. Lazertinib is a promising treatment option for patients with EGFR T790M-positive NSCLC following disease progression on prior EGFR-directed TKIs. Patients in LASER201 experienced prolonged OS, regardless of their EGFR mutation, brain metastases, or prior brain radiation status. Clearance of plasma EGFR mutations after lazertinib was associated with patient outcomes. ClinicalTrials.gov identifier NCT03046992.

FDA Approval Summary: Repotrectinib for Locally Advanced or Metastatic ROS1-Positive Non-Small Cell Lung Cancer.

On November 15, 2023, the U.S. Food and Drug Administration (FDA) granted traditional approval to repotrectinib (Augtyro, Bristol Myers Squibb Corporation) for the treatment of adult patients with locally advanced or metastatic receptor tyrosine kinase encoded by the ROS1 gene (ROS1)-positive non-small cell lung cancer (NSCLC). The approval was based on TRIDENT-1, a single-arm trial with multiple cohorts of patients with ROS1 fusion-positive (hereafter "ROS1-positive") NSCLC (NCT03093116), who were either treatment naïve or had received prior ROS1 tyrosine kinase inhibitor (TKI) and/or platinum-based chemotherapy. The primary efficacy outcome measure is objective response rate (ORR) assessed by blinded independent central review (BICR) using response evaluation criteria in solid tumors version 1.1. ORR was assessed in 71 patients who were ROS1 TKI naïve and 56 patients who had received a prior ROS1 TKI. Among the 71 patients who were ROS1 TKI naïve, the ORR was 79% (95% CI, 68-88), median duration of response was 34.1 months (95% CI, 26-NE). In patients who had received a prior ROS1 TKI and no prior chemotherapy, the ORR was 38% (95% CI, 25-52). The median duration of response was 14.8 months (95% CI, 7.6-NE); BICR-assessed responses were observed in CNS metastases in patients in both cohorts and in patients who developed resistance mutations following prior TKI therapy. The most common (>20%) adverse reactions were dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, ataxia, fatigue, cognitive disorders, and muscular weakness. A unique feature of this ROS1 TKI approval is the inclusion of robust evidence of efficacy in patients with ROS1-positive NSCLC who had progressed on prior ROS1 TKIs.

Abstract CT282: MK-2870-004: A phase 3 study of MK-2870 (SKB264) versus chemotherapy for previously treated advanced or metastatic nonsquamous non-small-cell lung cancer (NSCLC) with EGFR mutations or other genomic alterations

Abstract Background: Trophoblast cell-surface antigen 2 (TROP2), a cell surface glycoprotein involved in the regulation of tumor growth and invasion, is broadly expressed and upregulated in several cancers, including NSCLC. MK-2870 (SKB264) is an antibody-drug conjugate (ADC) composed of the humanized anti-TROP2 monoclonal antibody, a hydrolytically cleavable linker, and the cytotoxic drug KL610023. MK-2870 has demonstrated encouraging antitumor activity and manageable toxicity in phase 1 and 2 studies of patients with solid tumors, including heavily pretreated EGFR-mutant NSCLC. We describe the design of the ongoing phase 3 MK-2870-004 study (NCT06074588) that will evaluate the efficacy and safety of MK-2870 vs chemotherapy for previously treated advanced or metastatic nonsquamous NSCLC with EGFR mutations or other genomic alterations. Trial design: The global, randomized, open-label, phase 3 MK-2870-004 study will enroll ~556 patients, including 456 with exon 19del or L858R EGFR mutations, and 100 with other genomic alterations. Eligible patients are aged ≥18 years with histologically or cytologically documented advanced (stage III not eligible for resection or curative radiation) or metastatic nonsquamous NSCLC with exon 19del or exon 21 L858R EGFR mutations or other genomic alterations in ALK, ROS1, BRAF V600E, NTRK, MET exon 14 skipping, or RET and those with less common EGFR mutations (exon 20 S768I, exon 21 L861Q, and/or exon 18 G719X). Patients must have progressive disease on or after 1 or 2 lines of prior tyrosine kinase inhibitor (TKI) therapy and a platinum-based therapy (may contain anti-PD-[L]1), measurable disease per RECIST v1.1, an available tumor sample, and adequate organ function. Prior EGFR TKI therapy must include a third-generation TKI for patients with T790M EGFR-mutant NSCLC. Patients with active central nervous system metastases or carcinomatous meningitis are ineligible, although those with previously treated and untreated stable brain metastasis are eligible for enrollment. Patients will be randomized (1:1) to MK-2870 4 mg/kg Q2W on Days 1, 15, and 29 of every 6-week cycle, or chemotherapy (docetaxel 75 mg/m2 Q3W or pemetrexed 500 mg/m2 Q3W) on Days 1 and 22 of every 6-week cycle. Randomization will be stratified by EGFR mutations with prior third generation TKI vs EGFR mutations with no prior third generation TKI vs other genomic alterations, brain metastasis (yes vs no), and TROP2 expression (low vs medium vs high). Dual primary endpoints are PFS (per RECIST v1.1 by blinded independent central review) and OS in patients with EGFR-mutant NSCLC. Key secondary endpoints include PFS and OS in all patients with NSCLC, ORR, DOR, patient-reported outcomes, and safety. Enrollment started in November 2023 and is currently ongoing. Citation Format: Federico Cappuzzo, Edward B. Garon, Myung-Ju Ahn, Shun Lu, Terufumi Kato, Enriqueta Felip, Parneet Cheema, Nicolas Girard, Mark Shamoun, Guoqing Wang, Bin Zhao, Rina Hui. MK-2870-004: A phase 3 study of MK-2870 (SKB264) versus chemotherapy for previously treated advanced or metastatic nonsquamous non-small-cell lung cancer (NSCLC) with EGFR mutations or other genomic alterations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT282.

Асциминиб у больных хроническим миелолейкозом, не имеющих альтернативных методов лечения: результаты исследования в рамках программы расширенного доступа МАР (Managed Access Program, NCT04360005) в России

Aim. To assess the efficacy and tolerability of asciminib in chronic myeloid leukemia (CML) patients after failure of ≥ 2 lines of tyrosine kinase inhibitors (TKIs) therapy under the МАР (Managed Access Program, NCT04360005) in Russia. Materials & Methods. The study enrolled 68 patients with Ph-positive CML chronic phase (CF), over 18 years of age, after failure of ≥ 2 lines of TKI therapy. The analysis was conducted on data from 50 patients who were followed-up for at least 3 months and did not undergo allo-HSCT. Dosing regimens were prescribed depending on T315I mutation. Asciminib 200 mg per os was administered twice a day to 20 patients with this mutation, and asciminib 40 mg per os was administered twice a day to 30 patients without this mutation. By the time of admission into the MAP, there were 42 (82 %) CF CML patients as well as 8 patients with second CF after accelerated phase (AF, n = 7) and myeloid blast crisis (BC, n = 1). None of them could be treated with any therapeutic alternative. 92 % of patients had received ≥ 3 lines of prior TKI therapy. Overall survival (OS) and discontinuation-free survival were estimated by the Kaplan-Meier method. A cumulative incidence function (CIF) was used to calculate the probability of achieving response. Multivariate analysis was based on Cox regression model. Results. The median asciminib treatment duration was 11 months (range 4–30 months). The probable 2-year OS was 96 %. After 12 and 24 months, discontinuation-free survival was 92 % and 70 %, respectively. On asciminib therapy, complete cytogenetic (CCyR/МR2), major molecular (MMR), and deep molecular (MR4) responses were achieved in 17 (42 %), 14 (30 %), and 9 (19 %) patients who had not responded to prior treatment at the point of enrollment. After completing the 12- and 24-month therapy, the probability of CCyR/МR2 achievement was 44 % and 62 %, that of MMR achievement was 32 % and 40 %, and that of MR4 achievement was 26 % and 37 %, respectively. The patients treated with different doses did not significantly differ in achieving either CCyR/МR2 or MMR. By multivariate analysis, the independently significant factor impacting the probability of achieving MMR on asciminib treatment was the best MR (BCR::ABL1 < 1 % vs. 1–10 % vs. ≥ 10 %) after prior TKI therapy (hazard ratio 7.5873; p = 0.0072). In 22 (44 %) patients, adverse events (AEs) of all grades were observed, and 8 (16 %) patients showed AEs grade 3/4 (predominantly thrombocythemia and neutropenia). None of the patients discontinued asciminib treatment due to AEs. Conclusion. Asciminib demonstrated highly promising efficacy in previously TKI-treated patients with T315I mutation (200 mg BID) and without it (40 mg BID). Asciminib can be regarded as therapeutic option after failure of other TKIs. Different doses of asciminib were equally well tolerated, which makes it applicable for patients with intolerance to other TKIs and also provides ground for considering dose increases in non-responders. Good prospects are also expected for studying asciminib efficacy at earlier treatment stages (in first or second lines) as well as in combination with ATP-binding TKIs in CML patients with insufficient response to TKI treatment.

Результаты применения асциминиба, первого аллостерического ингибитора BCR::ABL1-тирозинкиназы, у больных хроническим миелолейкозом со множественной резистентностью к предшествующей терапии

Currently, there is a crucial need for new treatment approaches to overcome the resistance and intolerance of several tyrosine kinase inhibitor (TKI) therapy lines in chronic myeloid leukemia (CML) patients. Asciminib, the first in its class BCR::ABL1-tyrosine kinase inhibitor specifically targeting ABL myristoyl pocket (STAMP), demonstrated efficacy and safety in CML patients with prior TKI therapy failure, including the cases with pan-resistant T315I mutation in the chimeric BCR::ABL1 gene. The present review focuses on the asciminib mechanism of action, the results of both preclinical and clinical phase I and III studies. Due to the favorable cardiovascular toxicity profile of asciminib, the scope of its application can be extended to patients with cardiovascular co-morbidities. Asciminib is registered in the Russian Federation in January 2023, so treatment algorithms for CML patients with ineffectiveness or intolerance of prior therapy should be updated in line with this new option.

Abstract B024: KO-2806, a next-generation farnesyltransferase inhibitor, potentiates the antitumor activity of cabozantinib in clear cell renal cell carcinoma models

Abstract Conventional treatments for advanced clear cell renal cell carcinoma (ccRCC) include tyrosine kinase inhibitors (TKI) that target angiogenesis, a critical element for ccRCC tumor growth and survival. Cabozantinib, a TKI that inhibits VEGFR, AXL, and MET, is an approved therapy in advanced RCC. However, cabozantinib has limited therapeutic benefit; for example, patients with prior VEGFR TKI therapy had an overall response rate of 21% and median progression-free survival of 7.4 months. Thus, there is an urgent need to identify combination drug partners that can improve the depth and/or durability of clinical responses to cabozantinib. Here, we present preclinical evidence that supports combining the farnesyltransferase inhibitor (FTI), KO-2806, with cabozantinib in ccRCC. KO-2806 is a next-generation farnesyltransferase inhibitor with increased potency and improved pharmacokinetic properties relative to earlier FTI drug candidates and is poised to enter a first-in-human clinical trial. We demonstrate that addition of KO-2806 enhanced tumor growth inhibition of cabozantinib in multiple ccRCC cell line- and patient-derived xenograft models, resulting in either tumor stasis or regression. Immunohistochemical analysis of angiogenic markers in 786-O tumors revealed that, consistent with its mechanism of action, cabozantinib significantly reduced angiogenesis, an effect that was deepened by KO-2806. In support of this, cell viability experiments performed in primary human endothelial cells showed that the combination of KO-2806 and cabozantinib was more effective in reducing cell viability than cabozantinib alone. In addition, we investigated the mechanism underlying the improved response of tumors with the KO-2806-cabozantinib combination by analyzing the major growth signaling pathways in 786-O tumors. Cabozantinib alone reduced both MAPK and PI3K/AKT/mTOR signaling, but addition of KO-2806 resulted in enhanced inhibition of mTOR signaling and increased cell cycle arrest compared to either agent alone. We hypothesize that exposure to anti-angiogenic TKIs render ccRCC tumors more hypoxic, and thus more reliant on compensatory, oncogenic mechanisms like mTOR signaling that allow them to adapt to a nutrient- and oxygen-deprived environment. Mechanistically, KO-2806 potently inhibits the farnesylation, and hence the activity, of the farnesylation-dependent protein RHEB, a positive regulator of mTOR, suggesting that the improved anti-tumor efficacy of the combination may arise through RHEB inhibition in this model. Further in vitro and in vivo studies are underway to establish the scope and mechanistic underpinnings of the effects of the KO-2806-cabozantinib combination and strengthen the therapeutic rationale for the investigation of this approach in the treatment of patients with ccRCC. Citation Format: Jovylyn Gatchalian, Linda Kessler, Hetika Patel, Stacia Chan, Francis Burrows, Shivani Malik. KO-2806, a next-generation farnesyltransferase inhibitor, potentiates the antitumor activity of cabozantinib in clear cell renal cell carcinoma models [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B024.

Phase 2 Study of Dasatinib with and without Venetoclax in Patients with Early Chronic Phase Chronic Myeloid Leukemia (ECP-CML)

Background Treatment-free remission (TFR) is a therapeutic goal for patients with ECP-CML once patients maintain a deep molecular remission (DMR) on tyrosine kinase inhibitors (TKIs). Only a fraction of patients (pts) achieved sustained (3+ years) molecular remission with 4.0- to 4.5-log reduction (MR4.5). Preclinical studies showed that BCL-2 is a key survival factor for CML stem/progenitor cells. Therefore, the combination of TKIs and venetoclax, targeting BCR::ABL1 and BCL-2, has the potential to significantly improve DMR and subsequently the rates of TFR. The aim of this study is to evaluate the safety and efficacy of the combination. Methods Patients with ECP-CML or accelerated phase (AP; defined by clonal evolution only) were eligible; pts with < 1 month of prior TKI therapy were eligible. Pts received single-agent dasatinib 50 mg/d for the first 3 months. From Month 4 and onwards, venetoclax was administered from Days 1 to 14 each month concomitantly with dasatinib for a total of 3 years. The first 16 patients received venetoclax 200 mg/d, with a rapid ramp-up starting 50 mg on Day 1, then 100 mg on Day 2, then 200 mg daily on Day 3 and onwards. Due to neutropenia observed with continuous dose of venetoclax 200 mg/d, the protocol was ameded: from patient #17 and onwards, venetoclax was administered at 200 mg/d for 14 days per month and upon achievement of MR4.5, venetoclax was reduced to 100 mg/d for 7 days per month. After 3 years of combination, patients received single-agent dasatinib. TFR was offered after ≥ 3 years of DMR. The primary endpoint was the rate of major molecular response (MMR) by 12 months of the combination. The secondary endpoints were the 12-month rate of MR4.5 and the cumulative overall rate of MR4.5; the rates of MR4.5 at 6-, 12-, 18-, 24, and 36-months of the combination; the proportion of patients with sustained MR4.5 of 3 years and more; the TFR rate; overall survival; and the safety of the combination. Cumulative response rates were calculated with treatment failure as a competing event. Failure-free survival (FFS) was calculated from the initiation of therapy to loss of major cytogenetic response (MCyR), transformation to AP or blast phase, discontinuation of therapy for any reason except of TFR, or death. Results Sixty-five pts were enrolled and treated between April 2018 and August 2021. The median age at treatment initation was 46 years (range, 23-73) and 57% of the pts were females. Twenty-one (32%) pts had splenomegaly, 46 (71%) had low Sokal risk disease and 3 (5%) had high Sokal risk disease (Table 1). By 12 months of the combination, 85% of the pts had achieved MMR or deeper response. The median time to MMR, MR4, and MR4.5 were 6.2 months, 13 months, and 23.9 months from the time of TKI start, respectively. After a median follow-up of 25.7 months (range, 8.7-48.1), two pts discontinued therapy due to adverse events (GI intolerance, and pleural effusion); the 2 -year FFS was 96%. One pt switched TKI therapy due to the lack of 18-month complete cytogenetic response (CCyR); no loss of CCyR, transformation, or death was observed. We then compared the outcomes with the combination to the outcomes of 85 pts treated with single-agent dasatinib. From the start of TKI therapy, the 12-month cumulative MMR rates were 78% and 79% in the dasatinib single-agent and dasatinib + venetoclax groups, respectively. The cumulative 24-month rates of CCyR, MMR, MR4, and MR4.5 are summarized in Table 2. In the dasatinib single-agent group, 3 pts switched TKI therapy due to the lack of 12-month MCyR, 18-month CCyR, and the acquisition of ABL1 mutation (1 each); 3 pts switched TKI therapy due to loss of CCyR; 2 pts died during therapy (deaths unrelated to CML). Within one year of therapy, the incidence of grade 1/2 neutropenia (absolute neutrophil count, below lower range of normal to 1,000 x10 9/L) was 21% and 52% in the dasatinib single agent and dasatinib + venetoclax groups, respectively ( P<0.001); the incidence of grade 3/4 neutropenia (absolute neutrophil count, below 1,000 x10 9/L) was 8% and 17%, respectively ( P<0.001). There was no incidence of neutropenic fever in the dasatinib + venetoclax. Conclusion The combination of dasatinib 50 mg/d and venetoclax is safe and effective in pts with ECP-CML. With a median follow-up of 2 years, the cumulative resposne of dasatinib + venetoclax is similar to that of dasatinib single-agent without adding significant toxicities. Further follow-up is needed for the evaluation of TFR.

Safety and Efficacy of Tgrx-678, a Potent BCR-ABL Allosteric Inhibitor in Patients with Tyrosine Kinase Inhibitor (TKI) Resistant/Refractory Chronic Myeloid Leukemia (CML): Preliminary Results of Phase I Study

Background: TGRX-678 is a novel allosteric inhibitor of ABL kinases, specifically targeting the ABL Myristoyl Pocket (STAMP). In vitro data supports TGRX-678 targeting the most common BCR-ABL mutations, including T315I. Here we report an open-label, first-in-human study to evaluate the safety, preliminary efficacy, and pharmacokinetic properties of orally administered TGRX-678 in patients with resistant/refractory CML. Methods: This study included dose escalation and expansion phases. During dose escalation patients with CML in chronic or accelerated phase (CP or AP) and who had failed ≥3 prior TKIs were enrolled. Patients received orally a single dose, after a 3-5 day observation, continuously daily doses ranging from 10 to 80 mg (BID) or 40 to 240 mg (QD) were given. Dose escalation followed an adaptive Bayesian logistic regression model based on dose-limiting toxicities (DLTs) occurring in cycle 1 (28 Days). Dose-expansion had three cohorts: CML-CP without T315I mutation with ≥2 prior TKIs, CML-CP with T315I with ≥1 prior TKIs, and CML-AP with ≥1 prior TKIs. The eligible patients received continuous treatments until disease progression, intolerant toxicity, consent withdrawal, or death. Results: From April 30, 2021 to July11, 2023, 95 (CP n = 58, AP n = 37) patients were treated with TGRX-678 at the BID doses including 10 mg (n = 3), 20 mg (n = 6), 40 mg (n = 5), and 80 mg (n = 3), and QD doses including 40mg (n=18), 80 mg (n = 6), 160mg (n= 4) and 240mg (n=50). 40 (42%) patients were female. The median age was 45 (range 35-52) years and the median interval from diagnosis to initial TGRX-678 treatment was 97 (range 28-136) months. Median treatment duration was 8 (range 6-13) months. At baseline, 93 (98%) patients had received ≥2 lines of prior TKI therapy, among them, 78 (82%) received ≥3 lines of prior TKIs, 44 (46%) received ≥4 lines of prior TKIs. 46 (48%) patients had ≥1 ABL mutation and 28 (30%) had T315I mutation. Of 58 patients with CML-CP, 16 (89%) achieved complete hematologic responses (CHR), 25 (43%) major cytogenetic responses (MCyR), 19 (33%) complete cytogenetic responses (CCyR), and 11 (19%) major molecular responses (MMR). Of 14 CML-CP patients with T315I mutation, 9 (100%) achieved CHR, 9 (62%) MCyR, 8 (57%) CCyR and 7 (50%) MMR. Of 35 CML-CP patients without any ABL mutations, 12 (100%) achieved CHR, 11 (31%) MCyR, 6 (17%) CCyR and 1 (3%) MMR (Fig. A). Of 9 CML-CP patients with other ABL mutations, 4 (67%) achieved CHR, 5 (56%) MCyR, 5 (56%) CCyR and 3 (33%) MMR (Fig. B). Of 37 CML-AP patients, 31 (84%) had major hematologic response, 13 (35%) MCyR, and 9 (24%) CCyR (Fig. C). There were 22 CML-CP and 23 CML-AP patients previous received 3 rd Gen TKIs (ponatinib or HQP1351) or asciminib. Of 22 CP patients, 21 (95%) achieved CHR, 4 (18%) MCyR and 3 (14%) CCyR. Of 23 CML-AP patients, 17 (74%) achieved CHR, 5 (22%) MCyR and 3 (13%) CCyR. The PK results suggested that TGRX-678 exposure (C max and AUC tau) was dose-proportional within range of 10mg~80mg BID or 40mg~240mg QD. The elimination of TGRX-678 in human plasma is slow, and the half-life (T1/2) of which is about 120 hours. At steady state, the accumulation ratios of C max and AUC tau are 3.7-8.0 and 5.4-11.8, respectively. The high accumulation ratio of TGRX-678 resulted in not only an increase of plasma exposure, but also a decrease of the gap between C max and C trough (Fig. D). 7 DLTs were observed, one case of elevated alanine aminotransferase at 20 mg BID and five cases of thrombocytopenia at 40mg QD (1), 40mg BID (2) and 80mg QD (2) and one hepatic function abnormal at 240 mg QD. However, MTD was not reached according to protocol criteria. Most treatment-related adverse events (TRAEs) were grade 1-2. AEs ≥ grade 3 that happened more than 5% were thrombocytopenia (50%), neutropenia (42%), anemia (24%) and hypertriglyceridemia (9%). In total 15 patients discontinued the study due to disease progression (5, all APs), intolerance (2), physician's decision (2), consent withdrawal (6). There was one death occurred which was not drug related. Conclusions: Clinical activity of TGRX-678 was seen in all cohorts and across TKI-resistant mutations including T315I, providing a promising treatment option for CML CP/AP patients, including those who failed ponatinib or asciminib. Its unique PK properties might bring additional benefit to patients. TGRX-678 was well tolerated in heavily pretreated CML patients. Currently two doses were selected to optimize the RP2D. Study Identifier: NCT05434312.

Safety and Efficacy of Bezuclastinib (CGT9486), a Novel, Highly Selective, Potent KIT D816V Tyrosine Kinase Inhibitor, in Patients with Advanced Systemic Mastocytosis (AdvSM): Results from Part 1 of the Phase 2 Apex Trial

Background: Systemic mastocytosis (SM) is a rare disease characterized by the aberrant proliferation of mast cells (MC). In about 95% of adult patients, SM is driven by a gain-of-function mutation (D816V) in exon 17 of KIT. Advanced SM (AdvSM) is a life-threatening form of SM and includes three subtypes: aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN), and Mast Cell leukemia (MCL). Bezuclastinib is an oral, potent, and selective tyrosine kinase inhibitor (TKI) with activity against KIT D816V. Preliminary results from the on-going Apex study in patients with AdvSM (NCT04996875) were presented previously (DeAngelo et al. [abstract] In: Blood (ASH) 2022; 140 (Supplement 1): 1512-13). Methods: Apex is a randomized Phase 2, open-label, multicenter trial in adult patients diagnosed with AdvSM per 2022 WHO criteria with a baseline serum tryptase of ≥20 ng/mL. In Part 1, patients were randomized 1:1:1:1 to bezuclastinib 50mg BID, 100mg BID, 200mg BID, or 400mg QD. Patients with a history of prior TKI therapy (e.g., avapritinib, midostaurin) are permitted in the trial. Data from Part 1 informed dose selection for Part 2 of the trial. The primary efficacy endpoint for this trial is overall response rate (complete response [CR], CR with incomplete hematologic recovery [CRh], partial response [PR] and clinical improvement [CI]) as assessed by a central review committee based on mIWG-MRT-ECNM response criteria. Results: As of April 2023, Part 1 was fully enrolled with 33 AdvSM patients. Patients were randomized to 50mg BID (n=8), 100mg BID (n=8), 200mg BID (n=8), or 400mg QD (n=9). Disease subtypes included ASM (n=7), MCL (n=2), and SM-AHN (n=24); AHN subtypes included CMML (n=18), MDS (n=3), MPN (n=1), and MDS/MPN-U (n=2). The majority of patients were male (64%), ECOG PS 0-1 (82%) and KITD816V positive at baseline (91%). At baseline, 67% of patients were TKI-naïve; 33% had prior midostaurin, and 15% had prior avapritinib. Median (range) BM MC burden, serum tryptase, and KIT D816V VAF at baseline were 30% (5-90), 163 ng/mL (35-1578), and 7% (0-47), respectively. Of the 33 patients enrolled, 25 patients (76%) had C-findings evaluable per mIWG-MRT-ECNM criteria; 20 patients (61%) were positive for SRSF2/ASXL1/RUNX1 mutation which are associated with poor survival in SM. Conclusion: Enrollment in Part 1 of the Apex trial is complete. Patients enrolled in Part 1 of the Apex trial are generally representative of the population of patients with AdvSM based on patient characteristics and markers of disease. Part 1 includes a small subset of patients with prior use of TKIs. Safety, clinical activity, and clinical objective response for all patients in Part 1 will be presented.

Real-world outcomes among patients with advanced/metastatic renal cell carcinoma (mRCC) treated with cabozantinib or other tyrosine kinase inhibitors (TKIs) after checkpoint inhibitor (CPI) therapy.

4530 Background: CPI-based therapy is the first-line standard of care for patients with mRCC, but effectiveness data for subsequent targeted therapies are limited. Cabozantinib, a multi-targeted TKI, is indicated for patients with mRCC in the USA and may be prescribed after doublet CPI therapy. Methods: Retrospective study of cabozantinib vs other TKI treatment after CPI therapy for mRCC using the US Oncology Network electronic health record database and chart review. Patients initiated TKI therapy between May 1, 2016 and Nov 30, 2021, immediately after CPI therapy. The primary endpoint was real-world response rate over the first 6 months of treatment (rwRR6months) based on physician assessment (complete response (CR): documented CR/indication of remission/disappearance of all lesions/no evidence of disease, or partial response (PR): documented PR/improved disease/responding disease). Covariates were adjusted by inverse probability of treatment weighting. Noninferiority was assessed using a 90% confidence interval (CI) and 10% noninferiority margin; if noninferiority was met, superiority was evaluated using a 95% CI and chi-square test. Results: In total, 485 patients were included. Baseline characteristics were similar for the cabozantinib and other TKIs subgroups, including proportions of patients with ≥ 2 metastatic sites (74.7% vs 68.2%) and metastases in bone (45.0% vs 43.5%), brain (8.8% vs 7.1%), liver (18.1% vs 19.5%), lung (35.0% vs 44.2%) and lymph nodes (38.7% vs 31.8%). At 6 months, tumor assessment data were available for 75.5% of patients (cabozantinib, 79.8% of cabozantinib and 66.2% of other TKIs, 66.2%) patients. Adjusted rwRR6months was 62.5% for cabozantinib and 46.0% for other TKIs (rate difference: noninferiority, 16.5% [90% CI, 9.3–23.7], p < 0.0001; superiority, 16.5% [95% CI, 7.8–25.1], p = 0.0002). Conclusions: In patients with mRCC receiving standard of care treatment in the USA, cabozantinib was effective post-CPI therapy, including in patients without prior TKI therapy. Difference in adjusted rwRR6months significantly favored cabozantinib vs other TKIs. These data may inform global jurisdictions that restrict cabozantinib to the post TKI setting. [Table: see text]

Association of pre-treatment bone marrow morphology and achievement of BCR-ABL1 transcript milestones in CML

Chronic myeloid leukemia (CML) is characterized by the fusion gene BCR-ABL1 which encodes aberrantly functioning tyrosine kinase. Treatment with tyrosine kinase inhibitors (TKI) is a landmark of CML management and the main goal is to achieve major molecular response (MMR) which is defined as BCR-ABL1IS ≤ 0.1 % at 12 months of therapy. The aim of this study is to analyze histologic features of bone marrow (BM) in CML patients at the time of diagnosis and compare it to the level of BCR-ABL1IS transcript at 3 (BCR-ABL1IS ≤10 % early molecular response; EMR) and 12 months (MMR) as well as to so called molecularly undetectable leukemia (MUL) to see weather bone marrow morphology can be of value in predicting achievement molecular response milestones. Thirty-two bone marrow biopsies of CML patients, prior TKI therapy, were re-evaluated and CD34 immunohistochemistry was performed to examine microvessel density (MVD) and microvessel area (MVA) and subsequently compared it to the level of BCR-ABL1IS transcript. This study showed statistically significant association between BM hypercellularity and EMR (p = 0.048) and MUL (p = 0.034), peri-trabecular adipocyte distribution and EMR and MUL (p = 0.027 and p = 0.011, respectively), MMR and bone marrow fibrosis (p = 0.029), loose megakaryocyte clustering and EMR and MUL (p = 0.004 and p = 0.018, respectively), absence of naked nuclei and MUL (p = 0.033) but there was no statistically significant association with vascular parameters. These results suggest that some bone marrow morphologic features prior TKI therapy might be indicators of favorable molecular response.

Abstract CT257: First-in-human phase 1 studies of PTPN2/1 inhibitors ABBV-CLS-484 and ABBV-CLS-579 in locally advanced or metastatic tumors

Abstract Background: Protein tyrosine phosphatase non-receptor type 2 and type 1 (PTPN2/1) antagonists inhibit PTPN2/1-mediated negative regulation of immune response pathways. They may promote antitumor activity by increasing function of immune cells such as T cells and dendritic cells, inducing cytokine production, increasing antigen presentation, and amplifying interferon gamma-mediated tumor growth arrest. ABBV-CLS-484 and ABBV-CLS-579 are potent, orally bioavailable, first-in-class PTPN2/1 inhibitors that showed promising antitumor activity and were well tolerated in preclinical models. Preclinical data also indicated that PTPN2/1 inhibitors have improved efficacy when combined with PD-1-targeting agents (eg, pembrolizumab) or vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) in multiple tumor models. Here, we describe 2 first-in-human trials of ABBV-CLS-484 or ABBV-CLS-579 as monotherapy and in combination with pembrolizumab or VEGFR TKI in patients with locally advanced/metastatic tumors. Methods: These phase 1, open-label, multicenter, non-randomized trials (ABBV-CLS-484: NCT04777994; ABBV-CLS-579: NCT04417465) comprise dose-escalation (ESC) and dose-expansion (EXP) phases. ESC is guided by a Bayesian optimal interval design based on dose-limiting toxicities. ESC data are used to inform evaluation of EXP cohorts in select tumor types including relapsed/refractory (R/R) head and neck squamous cell carcinoma, R/R non-small cell lung cancer, advanced renal cell carcinoma, and microsatellite instability-high tumors. In both ESC and EXP phases, the study drug (ABBV-CLS-484 or ABBV-CLS-579) is administered orally either alone or in combination with pembrolizumab (200 mg intravenously once every 3 weeks) and is slated to also be administered in combination with a VEGFR TKI. Eligible patients have locally advanced/metastatic tumors for which no effective standard therapy exists (or has failed), and Eastern Cooperative Oncology Group performance status ≤2. Patients (≥18 years) must have received ≥1 prior systemic anticancer therapy for the indication being considered, have relapsed or be refractory to ≥1 prior anti-PD-1/PD-L1 therapy (EXP monotherapy and pembrolizumab combination), or have relapsed after ≤1 (ABBV-CLS-484) or ≥1 (ABBV-CLS-579) prior VEGFR TKI therapy (EXP VEGFR TKI combination). Primary objectives are to assess safety, tolerability, pharmacokinetics, and to determine the recommended expansion dose and/or maximum tolerated dose of ABBV-CLS-484 or ABBV-CLS-579, both as monotherapy and in combination. Evaluation of objective response rate (RECIST v1.1) is a primary objective in EXP phase and a secondary objective in ESC phase. Both studies are active, and as of 30 Nov 2022, 30 (ABBV-CLS-484) and 45 (ABBV-CLS-579) patients had been enrolled in ESC phase. Citation Format: Patricia M. LoRusso, Emiliano Calvo Aller, Noboru Yamamoto, Chia-Chi Lin, Thaddeus Beck, David Sommerhalder, Do-Youn Oh, John D. Powderly, Talia Golan, Linu Sara Abraham, Joel S. Hayflick, Tamar Uziel, Priya Brunsdon, Wijith Munasinghe, Marcia Paddock, Cathleen Brdlik Hartman, Jonathan Powell, Bruno Medeiros, Martha R. Neagu, Benedito A. Carneiro. First-in-human phase 1 studies of PTPN2/1 inhibitors ABBV-CLS-484 and ABBV-CLS-579 in locally advanced or metastatic tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT257.

Selected Articles from This Issue

Highlights| April 03 2023 Selected Articles from This Issue Author & Article Information Online ISSN: 1557-3265 Print ISSN: 1078-0432 ©2023 American Association for Cancer Research2023American Association for Cancer Research Clin Cancer Res (2023) 29 (7): 1161. https://doi.org/10.1158/1078-0432.CCR-29-7-HI Related Content A commentary has been published: Liquid Biopsy of Cerebrospinal Fluid Enables Selective Profiling of Glioma Molecular Subtypes at First Clinical Presentation A commentary has been published: Randomized Phase II Trial of Sunitinib or Cediranib in Alveolar Soft Part Sarcoma A commentary has been published: Targeting MDSC Differentiation Using ATRA: A Phase I/II Clinical Trial Combining Pembrolizumab and All-Trans Retinoic Acid for Metastatic Melanoma View more A commentary has been published: Application of Genomic Sequencing to Refine Patient Stratification for Adjuvant Therapy in Renal Cell Carcinoma View less Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Tools Icon Tools Get Permissions Cite Icon Cite Search Site Article Versions Icon Versions Version of Record April 3 2023 Citation Selected Articles from This Issue. Clin Cancer Res 1 April 2023; 29 (7): 1161. https://doi.org/10.1158/1078-0432.CCR-29-7-HI Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest Search Advanced Search Alveolar soft part sarcoma (ASPS) is a rare, highly vascular tumor with few treatment options. Prior research suggested treatment with a tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFRs) could benefit ASPS patients. Nguyen and colleagues conducted a randomized clinical trial of potent VEGFR TKIs cediranib and sunitinib in aggressive ASPS. The drugs were well tolerated, and the overall response rate was 6.7% and 7.1% for cediranib and sunitinib, respectively. Most patients had a best response of stable disease (86.7% and 78.6% for cediranib and sunitinib, respectively). The selection of patients with aggressive disease that progressed in the 6 months preceding enrollment may account for the lower objective response rates compared to previous reports. This data indicates that prior TKI therapy does not preclude clinical benefit from subsequent TKI treatments, suggesting that sequential TKI therapy may benefit patients with ASPS. Myeloid-derived suppressor cells (MDSCs) limit the efficacy... You do not currently have access to this content.

Safety and clinical activity of atezolizumab plus erlotinib in patients with non-small-cell lung cancer

Acquired resistance limits long-term epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) efficacy in patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC) in whom anti-programmed death-ligand 1 (PD-L1) efficacy is also limited. We hypothesized that combining atezolizumab with erlotinib could enhance antitumor immunity and extend efficacy in these patients. This open-label phase Ib trial was conducted in adults aged ≥18 years who had advanced, unresectable NSCLC. Stage 1 (safety evaluation) enrolled EGFR TKI-naive patients regardless of EGFR status. Stage 2 (expansion) enrolled patients with EGFR-mutant NSCLC treated with ≤1 prior non-EGFR TKI therapy. Patients received 150 mg erlotinib orally once daily. After a 7-day erlotinib run-in, atezolizumab 1200 mg was administered intravenously every 3 weeks. The primary endpoint was the safety and tolerability of the combination in all patients; secondary endpoints included antitumor activity per RECIST 1.1 in stage 2 patients. At the data cut-off on 7 May 2020, 28 patients (8 in stage 1, 20 in stage 2) were assessable for safety. No dose-limiting toxicities or grade 4 or 5 treatment-related adverse events occurred. Grade 3 treatment-related adverse events occurred in 46% of patients; the most common were increased alanine aminotransferase, diarrhea, pyrexia, and rash (each in 7% of patients). Serious adverse events occurred in 50% of patients. Pneumonitis (grade 1) was reported in a single patient (4%). The objective response rate was 75% [95% confidence interval (CI) 50.9% to 91.3%]), median response duration was 18.9 months (95% CI 9.5-40.5 months), median progression-free survival was 15.4 months (95% CI 8.4-39.0 months), and median overall survival was not estimable (NE) (95% CI 34.6-NE). Atezolizumab combined with erlotinib demonstrated a tolerable safety profile and encouraging, durable clinical activity in patients with advanced EGFR mutation-positive NSCLC.

Predicting survival of NSCLC patients treated with immune checkpoint inhibitors: Impact and timing of immune-related adverse events and prior tyrosine kinase inhibitor therapy.

Immune checkpoint inhibitors (ICIs) produce a broad spectrum of immune-related adverse events (irAEs) affecting various organ systems. While ICIs are established as a therapeutic option in non-small cell lung cancer (NSCLC) treatment, most patients receiving ICI relapse. Additionally, the role of ICIs on survival in patients receiving prior targeted tyrosine kinase inhibitor (TKI) therapy has not been well-defined. To investigate the impact of irAEs, the relative time of occurrence, and prior TKI therapy to predict clinical outcomes in NSCLC patients treated with ICIs. A single center retrospective cohort study identified 354 adult patients with NSCLC receiving ICI therapy between 2014 and 2018. Survival analysis utilized overall survival (OS) and real-world progression free survival (rwPFS) outcomes. Model performance matrices for predicting 1-year OS and 6-month rwPFS using linear regression baseline, optimal, and machine learning modeling approaches. Patients experiencing an irAE were found to have a significantly longer OS and rwPFS compared to patients who did not (median OS 25.1 vs. 11.1 months; hazard ratio [HR] 0.51, confidence interval [CI] 0.39- 0.68, P-value <0.001, median rwPFS 5.7 months vs. 2.3; HR 0.52, CI 0.41- 0.66, P-value <0.001, respectively). Patients who received TKI therapy before initiation of ICI experienced significantly shorter OS than patients without prior TKI therapy (median OS 7.6 months vs. 18.5 months; P-value < 0.01). After adjusting for other variables, irAEs and prior TKI therapy significantly impacted OS and rwPFS. Lastly, the performances of models implementing logistic regression and machine learning approaches were comparable in predicting 1-year OS and 6-month rwPFS. The occurrence of irAEs, the timing of the events, and prior TKI therapy were significant predictors of survival in NSCLC patients on ICI therapy. Therefore, our study supports future prospective studies to investigate the impact of irAEs, and sequence of therapy on the survival of NSCLC patients taking ICIs.

The Role of Bosutinib in Chronic Myeloid Leukemia: An Indian Perspective

AbstractManagement of chronic myeloid leukemia (CML) has been transformed by the use of tyrosine kinase inhibitors (TKIs). Presently in India, five TKIs are approved for the management of CML with distinct safety profiles. The selection of TKIs for chronic phase (CP)-CML patients is based on treatment goals, underlying comorbidities, and specific TKI toxicity profiles. Bosutinib is one of five TKIs indicated for the first-line treatment of CP-CML and patients with intolerance or resistance to prior TKI therapy. It possesses a distinct safety profile among other TKIs, with less cardiovascular adverse events (AEs), albeit the liver-related and gastrointestinal AEs have higher occurrence. The safety and efficacy of bosutinib have been examined in clinical trials; however, there is a paucity of data from Asia. A virtual expert panel meeting was convened to gather expert opinion from India on the selection of bosutinib as a treatment choice for patients with CP-CML. This is a white paper document drafted with the help of an expert panel of 14 oncologists and hematooncologists from India on bosutinib use in CP-CML. The experts concurred that bosutinib has proven efficacy for CP-CML in global randomized clinical trials and is well suited for CP-CML patients with existing cardiovascular comorbidities. However, it was not recommended for patients with gastrointestinal, pancreatic, or renal abnormalities. This review aims to put forth expert opinion and guidance document on key considerations for CP-CML clinical decision-making in India.

Outcome of Third-Line Tyrosine Kinase Inhibitors in Patients with Chronic Myeloid Leukemia in Chronic Phase: A Propensity Score Analysis

Background: Tyrosine Kinase Inhibitors (TKI) dramatically improve survival in patients with chronic myeloid leukemia in chronic phase (CML-CP). However, patients may develop intolerance of or resistance to TKI therapy over years. Given multiple effective therapies available, the optimal selection of third-line therapy is not clear. The aim of this study is to evaluate the outcomes of third-line TKI therapy in patients with CML-CP. Methods: We retrospectively combined patient-level data of third-line TKI therapy in the clinical trials of PACE and OPTIC studies with patients who received third-line TKI therapy at our institution. Given equivalent outcomes between second-generation TKIs (2G-TKI), we compared the outcomes of patients between 2G-TKI and ponatinib as third-line TKI therapy. Patients with T315I mutations were excluded in our study given the known resistance to all the 2G-TKI therapies. Multiple imputations was performed for missing covariates to reduce bias. Univariate and multivariate Cox regression analysis was performed for survival to identify prognostic factors with a p-value cutoff of 0.05 from univariate to multivariate analysis. One-to-one propensity score matching was performed with a caliper of 0.200, using matching covariates with age at the time of third-line therapy, gender, race, comorbidity, prior TKI therapy, the duration of prior TKI therapy, best prior response during the front-line and second-line TKI therapy, body mass index, white blood cell count, platelet count, percentages of basophils and blasts in peripheral blood, and BCR::ABL1 levels on the international scale. Progression-free survival (PFS) was defined from the start of third-line TKI therapy to the time of loss of major cytogenetic response during the study, progression to accelerated phase or blast phase at any time, death from any cause at any time, or the date of last follow-up; overall survival (OS) was defined as the start of third-line TKI therapy to death from any cause or the date of last follow-up. The Kaplan-Meier method was used for survival with the log-rank test and a significance p-value level of 0.05. Results: We identified 354 patients who received third-line TKI therapy [204 patients (58%) from our institution; 63 patients (18%) from the PACE study; 87 (25%) patients from the OPTIC study] with a median follow-up of 46 months (Table 1). Among them as third-line TKI therapy, 173 patients received 2G-TKI [69 patients (19%), dasatinib; 64 patients (18%), nilotinib; 40 patients (11%), bosutinib], and 181 patients received ponatinib (51%). Overall, the median age at the time of third-line TKI therapy was 54 years (range, 18-87). Prior to third-line TKI therapy, 313 patients (88%) received imatinib; 156 patients (44%), dasatinib; 161 patients (45%), nilotinib; 35 patients (10%), bosutinib. The overall median BCR::ABL1 level was 16.3% on the international scale at the time of third-line TKI therapy. Patients who received ponatinib had higher rates of non-ischemic cardiovascular comorbidity, shorter total duration of prior TKI therapies, higher percentage of basophiles in peripheral blood, and higher levels of BCR::ABL1 on the international scale. Propensity score matching minimized the baseline covariates and identified 96 patients at each group with a median follow-up of 46 months after propensity score matching. There is a tendency of deeper response with ponatinib at baseline BCR::ABL1 levels of >1-10% and >0.1-1% before and after propensity score matching. Using pre-matched data, multivariate Cox regression showed older age at the time of third-line TKI therapy and higher BCR::ABL1 levels as adverse prognostic factors for survival ; the third-line ponatinib therapy was associated with favorable survival [P=0.003; hazard ratio (HR), 0.435; 95% confidence internal (CI), 0.253-0.748]. The 4-year PFS rates were 58% and 75% in the 2G-TKI and ponatinib group, respectively, before matching (P<0.001); the 4-year PFS rates were 78% and 89%, respectively, after matching (P=0.0099). The 4-year OS rates were 57% and 80% in the 2G-TKI and ponatinib group, respectively, before matching; the 4-year OS rates were 78% and 87%, respectively, after matching (Figure 1). Conclusion: Third-line ponatinib therapy is optimal selection for patients with CML-CP who failed prior 2 TKI therapies in the absence of T315I mutation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Preliminary Safety and Efficacy from Apex, a Phase 2 Study of Bezuclastinib (CGT9486), a Novel, Highly Selective, Potent KIT D816V Tyrosine Kinase Inhibitor, in Adults with Advanced Systemic Mastocytosis (AdvSM)

Background: Systemic mastocytosis (SM) is a rare disease characterized by the proliferation of mast cells (MC). In about 95% of adult patients, SM is driven by a gain-of-function mutation (D816V) in exon 17 of the KIT gene. Advanced SM (AdvSM) is an aggressive, life-threatening form of SM and includes three subtypes; aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN), and MC leukemia (MCL). Bezuclastinib is an oral, highly selective, and potent tyrosine kinase inhibitor (TKI) with specificity for mutations in KIT exons 9, 11, 17, and 18, including D816V, while sparing closely related kinases (e.g., PDGFRα, PDGFRβ, and CSF1R). Results from a phase 1/2 study in patients with advanced solid tumors coupled with preclinical data have led to the on-going evaluation of bezuclastinib in patients with AdvSM, the Apex study (NCT04996875). The primary objective of this study is to evaluate the safety, efficacy, pharmacokinetic (PK), and pharmacodynamic (PD) profile of bezuclastinib in all AdvSM subtypes. Methods: Apex is a Phase 2, open-label, 2-part, multicenter study in adult patients with AdvSM per WHO diagnostic criteria, who have measurable SM-related organ damage according to modified IWG-MRT-ECNM consensus eligibility and response criteria (mIWG), and have a baseline serum tryptase of ≥20 ng/mL. Patients with a history of prior TKI therapy (e.g., avapritinib, midostaurin) are permitted in the study. In Part 1, patients are randomized 1:1:1:1 to bezuclastinib 50, 100, or 200 mg BID, or 400 mg QD. Data from Part 1 will inform dose selection for Part 2. The primary efficacy endpoint for this study is overall response rate (complete response [CR], CR with incomplete hematologic recovery [CRh], partial response [PR] and clinical improvement [CI]) as assessed by a Central Response Review Committee and based on mIWG response criteria. Results: As of May 24, 2022, 11 mIWG evaluable patients with AdvSM (ASM: n=2, SM-AHN: n=8, and MCL: n=1) were randomized in Part 1 to 50mg BID (n=3), 100mg BID (n=3), 200mg BID (n=3), and 400mg QD (n=2). The majority of patients were male (82%) and treatment naïve (82%) with ECOG PS 0-1 (82%) and positive for KIT D816V (91%). Median (range) BM MC burden and serum tryptase at baseline were 30% (7-80%) and 182 ng/mL (68-1578 ng/mL), respectively. Bezuclastinib was well-tolerated across all dose levels. Treatment Emergent Adverse Events (TEAEs) reported in >1 patient included anemia (n=3), neutropenia (n=2), and thrombocytopenia (n=2), a majority of which were low-grade. One serious AE of hypersensitivity (mediator flare) was reported. Two patients had an AE-related dose reduction with one patient subsequently re-escalating to the randomized dose. Preliminary clinical activity data showed that all 11 patients experienced a >50% reduction in serum tryptase from baseline, 10/11 (91%) within the first week of treatment; 6 (55%) patients achieved a serum tryptase level <20 ng/mL, 4/6 within the first cycle of treatment. Among patients with available data after ≥2 cycles of treatment, all 8 achieved a median reduction of 68% in KIT D816V variant allele fraction (VAF) and ≥50% reduction in BM MC, with 6/8 (75%) achieving complete clearance of MC aggregates. There were no reported instances of cognitive effects or intracranial bleeding. Conclusion: Early data suggest that bezuclastinib is well-tolerated and is associated with encouraging early signs of clinical activity as demonstrated by meaningful reductions in serum tryptase, MC burden, and KIT D816V VAF. Enrollment is currently ongoing. Updated safety and clinical activity as well as initial clinical objective response data will be presented.

CML-423 Trial in Progress: A Phase III Study of Asciminib vs an Investigator-Selected Tyrosine Kinase Inhibitor (TKI) in Patients With Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Four TKIs are approved for first-line (1L) use in CML-CP: the first-generation TKI imatinib and the second-generation (2G) TKIs bosutinib, dasatinib, and nilotinib. However, in 1L CML-CP, >50% of patients treated with imatinib develop resistance/intolerance to therapy, and 30%-40% of patients treated with a 2G TKI need to change therapy by 5 years. While 2G TKIs yield a higher major molecular response (MMR) than imatinib, they are associated with more adverse events (AEs). Asciminib is a recently approved BCR::ABL1 inhibitor that targets the ABL1 myristoyl pocket. In the phase III ASCEMBL trial in patients with CML-CP treated with ≥2 prior TKIs, asciminib resulted in improved MMR (25.5% vs 13.2%) at week 24 and fewer treatment discontinuations due to AEs (5.8% vs 21.1%) vs bosutinib. We present a phase III trial evaluating asciminib vs an investigator-selected approved TKI in 1L CML-CP. As of March 28, 2022, 69 patients were randomized and receiving treatment. To assess the efficacy of asciminib vs investigator-selected TKI and asciminib vs imatinib within the stratum of patients who selected imatinib as the prerandomization TKI, via the primary endpoint of MMR at week 48. The study will be positive if either of these objectives is met. This is a multicenter, open-label, randomized, phase III study (NCT04971226). Newly diagnosed adults with CML-CP who have not received prior TKI therapy for CML, except for ≤2 weeks of imatinib, bosutinib, dasatinib, or nilotinib therapy, are eligible. Prior to randomization, patients and investigators will select a prerandomization TKI; 50% of patients who select imatinib and 50% who select a 2G TKI as their prerandomization TKI will be randomized to the investigator-selected TKI arm; the remaining 50% from each group will be randomized to receive asciminib. End of Study (EOS) is 5 years from the last patient first treatment. Asciminib 80mg once daily (QD), or an investigator-selected TKI (imatinib, bosutinib, dasatinib, or nilotinib at their approved doses) until EOS or premature discontinuation. MMR at week 48 is the primary endpoint, with MMR at week 96, safety, and deep molecular responses as secondary endpoints.

Gilteritinib monotherapy for relapsed/refractory FLT3 mutated acute myeloid leukemia: a real-world, multi-center, matched analysis.

Patients with FLT3-mutated relapsed or refractory (R/R) acute myeloid leukemia (AML) have a dismal prognosis. Gilteritinib is a FLT3 tyrosine kinase inhibitor (TKI) recently approved for patients with R/R AML. We aimed to characterize real-world data regarding gilteritinib treatment in FLT3-mutated R/R AML and to compare outcomes with matched FLT3-mutated R/R AML patients treated with chemotherapy-based salvage regimens. Twenty-five patients from six academic centers were treated with gilteritinib for FLT3-mutated R/R AML. Eighty percent were treated with a prior intensive induction regimen and 40% of them received prior TKI therapy. Twelve patients (48%) achieved complete response (CR) with gilteritinib. The estimated median overall survival (OS) of the entire cohort was eight (CI 95% 0-16.2) months and was significantly higher in patients who achieved CR compared to those who did not (16.3months, CI 95% 0-36.2 vs. 2.6months, CI 95% 1.47-3.7; p value = 0.046). In a multivariate cox regression analysis, achievement of CR was the only predictor for longer OS (HR 0.33 95% CI 0.11-0.97, p = 0.044). Prior TKI exposure did not affect OS but was associated with better event-free survival (HR 0.15 95% CI 0.03-0.71, p = 0.016). An age and ELN-risk matched comparison between patients treated with gilteritinib and intensive salvage revealed similar response rates (50% in both groups); median OS was 9.6months (CI 95% 2.3-16.8) vs. 7months (CI 95% 5.1-8.9) in gilteritinib and matched controls, respectively (p = 0.869). In conclusion, in the real-world setting, gilteritinib is effective, including in heavily pre-treated, TKI exposed patients.