Selective Tyrosine Kinase Inhibitor Research Articles

Abstract P4-01-10: Evaluating the safety of tucatinib in combination with trastuzumab and capecitabine for human epidermal growth factor 2 (HER2)-positive metastatic breast cancer in a real-world setting

Abstract Background: Tucatinib, a highly selective tyrosine kinase inhibitor (TKI) for human epidermal growth factor 2 (HER2) receptor, received FDA approval in combination with trastuzumab and capecitabine for metastatic HER2-positive breast cancer based on the HER2CLIMB trial. While the efficacy data is promising, the tucatinib-containing triplet regimen is associated with significant toxicity and many drug-drug interactions (DDIs). The toxicity profile of tucatinib in regards to adverse events (AEs) and DDIs has not been reported outside of the HER2CLIMB trial. Additionally, with the development of many new HER2 targeted therapies including antibody-drug conjugates (ADCs) such as trastuzumab deruxtecan, efficacy in regards to therapy sequence is still unknown. Here, we describe the safety and efficacy of tucatinib in a real-world setting. Methods: This single-center, retrospective, cohort study included patients (pts) with a diagnosis of HER2- positive locally advanced or metastatic breast cancer pts that were newly initiated on tucatinib therapy at the Duke Breast Oncology Clinic following FDA approval from April 17, 2020 to June 9, 2021. Pts were evaluated for the pre-specified outcomes for the duration of tucatinib therapy, until progression of disease, or for at least 6 months follow-up. AEs reviewed included palmar-plantar erythrodysesthesia syndrome (PPE), diarrhea, fatigue, rash, anemia, thrombocytopenia, neutropenia, nausea, vomiting, mucositis, hepatotoxicity, and nephrotoxicity, defined according to the Common Terminology Criteria for Adverse Events (CTCAE) grading criteria. Overall response was categorized as complete response, partial response, stable disease, or progressive disease, defined according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, at first staging after therapy initiation. The overall response rate was stratified by prior standard therapies, pts who did not receive capecitabine therapy with tucatinib, and the presence or absence of brain metastases. Results: A total of 23 pts (N=23) were included in the cohort, 52% of which had brain metastases and 9% with leptomeningeal disease. Pts had a median of 3 prior lines of therapy in the metastatic setting including: lapatinib (9%), neratinib (30%), trastuzumab deruxtecan (13%), trastuzumab emtansine (74%). All pts experienced AEs, most of which were mild or moderate severity. The most common AEs reported were fatigue (70%), PPE (61%), nausea (61%), and anemia (61%). Severe AEs occurred in 6 pts (26%) with grade 3 or 4 hepatotoxicity in 13%. Only 2 pts discontinued therapy due to AEs (grade 4 hepatoxicity, grade 2 fatigue). Due to capecitabine intolerance, 13% received tucatinib and trastuzumab doublet therapy. There were 9 pts (39%) that experienced a DDI with tucatinib requiring therapy modification or close monitoring. At first staging, partial response was seen in 26% while 35% demonstrated stable disease and 30% progressive disease. Pts with previous neratinib therapy demonstrated a partial response of 14% and a stable disease response of 29%. No pts with previous trastuzumab deruxtecan or omission of capecitabine therapy experienced a partial or stable disease response. Conclusions: The rate of AEs were similar in a real-world setting compared to the HER2CLIMB trial with a lower rate of severe adverse events, however, a higher rate of hepatotoxicity. Given the high rate of drug interactions identified with tucatinib, concurrent medications should be reviewed for appropriate therapy adjustments and monitoring. Additional data is needed in regards to sequencing and impact on therapy efficacy. Citation Format: Heather Moore, Carey Anders, Sarah L. Sammons, Alaattin Erkanli, Alice Parish, Christina DiCola. Evaluating the safety of tucatinib in combination with trastuzumab and capecitabine for human epidermal growth factor 2 (HER2)-positive metastatic breast cancer in a real-world setting [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-10.

Dasatinib, a selective tyrosine kinase inhibitor, prevents joint destruction in rheumatoid arthritis animal model.

We aimed to evaluate the preventive role of the tyrosine kinase inhibitor dasatinib in an animal model of rheumatoid arthritis (RA). DBA/1J mice were injected with bovine type II collagen to induce arthritis (collagen-induced arthritis [CIA]). There were four experimental groups of mice, namely negative control (non-CIA), vehicle-treated CIA, dasatinib-pretreated CIA, and dasatinib-treated CIA. After collagen immunization, arthritis progression in the mice was clinically scored twice weekly for 5 weeks. Flow cytometry was used to evaluate in vitro CD4+ T-cell differentiation and ex vivo mast cell/CD4+ T-cell differentiation. Osteoclast formation was evaluated using tartrate-resistant acid phosphatase (TRAP) staining and by estimating the resorption pit area. We found that the clinical arthritis histological scores were lower in the dasatinib pretreatment group than in the vehicle and dasatinib post-treatment groups. Flow cytometry showed that FcεR1+ cells were downregulated and regulatory T cells were upregulated in splenocytes of the dasatinib pretreatment group compared with those in the vehicle group. Additionally, there was a decline in IL-17+ CD4+ T-cell differentiation and an increase in CD4+ CD24high Foxp3+ T-cell differentiation with in vitro dasatinib treatment of human CD4+ T cells. The number of TRAP+ osteoclasts and the area of the resorption were decreased in the bone marrow cells derived from dasatinib-pretreated mice compared with those derived from vehicle group. Dasatinib protected against arthritis in an animal model of RA by regulating the differentiation of regulatory T cells and IL-17+ CD4+ T cells and inhibiting osteoclastogenesis, indicating the therapeutic potential of dasatinib in the treatment of early RA.

Phase 2 study of the efficacy and safety of erdafitinib in patients (pts) with intermediate-risk non–muscle-invasive bladder cancer (IR-NMIBC) with FGFR3/2 alterations (alt) in THOR-2: Cohort 3 interim analysis.

504 Background: Current treatments (tx) of papillary NMIBC are not selective. Novel tx can be assessed on measurable disease (eg, a marker lesion) to rapidly and directly assess antitumor efficacy. FGFR inhibitor therapy may improve outcomes for pts with IR-NMIBC with FGFR3/2alt. Erdafitinib (erda) is an oral selective pan-FGFR tyrosine kinase inhibitor approved for locally advanced or metastatic urothelial cancer in adults with FGFR3/2alt who have progressed during or following ≥1 line of platinum-containing chemotherapy. THOR-2 (NCT04172675) is a multicohort phase 2 study of erda in pts with NMIBC. We report results in an exploratory cohort of pts with IR-NMIBC with FGFRalt (Cohort 3). Methods: Inclusion: age ≥18 y, with histologically confirmed NMIBC with FGFR3/2alt (local/central testing) and recurrent IR disease, with all previous tumors being low grade (Gr) (Gr 1-2), Ta/T1, no previous carcinoma in situ, risk of progression <5% in the next 2 y, and risk of recurrence >50%. All tumors were removed by transurethral resection of bladder tumor except for a marker lesion (single untouched 5-10 mm lesion). Pts received continuous oral erda 6 mg once daily without uptitration in 28-d cycles. Urine cytology was performed at the time of complete response (CR). Pts with a partial response (PR) or CR ≤3 mos of starting erda continued erda for up to a maximum of 2 y, until progressive disease, intolerable toxicity, withdrawal of consent, investigator decision to discontinue tx, or study closure. Primary exploratory end point: CR rate (CR = disappearance of the marker lesion without any new lesions; if there is a remnant of the marker lesion, no viable tumor should be seen on histopathological examination); key secondary end point: safety. Results: As of the data cutoff (Sep 2022) (median follow-up of 6.2 mos), 10/11 enrolled pts have received erda (enrolled population; median age: 66 y [range 47-77]; 9 Ta, 2 not staged). Pts received erda for a median duration of 2.9 mos (range 1.1-8.4). Efficacy (n=8 evaluable): 6 pts had CR (CR rate, 75.0%; 95% CI, 34.9-96.8%), and 1 had PR. Of 7 pts with CR or PR, median observed duration of response was 2.8 mos. Safety (≥1 dose of erda; n=10): the most common tx-emergent adverse events (TEAEs) were hyperphosphatemia (90.0%; n=9), diarrhea (60.0%; n=6), dry mouth (50.0%; n=5), dry skin (30.0%; n=3), dysgeusia (30.0%; n=3), and constipation (30.0%; n=3). One pt had Gr ≥3 dysuria (10.0%) and 1 (10.0%) had Gr ≥3 tx-related diarrhea. One pt (10.0%) had Gr 1 tx-related central serous chorioretinopathy. No pts had tx-related serious TEAEs or tx-related TEAEs leading to discontinuation. No deaths occurred. Conclusions: Data from Cohort 3 of THOR-2 demonstrate efficacy in adult pts with IR-NMIBC with FGFRalt. Safety data were consistent with the known safety profile of erda. Clinical trial information: NCT04172675 .

Safety and efficacy of the erdafitinib (erda) intravesical delivery system, TAR-210, in patients (pts) with non–muscle-invasive bladder cancer (NMIBC) or muscle-invasive bladder cancer (MIBC) harboring select FGFR mutations or fusions: Phase 1 first-in-human study.

TPS583 Background: Treatment options are limited for pts with NMIBC and MIBC who experience disease recurrence or who are ineligible for or refuse standard of care. Erda, an oral selective pan-FGFR tyrosine kinase inhibitor, is approved in adults with locally advanced or metastatic urothelial cancer with select FGFR3/2 alterations ( alt) who have progressed during or after ≥1 line of platinum-containing chemotherapy. FGFRalt are among the most common oncogenic drivers detected in NMIBC and MIBC, and are more prevalent in NMIBC. TAR-210 is an intravesical drug delivery system designed to provide local, continuous release of erda within the bladder, thus limiting systemic toxicity. This study evaluates the safety, pharmacokinetics (PK), and efficacy of TAR-210 in pts with NMIBC or MIBC with select FGFRalt. Methods: Open-label, multicenter phase 1 study of TAR-210 in pts with recurrent NMIBC or MIBC (NCT05316155). Eligible pts are aged ≥18 yrs with adequate organ function and tumors with select FGFRalt. A flexible molecular eligibility strategy is used to allow for local or central fresh/archival tissue-based FGFR testing by next-generation sequencing (NGS) or PCR, or urine cell-free DNA NGS testing. Four cohorts will be enrolled: pts with recurrent, bacillus Calmette-Guerin (BCG)-experienced papillary-only high-risk (HR) NMIBC (high-grade Ta/T1) refusing or ineligible for radical cystectomy (RC) (Cohort 1) or scheduled for RC (Cohort 2); pts with recurrent, intermediate-risk NMIBC (Ta/T1) with a history of low-grade disease (Cohort 3); pts with cT2-T3a MIBC scheduled for RC refusing or ineligible for neoadjuvant cisplatin (Cohort 4). Pts in Cohorts 1 and 2 will have TURBT with resection of all visible disease prior to dosing, whereas pts in Cohort 3 must have visible disease prior to dosing. The primary end point is safety (adverse events, including dose-limiting toxicity). Secondary end points include PK, recurrence-free survival (Cohorts 1 and 2), complete response (CR) rate and duration of CR (Cohort 3), and pathologic CR rate, pT0 rate, and rate of downstaging to <pT2 (Cohort 4). Dose escalation (Part 1; n≈12, Cohorts 1 and 3 only) will be followed by dose expansion (Part 2; n≈50-80). Cohorts 1 and 3: response assessment will be after a 3-mo dosing cycle; pts with CR may receive ≤3 additional 3-mo dosing cycles if no recurrence, progression, or unacceptable toxicity. Cohorts 2 and 4: response assessment will be at RC after 8 wks of dosing. Follow-up disease surveillance (cystoscopy, urine cytology, imaging) will be every 3 mos to end of Yr 2 and every 6 mos in Yr 3 in Cohorts 1 and 3 and at 3 mos post-RC in Cohorts 2 and 4. Four pts were enrolled since April 2022 (1 in Cohort 1, 3 in Cohort 3); enrollment for Cohorts 2 and 4 is planned soon. Clinical trial information: NCT05316155 .

Phase 2 study of the efficacy and safety of erdafitinib in patients (pts) with bacillus Calmette-Guérin (BCG)-unresponsive, high-risk non–muscle-invasive bladder cancer (HR-NMIBC) with FGFR3/2 alterations (alt) in THOR-2: Cohort 2 interim analysis results.

503 Background: Pts presenting with NMIBC carcinoma in situ (CIS) have a high risk of progression. FGFR inhibition may benefit CIS pts with FGFRalt who are unresponsive to first-line BCG, for whom treatment (tx) options, other than radical cystectomy, are limited. Erdafitinib (erda), an oral selective pan-FGFR tyrosine kinase inhibitor, is approved for locally advanced or metastatic urothelial cancer in adults with FGFR3/2alt who have progressed during or after ≥1 line of platinum-containing chemotherapy. THOR-2 (NCT04172675) is a multicohort phase 2 study of erda in pts with HR-NMIBC. Here we report results from an exploratory cohort of pts with BCG-unresponsive CIS with FGFRalt with or without papillary disease (Cohort 2). Methods: Inclusion criteria: age ≥18 y, with histologically confirmed, BCG-unresponsive HR-NMIBC with FGFR3/2alt (by local/central testing) presenting as CIS, with or without a papillary tumor and who refused or were not eligible for cystectomy. In this cohort, pts received continuous oral erda 6 mg once daily without uptitration in 28-d cycles (dose selected to improve tolerability while maintaining activity to prevent disease recurrence, for this population). Erda was discontinued if no complete response (CR) was observed within 3 mos. Exploratory efficacy end points are CR rates at the Cycle 3 Day 1 (C3D1) disease evaluation and the Cycle 6 Day 1 (C6D1) disease evaluation; safety was a key secondary end point. Results: As of the data cutoff (Sep 2022) (median follow-up of 10 mos), 10 pts have received erda (enrolled population; median age 72 y [range 52-83]; 90% CIS [1 pt with Ta was mis-enrolled]). Pts received erda for a median duration 5.9 mos (range 1.1-17.0). Of 10 enrolled pts, the CR rates at first evaluation (C3D1) and second evaluation (C6D1) were 100% (9/9 evaluable pts) and 75% (6/8 evaluable pts), respectively. The median duration of response was 3.0 mos. The most common tx-emergent adverse events (TEAEs) were dry mouth (60%; n=6), hyperphosphatemia (50%; n=5), dysgeusia (50%; n=5), and diarrhea (50.0%; n=5). 1 pt (10%) had Gr 2 retinal detachment which led to tx discontinuation and 1 pt (10%) had Gr 1 subretinal fluid; both reported as resolved. Gr ≥3 tx-related TEAEs occurred in 3 pts (30%), and included dry mouth, stomatitis, nail disorder, onychomadesis, acute kidney injury, chronic kidney disease, sepsis, and hypotension in 1 pt each. 1 pt (10%) had serious tx-related TEAEs (dry mouth, hypotension, pneumonitis, acute kidney injury, and sepsis), and 1 pt (10%) discontinued tx due to a tx-related TEAE. No tx-related deaths were observed. Conclusions: Data from Cohort 2 of THOR-2 demonstrate efficacy at C3D1 and C6D1 evaluations in pts with HR-NMIBC with FGFRalt. Safety data were consistent with the known safety profile of erda. Clinical trial information: NCT04172675 .

Efficacy of THB001, a Potent and Selective Oral Small Molecule Inhibitor of Wild Type KIT Receptor Tyrosine Kinase, in a Rat Passive Cutaneous Anaphylaxis Model

Mast cells play a central role in the pathophysiology of allergic inflammation. Mast cell activation, migration, proliferation and survival are dependent on KIT (CD117) signaling. THB001 is a potent and selective inhibitor of wild type KIT being studied clinically as a therapy for mast cell driven diseases. The current study correlated target engagement, mast cell depletion and efficacy in an in vivo model of anaphylaxis.

First-in-human Safety, Pharmacokinetics and Pharmacodynamics of THB001: An Orally Available, Potent and Highly Selective Small Molecule Inhibitor of Wild Type KIT Receptor Tyrosine Kinase

Mast cells play a central role in the pathophysiology of allergic diseases. Mast cell activation, proliferation and survival is dependent on KIT (CD117) signaling. THB001 is an inhibitor of wild type KIT being developed as a potential therapy for mast cell driven diseases. A first-in-human study was performed to determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of THB001.

The Role of a Neoadjuvant RET Inhibitor in Medullary Thyroid Cancer

The Role of a Neoadjuvant <i>RET</i> Inhibitor in Medullary Thyroid Cancer

Efficacy and safety of erdafitinib in adults with cholangiocarcinoma (CCA) with prespecified fibroblast growth factor receptor alterations (FGFRalt) in the phase 2 open-label, single-arm RAGNAR trial: Expansion cohort results.

610 Background: Erdafitinib (erda) is an oral selective pan-FGFR tyrosine kinase inhibitor approved to treat locally advanced or metastatic urothelial carcinoma in adults with susceptible FGFR3/2alt who have progressed during or after ≥1 line of platinum-containing chemotherapy . Interim results from the ongoing phase 2 RAGNAR study (NCT04083976) demonstrated tumor agnostic efficacy and safety of erda in adults with advanced solid tumors harboring prespecified FGFRalt after failure of standard therapies (Loriot Y, et al. J Clin Oncol 2022;40(suppl 16):3007). Here we report results from an expansion cohort of the RAGNAR study that enrolled only patients (pts) with CCA. Methods: Adults (aged ≥18 y) with advanced or metastatic CCA with predefined FGFR1-4alt (mutations/fusions [excluding amplifications] based on local/central test) and documented disease progression on ≥1 prior line of systemic therapy received oral erda until disease progression or intolerable toxicity. The primary end point is objective response rate (ORR) by independent review committee (IRC). Secondary end points include duration of response (DOR), disease control rate (DCR), clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), investigator-assessed efficacy end points, and safety. Results: At data cutoff (median follow-up 20.4 mo), 35 pts with CCA received erda (median age 57 y [range 40-74], median 2 prior systemic therapy [range 1-6]); 90.9% had visceral metastasis, and 17.1% responded to last line of therapy. ORR by IRC was 60.0% (95% CI 42.1-76.1). Median time to onset of response was 1.5 mo (range 1.1-8.2). Responses were observed in pts harboring FGFR mutations and fusions and in pts with co-occurring genomic alterations. Median DCR and CBR were 100.0% (95% CI 90.0-100.0) and 71.4% (95% CI 53.7-85.4), respectively. Median DOR, PFS, and OS were 5.6 mo (95% CI 2.8-8.3), 8.4 mo (95% CI 5.5-9.7), and 18.7 mo (95% CI 8.9-not evaluable), respectively. Investigator-assessed efficacy end points were aligned with IRC results. The most common treatment-emergent adverse events (TEAEs) were hyperphosphatemia (82.9%), diarrhea (80.0%), and stomatitis (74.3%). The majority of pts (80.0%) had grade ≥3 TEAEs, the most common being anemia (22.9%), stomatitis (20.0%), and acute kidney injury (11.4%); 42.9% had serious TEAEs; 11.4% discontinued treatment due to TEAEs. No treatment-related deaths were observed. Conclusions: Data from the CCA expansion cohort of the phase 2 RAGNAR study demonstrate robust efficacy of erda in heavily pretreated adults with CCA harboring prespecified FGFR fusions or mutations, irrespective of co-occurring genomic alterations. Safety data were consistent with the known safety profile of erda. Clinical trial information: NCT04083976 .

Development and validation of an LC-MS/MS method for simultaneous determination of SH-1028, an irreversible third-generation EGFR TKI, and two of its metabolites in human plasma: application in clinical pharmacokinetics

SH-1028 is a novel, potent, and highly selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) developed for the treatment of T790M Mutation-positive non-small cell lung cancer (NSCLC). The objective was to develop an LC-MS/MS method for the simultaneous determination of SH-1028 and its metabolites, Imp2 and Imp3, in human plasma. The plasma samples were extracted through protein precipitation with acetonitrile on wet ice conditions. A rapid, sensitive, and specific method was developed and successfully applied to evaluate the pharmacokinetic (PK) properties of SH-1028 in patients with advanced NSCLC following single and multiple doses of SH-1028 (60 mg). After single-dose administration, the C max of SH-1028, Imp2, and Imp3 was 11.2, 50.2, and 7.99 ng/mL, respectively. The mean AUC0–24 h was 138, 602, and 76.7 h*ng/mL, respectively. And the terminal half-life time was 19.9, 14.4, and 26.1 h, respectively. After multiple-dose administration, SH-1028 exhibited a slight accumulation, with a mean accumulation ratio (R AUC) of 2.00. The study assessed the PK properties of SH-1028 following single and multiple doses in patients with advanced NSCLC and would provide meaningful information for the further development of SH-1028.

Orelabrutinib in relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma patients: Multi-center, single-arm, open-label, phase 2 study.

Orelabrutinib is a novel, small molecule, selective irreversible Bruton's tyrosine kinase inhibitor. The aim of this study was to evaluate the efficacy and safety in patients with refractory or relapsed chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). This is single-arm, multi-center, open-label, phase 2 study in 80 eligible Chinese patients, who were treated with monotherapy of orelabrutinib at 150 mg once daily. Overall response rate evaluated by an independent review committee was the primary endpoint, and secondary endpoints include progression-free survival, overall survival, and safety. Independent review committee assessed overall response rate was 92.5% (74/80); complete response 21.3% (17/80), partial response 60.0% (48/80), partial response with lymphocytosis 11.3% (9/80). At a 32.3-month median follow-up, the median progression-free survival had not been achieved, while the 30-month progression-free survival rate and overall survival rates were 70.9% (95% confidence interval [CI], 59.5-79.6) and 81.3% (95% CI, 70.8-88.2), respectively. Orelabrutinib also revealed substantial response in patients with high prognostic risks: overall response rates of patients carrying positive TP53 mutational status or del(17p), del(11q), as well as unmutated immunoglobulin heavy-chain variable region gene were 100%, 94.7%, and 93.9%, respectively. Most adverse events were in low grade, with 86.8% of AEs being Grade 1 or 2. Nearly 67% of patients were still receiving orelabrutinib after almost a 3-year follow-up. In conclusion, Orelabrutinib demonstrated compelling efficacy as well as safety profiles, with a noteworthy number of patients obtaining complete response in refractory or relapsed CLL/SLL.

Downregulation of Stearoyl-CoA Desaturase 1 (SCD-1) Promotes Resistance to Imatinib in Chronic Myeloid Leukemia.

Chronic myeloid leukemia (CML) is a malignant hematopoietic stem cell disease resulting in the fusion of BCR and ABL genes and characterized by the presence of the reciprocal translocation t(9;22)(q34;q11). BCR-ABL, a product of the BCR-ABL fusion gene, is a structurally active tyrosine kinase and plays an important role in CML disease pathogenesis. Imatinib mesylate (IMA) is a strong and selective BCR-ABL tyrosine kinase inhibitor. Although IMA therapy is an effective treatment, patients may develop resistance to IMA therapy over time. This study investigated the possible genetic resistance mechanisms in patients developing resistance to IMA. We did DNA sequencing in order to detect BCR-ABL mutations, which are responsible for IMA resistance. Moreover, we analyzed the mRNA expression levels of genes responsible for apoptosis, such as BCL-2, P53, and other genes (SCD-1, PTEN). In a group of CML patients resistant to IMA, when compared with IMA-sensitive CML patients, a decrease in SCD-1 gene expression levels and an increase in BCL-2 gene expression levels was observed. In this case, the SCD-1 gene was thought to act as a tumor suppressor. The present study aimed to investigate the mechanisms involved in IMA resistance in CML patients and determine new targets that can be beneficial in choosing the effective treatment. Finally, the study suggests that the SCD-1 and BCL-2 genes may be mechanisms responsible for resistance.

Savolitinib for non-small cell lung cancer

Savolitinib is a highly selective MET tyrosine kinase inhibitor. MET is involved in numerous cellular processes such as proliferation, differentiation and the formation of distant metastases. MET amplification and MET overexpression are quite common in many cancers, but MET exon 14 skipping alteration is most common in non-small cell lung cancer (NSCLC). The role of MET signaling as a bypass pathway in the development of acquired resistance to tyrosine kinase inhibitor (TKI) epidermal growth factor receptor (EGFR) therapy in cancer patients with EGFR gene mutation was documented. Potential beneficiaries of savolitinib therapy are patients with NSCLC and initial diagnosis of MET ex 14 skipping mutation. Savolitinib therapy can be effective in NSCLC patients with EGFR-mutant MET with progression during first-line treatment with an EGFR-TKI. Antitumor activity of savolitinib in combination with osimertinib is very promising as first-line therapy of patients with advanced EGFR-mutated NSCLC, initially with MET expression. The safety profile of savolitinib as monotherapy and in combination with osimertinib or gefitinib is so favorable in all available studies that this drug has become a very promising therapeutic option and is being intensively investigated in ongoing clinical trials.

BIBF1120 Protects against Diabetic Retinopathy through Neovascularization-Related Molecules and the MAPK Signaling Pathway.

Diabetic retinopathy (DR) is one of the microvascular complications of diabetes mellitus and a major pathological feature of neovascular DR. These patients potentially experience vision impairment and blindness. Platelet-derived growth factor receptor β (PDGFRβ), fibroblast growth factor receptor 1 (FGFR1), and vascular endothelial growth factor receptor 2 (VEGFR2) are implicated in the DR pathogenesis. Nintedanib (BIBF1120) is an oral selective dual receptor tyrosine kinase (RTK) inhibitor of VEGFR2, FGFR1, and PDGFRβ. In this study, intravitreal injection of BIBF1120 blocked the phosphorylation of VEGFR2, FGFR1, PDGFRβ, and MAPK signaling pathway proteins in a streptozotocin (STZ)-induced diabetic retinopathy mouse model. In in vitro cell experiments, BIBF1120 did not change cellular activity under normal conditions, while it further suppressed the tube formation, migration, and proliferation of high glucose-induced human retinal microvascular endothelial cells (HRMECs). Additionally, BIBF1120 blocked the phosphorylation of p38, JNK, and ERK1/2 in high glucose-treating HRMECs. Our results indicate that the BIBF1120 treatment can be a novel potential drug to protect against DR.

Comparable Outcomes of Pre- Versus Post-Tyrosine Kinase Inhibitor Era Treatment in Chronic Myeloid Leukemia: A Retrospective Cohort Study With Long-term Follow-up

Imatinib, a selective BCR-ABL tyrosine kinase inhibitor (TKI), was introduced after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with chronic myeloid leukemia (CML). However, the long-term effects of allo-HSCT in chronic phase CML patients are mostly unknown. We retrospectively analyzed the outcomes of 204 patients with sibling donors who received peripheral stem cells and underwent allo-HSCT of chronic phase I (CP1) in the pre- and post-TKI era at Shariati Hospital in Tehran, Iran, from 1998 to 2017 and followed up till the end of 2021. The median follow-up time for all patients was 8.7 (SD = 0.54) years. Fifteen-year overall survival (OS), disease-free survival (DFS), graft-versus-host disease-free relapse-free survival (GRFS), relapse, and non-relapse mortality (NRM) incidence were 65.70%, 57.83%, 17.56%, 13.17%, and 28.98%, respectively. Using multivariable analyses, the only risk factor increasing the hazard of death was the time between diagnosis to allo-HSCT greater than 1 year compared to this time less than 1 year by 74% [hazard ratio (HR) = 1.74, P = 0.039]. Also, age is a significant risk factor for DFS (HR = 1.03, P = 0.031). Our findings suggested that allo-HSCT is still an important treatment option for CP1 patients, especially those resistant to TKI treatment. TKI consumption can have a desirable effect on NRM after allo-HSCT for CP1 CML.

Lestaurtinib induces DNA damage that is related to estrogen receptor activation

A number of chemicals in the environment pose a threat to human health. Recent studies indicate estradiol induces DNA damage through the activation of the estrogen receptor alpha (ERα). Given that many environmental chemical compounds act like hormones once they enter the human body, it is possible that they induce DNA damage in the same way as estradiol, which is of great concern to females with the BRCA1 mutation. In this study, we developed an antibody-based high content method measuring γH2AX, a biomarker for DNA damage, to test a subset of 907 chemical compounds in MCF7 cells. The assay was optimized for a 1536 well plate format and had a satisfactory assay performance with Z-factor of 0.67. From the screening, we identified 128 compounds that induce γH2AX expression in the cells. These compounds were further examined for their γH2AX induction in the presence of an ER inhibitor, tamoxifen. After tamoxifen treatment, four compounds induced less γH2AX expression compared to those without tamoxifen treatment, suggesting these compounds induced γH2AX that is related to ERα activation. These four compounds were chosen for further studies to assess their ERα activating capability and c-MYC induction. Only lestaurtinib, a selective tyrosine kinase inhibitor, induced ERα activation, which was confirmed by both ERα beta-lactamase reporter gene assay and molecular docking analysis. Lestaurtinib also increased c-MYC expression, a target gene of ERα signaling, measured by the quantitative PCR method. This data suggests that lestaurtinib acts as a DNA damage inducer that is related to ERα activation.

Experience of using acalabrutinib therapy in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma

Introduction. Thanks to scientific advances and discoveries in the study of tumor cell biology, new effective drugs for the treatment of chronic lymphocytic leukemia/ small lymphocytic lymphoma have emerged. Currently, there are drugs with different application points at the molecular level. One such drug is acalabrutinib, which is a selective second-generation inhibitors of Bruton tyrosine kinase and has a more favorable toxicity profile.Objective. To evaluate the efficacy of acalabrutinib in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma.Materials and methods. Since February 2020 acalabrutinib (100 mg 2 p/day orally) has been administered to 7 patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (mean age 64 years) at the Hematology Research Center. Six patients received acalabrutinib in 1st-line therapy and one patient received acalabrutinib in 2nd-line therapy. The mean comorbidity index (CIRS) of the patients was 10 points (range, 8 to 14). Most patients had at least one of the adverse prognostic factors - IGHV nonmutated gene status, TP53 gene aberration (del17p13 and/or TP53 gene mutation), complex karyotype disorders.Results. All patients achieved partial remission of the disease (overall response 100% in the form of regression of B-symptoms, lymphocytic leukocytosis, splenomegaly) at the control period of treatment with acalabrutinib +12 months. The most frequent adverse events when taking acalabrutinib were the occurrence of headache in the first month of taking the drug, spontaneous subcutaneous hematomas. No hematologic toxicity, infectious complications, or cardiac complications were noted. At a median follow-up of 34 months, no patient showed disease progression.Conclusions. The selective Bruton tyrosine kinase inhibitor acalabrutinib has demonstrated high efficacy in patients with adverse risk factors, good tolerability and minimal toxicity, including in comorbid patients.

Pan-tumor landscape of fibroblast growth factor receptor 1-4 genomic alterations

Selective tyrosine kinase inhibitors targeting fibroblast growth factor receptor (FGFR) 1-4 genomic alterations are in development or have been approved for FGFR-altered cancers (e.g. bladder cancer and advanced intrahepatic cholangiocarcinoma). Understanding FGFR inhibitor-resistance mechanisms is increasingly relevant; we surveyed the pan-tumor landscape of FGFR1-4 genomic alterations [short variants (SVs), gene rearrangements (REs), and copy number alterations (CNAs)], including their association with tumor mutational burden (TMB) and the genomic comutational landscape. Comprehensive genomic profiling of 355 813 solid tumor clinical cases was performed using the FoundationOne and FoundationOne CDx assays (Foundation Medicine, Inc.) to identify genomic alterations in >300 cancer-associated genes and TMB (determined on ≤1.1 megabases of sequenced DNA). FGFR1-4 SVs and REs occurred in 9603/355 813 (2.7%), and CNAs in 15 078/355 813 (4.2%) samples. Mostcommon FGFR alterations for bladder cancer, intrahepatic cholangiocarcinoma, and glioma were FGFR3 SVs (1051/7739, 13.6%), FGFR2 REs (618/6641, 9.3%), and FGFR1 SVs (239/11 550, 2.1%), respectively. We found several, potentially clinically relevant, tumor-specific associations between FGFR1-4 genomic alterations and other genomic markers. FGFR3 SV-altered bladder cancers and FGFR1 SV-altered gliomas were significantly less likely to be TMB-high versus unaltered samples. FGFR3 SVs in bladder cancer significantly co-occurred with TERT and CDKN2A/B alterations; TP53 and RB1 alterations were mutually exclusive. In intrahepatic cholangiocarcinoma, FGFR2 REs significantly co-occurred with BAP1 alterations, whereas KRAS, TP53, IDH1, and ARID1A alterations were mutually exclusive. FGFR1 SVs in gliomas significantly co-occurred with H3-3A and PTPN11 alterations, but were mutually exclusive with TERT, EGFR, TP53, and CDKN2A/B alterations. Overall, our hypothesis-generating findings may help to stratify patients in clinical trials and guide optimal targeted therapy in those with FGFR alterations.

Zanubrutinib in patients with previously treated B-cell malignancies intolerant of previous Bruton tyrosine kinase inhibitors in the USA: a phase 2, open-label, single-arm study

We hypothesised that zanubrutinib, a highly selective next-generation Bruton tyrosine kinase (BTK) inhibitor, would be a safe and active treatment for patients intolerant of ibrutinib, acalabrutinib, or both. We aimed to assess whether zanubrutinib would prolong treatment duration by minimising treatment-related toxicities and discontinuations in patients with previously treated B-cell malignancies. This ongoing, phase 2, multicentre, open-label, single-arm study was done in 20 centres in the USA. Patients aged 18 or older with previously treated B-cell malignancies (chronic lymphocytic leukaemia, small lymphocytic lymphoma, mantle cell lymphoma, Waldenström macroglobulinaemia, or marginal zone lymphoma) who became intolerant of ibrutinib, acalabrutinib, or both, were orally administered zanubrutinib 160 mg twice daily or 320 mg once daily per investigator. The primary endpoint was recurrence and change in severity of ibrutinib or acalabrutinib intolerance events based on investigator-assessed adverse events. Secondary endpoints were investigator-assessed overall response rate; duration of response; disease control rate; and progression-free survival. Analyses included all patients who received any dose of the study drug. This study is registered with ClinicalTrials.gov, NCT04116437. Between Oct 14, 2019, and Sept 8, 2021, 67 patients (36 [54%] men and 31 [46%] women) who were intolerant of ibrutinib (n=57; cohort 1) or of acalabrutinib or acalabrutinib and ibrutinib (n=10; cohort 2) were enrolled. 63 (94%) patients were White, one (2%) had multiple ethnicities, and three (5%) had unreported or unknown ethnicity. Most intolerance events (81 [70%] of 115 for ibrutinib; 15 [83%] of 18 for acalabrutinib) did not recur with zanubrutinib. Of the recurring events, seven (21%) of 34 ibrutinib intolerance events and two (67%) of three acalabrutinib intolerance events recurred at the same severity with zanubrutinib; 27 (79%) ibrutinib intolerance events and one (33%) acalabrutinib intolerance event recurred at a lower severity with zanubrutinib. No events recurred at higher severity. No grade 4 intolerance events recurred. 64 (96%) of 67 patients had one or more adverse events with zanubrutinib; the most common adverse events were contusion (in 15 [22%] of 67 patients), fatigue (14 [21%]), myalgia (ten [15%]), arthralgia (nine [13%]), and diarrhoea (nine [13%]). Atrial fibrillation occurred in three (4%) patients (all grade 2). Eight (12%) of 67 patients had serious adverse events (anaemia, atrial fibrillation, bronchitis, COVID-19, COVID-19 pneumonia, febrile neutropenia, salmonella gastroenteritis, transfusion reaction, trigeminal nerve disorder, and urinary tract infection). No treatment-related deaths occurred. The median follow-up time was 12·0 months (IQR 8·2-15·6). Among the 64 efficacy-evaluable patients, disease control rate was 93·8% (60; 95% CI 84·8-98·3) and overall response rate was 64·1% (41; 95% CI 51·1-75·7). The median duration of response was not reached; the 12-month event-free duration of response rate was 95·0% (95% CI 69·5-99·3). Similarly, median progression-free survival was not reached; 18-month progression-free survival was 83·8% (95% CI 62·6-93·6). Patients intolerant of previous BTK inhibitors have limited treatment options. These results suggest that zanubrutinib, a safe and viable treatment for patients with B-cell malignancies, might fill that unmet need for those who exhibit intolerance to ibrutinib or acalabrutinib. BeiGene.

Pharmacokinetics, Safety, and Efficacy of Acalabrutinib in Chinese Patients with Relapsed/Refractory Mantle Cell Lymphoma and Other B-Cell Malignancies: An Open-Label, Multicenter Phase 1/2 Trial

Background: Acalabrutinib (Acala), a highly selective covalent inhibitor of Bruton tyrosine kinase with minimal off-target activity, is approved by the Food and Drug Administration (FDA) for the treatment of relapsed/refractory (R/R) mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). The pivotal studies that supported Acala's approval were conducted predominantly in Europe and North America, with limited representation from Asian populations. This phase 1/2 study (NCT03932331) assessed the pharmacokinetics (PK), safety, and efficacy of Acala in Chinese patients (pts) with R/R MCL and other advanced B-cell malignancies. Methods: In phase 1, adult pts with R/R B-cell malignancies received a single dose of Acala 100 mg orally (day 1/cycle 0) followed by a 2-day washout period and subsequent treatment with Acala 100 mg orally twice daily in 28-day cycles, until progressive disease (PD) or treatment discontinuation (TD) for any other reason. Blood samples were collected to assess PK characteristics of Acala and its major metabolite, ACP-5862. In phase 2, adult pts with R/R MCL and ECOG status ≤2 received Acala 100 mg orally twice daily in 28-day cycles until PD or TD. Primary efficacy endpoint was overall response rate (ORR) per Lugano classification for non-Hodgkin lymphoma (Cheson 2014) assessed by blinded independent central review (BICR). Secondary endpoints were investigator (INV)-assessed ORR; BICR- and INV-assessed time to response (TTR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs). Results: Patients were enrolled at 14 sites in China from April 29, 2020, to March 2, 2021. In phase 1, 14 pts were screened and 12 received treatment (CLL, n=4; follicular lymphoma, n=4; MCL, n=1; diffuse large B-cell lymphoma, n=1; SLL, n=2). At data cutoff (May 6, 2022), 7 pts were receiving Acala and 5 had TD (PD, n=4; AE, n=1). Acala exhibited time-independent PK and moderate to high variability (parent drug and metabolite), rapid drug absorption, approximately 2-fold higher exposure of metabolite than parent drug, rapid elimination of Acala and ACP-5862, and no significant accumulation of either parent drug or metabolite after multiple dosing (Table 1). In phase 2 (MCL cohort), 45 pts were screened; 34 were enrolled (phase 1, n=1; phase 2, n=33), all received ≥1 dose of Acala, and were included in the safety and efficacy analyses. The MCL cohort was predominantly male (88.2%), median age was 63 y, 73.5% had ECOG status 0, 64.7% had extranodal disease, 35.3% had bone marrow involvement, 5.9% had high simplified MCL International Prognostic Index score, and median number of prior anticancer therapy regimens was 3 (range 1-5). Median duration of treatment was 14.0 mo (range 1.2-23.6). ORR by BICR was 82.4% (95% CI 65.5-93.2); CR rate was 35.3%, median TTR was 1.8 mo (range 1.6-3.7), and estimated 12-mo DOR rate was 62.7% (95% CI 41.5-78.0); median DOR was not reached. INV assessments were generally concordant with BICR assessments for ORR (73.5% [95% CI 55.6-87.1]), CR rate (38.2%), median TTR (1.9 mo; range 1.6-3.7), and estimated 12-mo DOR rate (65.5% [95% CI 42.1-81.3]). Estimated 12-mo PFS rate was 51.5% (95% CI 33.3-67.0) by BICR and 58.3% (95% CI 39.9-72.9) by INV. Estimated 12-mo OS was 84.5% (95% CI 66.6-93.3).Twenty-nine pts (85.3%) reported AEs of any grade; 15 pts (44.1%) had grade ≥3 AEs, most commonly anemia (8.8%, n=3) and decreased neutrophil count (8.8%, n=3) (Table 2). AEs led to treatment discontinuation in 3 pts (8.8%) due to aplastic anemia (n=1), thrombocytopenia (n=1), and gastrointestinal infection (n=1). Six pts (17.6%) had serious AEs. Fatal AEs were reported in 2 pts (aplastic anemia [n=1], multiple organ dysfunction syndrome [n=1]). There were no cases of atrial fibrillation, major hemorrhage, hypertension, second primary malignancies, or tumor lysis syndrome. Conclusions: This is the first study to evaluate Acala PK, safety, and efficacy in a Chinese population with R/R B-cell malignancies. Acala was rapidly absorbed and showed no signs of accumulation after multiple doses. Treatment with Acala provided high response rates in the R/R MCL cohort, with efficacy results similar to those of the pivotal, global ACE-LY-004 study in a predominantly Caucasian population with R/R MCL (Wang M et al. Lancet 2018;391:659-67). Acala had a tolerable safety profile in Chinese pts. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal