Showing papers on "Tyrosine-kinase inhibitor published in 2022"

Ritlecitinib and brepocitinib demonstrate significant improvement in scalp alopecia areata biomarkers

Abstract: Janus kinase (JAK) inhibitors have shown encouraging results in the treatment of alopecia areata (AA), an autoimmune form of hair loss, in small, uncontrolled studies and case reports.We conducted a biopsy substudy during the randomized, double-blind, placebo-controlled first 24 weeks of a phase 2a clinical trial that evaluated the efficacy and safety of ritlecitinib, an inhibitor of JAK3 and the tyrosine kinase expressed in hepatocellular carcinoma (TEC) kinase family, and brepocitinib, an inhibitor of tyrosine kinase 2 (TYK2)/JAK1 in the treatment of AA.Change in biomarkers in lesional scalp biopsy samples between baseline and weeks 12 and 24 was an exploratory end point, and 46 patients participated from the ritlecitinib (n = 18), brepocitinib (n = 16), and placebo (n = 12) groups. Correlations of biomarkers with hair regrowth, measured using the Severity of Alopecia Tool (SALT) score, were also evaluated.NCT02974868.At week 24, both ritlecitinib and brepocitinib demonstrated improvement exceeding 100% in the lesional scalp transcriptome toward a nonlesional profile. At week 12, the improvements in scalp tissue were greater with brepocitinib than ritlecitinib; however, at week 24, the improvements were greater with ritlecitinib.For both ritlecitinib and brepocitinib, improvement in the SALT scores was positively associated with expression of TH1 markers and negatively associated with expression of hair keratins. Larger, long-term clinical trials are warranted.

Analysis of lorlatinib analogs reveals a roadmap for targeting diverse compound resistance mutations in ALK-positive lung cancer

Abstract: Lorlatinib is currently the most advanced, potent and selective anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor for the treatment of ALK-positive non-small cell lung cancer in the clinic; however, diverse compound ALK mutations driving therapy resistance emerge. Here, we determine the spectrum of lorlatinib-resistant compound ALK mutations in patients, following treatment with lorlatinib, the majority of which involve ALK G1202R or I1171N/S/T. We further identify structurally diverse lorlatinib analogs that harbor differential selective profiles against G1202R versus I1171N/S/T compound ALK mutations. Structural analysis revealed increased potency against compound mutations through improved inhibition of either G1202R or I1171N/S/T mutant kinases. Overall, we propose a classification of heterogenous ALK compound mutations enabling the development of distinct therapeutic strategies for precision targeting following sequential tyrosine kinase inhibitors. Hata and colleagues identify lorlatinib analogs that overcome acquired therapy resistance to current ALK inhibitors and show their efficacy in preclinical models of non-small cell lung cancer bearing compound therapy-resistant ALK alterations.

Clinical outcomes in patients with relapsed/refractory FLT3-mutated acute myeloid leukemia treated with gilteritinib who received prior midostaurin or sorafenib

Abstract: The fms-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib is indicated for relapsed or refractory (R/R) FLT3-mutated acute myeloid leukemia (AML), based on its observed superior response and survival outcomes compared with salvage chemotherapy (SC). Frontline use of FLT3 tyrosine kinase inhibitors (TKIs) midostaurin and sorafenib may contribute to cross-resistance to single-agent gilteritinib in the R/R AML setting but has not been well characterized. To clarify the potential clinical impact of prior TKI use, we retrospectively compared clinical outcomes in patients with R/R FLT3-mutated AML in the CHRYSALIS and ADMIRAL trials who received prior midostaurin or sorafenib against those without prior FLT3 TKI exposure. Similarly high rates of composite complete remission (CRc) were observed in patients who received a FLT3 TKI before gilteritinib (CHRYSALIS, 42%; ADMIRAL, 52%) and those without prior FLT3 TKI therapy (CHRYSALIS, 43%; ADMIRAL, 55%). Among patients who received a prior FLT3 TKI in ADMIRAL, a higher CRc rate (52%) and trend toward longer median overall survival was observed in the gilteritinib arm versus the SC arm (CRc = 20%; overall survival, 5.1 months; HR = 0.602; 95% CI: 0.299, 1.210). Remission duration was shorter with prior FLT3 TKI exposure. These findings support gilteritinib for FLT3-mutated R/R AML after prior sorafenib or midostaurin.

The GIST of Advances in Treatment of Advanced Gastrointestinal Stromal Tumor

Abstract: Gastrointestinal stromal tumor (GIST) is the most common malignant neoplasm of mesenchymal origin and a compelling clinical and biologic model for the rational development of molecularly targeted agents. This is because the majority of GISTs are driven by gain-of-function mutations in KIT or PDGFRA receptor tyrosine kinases. Specific GIST mutations circumscribe well-defined molecular subgroups that must be determined during the diagnostic work-up to guide clinical management, including therapeutic decisions. Surgery is the cornerstone treatment in localized disease and can also be clinically relevant in the metastatic setting. The correct combination and sequence of targeted agents and surgical procedures improves outcomes for patients with GIST and should be discussed individually within multidisciplinary expert teams. All currently approved agents for the treatment of GIST are based on orally available tyrosine kinase inhibitors targeting KIT and PDGFRA oncogenic activation. Although first-line imatinib achieves remarkable prolonged disease control, the benefit of subsequent lines of treatment is more modest. Novel therapeutic strategies focus on overcoming the heterogeneity of KIT or PDGFRA secondary mutations and providing more potent inhibition of specific challenging mutations. This article reviews the current understanding and treatment of GIST, with an emphasis on recent advances.

Multi-target tyrosine kinase inhibitor nanoparticle delivery systems for cancer therapy

Abstract: Multi-target Tyrosine Kinase Inhibitors (MTKIs) have drawn substantial attention in tumor therapy. MTKIs could inhibit tumor cell proliferation and induce apoptosis by blocking the activity of tyrosine kinase. However, the toxicity and drug resistance of MTKIs severely restrict their further clinical application. The nano pharmaceutical technology based on MTKIs has attracted ever-increasing attention in recent years. Researchers deliver MTKIs through various types of nanocarriers to overcome drug resistance and improve considerably therapeutic efficiency. This review intends to summarize comprehensive applications of MTKIs nanoparticles in malignant tumor treatment. Firstly, the mechanism and toxicity were introduced. Secondly, various nanocarriers for MTKIs delivery were outlined. Thirdly, the combination treatment schemes and drug resistance reversal strategies were emphasized to improve the outcomes of cancer therapy. Finally, conclusions and perspectives were summarized to guide future research.

Stimulation of Let-7 Maturation by Metformin Improved the Response to Tyrosine Kinase Inhibitor Therapy in an m6A Dependent Manner

Abstract: The molecular mechanism of the tyrosine kinase inhibitor (TKI) resistant lung adenocarcinoma is currently unclear, and the role of methylated adenosine at the N6 position in the resistance of cancer stem cells (CSCs) therapy is unknown. This study identified a novel and effective strategy to enhance TKIs therapy response. We first confirmed the sensitization of Metformin enforcing on Osimertinib treatment and revealed the mature miRNAs signatures of the Osimertinib resistant H1975 and HCC827 cells. Let-7b expression was stimulated when adding Metformin and then increasing the therapy sensitivity by decreasing the stem cell groups expanding. Methyltransferase-like 3 (METTL3) increased the pri-Let-7b, decreased both the pre-Let-7b and mature Let-7b, attenuating the Let-7b controlling of stem cell renewal. The addition of Metformin increased the bindings of DNA methyltransferase-3a/b (DNMT3a/b) to the METTL3 promoter. With the help of the readers of NKAP and HNRNPA2B1, the cluster mediated m6A formation on pri-Let-7b processing increased the mature Let-7b, the key player in suppressing Notch signaling and re-captivating Osimertinib treatment. We revealed that the maturation processing signaling stimulated the methylation regulation of the miRNAs, and may determine the stemness control of the therapy resistance. Our findings may open up future drug development, targeting this pathway for lung cancer patients.

Reviewing Treatment Options for Advanced Renal Cell Carcinoma: Is There Still a Place for Tyrosine Kinase Inhibitor (TKI) Monotherapy?

Abstract: Renal cell carcinoma (RCC) comprises a highly heterogeneous group of kidney tumours built upon distinct genetic- and epigenetic-driven mechanisms and molecular pathways. Therefore, responsiveness to treatment is considerably variable across patients, adding an extra layer of complexity to the already challenging therapeutic decision process. The last decade brought an unprecedented shift in the medical approach to advanced or metastatic RCC; in fact, immunotherapy-based combinations have significantly transformed the therapeutic arsenal and clinical outcomes of these patients. These strategies were quickly adopted by international guidelines committees as the new standards of care. However, this enhanced efficacy comes at the expense of tolerability, with a predictable negative impact on patients' quality of life. Moreover, subgroup and post hoc analyses of the major clinical trials have shown that not all patients benefit equally from these innovative approaches. In this context, a group of experts on kidney cancer met and discussed the state of the art in the field, with a special emphasis on the appropriateness of using monotherapy with an anti-angiogenesis tyrosine kinase inhibitor (TKI) to treat specific subgroups of patients with RCC. This article reviews the main topics that were considered to be pertinent for that discussion and establishes the profile of patients for whom TKI monotherapy remains a sensible frontline option by avoiding overtreatment and an unnecessary exposure to treatment-related toxicity.

Lapatinib as first-line treatment for muscle-invasive urothelial carcinoma in dogs

Abstract: Epidermal growth factor receptors 1 and 2 (EGFR and HER2) are frequently overexpressed in various malignancies. Lapatinib is a dual tyrosine kinase inhibitor that inhibits both EGFR and HER2. Although a phase III trial failed to show the survival benefits of lapatinib treatment after first-line chemotherapy in patients with EGFR/HER2-positive metastatic urothelial carcinoma, the efficacy of lapatinib for untreated urothelial carcinoma is not well defined. Here, we describe the therapeutic efficacy of lapatinib as a first-line treatment in a canine model of muscle-invasive urothelial carcinoma. In this non-randomized clinical trial, we compared 44 dogs with naturally occurring urothelial carcinoma who received lapatinib and piroxicam, with 42 age-, sex-, and tumor stage-matched dogs that received piroxicam alone. Compared to the dogs treated with piroxicam alone, those administered the lapatinib/piroxicam treatment had a greater reduction in the size of the primary tumor and improved survival. Exploratory analyses showed that HER2 overexpression was associated with response and survival in dogs treated with lapatinib. Our study suggests that lapatinib showed encouraging durable response rates, survival, and tolerability, supporting its therapeutic use for untreated advanced urothelial carcinoma in dogs. The use of lapatinib as a first-line treatment may be investigated further in human patients with urothelial carcinoma.

Current treatment strategies and future perspectives for gastrointestinal stromal tumors

Abstract: Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors that originate from the gastrointestinal tract, mostly from the stomach. GISTs are derived from the myenteric interstitial cells of Cajal and are caused by several mutations in the c-kit and platelet-derived growth factor receptor genes. Clinically, GISTs are detected by endoscopic and imaging findings and are diagnosed by immunostaining. Surgery is the first line of treatment, and if the tumor is relatively small, minimally invasive surgery such as laparoscopy is performed. In recent years, neoadjuvant therapy has been administered to patients with GISTs that are suspected of having a large size or infiltration to other organs. Postoperative adjuvant imatinib is the standard therapy for high-risk GISTs. It is important to assess the risk of recurrence after GIST resection. However, the effect of tyrosine kinase inhibitor use will vary by the mutation of c-kit genes and the site of mutation. Furthermore, information regarding gene mutation is indispensable when considering the treatment policy for recurrent GISTs. This article reviews the clinicopathological characteristics of GISTs along with the minimally invasive and multidisciplinary treatment options available for these tumors. The future perspectives for diagnostic and treatment approaches for these tumors have also been discussed.

Real-world circulating tumor DNA analysis depicts resistance mechanism and clonal evolution in ALK inhibitor-treated lung adenocarcinoma patients

Abstract: Sequential treatment with different generations of anaplastic lymphoma kinase (ALK) inhibitors have been widely applied to ALK-positive lung cancer; however, resistance mutations inevitably developed. Further characterization of ALK resistance mutations may provide key guidance to subsequent therapies. Here we explored the emergence of secondary ALK mutations during sequential ALK tyrosine kinase inhibitor (TKI) treatment in a real-world study of Chinese lung adenocarcinoma (ADC) patients.A clinical-genomic database was queried for lung ADC patients with at least one ALK inhibitor treatment and at least one plasma sample collected following ALK inhibitor treatment. Targeted genome profiling was performed with a 139-gene panel in baseline tumor tissue and serial plasma samples of patients.A total of 116 patients met inclusion criteria. ALK G1202R was more common in patients with echinoderm microtubule-associated protein-like 4 (EML4)-ALK v3 fusion, whereas ALK L1196M was more common in v1. TP53 mutant patients were significantly associated with harboring multiple ALK resistance mutations (P = 0.03) and v3+/TP53 mutant patients had the highest rate of multiple ALK resistance mutations. The sequential use of ALK TKI led to an increased incidence of concurrent ALK mutations along the lines of therapies. Alectinib had a lower rate (9%) harboring ALK resistance mutation as first-line ALK TKI compared with crizotinib (36%). ALK compound mutations identified included ALK D1203N/L1196M, ALK G1202R/L1196M, and ALK G1202R/F1174C, which may be lorlatinib resistant. Using paired pretreatment and post-treatment samples, we identified several ALK-independent resistance-related genetic alterations, including PTPRD and CNKN2A/B loss, MYC, MYCN and KRAS amplification, and EGFR19del.Sequential postprogression plasma profiling revealed that increased lines of ALK inhibitors can accelerate the accumulation of ALK resistance mutations and may lead to treatment-refractory compound ALK mutations. The selection for optimal first-line TKI is very important to achieve a more efficacious long-term strategy and prevent the emergence of on-target resistance, which may provide guidance for clinical decision making.

Tumor Drug Concentration and Phosphoproteomic Profiles After Two Weeks of Treatment With Sunitinib in Patients with Newly Diagnosed Glioblastoma

Abstract: Abstract Purpose: Tyrosine kinase inhibitors (TKI) have poor efficacy in patients with glioblastoma (GBM). Here, we studied whether this is predominantly due to restricted blood–brain barrier penetration or more to biological characteristics of GBM. Patients and Methods: Tumor drug concentrations of the TKI sunitinib after 2 weeks of preoperative treatment was determined in 5 patients with GBM and compared with its in vitro inhibitory concentration (IC50) in GBM cell lines. In addition, phosphotyrosine (pTyr)-directed mass spectrometry (MS)-based proteomics was performed to evaluate sunitinib-treated versus control GBM tumors. Results: The median tumor sunitinib concentration of 1.9 μmol/L (range 1.0–3.4) was 10-fold higher than in concurrent plasma, but three times lower than sunitinib IC50s in GBM cell lines (median 5.4 μmol/L, 3.0–8.5; P = 0.01). pTyr-phosphoproteomic profiles of tumor samples from 4 sunitinib-treated versus 7 control patients revealed 108 significantly up- and 23 downregulated (P < 0.05) phosphopeptides for sunitinib treatment, resulting in an EGFR-centered signaling network. Outlier analysis of kinase activities as a potential strategy to identify drug targets in individual tumors identified nine kinases, including MAPK10 and INSR/IGF1R. Conclusions: Achieved tumor sunitinib concentrations in patients with GBM are higher than in plasma, but lower than reported for other tumor types and insufficient to significantly inhibit tumor cell growth in vitro. Therefore, alternative TKI dosing to increase intratumoral sunitinib concentrations might improve clinical benefit for patients with GBM. In parallel, a complex profile of kinase activity in GBM was found, supporting the potential of (phospho)proteomic analysis for the identification of targets for (combination) treatment.

Combining immune checkpoint inhibition plus tyrosine kinase inhibition as first and subsequent treatments for metastatic renal cell carcinoma

Abstract: Immune checkpoint inhibitor/tyrosine kinase inhibitor (ICI/TKI) combinations are a new standard of care for the initial treatment of metastatic renal cell carcinoma (mRCC). Their efficacy and toxicity beyond the first‐line setting remain poorly defined.

Chronic myeloid leukaemia patients at diagnosis and resistant to tyrosine kinase inhibitor therapy display exhausted T‐cell phenotype

Abstract: The search for novel targets in chronic myeloid leukaemia (CML) is ongoing, to improve treatment efficacy in refractory disease and increase eligibility for tyrosine kinase inhibitor (TKI) discontinuation. Increased frequency of Tregs and effector Tregs was evident at diagnosis, together with increased expression of T‐cell exhaustion markers, including in regulatory T cells at diagnosis and in patients with refractory disease. Plasma analysis revealed significantly increased levels of cytokines including tumour necrosis factor (TNF)‐a and interleukin (IL)‐6 at diagnosis, in keeping with a pro‐inflammatory state prior to treatment. We hence demonstrate T‐cell exhaustion and a pro‐inflammatory state at diagnosis in CML, likely secondary to leukaemia‐associated antigenic overload associated with increased disease burden.

Treatment of Refractory Metastatic Renal Cell Carcinoma

Abstract: First-line treatment for metastatic renal cell carcinoma (mRCC) rapidly shifted in recent years with the advent of combination therapies, including immune checkpoint inhibitor (ICI) doublets and combinations of an ICI with a vascular endothelial growth factor receptor (VEGFR) targeted tyrosine kinase inhibitor (TKI). Despite improvements in overall survival and many durable responses, there exists a significant number of patients who fail to respond to these agents, and many patients eventually progress. Given the rapid changes in the front-line setting, it is essential to understand treatment options in refractory mRCC. Here, we review the evidence behind current options for later-line therapies, often involving additional VEGFR-TKIs alone or in combination with mammalian target of rapamycin (mTOR) targeted agents, as well as situations where consideration of immunotherapy rechallenge may be appropriate. Additionally, we describe ongoing clinical trials examining concurrent ICI and TKI in the refractory setting, as well as those studying novel agents, such as targeted drug-antibody conjugates and hypoxia inducible factor 2α (HIF-2α) inhibitors. Finally, we review considerations for non-clear cell histologies in the refractory setting and mechanisms of resistance in mRCC.

The Irreversible FLT3 Inhibitor FF-10101 Is Active Against a Diversity of FLT3 Inhibitor Resistance Mechanisms

Abstract: Abstract Small-molecule FLT3 inhibitors have recently improved clinical outcomes for patients with FLT3-mutant acute myeloid leukemia (AML) after many years of development, but resistance remains an important clinical problem. FF-10101 is the first irreversible, covalent inhibitor of FLT3 which has previously shown activity against FLT3 tyrosine kinase inhibitor resistance–causing FLT3 F691L and D835 mutations. We report that FF-10101 is also active against an expanded panel of clinically identified FLT3 mutations associated with resistance to other FLT3 inhibitors. We also demonstrate that FF-10101 can potentially address resistance mechanisms associated with growth factors present in the bone marrow microenvironment but is vulnerable to mutation at C695, the amino acid required for covalent FLT3 binding. These data suggest that FF-10101 possesses a favorable resistance profile that may contribute to improved single-agent efficacy when used in patients with FLT3-mutant AML.

Discontinuation of tyrosine kinase inhibitors in pediatric chronic myeloid leukemia

Abstract: The feasibility of tyrosine kinase inhibitor (TKI) discontinuation in pediatric chronic myeloid leukemia (CML) remains to be fully elucidated.

An Evaluation of Cabozantinib for the Treatment of Renal Cell Carcinoma: Focus on Patient Selection and Perspectives

Abstract: Cabozantinib is an oral tyrosine kinase inhibitor (TKI) with activity against several receptors involved in the angiogenesis pathway, including vascular endothelial growth factor receptor (VEGFR), c-MET and AXL. The antiangiogenic properties of cabozantinib led to its use as a monotherapy for the treatment of metastatic renal cell cancer (RCC), and quickly resulted in this treatment becoming part of the standard of care for these tumors. Since the advent of immune checkpoint inhibitors (ICIs), new standards of care have emerged in first-line settings, involving dual ICI or ICI-VEGF-TKI (including ICI-cabozantinib) combination treatments, and leading to a more complex algorithm of care. Cabozantinib remains an option in second-line settings and is still a first-line standard of care treatment in cases where the use of ICIs is contraindicated. This review focuses on the selection of patients who may benefit most from cabozantinib therapy, including those with bone and brain metastases and those with a non-clear cell RCC histology. The need to consider disease-related symptoms, comorbidities, age, drug interactions and biomarker analyses in the choice of therapeutic strategy is also highlighted. Finally, the perspectives for the use of cabozantinib in RCC treatment are discussed.

Combined stereotactic radiosurgery and tyrosine kinase inhibitor therapy versus tyrosine kinase inhibitor therapy alone for the treatment of non–small cell lung cancer patients with brain metastases

Abstract: Whether combined radiation and tyrosine kinase inhibitor (TKI) therapy in non-small cell lung cancer (NSCLC) patients with brain metastases (BMs) and epidermal growth factor receptor (EGFR) mutations confers additional benefits over TKI therapy alone remains a matter of debate. The goal of this study was to compare outcomes between combined TKI therapy with stereotactic radiosurgery (SRS) versus TKI therapy alone in NSCLC patients with BMs and EGFR mutations.Consecutive cases of NSCLC patients with EGFR mutations and BMs treated with TKIs were selected for inclusion in this study. Patients were categorized into two groups based on SRS: TKI therapy alone (group I) and combined SRS and TKI therapy (group II). Patients who had SRS or TKI as salvage therapy and those with prior radiation treatment for BMs were excluded. Tumor control (< 10% increase in tumor volume) and overall survival (OS) rates were compared using Kaplan-Meier analyses. Independent predictors of tumor control and OS were identified using multivariable Cox regression analyses.The study cohort comprised 280 patients (n = 90 in group I and n = 190 in group II). Cumulative tumor control rates were higher in group II than in group I (79.8% vs 31.2% at 36 months, p < 0.0001). Cumulative OS rates were comparable between groups I and II (43.8% vs 59.4% at 36 months, p = 0.3203). Independent predictors of tumor control were older age (p < 0.01, HR 1.03), fewer BMs (p < 0.01, HR 1.09), lack of extracranial metastasis (p < 0.02, HR 0.70), and combined SRS and TKI therapy (p < 0.01, HR 0.25). Independent predictors of OS were fewer BMs (p < 0.01, HR 1.04) and a higher Karnofsky Performance Status score (p < 0.01, HR 0.97).Although the OS rate did not differ between TKI therapy with and without SRS, the addition of SRS to TKI therapy resulted in improvement of intracranial tumor control. The lack of effect on survival rate with the addition of SRS may be attributable to extracranial disease progression. The addition of SRS to TKI therapy is recommended for intracranial disease control in NSCLC patients with BMs and EGFR mutations. Potential benefits may include prevention of neurological deficits and seizures. Future prospective studies may help clarify the clinical outcome benefits of SRS in these patients.

Late Responses in Patients With Chronic Myeloid Leukemia Initially Refractory to Tyrosine Kinase Inhibitors

Abstract: The introduction of tyrosine kinase inhibitor (TKI) therapy has dramatically improved outcomes for patients with chronic myeloid leukemia (CML); however, the prognosis for those who do not meet treatment milestones remains guarded. Here, we report our experience of patients with CML treated at a single center who did not achieve a complete cytogenetic response (CCyR) at 24 months.We retrospectively evaluated 305 patients who were diagnosed with CML at the University of Michigan between 2001 and 2014 and were treated with TKIs. We assessed rates of CCyR at 24 months correlated to clinical outcomes.The majority of patients (79%) achieved CCyR at 24 months and were classified as responders. At a median follow-up of 8.1 years from TKI initiation, overall survival among responders was significantly greater than nonresponders (93% vs. 85%, P < .001). Progression to blast phase was more common in nonresponders (1.9% vs. 10.4%, P = .004). However, 34% of nonresponders (at 24 months) went on to achieve CCyR with continued TKI therapy.Here, we re-demonstrate the importance of early CCyR in predicting survival and prevention of progression to blast phase. In addition, late CCyR appears to have prognostic implications, and continued TKI therapy with the goal of achieving a later CCyR may be a reasonable strategy in patients with limited alternate treatment options.

Olaparib Combined With Dacomitinib in Osimertinib-Resistant Brain and Leptomeningeal Metastases From Non-Small Cell Lung Cancer: A Case Report and Systematic Review

Abstract: Lung cancer patients with brain and leptomeningeal metastases usually have poor prognosis. For those patients with EGFR mutations, osimertinib, a third-generation tyrosine kinase inhibitor (TKI), is the first choice of treatment. However, drug resistance to osimertinib frequently occurs; and to date, the available follow-up treatment strategies have limited efficacy. In this case study, we report that treatments with olaparib, a Poly (ADP-ribose) polymerase (PARP) inhibitor, combined with dacomitinib, a second-generation EGFR TKI, benefited a lung cancer patient with osimertinib-resistant brain and leptomeningeal metastases. This 55-year-old male patient was found to have a pL858R mutation on EGFR exon 21 combined with TP53 and ERBB2 mutations after developing drug resistance to osimertinib treatment. Based on the genetic testing results, he was treated with olaparib and dacomitinib, and obtained 6 months of progression-free survival (PFS) and 13 months of overall survival (OS) after the diagnosis of leptomeningeal metastasis. This case report represents the first study applying PARP inhibitor in combination with dacomitinib in the treatment of leptomeningeal metastases after osimertinib resistance.

Side effects of tyrosine kinase inhibitors therapy in patients with non-small cell lung cancer and associations with EGFR polymorphisms: A systematic review and meta-analysis.

Abstract: Rash and diarrhea are common side effects of tyrosine kinase inhibitor (TKI) therapy administered to patients with non-small cell lung cancer (NSCLC). The polymorphisms of the epidermal growth factor receptor (EGFR) gene may be a potential predictor of these side effects. The aim of the present meta-analysis was to examine the association of EGFR polymorphisms and TKI-associated toxicities. Electronic databases (PubMed, Scopus and ISI Web of Science) were searched for relevant studies. According to the inclusion and exclusion criteria, a search of the databases identified 4,918 results, among which 6 clinical trials were obtained with 1,318 patients with NSCLC. A total of 9 EGFR single nucleotide polymorphisms (SNPs) associated with TKI toxicity were identified including, rs11568315, rs712829, rs712830, rs2227983, rs2075102, rs2293347, rs11977388, rs4947492 and rs884225. The data associated with skin toxicity from rs11568315, rs712829 and rs712830 were analyzed in the present meta-analysis. Data from rs11568315 were also analyzed in relation to diarrhea. Among all the examined SNPs, statistically significant results were obtained under the dominant genetic model for CA repeats in rs11568315 (SS vs. SL+LL) with skin toxicity. The long CA repeat (SL+LL) carriers were more likely to experience skin toxicity associated with TKIs (P=0.005). By contrast, there was no significant result for diarrhea (P=0.661) under dominant genetic model for CA repeats.

Discovery of mobocertinib, a new irreversible tyrosine kinase inhibitor indicated for the treatment of non-small-cell lung cancer harboring EGFR exon 20 insertion mutations

Abstract: Epidermal growth factor receptor (EGFR) is essential for normal cellular functions. Mutations of EGFR’s kinase domain can cause dysregulation leading to non-small cell lung cancer (NSCLC). Exon 20 insertion (ex20ins) mutations in EGFR are one of the leading contributors to oncogenesis and confer insensitivity to most available therapeutics. Mobocertinib is a novel tyrosine kinase inhibitor (TKI) recently approved by the US FDA as a first-in-class small molecule therapeutic for EGFR ex20ins-positive NSCLC. When compared to osimertinib, a TKI indicated for the treatment of EGFR T790M-positive NSCLC, mobocertinib differs only by the presence of an additional C5-carboxylate isopropyl ester group on the middle pyrimidine core. Together with the acrylamide side chain that is responsible for irreversible inhibition, this additional C5-substituent affords mobocertinib high anticancer potency and specificity to EGFR ex20ins-positive lung cancer that is resistant to other EGFR TKIs. This review article provides an overview of the discovery of mobocertinib from osimertinib including their structure-activity relationships, mechanisms of action, preclinical pharmacology, pharmacokinetics, and clinical applications. The discovery and use of mobocertinib and other EGFR TKIs demonstrate the power of structure-based drug design and promising therapeutic outcomes of using precision medicine approaches in the management of molecularly defined tumors.

KIT Exon 9-Mutated Gastrointestinal Stromal Tumours: Biology and Treatment

Abstract: Background: The majority of gastroinstestinal stromal tumours (GISTs) harbour oncogenic mutations in the gene encoding for the tyrosine kinase (TK) KIT. The most common mutations are found in exon 11, followed by mutations in exon 9. The latter mutations are associated more frequently with GISTs in extra-gastric locations and with a more aggressive clinical behaviour. Summary: Here, we review the unique and often poorly recognized molecular, biological, and clinical characteristics that differentiate KIT exon 9-mutant GISTs from other GIST subtypes. In particular, KIT exon 9 mutations are associated to KIT mutants with retained sensitivity to stimulation by stem cell factor and localization to the cell membrane. Moreover, KIT exon 9-mutant GISTs display significant activation of KIT-independent oncogenic pathways. These characteristics may explain the limited activity of the TK inhibitor imatinib in the adjuvant setting in KIT exon 9-mutant GISTs, as well as their lower sensitivity to standard dose imatinib in the advanced setting. In contrast, the multi-TK inhibitor sunitinib displays better activity in KIT exon 9-mutant GISTs compared to others. Key Messages: KIT exon 9-mutant GISTs represent a subtype of GIST distinct from other GISTs, including the more common KIT exon 11-mutant GISTs. A better understanding of the molecular biology and clinical behaviour of KIT exon 9-mutant GISTs may help identify more improved treatment options.

Treatment-Related Adverse Events of Combination EGFR Tyrosine Kinase Inhibitor and Immune Checkpoint Inhibitor in EGFR-Mutant Advanced Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis

Abstract: Simple Summary The use of combination epidermal growth factor tyrosine kinase inhibitor (EGFR-TKI) and immune checkpoint inhibitor (ICI) in EGFR-mutant, advanced non-small cell lung cancer (NSCLC) has raised concerns over the risk of overlapping toxicities. Although a higher proportion of interstitial lung diseases was reported with the combination of osimertinib and durvalumab, the current evidence on the treatment-related adverse events (trAEs) of EGFR-TKI and ICI remains limited to pneumonitis and the use of osimertinib. This systematic review and meta-analysis investigates whether combination EGFR-TKI and ICI increases the incidence of overall and organ-specific trAEs compared to TKI monotherapy. A higher proportion of high-grade organ-specific trAEs was observed in combination TKI and ICI including skin, gastrointestinal adverse events, and interstitial lung diseases. Further prospective studies are warranted to determine the optimal drug of choice of ICI and the best timing of initiation of ICI after failure to prior EGFR-TKI. Abstract (1) Background: We performed a meta-analysis to examine whether combined epidermal growth factor tyrosine kinase inhibitor (EGFR-TKI) and immune checkpoint inhibitor (ICI) increases treatment-related adverse events (trAEs) in advanced non-small cell lung cancer (NSCLC). (2) Methods: Articles from MEDLINE, EMBASE, and Cochrane databases were searched. Proportions and odds ratios (ORs) of the pooled incidence of overall and organ-specific trAEs in combination EGFR-TKI and ICI were compared to TKI monotherapy. (3) Results: Eight studies fulfilled our selection criteria. Any-grade organ-specific trAEs were more common in combination EGFR-TKI and ICI than TKI monotherapy (skin: OR = 1.19, p = 0.012; gastrointestinal tract: OR = 1.04, p = 0.790; ILD: OR = 1.28, p = 0.001). Grade ≥ 3 trAEs were also more frequent in combination treatment (skin: OR = 1.13, p = 0.082; gastrointestinal tract: OR = 1.13, p = 0.076; ILD: OR = 1.16, p = 0.003). (4) Conclusions: A higher proportion of grade ≥3 skin and gastrointestinal trAEs and ILDs was observed in combination TKI and ICI compared to TKI alone. Caution has to be taken when interpreting the results owing to the small number of studies included in this meta-analysis.