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Imatinib is a BCR-ABL tyrosine kinase inhibitor used for the treatment of a variety of diseases including Philadelphia chromosome positive (Ph+) leukemia. We report a 15 year old male patient presenting with symptomatic acute intracerebral hemorrhage (ICH) in midbrain while on imatinib more than three years after completion of therapy for Ph + B-ALL. The patient denied recent trauma history and consumption of other medication. Laboratory findings did not show any signs of relapse, coagulopathy nor thrombocytopenia. Under the impression of imatinib related ICH, imatinib was discontinued and with conservative management the patient recovered without neurologic sequalae. This case demonstrates the first pediatric case of spontaneous ICH as a rare complication of imatinib.

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A physician survey (July 2019-August 2019) and a retrospective patient medical chart review (November 2019-December 2019) were conducted to assess TKI therapy discontinuation practice in patients with Ph + CML-CP in the US after the publication of practice guidelines updated with recommendations for TKI discontinuation. After guideline updates, 90% of physicians from the survey reported attempting TKI discontinuation and 24% of their patients discontinued TKI after achieving an adequate response. Although TKI therapy discontinuation practice is increasing, particularly in community-based practice, a little more than half of physicians were aware of these updated guidelines resulting in TKI discontinuation attempted under suboptimal conditions, mainly limited to first-line TKI therapy, with more than half of physicians without access to at least MR4.5 sensitivity level of detection monitoring. Stricter response criteria per guideline recommendations were observed to relate to lower relapse rates following TKI discontinuation, emphasizing the importance of communicating these recommendations and access to adequate monitoring tools.

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib, in combination with gemcitabine, has been shown to be a promising therapy in the treatment of pancreatic cancer. Our previous study showed that DJ-1 promotes invasion and metastasis of pancreatic cancer cells by activating SRC/extracellular signal-regulated kinase (ERK)/uPA. The aim of this study was to evaluate whether knockdown of DJ-1 expression can sensitize pancreatic cancer cells to erlotinib treatment. Knockdown of DJ-1 expression accelerated erlotinib-induced cell apoptosis and improved the inhibitory effect of erlotinib on pancreatic cancer cell proliferation (for the BxPC-3, PANC-1, and MiaPACa-2 cell lines, regardless of KRAS mutation status) in vitro and in xenograft tumor growth in vivo. Knockdown of DJ-1 decreased K-RAS expression, membrane translocation, and activity in BxPC-3 cells. Knockdown of DJ-1 also decreased K-RAS, H-RAS, and N-RAS expression in PANC-1 and MiaPACa-2 cells. Knockdown of DJ-1 synergistically inhibited AKT and ERK1/2 phosphorylation with erlotinib in pancreatic cancer cells. These findings indicate that DJ-1 may activate the RAS pathway, reinforcing erlotinib drug resistance. Therefore, blocking DJ-1 in combination with the EGFR tyrosine kinase inhibitor erlotinib may be an attractive therapeutic target in pancreatic cancer.

Nilotinib is a second-generation tyrosine kinase inhibitor (TKI) that is widely used to treat patients with Philadelphia chromosome-positive chronic myeloid leukaemia (CML). TKIs provided a significant improvement in terms of survival rates and disease-free period in CML; however, there is insufficient knowledge about their side effects, including reproductive toxicity. Since nearly half of the CML patients are in their reproductive age, and newly announced indications cover the treatment of the paediatric age groups, concerns arise about the effects of these drugs on the reproductive system, as there are no controlled preclinical studies. We investigated acute and long-term gonadotoxic and teratogenic effects of nilotinib, utilising a mouse model that simulates various clinical scenarios. We observed significant testicular damage in mice receiving nilotinib according to Johnsen’s score analysis. Alterations were observed in female mice’s number of follicles, as the primordial follicle numbers significantly decreased. Proliferating cell number in both genders’ gonads decreased and apoptosis rate increased significantly. The nilotinib-received female and male mice’s pregnancy rates were low compared to controls. A significant decrease in the thickness of the spongiotrophoblast and decidual layers of the placenta was detected in pregnancies consisting of male and/or female mice treated with nilotinib. The results of this study establish a critical point of view for clinical translation and indicate the importance of consulting patients for directing them to fertility preservation and contraception options for both genders before nilotinib treatment.

Introduction: Lenvatinib has been approved as a systemic therapy for patients with unresectable hepatocellular carcinoma (HCC). We recently experienced lenvatinib-induced tumor-related hemorrhage in patients with HCC. The full details of tumor-related hemorrhage as a lenvatinib-related adverse event have not been elucidated. Methods: This was a retrospective single-center study that enrolled consecutive patients treated with lenvatinib for unresectable HCC from April 2018 to February 2020. Results: Sixty-eight consecutive patients were enrolled in this study. Among them, 5 cases developed intraperitoneal or intratumoral hemorrhages. The patients with hemorrhage had larger tumors (maximum tumor size, 97.5 ± 46.4 and 38.2 ± 28.8 mm, respectively; p = 0.009) than the patients without hemorrhage. The dosing period of lenvatinib (median, 3 and 93 days, respectively; p < 0.001) and the survival time from initial administration of lenvatinib (median, 77 and 495 days, respectively; p < 0.001) of the patients with hemorrhage were shorter than those of the patients without hemorrhage. Especially, in 4 cases with large HCCs (maximum tumor diameter was >90 mm), tumor hemorrhage with vascular lake-like phenomenon was evident, although most tumor blood flow was suppressed. Discussion/Conclusion: It becomes clear that lenvatinib treatment brings about tumor-related hemorrhages despite rapid suppression of tumor blood flow. We speculate that lenvatinib quickly blocks the feeding circulation, resulting in tumor hemorrhage by necrosis. Clinicians should pay careful attention to the development of life-threatening hemorrhages when treating large HCCs with lenvatinib.

Background Alhtough anti-HER2 tyrosine kinase inhibitors (TKIs) have radically prolonged survival and improved prognosis in HER2-positive breast cancer patients, resistance to these therapies is a constant obstacle leading to TKIs treatment failure and tumour progression. Methods To develop new strategies to enhance TKIs efficiency by combining synergistic gene targets, we performed panel library screening using the CRISPR/Cas9 knockout technique based on data mining across TCGA data sets and verified the candidate target in preclinical models and breast cancer high-throughput sequencing data sets. Results We identified that CDK12, co-amplified with HER2 in a high frequency, is powerful to sensitise or resensitise HER2-positive breast cancer to anti-HER2 TKIs lapatinib, evidenced by patient-derived organoids in vitro and cell-derived xenograft or patient-derived xenograft in vivo. Exploring mechanisms, we found that inhibition of CDK12 attenuated PI3K/AKT signal, which usually serves as an oncogenic driver and is reactivated when HER2-positive breast cancers develop resistance to lapatinib. Combining CDK12 inhibition exerted additional suppression on p-AKT activation induced by anti-HER2 TKIs lapatinib treatment. Clinically, via DNA sequencing data for tumour tissue and peripheral blood ctDNA, we found that HER2-positive breast cancer patients with CDK12 amplification responded more insensitively to anti-HER2 treatment than those without accompanying CDK12 amplification by harbouring a markedly shortened progression-free survival (PFS) (median PFS: 4.3 months versus 6.9 months; hazards ratio [HR] = 2.26 [95% confidence interval [CI] = 1.32–3.86]; P = 0.0028). Conclusions Dual inhibition of HER2/CDK12 will prominently benefit the outcomes of patients with HER2-positive breast cancer by sensitising or resensitising the tumours to anti-HER2 TKIs treatment.

The emergence of acquired resistance is a major concern associated with molecularly targeted kinase inhibitors. The C797S mutation in the epidermal growth factor receptor (EGFR) confers resistance to osimertinib, a third‐generation EGFR‐tyrosine kinase inhibitor (EGFR‐TKI). We report that the derivatization of the marine alkaloid topoisomerase inhibitor lamellarin N provides a structurally new class of EGFR‐TKIs. One of these, lamellarin 14, is effective against the C797S mutant EGFR. Bioinformatic analyses revealed that the derivatization transformed the topoisomerase inhibitor‐like biological activity of lamellarin N into kinase inhibitor‐like activity. Ba/F3 and PC‐9 cells expressing the EGFR in‐frame deletion within exon 19 (del ex19)/T790M/C797S triple‐mutant were sensitive to lamellarin 14 in a dose range similar to the effective dose for cells expressing EGFR del ex19 or del ex19/T790M. Lamellarin 14 decreased the autophosphorylation of EGFR and the downstream signaling in the triple‐mutant EGFR PC‐9 cells. Furthermore, intraperitoneal administration of 10 mg/kg lamellarin 14 for 17 days suppressed tumor growth of the triple‐mutant EGFR PC‐9 cells in a mouse xenograft model using BALB/c nu/nu mice. Thus, lamellarin 14 serves as a novel structural backbone for an EGFR‐TKI that prevents the development of cross‐resistance against known drugs in this class., The emergence of acquired resistance is a major concern associated with molecularly targeted kinase inhibitors. We report that the derivatization of the marine alkaloid topoisomerase inhibitor lamellarin N provides a structurally new class of epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (TKIs). One of these EGFR‐TKIs, lamellarin 14, is effective against the C797S mutant EGFR.

Background: Axitinib is a tyrosine kinase inhibitor (TKI) that inhibits vascular endothelial growth factor receptor signaling and is approved for second-line treatment of advanced renal cell carcinoma (RCC). Although the occurrence of hypertension with axitinib use has been documented, it is unclear whether a first-line TKI regimen can significantly affect the development of hypertension when axitinib is used as second-line therapy. Methods and Results: In this single-center retrospective study, advanced RCC patients treated with axitinib after first-line chemotherapy were divided into 2 groups according to the use of TKIs as part of first-line treatment before the initiation of axitinib. Clinical outcomes were compared between patients who were treated with (TKI(+); n=11) or without (TKI(-); n=11) a TKI. Although 63.6% of all patients had hypertension at baseline, axitinib-induced hypertension developed in 81.8% of patients, and 36.4% of patients experienced Grade 3 hypertension. After initiation of axitinib, both systolic and diastolic blood pressures and the hypertension grade were significantly elevated both in the TKI(+) and TKI(-) groups, and the number of antihypertensive drugs was significantly increased among all patients. Conclusions: This study suggests the need for proper monitoring and management of blood pressure in RCC patients treated with axitinib, regardless of a prior regimen with or without TKIs.

Objectives The purposes of this study are to clarify the details of the ALK tyrosine kinase inhibitor (TKI) resistance mechanism in rebiopsy cases and to predict novel resistance gene alterations using molecular dynamics simulation. Methods A total of 21 patients with ALK-positive NSCLC who underwent a rebiopsy after ALK TKI failure were included in this analysis. ALK fluorescence in situ hybridization and reverse transcription polymerase chain reaction were performed with paired initial and rebiopsy tumor specimens. Results Nine patients had no known ALK resistance mechanisms. Four had ALK amplification. L1196M, I1171N, and G1269A, mutations that are known to indicate resistance to ALK TKIs, were detected in one patient each. Small cell carcinoma and sarcomatoid transition were found in one case each. L1196Q, P1094H, and exon 24 76-base pair insertion were detected after the second-generation ALK TKIs. Conclusions The combination of a genetic analysis and a computational simulation model may make a prediction of resistance mechanisms for overcoming ALK TKI resistance, and the construction of a genomic and simulation fused database is important for the development of personalized medicine in this field.

Introduction This phase 2 trial evaluated the efficacy and safety of brigatinib in patients with advanced ALK-positive NSCLC refractory to alectinib or other ALK tyrosine kinase inhibitors (TKIs). Methods This single-arm, multicenter, open-label study in Japanese patients consisted of a safety lead-in followed by an expansion stage in patients refractory to ALK TKI or those naive for ALK TKI. Patients received brigatinib 180 mg once daily with 7-day lead-in at 90 mg once daily. Primary end point was independent review committee (IRC)–assessed confirmed objective response rate per the Response Evaluation Criteria in Solid Tumors version 1.1. Results We report the results of the lead-in and expansion in the patients refractory to ALK TKI. Of 72 patients enrolled, 47 had alectinib as most recent ALK TKI (with or without previous crizotinib). At analysis cutoff, 14 of the 47 remained on brigatinib (median follow-up: 12.4 mo). In the alectinib-refractory population, IRC-assessed confirmed objective response rate was 34% (95% confidence interval [CI]: 21%–49%) with median duration of response of 11.8 months (95% CI: 5.5–16.4). Disease control rate was 79% (95% CI: 64%–89%). Median IRC-assessed progression-free survival was 7.3 months (95% CI: 3.7–9.3). Two of eight patients with measurable brain lesions at baseline had confirmed intracranial partial response. Brigatinib has been found to have antitumor activity in patients with G1202R, I1171N, V1180L, and L1196M secondary mutations. The safety profile in Japanese patients was consistent with that in previous reports in broader populations. Conclusions Brigatinib has been found to have clinically meaningful efficacy in Japanese patients with ALK+ NSCLC refractory to alectinib (with or without previous crizotinib).

Despite the enormous success of molecularly targeted therapy in advanced non-small cell lung cancer (NSCLC), long-term disease control remains challenging. Almost all patients on targeted therapy ultimately progress due to plethora of acquired resistance mechanisms. While acquired resistance mechanisms in BRAF-V600 mutant malignant melanomas treated with targeted therapy are well studied, little is known about resistance mechanisms in BRAF-V600 mutant lung cancer so far. Therefore, patients progressing on the standard BRAF and MEK inhibitor combination are uniformly switched to immune- and/or chemotherapy. We describe the case of a metastatic BRAF-V600E mutant pulmonary adenocarcinoma of the left lung with presumed progression of a single lung lesion at the right side during targeted therapy. Due to oligo-progression, resection was performed. Molecular re-assessment for analysis of acquired resistance mechanisms surprisingly revealed a genetically distinct second primary malignancy. Following curative resection of the right sided second primary NSCLC, primary tyrosine kinase inhibitor therapy was continued and to date the patient is still responding with a cumulative treatment duration of now 34 months. This case report illustrates that a thorough molecular re-assessment upon progression on targeted therapies may have a decisive influence on subsequent treatment decisions and should therefore be considered on a routine basis.

We present the case of a patient with multiple tyrosine kinase inhibitor (TKI)-refractory chronic phase chronic myeloid leukemia (CP-CML) with a T315I mutation of abl1. Dasatinib, a second-generation TKI, was administered as the initial treatment but achieved neither a cytogenetic nor molecular response. A mutational analysis of abl1 revealed that the patient had a T315I mutation. The patient was then administered ponatinib, a third-generation TKI, which is thought to be effective against T315I; however, the complete blood counts became within normal limits, and neither a cytogenetic nor molecular response was achieved. However, the patient has maintained a healthy chronic phase (with no blast crises) for more than 5½ years since the diagnosis of CP-CML. T-cell receptor (TCR) repertoire analyses using peripheral blood revealed a remarkable clonal expansion of effector cytotoxic T lymphocytes (CTLs) that contained TCR V beta 13.6. We observed the clonal expansion of naïve CTLs with TCR V beta 13.6; however, no clonality was observed in the memory CTLs. The naïve and effector CTLs persisted at very high percentages since the seventh month after starting dasatinib. The CTLs could not have led to the molecular response; therefore, there might be plenty of CML stem cells remaining in the bone marrow. Therefore, although the CTLs might have prevented the disease from developing blast crises over more than 5 years, the CTLs might not have been able to become memory CTLs.

Sunitinib (Sun), a tyrosine kinase inhibitor of vascular endothelial growth factor receptor, is the standard first‐line treatment against advanced clear cell renal cell carcinoma (RCC), but resistance to therapy is inevitable. Reactive oxygen species production is associated with sensitivity to chemotherapy, but the underlying mechanisms are not completely understood. Here, we investigated the mechanisms contributing to Sun resistance using the RCC cell lines ACHN and 786‐O. We report that Sun‐resistant cells exhibited reduced apoptosis, increased cell viability, increased reactive oxygen species production and disrupted mitochondrial function. Furthermore, chronic Sun treatment resulted in an up‐regulation of Sirt5/isocitrate dehydrogenase 2 (IDH2) expression levels. Knockdown of Sirt5/IDH2 impaired mitochondrial function and partially attenuated Sun resistance. Finally, up‐regulation of Sirt5 enhanced the expression of IDH2 via modulation of succinylation at K413 and promoted protein stability. In conclusion, dysregulation of Sirt5/IDH2 partially contributes to Sun resistance in RCC cells by affecting antioxidant capacity., Sunitinib‐resistant cells exhibited up‐regulation of Sirt5/isocitrate dehydrogenase 2 (IDH2) expression levels, which confer drug resistance. Up‐regulation of Sirt5 enhanced the expression of IDH2 via modulation of succinylation at K413 and promotion of protein stability. Dysregulation of Sirt5/IDH2 partially contributes to Sun resistance by disturbing mitochondrial functions and affecting antioxidant capacity of renal cell carcinoma cells.

Background Although, molecular genetic analyses became more and more important to guide therapy decisions in leukemia, banding cytogenetic analysis has retained its vital role in diagnosis and monitoring of chronic myeloid leukemia (CML), by quick and easy enabling identification of pathognomonic Philadelphia chromosome (Ph). Case presentation A 45 year old female presented with characteristic hematological features of CML in chronic phase; cytogenetic studies revealed the presence of the typical Ph and a deletion of almost entire long arm of a chromosome 5. Conclusion 5q deletions have rarely been reported in CML. Those seen yet were either associated with tyrosine kinase inhibitor therapy or detected post allogeneic stem cell transplantation. To our knowledge, this is the first case of Ph positive CML accompanied by a 5q deletion.

Introduction Prior to the advent of tyrosine kinase inhibitors (TKI), expected overall survival (OS) for patients with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) was estimated at best ~20%, and thus consolidation with allogeneic hematopoietic cell transplantation (HCT) was uniformly recommended. The international ALL trial MRC UKALLXII/ECOG2993 showed that allogeneic HCT was superior to chemotherapy in 267 adults with Ph+ ALL (5-year OS was 44% after matched sibling allogeneic HCT, 36% after MUD HCT, and 19% after chemotherapy only).1 However, the introduction of BCR-ABL1 targeted therapy with highly potent TKIs has significantly improved outcomes for this subset of ALL patients, resulting in greater numbers of remissions, and more transplant-eligible patients.2–4 Furthermore, some retrospective analyses suggest that transplant may not be needed in patients who go into a deep remission, without detectable measurable residual disease (MRD), following TKI therapy. Herein, we will review data from recent studies that are used to inform our recommendations regarding therapy in the contemporary era for newly diagnosed patients with Ph+ ALL.

Introduction: Nilotinib is a second-generation tyrosine kinase inhibitor (TKI) targeting BCR/ABL, which is used for the first-line treatment of newly diagnosed chronic myeloid leukemia (CML) patients and the second-line treatment of most CML patients who are resistant or intolerant to prior therapy that includes imatinib. In addition to common adverse reactions, long-term use of nilotinib shows some toxicities that are different from those of occurring during other BCR/ABL TKI treatments, such as cardiovascular toxicity. It is life-threatening, which would affect not only the choice of initial treatment of CML patients but also the safety of long-term medication.Areas covered: Through searching literature and reports from PubMed and clinical trials, here we review a profile of the adverse effects induced by nilotinib. We also discuss the potential molecular toxicological mechanisms and clinical management, which may provide strategies to prevent or intervene the toxicity associated with nilotinib.Expert opinion: Severe adverse effects associated with nilotinib limit its long-term clinical application. However, the exact mechanisms underlying these toxicities remain unclear. Future research should focus on the developing strategies to reduce the toxicities of nilotinib as well as to avoid similar toxicity in the development of new drugs.

Összefoglaló. A Bruton-féle tirozin-kinázt gátló ibrutinib és a B-sejtes lymphoma-2-t gátló venetoklax a krónikus lymphoid leukaemia (CLL) kezelésének egyre korábbi vonalában alkalmazható, és ezek mellett a progressziómentes túlélés növekedése figyelhető meg. A célzott kismolekulákkal végzett kezelés nemcsak a CLL lefolyását, de a betegek gondozását is alapvetően megváltoztatta. A tartósan adagolt orális szerek mellett a betegek nagyobb valószínűséggel jelennek meg a panaszaiknak megfelelő szakrendeléseken. Az új típusú szerek hatásai és mellékhatásai mellett az alapvető gyógyszer-interakciókra is fel kell hívni a figyelmet. Kiemelt fontosságú az ibrutinib hypertoniát provokáló hatása, illetve a 6–16%-ban megjelenő pitvarfibrilláció. Ez utóbbi ellátását a gyógyszer-interakciókon túl az ibrutinib vérzékenységet okozó hatása is nehezíti. A CLL-lel, illetve annak kezelésével kapcsolatos ismeretek a másodlagos daganatok, néhány gastrointestinalis és bőrgyógyászati betegség megközelítése szempontjából is fontosak. A venetoklax mellett potenciálisan kialakuló tumorlízis-szindróma alkalmanként a nefrológusok bevonását igényli. A betegek gondozása, megfelelő szakszerű ellátása és a betegutak optimalizálása érdekében a háziorvosok, a sürgősségi ellátók és az egyéb szakellátó helyek szoros együttműködése szükséges szakorvosi konzultáció keretei között. Orv Hetil. 2021; 162(9): 336–343. Summary. Chronic lymphocytic leukemia (CLL) is ubiquitously treated with novel agents. The Bruton’s tyrosine kinase inhibitor ibrutinib and the B-cell lymphoma 2 inhibitor venetoclax can be used increasingly in earlier lines of treatment with improved progression-free survival. Treatment with targeted small molecules fundamentally changed not only the course of CLL but also the care of patients. With the administration of long-term oral medications, patients are more likely to show up at specialist clinics that match their complaints. In addition to the effects and side effects of the new drugs, attention should also be drawn to basic drug interactions. The effect of ibrutinib on blood pressure and the ability to provoke atrial fibrillation in 6–16% of cases are of paramount importance. In addition to drug interactions, the treatment of the latter is also complicated by the hemorrhagic effect of ibrutinib. Knowledge on CLL and its treatment is also important in the approach to secondary tumors, some gastrointestinal and dermatological diseases. The potential for tumor lysis syndrome of venetoclax requires close collaboration with nephrologists. In order to provide appropriate professional care and optimize patient pathways, close co-operation between GPs, emergency care providers and other specialist care facilities is required within the framework of professional consultation. Orv Hetil. 2021; 162(9): 336–343.

We have experienced several paradigm shifts and substantial changes in the treatment of metastatic renal cell carcinoma (mRCC) over the last two decades. Combination therapy with immune checkpoint inhibitors (ICI) as a dual combination (ICI-ICI) or with VEGFR-tyrosine kinase inhibitors (VEGF-TKI) has shown remarkable efficacy in mRCC patients and has become the standard of care in first-line therapy.In this review, we will discuss the background as well as the benefits of combining ICI with TKI compared to ICI-ICI combination therapy for mRCC treatment and will also briefly highlight biomarkers for patient selection on therapies to improve patient outcomes and limit toxicities.Due to the mediated additional anti-tumor effects, there is a strong rationale to combine ICIs and TKIs for mRCC therapy. When comparing first-line therapy options, the exceptionally higher ORR and PFS for the ICI-TKI combinations should be highlighted, whereas, nevertheless, the complete response rate is slightly higher for the ICI-ICI combination. In terms of an individualized therapeutic approach, biomarkers predicting the success or failure of an anti-VEGF-based regimen or ICI therapy as a corresponding mono - or combination therapy are lacking so far, however, gene expression signatures can be a landmark in this field.

The association between the pharmacokinetics and pharmacodynamics of regorafenib, a multiple tyrosine kinase inhibitor, remains unclear. This study assessed the trough plasma concentrations (Ctrough) of regorafenib and its N-oxide (M2) and N-oxide/desmethyl (M5) metabolites, and evaluated the associations among these levels, adverse events, and pharmacokinetic-related genetic polymorphisms in patients with metastatic colorectal cancer. The Ctrough levels of regorafenib and its metabolites were assessed in a single-center, prospective, observational study, 7 days after the initial treatment. The correlation between those values and adverse events was then examined. In addition, the genetic polymorphisms of ABCG2, SLCO1B1, and UGT1A9 were determined and evaluated for associations with the levels of regorafenib, M2, and M5. We analyzed 43 patients who received regorafenib 40–120 mg/day; among them, 35 patients started at 120 mg/day. With regard to bilirubin increase, the Ctrough values of regorafenib were significantly higher in the group with grade ≥ 2 than in groups with grades 0 and 1 (p = 0.010). The M5 Ctrough levels were significantly associated with the severity of hypertension or rash (p

Introduction: Osimertinib is a third-generation anti-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), that irreversibly binds to mutant EGFR, specifically to the T790M EGFR ...

Reversible phosphorylation has emerged as an important mechanism for regulating 26S proteasome function in health and disease. Over 100 phospho-tyrosine (pTyr) sites of the human proteasome have been detected, and yet their function and regulation remain poorly understood. Here we show that the 19S subunit Rpt2 is phosphorylated at Tyr439, a strictly conserved residue within the C-terminal HbYX motif of Rpt2 that is essential for 26S proteasome assembly. Unexpectedly, we found that Y439 phosphorylation depends on Rpt2 membrane localization mediated by its N-myristoylation. Multiple receptor tyrosine kinases (RTKs) can trigger Rpt2-Y439 phosphorylation by activating Src, a N-myristoylated tyrosine kinase. Src directly phosphorylates Rpt2-Y439 in vitro and negatively regulates 26S proteasome integrity and activity at cellular membranes, which can be reversed by the membrane-associated isoform of protein tyrosine phosphatase non-receptor type 2 (PTPN2). In H1975 lung cancer cells with activated Src, blocking Rpt2-Y439 phosphorylation by the Y439F mutation conferred partial resistance to the Src inhibitor saracatinib both in vitro and in a mouse xenograft tumor model, and caused significant changes of cellular responses to saracatinib at the proteome level. Our study has defined a novel mechanism involved in the spatial regulation of proteasome function and provided new insights into tyrosine kinase inhibitor-based anti-cancer therapies.

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Introduction: Submucosal fat deposition (SMF) in the gastrointestinal tract can be seen in patients treated with vascular endothelial growth factor receptor multitarget tyrosine kinase inhibitors (mtTKIs). We aimed to assess the association between mtTKIs treatment and appearance of SMF on computed tomography (CT). Methods: We performed retrospective evaluation of patients who started mtTKI treatment between 2016 and 2018, with a comparison patient cohort treated with single-target tyrosine kinase inhibitors (stTKIs). SMF amount for each gastrointestinal tract segment (stomach, duodenum, jejunum, ileum, terminal ileum, right colon, left colon) was scored as follows: 0 = none; 1 = low amount (2 mm layer). For each CT, segment scores were aggregated to create an SMF index (SMFI). Maximal increase in SMFI between pretreatment and posttreatment CTs was documented. SMF ⩾3 was defined as positive. Results: Forty patients treated with mtTKIs and 23 patients receiving stTKIs were included. Maximal increase in SMFI during treatment was 0–1 in 56/63 patients (89%) and 3–6 in 7/63 patients (11%). All patients with positive SMFI received mtTKIs compared to 0 patients treated with stTKIs (17.5% vs. 0%; p = 0.04). mtTKI treatment was associated with higher incidence of nausea/vomiting (4/7) and diarrhea (4/7) when positive SMF was noted, as compared to patients with negative SMF (6/33 patients each; p = 0.048). Conclusion: Gastrointestinal tract SMF deposition occurs in a considerable proportion of patients treated with mtTKIs with association to abdominal symptoms. This may be unique to mtTKIs and was not found in patients receiving stTKIs.

Comprehensive molecular testing of individual tumors has led to the identification of novel molecularly defined cancer therapies and treatment indications. Given low frequencies of many molecular alterations, efficacy of therapies used to target them are often undefined, especially in the context of rare malignancies. Here we describe the first reported case of MET amplification in sinonasal undifferentiated carcinoma (SNUC), a rare cancer with a poor prognosis. The patient was treated with crizotinib, a tyrosine kinase inhibitor that targets c-MET, and experienced a complete response. Our report demonstrates the potential of employing precision oncology approaches in SNUC and other rare cancers.

Background: It is well-known that tumor biology may change during the course of the disease due to clonal evolution, and such changes might have important implications for response to targeted treatments. Circulating tumor cells (CTCs) could serve as a real-time liquid biopsy to detect changes in tumor biology. It has been demonstrated that patients with HER2-negative metastatic breast cancer (MBC) may have discordant, HER2-positive CTCs in the peripheral blood. However, up to now there is no randomized clinical trial investigating whether treatment decisions based on CTC phenotype provide benefits in terms of improved outcome. The aim of the DETECT III study is to investigate whether patients with initially HER2-negative MBC and HER2-positive CTCs benefit from HER2-targeted therapy with the tyrosine kinase inhibitor lapatinib. In addition, the significance of CTCs as an early predictive marker for response to therapy will be analyzed. Methods: The randomized phase III DETECT III trial (NCT01619111) compares lapatinib in combination with standard therapy versus standard therapy alone in patients with initially HER2-negative MBC and HER2-positive CTCs. Efficacy of lapatinib treatment is evaluated by CTC clearance rate, progression-free survival (PFS) and overall survival (OS). In addition, we investigate the association between CTC results and both PFS and OS to assess the utility of CTCs as an early predictive marker for treatment response. CTC enumeration and phenotyping was performed using the CellSearch® technology (Menarini Silicon Biosystems; Bologna, Italy). Survival data are analyzed using log rank tests, univariable and adjusted multivariable cox regressions. Results: First results on CTC clearance rates, PFS and OS of 105 prospectively randomized patients will be presented. Conclusion: This first randomized clinical trial in breast cancer patients with treatment decisions being based on the phenotype of CTCs will show whether patients with HER2 negative MBC and HER2 positive CTCs benefit from additional HER2-targeted therapy with lapatinib. This finding might be increasingly important as novel HER2-targeted drugs become available. Citation Format: Tanja Fehm, Volkmar Mueller, Maggie Banys-Paluchowski, Peter A Fasching, Thomas WP Friedl, Andreas Hartkopf, Jens Huober, Christian Loehberg, Brigitte Rack, Sabine Riethdorf, Andreas Schneeweiss, Diethelm Wallwiener, Franziska Meier-Stiegen, Oliver Hoffmann, Lothar Müller, Pauline Wimberger, Eugen Ruckhaeberle, Jens Blohmer, Wolfgang Janni. Efficacy of the tyrosine kinase inhibitor lapatinib in the treatment of patients with HER2-negative metastatic breast cancer and HER2-positive circulating tumor cells - results from the randomized phase III DETECT III trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD3-12.

Background: Poziotinib is a novel pan-HER inhibitor that irreversibly blocks the EGFR family of tyrosine-kinase receptors and inhibits the proliferation of tumor cells. This study evaluates the safety and clinical activity of poziotinib in patients with HER2-positive metastatic breast cancer (MBC) who received at least 2 therapies (trastuzumab and TDM-1) in dose-schedule ranging study. Methods: Patients were treated with oral poziotinib in 2 dose cohorts: 24mg daily 2 weeks/1 week off and 16mg daily continuously in a 21-day cycle. Dose reduction was allowed if toxicity observed. Patients continued treatment until disease progression, death, intolerable AE, or for a maximum of 24 months. The primary endpoint was the objective response rate (ORR), evaluated using RECIST 1.1. Secondary endpoints included disease control rate (DCR), duration of response (DOR), progression-free survival (PFS) and safety. Results: Sixty-seven patients (33 in 24mg; 34 in 16mg) were enrolled (57 evaluable) in 2 cohorts; all patients either completed or discontinued (36 PD, 5 deaths due to PD, 16 AEs) the study with 1 completed 25 months of treatment. The median (range) age was 57 (29-94) years. Patients were heavily pretreated and the median (range) lines of previous therapy were 7 (2-13) and 4 (2-16) in 2 cohorts respectively [unique drugs 3 (2-5) and 3 (1-9)]; 75% received pertuzumab in addition to trastuzumab and TDM-1 and 37% received at least one tyrosine kinase inhibitor (TKI). The mean relative dose intensity was 57% and 51% with 67% and 47% had dose reductions in 2 cohorts respectively. Common Grade ≥3 treatment-related AEs were similar to other 2nd generation TKIs and include diarrhea (30%), rash (28%) and stomatitis (7%). The ORRs were 27% and 26% with the corresponding median DORs of 5.6 and 13 months respectively. 3 patients in 16mg dose had a CR and another 2 patients had an unconfirmed CR. The DCRs were 50% and 70% in 2 cohorts along with median PFS of 4.1 and 5.8 months respectively. The ORRs were 25% each in 2 cohorts in 24 and 20 heavily pre-treated patients with ≥4 lines of therapy that included trastuzumab, TDM1 and pertuzumab. The ORRs were 23% and 0% in 2 cohorts with 13 and 10 patients received at least one tyrosine kinase inhibitor (TKI) as the sample sizes were small to make any meaningful evaluation. Conclusion: Poziotinib has demonstrated clinical activity in this dose-ranging study with tumor reduction shown in the majority of patients along with durable responses in this heavily pre-treated MBC patients. Safety profile was mechanism related and was similar to other 2nd generation TKIs. Citation Format: Adam Brufsky, Malik Zulfiqar, Julio Peguero, Kate Lathrop, Gajanan Bhat, Francois Lebel. A Phase 2 study of poziotinib in patients with HER2-positive metastatic breast cancer heavily pre-treated with HER2-targeted therapy [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD1-07.

Background T790M mutation causes resistance to tyrosine kinase inhibitors (TKIs) in approximately 49% of patients with epidermal growth receptor-mutant non-small cell lung cancer (NSCLC). The cause of resistance in the remaining half of the cases is a minor mutation or unknown. Here, we conducted a retrospective study of epidermal growth receptor-mutant NSCLC patients with T790M-negative or an unidentified mutation to appraise the therapeutic response to first- or second-generation tyrosine kinase inhibitors as a second-line treatment. Methods The study included 39 patients treated in our institution from April 2012 through March 2020 with second-line tyrosine kinase inhibitors or chemotherapy after completing a first-line therapy with tyrosine kinase inhibitors. Results The patients were allocated to two groups: chemotherapy (n = 28) and a tyrosine kinase inhibitor (n = 11) groups. The median progression-free survival (PFS) was 5.4 months in the chemotherapy group and 3.4 months in the tyrosine kinase inhibitor group (p-value = 0.36), while the median overall survival (OS) was 16.1 months in the chemotherapy group and 12.8 months in the tyrosine kinase inhibitor group (p- value = 0.20). This study showed no significant difference in PFS and OS between the chemotherapy and tyrosine kinase inhibitor groups. Conclusions These observations suggest that first- and second-generation tyrosine kinase inhibitors are not recommended for second-line treatment in epidermal growth factor receptor-mutated NSCLC patients with T790M-negative mutation who have received tyrosine kinase inhibitors as first-line treatment.

Chronic myeloid leukaemia (CML) is a malignancy of the haematopoietic stem cells. The first line of treatment for CML, especially in developing countries, remains the first-generation tyrosine kinase inhibitor, Imatinib. Patients with CML are frequently diagnosed with platelet abnormalities. However, the specific mechanism of platelet abnormalities in CML remains unclear and poorly understood. The aim of this study was therefore to determine the apoptotic profiles of CML patients ex vivo on platelets before and after treatment with Imatinib. Blood samples of healthy volunteers and CML patients at diagnosis and after 6 months treatment with Imatinib were collected. Platelet counts, viability and activation were determined. Results showed that CML patients' platelet counts were elevated upon diagnosis and these levels statistically significantly decreased after 6 months of treatment. Platelet activation was significantly increased after 6 months of treatment compared to levels at diagnosis (P-value < .05). Similarly, platelet apoptosis was also increased after 6 months of treatment. Abnormalities in platelet functioning found in this study may partly be due to clonal proliferation of haematopoietic cells in CML patients, specifically of megakaryocyte precursors as well as the inhibition of platelet tyrosine kinase's and the inhibition of platelet-derived growth factor.

Patients with distant metastases of borderline phyllodes tumors (PT) are rare, and their prognosis is very poor. Here, we report the case of a 59-year-old Japanese woman with metastatic brain, lung, stomach, and colon lesions originating from a borderline PT in her left breast. After surgical treatment of the left frontal lobe tumor and the right upper lung tumor, and first-line chemotherapy with doxorubicin monotherapy, magnetic resonance imaging (MRI) revealed new metastatic lesions in the left cerebrum and bilateral frontal lobe. A next-generation sequencing clinical assay revealed that her tumor had platelet-derived growth factor receptor beta (PDGFRB) point mutation (p.N666K). On the basis of genetic analysis, a multitargeted tyrosine kinase inhibitor, pazopanib, was administered as the second-line chemotherapy. Most of her metastatic lesions, including brain metastases, showed a deep shrinkage, which persisted for 12 months. This is the first report that PDGFRB, which is a druggable pathogenic alteration, exists in PT. Genotype-matched therapy can be effectively used to treat rare malignant tumors.

To explore the relationship between Mycoplasma hyorhinis infection and tyrosine kinase inhibitor (TKI) resistance in lung adenocarcinoma patients. Mycoplasma hyorhinis infection can be verified with the monoclonal antibody PD4, which specifically recognizes a distinct protein of M. hyorhinis. Immunohistochemistry (IHC), using PD4 to detect M. hyorhinis, was performed on paraffin-embedded lung adenocarcinoma tissues of patients who had epidermal growth factor (EGFR) mutations and had received oral TKI. The number of patients enrolled in our study was 101. Assessments following TKI treatment were performed until objective disease progression or stable disease at the cutoff date was reached. In all of the patients, the primary endpoint was investigator-assessed progression-free survival (PFS). Immunohistochemistry revealed that 61 of 101 cases (60.4%) of lung adenocarcinoma were positive for M. hyorhinis, which comprised of 31 low-positive cases and 30 high-positive cases; the remaining 40 cases (39.6%) were negative. The median PFS was significantly longer in the negative group [18 months (95% CI 14.15–21.85)] than in the low-positive group [10 months (95% CI 7.70–12.30); hazard ratio (HR) 4.095, 95% CI 2.254–7.438; p

We have three drugs for treatment of gastrointestinal stromal tumors (GIST): imatinib, sunitinib and regorafenib. Avapritinib (Ayvakit, BLU-285) is one more drug that was approved in January 2020. Avapritinib is a new selective tyrosine kinase inhibitor of PDGFRA and KIT mutations. Based on NAVIGATOR trial avapritinib was approved by FDA for treatment of PDGFRA exon 18 mutant GIST including D842V. Avapritinib was included in NCCN guidelines in the first line therapy PDGFRA D842V mutant GIST. There are only several cases describe imatinib and regorafenib efficacy in D842V mutation in the literature. Avapritinib is the first drug with high efficacy in D842V mutant GIST. Avapritinib has high efficacy against second mutations that explain its activity in 4 lines of treatment. This article summarizes the results of NAVIGATOR trial and describes a clinical case of the patient with advanced GIST who received avapritinib in 6th line of treatment. Partial response was achieved that lasted 9 months. The earliest side effects were periorbital edema and increased lacrimation. Three months later the dose of аvapritinib was reduced because of hematological toxicity.

Ponatinib is a third-generation tyrosine kinase inhibitor (TKI) reported to show a higher efficacy for adult Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) than other TKIs. However, few studies describe ponatinib for pediatric Ph+ALL; therefore, the efficacy, safety, and optimal dosage have not been determined. Here, we report a 3-year-old girl with Ph+ALL treated by a ponatinib-containing regimen with therapeutic drug monitoring in the plasma and cerebrospinal fluid (CSF). In our case, a ponatinib-containing regimen was able to keep minimal residual disease negative, and the pharmacokinetics (PKs) of plasma ponatinib resembled that previously reported in adults. Penetration to the CSF was extremely limited. Thus, ponatinib was feasible and effective for a child with Ph+ALL, although the plasma concentration of ponatinib varied significantly throughout the treatment. The appropriate dosage should be confirmed in a prospective trial, including a detailed PK study.

Clinical trial and real-world data in non-small-cell lung cancer indicate that 10–60% of patients that progressed on first- or second-generation EGFR-targeting tyrosine kinase inhibitors (TKI) do not receive systemic second-line therapy. In our article, we discuss efficacy, safety and treatment duration with different EGFR-TKIs and stress the need for delivery of the most efficacious therapy in the first-line. We also provide our perspective on analysis of circulating tumor DNA and the role of EGFR-TKI in combined therapies. Finally, we review new therapeutic options to overcome resistance to EGFR-TKI. We believe that overall treatment duration and access to different medications in subsequent lines of therapy should be considered when planning the optimal treatment strategy.

Objectives Exon 20 insertion mutations of epidermal growth factor receptor (EGFR) have been identified as oncogenic mutations in general; however, the functional relevance of each remains largely uninvestigated. Herein, we comprehensively assessed the functional significance of insertion mutations of EGFR exon 20. Materials and methods The transforming potential and drug sensitivities of 25 EGFR recurrent mutants, including twenty-one exon 20 insertions, were evaluated using the mixed-all-nominated-in-one method. Results The sensitivity of EGFR exon 20 insertions to EGFR tyrosine kinase inhibitors (TKIs) was generally lower than that of the L858R mutation or exon 19 deletions. The results were also confirmed through an in vivo drug test. All of the exon 20 insertions were resistant to gefitinib and afatinib, whereas several mutants were sensitive to osimertinib. EGFR exon 20 insertions exhibited relatively good responses to poziotinib and mobocertinib. Conclusions EGFR exon 20 insertions were shown to have different degrees of sensitivity to EGFR TKIs. This extensive assessment of EGFR exon 20 insertions may provide a fundamental database for aiding in a customized mode of therapy for cancers having insertional mutations within exon 20 of EGFR, although the clinical impact of preclinical data should be validated by clinical evidence in the future.

The brain is a common metastatic site of small cell lung cancer (SCLC), but systematic treatment options are limited by the blood-brain barrier. Currently, the optimal treatment regimen remains controversial, especially for patients already treated by brain radiotherapy. Anlotinib is a novel oral multitarget tyrosine kinase inhibitor which has shown significant improvement in progression-free survival and overall survival in third-line or beyond therapy of advanced SCLC in a randomized, double-blind phase II study (ALTER1202 trial) based on a Chinese population sample. Emerging data has also suggested that immunotherapy, such as the programmed death ligand 1 (PD-L1) inhibitor, has a relatively high response rate in brain metastatic SCLC, although there is a lack of large sample-size studies. Integrating anlotinib and immunotherapy for recurrent or relapsing brain metastases (BMs) of SCLC has not been previously reported, but it is possible that these two treatments may have synergistic effects and provide even better outcomes. Here, we present a case of stage III SCLC who developed lung and BMs after concurrent chemoradiotherapy (cCRT) and achieved radiographic locally complete regression following whole brain irradiation (WBI) with a simultaneous integrated boost (SIB) technique. Durvalumab was delivered as maintenance therapy. Asymptomatic multifocal recurrence of BMs occurred after the administration of the second dose of durvalumab. After administration of combined durvalumab and anlotinib, the BMs achieved near-complete regression and no severe toxicity was reported. This suggests a potential synergistic effect of combined durvalumab and anlotinib in previously treated BMs in a patient with SCLC and may provide a direction for future clinical decisions.

An 8-year-old 28-kg male castrated rough collie was evaluated for persistent chylothorax secondary to right atrial mass. Cardiac ultrasound and computed tomography revealed a right atrial intra- and extraluminal mass with partial obstruction of the cranial vena cava and secondary chylothorax. Vascular stent placement was elected to alleviate cranial vena cava obstruction and secondary chylothorax. An 18 mm × 180 mm self-expanding stent was deployed in the region of the stricture, spanning the cranial vena cava and right atrium. An intrathoracic drainage catheter and subcutaneous port were placed within the right hemithorax, and antiplatelet therapy was initiated. Four weeks later, the dog underwent stereotactic body radiation therapy. Three months following treatment, the dog was diagnosed with supraventricular tachycardia and received antiarrhythmic therapy and antiangiogenic/antiproliferative medication (Palladia™). Subsequent evaluations confirmed the resolution of arrhythmia and pleural effusion. Combined vascular stent placement and stereotactic body radiation therapy for the treatment of a right atrial intraluminal and extraluminal mass leading to cranial vena cava compression and subsequent chylothorax may lead to long-term survival. A good outcome was achieved in this patient due to resolution of pleural effusion, as well as cytoreduction and presumably delayed progression of tumor growth.

Simple Summary COVID-19 pneumonia can be confused with Pneumocystis jirovecii pneumonia (PJP) on computed tomography and is a source of misdiagnosis. This can lead to mistreatment and an increased risk of mortality. Gefitinib, a tyrosine kinase inhibitor anti-EGFR used in cancer therapy and corticosteroids, could increase the risk of PJP. Abstract An 82-year-old woman treated for advanced lung cancer with gefitinb was admitted to the emergency unit complaining of dyspnea. Chest computed tomography found abnormalities classified as possible diffuse COVID-19 pneumonia. RT-PCR for Sars-Cov-2 was twice negative. PCR for Pneumocystis jirovecii was positive on bronchoalveolar lavage. The final diagnosis was Pneumocystis jirovecii pneumonia. Therefore, physicians must be careful not to misdiagnose COVID-19, especially in cancer patients on small-molecule therapeutics like gefitinib and corticosteroids.

A major barrier to the successful application of nanotechnology for cancer treatment is the suboptimal delivery of therapeutic payloads to metastatic tumor deposits. We previously discovered that cabozantinib, a tyrosine kinase inhibitor, triggers neutrophil-mediated anticancer innate immunity, resulting in tumor regression in an aggressive PTEN/p53-deficient genetically engineered murine model of advanced prostate cancer. Here, we specifically investigated the potential of cabozantinib-induced neutrophil activation and recruitment to enhance delivery of BSA-coated polymeric nanoparticles (BSA-NPs) into murine PTEN/p53-deficient prostate tumors. On the basis of the observation that BSA coating of NPs enhanced association and internalization by activated neutrophils by approximately 6-fold in vitro, relative to uncoated NPs, we systemically injected BSA-coated, dye-loaded NPs into prostate-specific PTEN/p53-deficient mice that were pretreated with cabozantinib. Flow cytometric analysis revealed an approximately 4-fold increase of neutrophil-associated BSA-NPs and an approximately 32-fold increase in mean fluorescent dye uptake following 3 days of cabozantinib/BSA-NP administration, relative to BSA-NP alone. Strikingly, neutrophil depletion with Ly6G antibody abolished dye-loaded BSA-NP accumulation within tumors to baseline levels, demonstrating targeted neutrophil-mediated intratumoral NP delivery. Furthermore, we observed an approximately 13-fold decrease in accumulation of BSA-NPs in the liver, relative to uncoated NPs, post-cabozantinib treatment, suggesting that BSA coating of NPs can significantly enhance cabozantinib-induced, neutrophil-mediated targeted intratumoral drug delivery, while mitigating off-target toxicity. Collectively, we demonstrate a novel targeted nano-immunotherapeutic strategy for enhanced intratumoral delivery of BSA-NPs, with translational potential to significantly augment therapeutic indices of cancer medicines, thereby overcoming current pharmacologic barriers commonly encountered in preclinical/early-phase drug development.

Recent studies have shown that programmed cell death 4 (PDCD4) modulates distinct signal transduction pathways in different pathological conditions. Despite acute and chronic immune responses elicited by ischemia contributing to the functional deterioration of the kidney, the contributions and mechanisms of PDCD4 in acute kidney injury (AKI) have remained unclear. Using two murine AKI models including renal ischemia/reperfusion injury (IRI) and cisplatin-induced AKI, we found that PDCD4 deficiency markedly ameliorated renal dysfunction and inflammatory responses in AKI mice. Consistently, upregulation of PDCD4 was also confirmed in the kidneys from patients with biopsy confirmed acute tubular necrosis from a retrospective cohort study. Moreover, we found that overexpression of Fgr, a member of the tyrosine kinase family, dramatically aggravated renal injury and counteracted the protective effects of PDCD4 deficiency in AKI mice. We discovered that FGR upregulated NOTCH1 expression through activating STAT3. Most importantly, we further found that systemic administration of ponatinib, a tyrosine kinase inhibitor, significantly ameliorated AKI in mice. In summary, we identified that PDCD4 served as an important regulator, at least in part, of FGR/NOTCH1-mediated tubular apoptosis and inflammation in AKI mice. Furthermore, our findings suggest that ponatinib-mediated pharmacologic targeting of this pathway had therapeutic potential for mitigating AKI., Graphical abstract Programmed cell death 4 (PDCD4) contributes to inflammation and promotes tubular epithelial cell death in acute kidney injury (AKI), which is associated with the FGR-mediated NOTCH1 signaling pathway. Using ponatinib or other drugs targeting this pathway may represent novel therapeutic strategies for the treatment of AKI.Image 1

Background In the global FLAURA study, first-line osimertinib, a third-generation irreversible tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR), significantly improved progression-free survival (PFS) and overall survival (OS) versus comparator EGFR TKIs in patients with EGFR mutation-positive (EGFRm) advanced non-small-cell lung cancer (NSCLC). Objective The FLAURA China study assessed first-line osimertinib in Chinese patients with EGFRm advanced NSCLC (NCT02296125). Methods FLAURA China was a double-blind, randomized, phase III study. Adults from mainland China with previously untreated EGFRm (Exon 19 deletion or L858R) advanced NSCLC were enrolled in the global study or a China-only study under the same protocol; 136 patients were randomized to osimertinib (80 mg once daily [od]; n = 71) or comparator EGFR TKI (gefitinib or erlotinib; all sites selected gefitinib 250 mg od; n = 65). Patients were randomized and allocated to treatment groups by a central computer system. Treatment continued until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was investigator-assessed PFS; OS was a secondary endpoint. Results All 136 randomized patients were analyzed. Osimertinib extended median PFS by 8.0 months versus comparator EGFR TKI (17.8 vs. 9.8 months; hazard ratio [HR] 0.56; 95% confidence interval [CI] 0.37–0.85). Median OS was 33.1 months in the osimertinib group versus 25.7 months in the comparator group (HR 0.85; 95% CI 0.56–1.29). At 3 years, 20% of patients on osimertinib and 8% on the comparator remained on randomized treatment. Grade 3 or higher adverse events (AEs) were reported in 54 and 28% of patients in the osimertinib and comparator groups, respectively, driven by increased local reporting of laboratory- and disease-related AEs. No new safety signals were identified. Conclusions First-line osimertinib treatment resulted in a clinically meaningful PFS and OS benefit versus comparator EGFR TKI in Chinese patients with EGFRm advanced NSCLC. Safety data were consistent with the known safety profile of osimertinib. Clinical Trial Registration ClinicalTrials.gov NCT02296125, registered 20 November 2014 Supplementary Information The online version contains supplementary material available at 10.1007/s11523-021-00794-6.

Zhiyong Liu,1 Weitao Yao,1 Yao Zhao,2 Oufei Liu,3 Peng Zhang,1 Hong Ge4 1Department of Orthopedics, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, Henan, People’s Republic of China; 2Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 3Department of Oncology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 4Department of Radiation Oncology, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, Henan, People’s Republic of ChinaCorrespondence: Hong Ge Email doctorgehong@163.comPurpose: Anlotinib is a novel tyrosine kinase inhibitor with promising anti-tumor activity in patients with advanced soft tissue sarcomas (STS) in China. Liposomal doxorubicin monotherapy showed an encouraging effect on this disease. The aim of this study was to evaluate the efficacy and safety of anlotinib combined with liposomal doxorubicin followed by anlotinib maintenance in patients with metastatic STS.Patients and Methods: This is a multicenter, retrospective, observational study. We reviewed 27 patients with metastatic STS from July 2018 to December 2019, who were treated with anlotinib combined with liposomal doxorubicin followed by anlotinib maintenance in the absence of the tumor progression or intolerable adverse events (AEs).Results: Of the 27 patients included, 2 patients had complete response (CR), 9 patients obtained partial response (PR), 11 patients achieved stable disease (SD). The objective response rate was 40.7%, the disease control rate was 81.5%, and the median progression-free survival (PFS) was 7 months (95% CI, 5.3– 8.1 months). The progression-free rate (PFR) at 3 and 6 months was 81.5% and 59.3%, respectively. Most AEs were mild and acceptable. The most frequent grade 3/4 AEs were leukopenia (33.3%), febrile neutropenia (7.4%), and anemia (7.4%). No deaths related to the treatment were reported.Conclusion: This study shows that anlotinib combined with liposomal doxorubicin followed by anlotinib maintenance is effective in patients with metastatic STS, and most AEs of this combined therapy are mild and acceptable. Further investigation on its efficacy is warranted.Keywords: anlotinib, liposomal doxorubicin, soft tissue sarcomas, efficacy, safety

Objectives Epidermal growth factor receptor (EGFR) exon 20 insertion (ex20 ins) mutations are generally associated with de novo resistance to first- or second-generation EGFR tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC). However, the real efficacy of osimertinib for this subset remains elusive. We performed this study to investigate the real efficacy of osimertinib for Chinese advanced NSCLC patients harboring EGFR ex20 ins mutations. Materials and methods We retrospectively collected data of metastatic NSCLC patients with EGFR ex20 ins mutations who were treated with osimertinib 80 mg or 160 mg once daily in our center from June 2017 to May 2020. Progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) were assessed. Results A total of 62 cases with EGFR ex20 ins mutations were included, and the major insertion variant was D770_N771insSVD and V769_D770insASV (45.1 %). Concurrent TP53 mutation was most commonly observed (59.7 %). Four patients showed partial response, 29 cases with stable disease and 29 showed progressive disease as best response to osimertinib (ORR: 6.5 %, DCR: 53.2 %). The median PFS (mPFS) in total patients was 2.3 (95 %CI, 1.5–3.1) months. Patients harboring A763_Y764insFQEA/D770delinsGY variants showed numerically longer mPFS than those with other variants (4.2 vs. 2.2 months, P = 0.164). Patients who failed to osimertinib and occurred extracranial progression showed similar mPFS to those with intracranial progression (2.3 vs. 1.9 months, P = 0.142). Median PFS was not significantly different between patients who received osimertinib 80mg or 160mg once daily (2.5 vs. 1.3 months, P = 0.161), either with no significance when it used in fist-line setteing or bove (3.0 vs. 2.2 months, P = 0.639). Conclusion The unique insertion variant A763_Y764insFQEA and D770delinsGY might better respond to osimertinib than other ex20 ins subtypes. Osimertinib either 80 mg or 160 mg once daily showed less activity in Chinese NSCLC patients harboring diverse EGFR ex20 ins mutations.

Hongfei Xu,1,* Hongyu Ji,1,2,* Zerong Li,1,3 Wenmei Qiao,1,4 Chenghao Wang,1 Jingling Tang1 1Department of Pharmaceutics, School of Pharmacy, Harbin Medical University, Harbin, 150086, People’s Republic of China; 2Department of Pharmacy, The Second Affiliated Hospital, Harbin Medical University, Harbin, 150086, People’s Republic of China; 3Department of Pharmacy, The Second People’s Hospital of Shenzhen, The First Affiliated Hospital of Shenzhen University, Shenzhen, 518028, People’s Republic of China; 4Department of Pharmacy, Shenzhen Luohu Hospital Group-Shenzhen Luohu Traditional Chinese Medicine Hospital, Shanghai University of Traditional Chinese Medicine-Shenzhen Hospital, Shenzhen, 518001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jingling TangDepartment of Pharmaceutics, School of Pharmacy, Harbin Medical University, Harbin, 150086, People’s Republic of ChinaTel +86-0451-86660103Fax +86-0451-86664073Email tangjl430@hotmail.comBackground: Pulmonary arterial hypertension (PAH) is characterized by abnormal proliferation of vascular endothelial and smooth muscle cells and causes occlusion of pulmonary arterioles that eventually results in right heart failure and death. The platelet-derived growth factor (PDGF) plays a prominent role in abnormal remodeling of pulmonary resistance vessels. Imatinib mesylate (IM), a PDGF-receptor tyrosine kinase inhibitor, was able to ameliorate PAH by reversing pulmonary vascular remodeling.Methods: In the present study, IM-loaded liposomes (IM-LPs) were developed and administered via the pulmonary route to delay the drug release and improve patient compliance for the treatment of PAH. The IM-LPs were prepared by the transmembrane gradient method with the spherical vesicles. The compatibility of the IM-LPs was studied by determining the viability of pulmonary arterial smooth muscle cells (PASMCs). Particle uptake by rat PASMCs was evaluated by incubating the particles with rat PASMCs. Pharmacokinetic studies were performed in male SD rats.Results: The IM-LPs showed an average size of 101.6 ± 50.80 nm with a zeta potential value of 19.66 ± 0.55 mV, a PDI of 0.250 and 81.96% ± 0.98% drug entrapment efficiency, meanwhile displayed a sustained release profile. Liposomes obviously increased intracellular accumulation of Rhodamine B by PASMCs using the fluorescence microscopic. Following intratracheal administration to rats, IM-LPs not only extended the half-life of IM, but also prolonged retention of IM compared with plain IM solution after intratracheal and intravenous administration.Conclusion: The study show potential applications of the LPs for pulmonary delivery of IM and the method for the development of LPs in sustained release of IM for better therapeutic outcomes. Conclusively, the prepared IM-LPs were well designed in nanosized ranges and may be a promising formulation for pulmonary delivery of IM.Keywords: imatinib mesylate, pulmonary arterial hypertension, liposomes, pulmonary delivery, pharmacokinetics

Lessons Learned Apatinib has potential as an effective and safe second-line or higher treatment for patients with chemotherapy-refractory esophageal squamous cell carcinoma (ESCC). Clinical safety is of potential concern when administering apatinib to patients with uncontrolled esophageal lesions or severe invasion of trachea, bronchi, or major blood vessels. To the best of the authors' knowledge, this is the first prospective phase II study to investigate apatinib for patients with chemotherapy-refractory ESCC. Apatinib could provide an alternative option for ESCC after first-line or higher therapy in carefully selected patients. Background The aim of this study was to evaluate the efficacy and adverse effects of the oral vascular endothelial growth factor receptor 2 (VEGFR-2) tyrosine kinase inhibitor apatinib in patients with chemotherapy-refractory esophageal squamous cell carcinoma (ESCC). Methods We enrolled patients with chemotherapy-refractory ESCC. All patients received continuous apatinib 500 mg once daily. Results Between July 2017 and August 2018, 40 patients were recruited, of whom 5 (12.5%) had uncontrolled primary tumors. Additionally, three patients with partial response (PR) and 23 with stable disease (SD) were observed for overall response rate (ORR) of 7.5% and disease control rate (DCR) of 65.0%. Median progression-free survival (PFS) was 3.8 months (95% confidence interval [CI], 2.2–5.4); median overall survival (OS) was 5.8 months (95% CI, 3.2–8.4). Common adverse effects were fatigue (15%), hypertension (12.5%), and palmar-plantar erythrodysesthesia syndrome (10%). Two cases of death from massive bronchopulmonary hemorrhage were observed, and esophageal fistula occurred in another two patients. Notably, both patients with esophageal fistula and one patient with massive fatal bronchopulmonary hemorrhage were individuals with uncontrolled primary tumors (3/5, 60%). Fatal bronchopulmonary hemorrhage in a second patient was associated with major blood vessel invasion. Conclusion Apatinib has potential as an effective and safe treatment for patients with chemotherapy-refractory ESCC whose primary tumors are controlled and without severe invasion of trachea, bronchi, or major blood vessels.

Renal cell carcinoma is no longer considered a monolithic disease, but a group of different entities exhibiting unique molecular alterations requiring a tailored systemic approach. One of the remaining challenges is the identification of the best candidate for a particular therapeutic regimen.: Current literature regarding the recent advances and treatment options in systemic therapy for metastatic RCC, and issues pertaining to the available biomarkers tested to date for a correct treatment stratification.: Underlying biology of RCC will still drive the development of new treatment agents/combinations that will be tested in earlier stages of the disease, and probably prove to have a role in the neoadjuvant/adjuvant settings. The correct characterization of the tumor microenvironment through transcriptomic analysis should help to overcome the issues related to tumor heterogeneity. Preclinical ex-vivo models will enlarge our current knowledge regarding the potential immune-escape mechanisms exhibited by RCC, and facilitate a better monitoring of the response to therapy. New tracers, image modalities, and tests aimed at detecting and analyzing tumor-circulating cells will improve our clinical performance through a better identification of the metastatic site locations and their variable histologic patterns, and ultimately their behavior in response to treatment.

Background Preventing premature ovarian failure (POF) is a major challenge in oncology. With conventional regimens, cytotoxicity-associated POF involves primordial follicles (PF) pool depletion by apoptosis or overactivation mechanisms, notably mediated by the ABL/TAp63 and PI3K/Akt/mTOR pathways. New anticancer treatments have been designed to target pathways implicated in tumor growth. Although concerns regarding fertility arise with these targeted therapies, we hypothesized that targeted therapies may exert off-tumor effects on PF that might delay POF. We provide an overview of evidence concerning these off-tumor effects on PF. Limitations and future potential implications of these findings are discussed. Design PubMed was searched by combining Boolean operators with the following keywords: fertility, ovarian, follicle, anti-tumoral, cancer, targeted, cytotoxic, and chemotherapy. Results Cisplatin-related PF apoptosis via the ABL/TAp63 pathway was targeted with a tyrosine kinase inhibitor, imatinib, in mice, but effects were recently challenged by findings on human ovarian xenografts in mice. In cyclophosphamide-treated mice, PI3K/Akt/mTOR pathway inhibition with mTOR inhibitors and AS101 preserved the PF pool. Proteasome and GSK3 inhibitors were evaluated for direct and indirect follicle DNA damage prevention. Surprisingly, evidence for cytotoxic drug association with PF pool preservation was found. We also describe selected non-anticancer molecules that may minimize gonadotoxicity. Conclusion Not all anticancer treatments are associated with POF, particularly since the advent of targeted therapies. The feasibility of associating a protective drug targeting PF exhaustion mechanisms with cytotoxic treatments should be evaluated, as a way of decreasing the need for conventional fertility preservation techniques. Further evaluations are required for transfer into clinical practice. Implications for Practice Anticancer therapies are associated with infertility in 10%–70% of patients, which is the result of primordial follicles pool depletion. Alone or associated with gonadotoxic treatments, some targeted therapies may exert favorable off-targets effects on the primordial follicle pool by slowing down their exhaustion. Current evidence of these effects relies on murine models or human in vitro models. Evaluation of these protective strategies in humans is challenging; however, if these results are confirmed with clinical and biological data, it not only could be a new approach to female fertility preservation but also would change standard fertility strategies.