Efficacy Of Tyrosine Kinase Inhibitors Research Articles

ALK fusion variant 3a/b, concomitant mutations, and high PD-L1 expression were associated with unfavorable clinical response to second-generation ALK TKIs in patients with advanced ALK-rearranged non-small cell lung cancer (GASTO 1061)

ObjectivesSecond-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have significantly improved clinical outcomes in patients with advanced ALK-positive non-small cell lung cancer (NSCLC), but clinical responses vary widely. In this study, the impacts of ALK fusion variants, concomitant mutations, and PD-L1 expression on the clinical response were evaluated in patients receiving second-generation ALK TKIs. Materials and methodsWe retrospectively enrolled 193 patients with ALK-rearranged advanced NSCLC who received second-generation ALK TKIs at Sun-yat Sen University Cancer Center from January 2015 to December 2020. The ALK fusion variants and concomitant mutations were identified with next-generation sequencing, while PD-L1 expression was assessed by immunohistochemistry. ResultsThe median progression-free survival (PFS) was significantly shorter for variant 3a/b than for other variants (9.93 months vs 16.97 months, HR 1.941, P = 0.0014). Baseline concomitant mutations were significantly associated with shorter PFS while on ALK TKIs (median PFS, 10.87 months vs 22.47 months, HR 1.984, P = 0.002). A subset of 68 patients was analyzed for PD-L1 expression: TPS 0% in 32.4% (22/68) of the patients, 1–49% in 30.9% (21/68) of the patients, and ≥ 50% in 36.7% (25/68) of the patients. Expression of PD-L1 was significantly associated with variant 3a/b and concomitant mutations. Median PFS was shorter in patients with high PD-L1 expression (median PFS in patients with PD-L1 TPS of 0% vs 1–49% vs ≥ 50% were 27.43 months vs 30.63 months vs 9.50 months, respectively, P = 0.001). In multivariate analysis, PD-L1 expression (TPS ≥ 50%), concomitant mutations, and variant 3a/b remained negative prognostic factors for the clinical efficacy of second-generation ALK TKIs in ALK-rearranged non-small cell lung cancer. ConclusionALK fusion variant 3a/b, concomitant mutations, and high PD-L1 expression were associated with unfavorable clinical response to second-generation TKIs in ALK-rearranged NSCLC.

Systemic Treatments with Tyrosine Kinase Inhibitor and Platinum-Based Chemotherapy in Patients with Unresectable or Metastatic Hepatocholangiocarcinoma

Backgrounds and Aims: Even if no systemic treatment is currently validated for unresectable hepatocellular-cholangiocarcinoma (cHCC-CCA), tyrosine kinase inhibitors (TKIs) and platinum-based chemotherapy are frequently used in clinical practice. Our study aims to describe the effectiveness of first-line systemic treatments in patients with cHCC-CCA. Patients and Methods: Patients with histological diagnosis of unresectable or metastatic cHCC-CCA confirmed by a centralized review (WHO classification 2019) and who received systemic treatment from 2009 to 2020 were included retrospectively in 11 centers. The outcomes of patients with cHCC-CCA were compared with patients with hepatocellular carcinoma (HCC) treated by sorafenib (n = 117) and with intrahepatic cholangiocarcinoma (iCCA, n = 94) treated mainly by platinum-based chemotherapy using a frailty Cox model. The efficacy of TKIs and platinum-based chemotherapies in patients with cHCC-CCA was assessed using a doubly robust estimator. Results: A total of 83 patients with cHCC-CCA were included and were predominantly male (72%) with underlying cirrhosis (55%). 67% of patients had extrahepatic metastases and 31% macrovascular tumor invasion. cHCC-CCAs were more often developed on cirrhosis (55.4%) than iCCA (26.6%) but less frequently than HCC (80.2%) (p < 0.001). Both HCC (36.8% and cHCC-CCA (66.2%) had less frequent extrahepatic metastases than iCCA (81%) (p < 0.001). Unadjusted overall survival (OS) was better in iCCA (13 months) compared to cHCC-CCA (12 months) and HCC (11 months) (p = 0.130). In multivariable analysis, after adjustment by a Cox frailty model, patients with cHCC-CCA had the same survival as HCC and iCCA (HR = 0.67, 95% CI: 0.37–1.22, p = 0.189 and HR = 0.66, 95% CI: 0.43–1.02, p = 0.064, respectively). ALBI score (HR = 2.15; 95% CI: 1.23–3.76; p = 0.009), ascites (HR = 3.45, 95% CI: 1.31–9.03, p = 0.013), and tobacco use (HR = 2.29, 95% CI: 1.08–4.87, p = 0.032) were independently associated with OS in patients with cHCC-CCA. Among patients with cHCC-CCA, 25 patients treated with TKI were compared with 54 patients who received platinum-based chemotherapies. Patients treated with TKI had a median OS of 8.3 months compared to 11.9 months for patients treated with platinum-based chemotherapy (p = 0.86). After a robust doubly adjustment on tumor number and size, vascular invasion, ALBI, MELD, and cirrhosis, the type of treatment did not impact OS (HR = 0.92, 95% CI: 0.27–3.15, p = 0.88) or progression-free survival (HR = 1.24, 95% CI: 0.44–3.49, p = 0.67). Conclusions: First-line systemic treatments with TKIs or platinum-based chemotherapies have similar efficacy in patients with unresectable/metastatic cHCC-CCA. The ALBI score predicts OS.

Efficacy Predictors of the Third-Line Tyrosine Kinase Inhibitor Therapy in Patients with Chronic Phase of Chronic Myeloid Leukemia: Results of a Multi-Center Study

Background. The introduction of tyrosine kinase inhibitors (TKIs) into real-world clinical practice considerably improved the prognosis for patients with chronic myeloid leukemia (CML). However, during long-term follow-up, almost 1/2 and 2/3 of patients in the chronic phase (CP) discontinue TKI therapy of the first or second line, respectively. According to the Russian and International clinical guidelines, the third-line therapy should include allogeneic hematopoietic stem cell transplantation (allo-HSCT). And yet, some patients on the third-line therapy achieve and sustain optimal response on long-term TKI administration. Up to now, no clear-cut prognostic factors of TKI efficacy in the third-line therapy have been identified. This creates a challenge for treatment decision making after the failures of two lines of TKI therapy. Aim. To assess the efficacy of the third-line TKI therapy in real-world clinical practice and to identify the factors affecting the long-term therapy outcomes in CML-CP. Materials &amp; Methods. The retrospective study enrolled 73 CML-CP patients aged &gt; 18 years, treated with TKIs in the third-line at 5 specialized institutions in Saint Petersburg and Leningrad Region. Among the patients there were 26 men (35 %). The median age of the patients was 51 years (range 25-88 years). Results. With the median (range) third-line TKI therapy duration of 14 (1-120) months, the rate of complete cytogenetic response (CCR) was 30 % (п = 22) in the total cohort. The median time before achieving CCR was 9 (4-25) months. With the median follow-up time from the beginning of third-line TKI therapy till the last visit of 25 (3-136) months, progression to accelerated phase or blast crisis was observed only in 13 (17 %) out of 73 patients. Death was reported in 26 % (n = 19) of cases, among them 5 patients whose death was not CML-associated. At the last visit, 13/73 (18 %) patients were still on third-line TKI therapy. Direct and longterm therapy outcomes, including achievement of CCR and assessment of overall and progression-free survivals, were significantly better in patients with any cytogenetic response (CR) than in those without it or without complete hematologic response. Conclusion. The implementation of TKIs in the third-line CML-CP therapy seems to be suitable for patients with at least some CR, especially if an optimal donor of hematopoietic stem cells is unavailable or if the risk of severe allo-HSCT complications is too high.

Clinical Effect of Tyrosine Kinase Inhibitors in the Treatment of P230 Chronic Myeloid Leukemia

To observe the curative efficacy of tyrosine kinase inhibitors (TKIs) in the treatment of e19a2 transcript (P230) CML chronic phase (CML-CP) patients. The clinical data of 11 P230 CML-CP patients were collected from July 2008 to December 2019. Blood routine examination, bone marrow cytology, chromosome, and BCR-ABL qualitative and quantitative tests were performed at initial diagnosis. After TKIs treatment, BCR-ABL (P230)/ABL in peripheral blood was regularly detected to evaluate molecular response by real-time quantitative PCR. There were 11 patients (7 males and 4 females) in chronic phase from 6 domestic hospitals enrolled, their median age was 46 years old (range from 19 to 56 years old). Among 4 patients treated with imatinib (400 mg, qd) firstly, 3 cases switched to nilotinib (400 mg, bid) and 1 case switched to dasatinib (100 mg, qd) due to failure to achieve best molecular response at the landmark time or mutation of ABL kinase. Then major molecular response (MMR) was obtained within 1 year. In addition, 5 patients were treated with nilotinib (300 mg, bid) and 2 patients with dasatinib (100 mg, qd) as first-line treatment, all of them got MMR within 6 months. For intolerance or resistance to imatinib, second-generation TKIs can enable P230 CML patients to achieve deeper molecular response, and MMR in a short time.

Antimetabolic cooperativity with the clinically approved l-asparaginase and tyrosine kinase inhibitors to eradicate CML stem cells

ObjectiveLong-term treatment with tyrosine kinase inhibitors (TKI) represents an effective cure for chronic myeloid leukemia (CML) patients and discontinuation of TKI therapy is now proposed to patient with deep molecular responses. However, evidence demonstrating that TKI are unable to fully eradicate dormant leukemic stem cells (LSC) indicate that new therapeutic strategies are needed to control LSC and to prevent relapse. In this study we investigated the metabolic pathways responsible for CML surviving to imatinib exposure and its potential therapeutic utility to improve the efficacy of TKI against stem-like CML cells. MethodsUsing complementary cell-based techniques, metabolism was characterized in a large panel of BCR-ABL+ cell lines as well as primary CD34+ stem-like cells from CML patients exposed to TKI and L-Asparaginases. Colony forming cell (CFC) assay and flow cytometry were used to identify CML progenitor and stem like-cells. Preclinical models of leukemia dormancy were used to test the effect of treatments. ResultsAlthough TKI suppressed glycolysis, compensatory glutamine-dependent mitochondrial oxidation supported ATP synthesis and CML cell survival. Glutamine metabolism was inhibited by L-asparaginases such as Kidrolase or Erwinase without inducing predominant CML cell death. However, clinically relevant concentrations of TKI render CML cells susceptible to Kidrolase. The combination of TKI with Lasparaginase reactivates the intinsic apoptotic pathway leading to efficient CML cell death. ConclusionTargeting glutamine metabolism with the FDA-approved drug, Kidrolase in combination with TKI that suppress glycolysis represents an effective and widely applicable therapeutic strategy for eradicating stem-like CML cells.

Perturbation of p38α MAPK as a Novel Strategy to Effectively Sensitize Chronic Myeloid Leukemia Cells to Therapeutic BCR-ABL Inhibitors.

Chronic myeloid leukemia (CML) is a hematopoietic malignancy characterized by the presence of the BCR-ABL oncogene. Therapeutic regimens with tyrosine kinase inhibitors (TKIs) specifically targeting BCR-ABL have greatly improved overall survival of CML. However, drug intolerance and related toxicity remain. Combined therapy is effective in reducing drug magnitude while increasing therapeutic efficacy and, thus, lowers undesired adverse side effects. The p38 MAPK activity is critically linked to the pathogenesis of a number of diseases including hematopoietic diseases; however, the role of each isozyme in CML and TKI-mediated effects is still elusive. In this study, we used specific gene knockdown to clearly demonstrate that the deficiency of p38α greatly enhanced the therapeutic efficacy in growth suppression and cytotoxicity of TKIs, first-generation imatinib, and second generation dasatinib by approximately 2.5–3.0-fold in BCR-ABL-positive CML-derived leukemia K562 and KMB5 cells. Knockdown of p38β, which displays the most sequence similarity to p38α, exerted distinct and opposite effects on the TKI-mediated therapeutic efficacy. These results show the importance of isotype-specific intervention in enhancing the therapeutic efficacy of TKI. A highly specific p38α inhibitor, TAK715, also significantly enhanced the imatinib- and dasatinib-mediated therapeutic efficacy, supporting the feasibility of p38α deficiency in future clinic application. Taken together, our results demonstrated that p38α is a promising target for combined therapy with BCR-ABL-targeting tyrosine kinase inhibitors for future application to increase therapeutic efficacy.

A Multicenter, Prospective Study for Pediatric Chronic Myeloid Leukemia in Chronic Phase: The JPLSG CML-08 Study

Background: Tyrosine kinase inhibitor (TKI) has been used in pediatric chronic myeloid leukemia (CML) for more than 10 years, but only a few prospective clinical studies have been conducted in pediatric patients with CML due to their rarity. We conducted the JPLSG CML-08 study to determine the efficacy and tolerability of TKIs in children and adolescents with newly diagnosed CML in chronic phase (CML-CP).Methods: The JPLSG CML-08 study was a prospective multicenter observational study (UMIN000002581). Patients under 18 years of age with untreated BCR-ABL1-positive CML-CP were eligible and treated according to the modified ELN-2009 recommendation, and the efficacy and safety of TKIs were evaluated.Results: From October 2009 until September 2014, 79 patients were enrolled in 46 hospitals in Japan. A total of 78 patients (49 males and 29 females) were eligible for inclusion. Median age at diagnosis was 11 years (range, 1-17). Median observational period for survivors was 82 months (range, 48-118). Median WBC, Hb and platelet counts were 275x10 9/L (range, 8-765), 9.6g/dL (range, 5.8-14.6) and 560x10 9/L (range, 110-2875), respectively. Splenomegaly was found in 76%. High risk of Sokal, Hasford, EUTOS, and ELTS scores were observed in 21, 13, 27, and 9%, respectively. Clonal chromosome abnormalities in Ph-positive cells occurred in 1 patient at diagnosis. Imatinib, dasatinib, and, nilotinib were used as a first-line treatment in 69 (88%), 7 (9%), and 2 (3%) patients, respectively. The median initial dose of imatinib, dasatinib, and nilotinib was 276, 63, and 262mg/m2, respectively. 5y-PFS and OS was 96.2% (95%CI, 88.6 to 98.7%) and 97.4% (95%CI, 90.1 to 99.4%), respectively. Deaths were observed in 2 patients due to transplant complications. Hematopoietic cell transplantation was conducted in 14 patients (18%). Nine patients (12%) discontinued TKI with the aim of treatment-free remission (TFR), and five of them achieved TFR. In 69 patients with first-line imatinib, complete hematologic response was achieved in 95.7% at 3 months, complete cytogenetic response in 75.4% at 12 months, major molecular response (MMR) in 40.1% at 18 months, and MR4.0 in 52.8% at 60 months; If a transplant was performed, the follow-up period was censored at the date of transplant. Of the 69 patients, 52% changed treatment from imatinib to another TKI or transplant due to poor response, and 20% did due to intolerance. The most common cause of intolerance to imatinib was musculoskeletal events. BCR-ABL1 (IS) <10% at 3 months strongly correlated with higher achievement of MMR, MR4.0, and MR4.5. The EUTOS score was significantly associated with achievement of IS <10% at 3 months. Patients with a first-line second-generation TKI had a higher cumulative incidence of MR4.5 (P = 0.0191) than patients with a first-line imatinib. Second-generation TKI was used as first-line therapy only in patients older than 9 years, but other clinical characteristics, including risk scores, did not differ significantly between the two groups. The incidence of grade 3/4 adverse events (≥ 10%) included neutropenia (47%), anemia (39%), leukopenia (13%), arthralgia (13%), and myalgia (11%) for imatinib, neutropenia (21%), anemia (13%), and thrombocytopenia (11%) for dasatinib, and neutropenia (14%), elevated ALT (14%), hyperbilirubinemia (14%), skin rash (14%), and high CPK (14%) for nilotinib. Gastrointestinal bleeding was an adverse event specific to dasatinib (11% in all grades).Conclusion: This clinical study extends and confirms previous data showing that first-line treatment with imatinib is effective in children and adolescents, with response rates similar to those seen in adults. Although longer follow-up is needed to fully assess the long-term toxic effects, adverse events with imatinib, dasatinib, and nilotinib have been acceptable. As reported in adults, there was an advantage in selecting second-generation TKI over imatinib as first-line therapy to achieve deep molecular remission (DMR). Since discontinuation of TKI after achieving DMR is the preferred strategy, second-generation TKI is expected to become the standard therapy for children and adolescents. DisclosuresNo relevant conflicts of interest to declare.

RNA Polymerase II Is a Therapeutic Target to Overcome FLT3 Inhibitor Resistance Mediated By the Bone Marrow Microenvironment

Background: Gilteritinib is a clinically active FLT3 tyrosine kinase inhibitor (TKI) approved for relapsed/refractory FLT3-mutant AML, but nearly all patients treated with gilteritinib and other FLT3 TKIs eventually develop clinical resistance. Activating RAS/MAPK pathway mutations are a predominant non-FLT3 dependent resistance mechanism in patients treated with gilteritinib. AML blasts can also develop FLT3 TKI resistance secondary to paracrine MAPK activation stimulated by FLT3 Ligand, FGF2, or other protective cytokines within the bone marrow microenvironment (BME). To identify potential targets that sensitize AML cells to gilteritinib-induced apoptosis in a model of the BME, we performed a genome-wide CRISPR/Cas9 death screen in MOLM-14 FLT3-ITD+ human AML cells cultured in bone marrow stromal cell conditioned media. We hypothesize that identified genes represent promising combinatorial therapeutic targets that can enhance clinical efficacy of FLT3 TKIs in AML.Methods: To model stroma-mediated TKI resistance, we used the HS5 human bone marrow stromal cell line that secretes multiple cytokines (G-CSF, GM-CSF, FGF2) and supports myeloid progenitor proliferation in co-culture. MOLM-14 CRISPRi cells transduced with CRISPRi-v2 genome-wide sgRNA library were cultured in HS5 conditioned media for 24 hours and then treated with gilteritinib 250 nM. Cells were stained with a fluorogenic caspase 3/7 reagent and then fixed after 24 hours of drug treatment. Caspase-3 positive cells were sorted from the entire drug-treated cell population by FACS and guide RNAs enriched or depleted in this sample as compared to an untreated T0 sample were determined by NGS.Results: We identified several gene-level hits that were enriched in the apoptotic population (FDR <0.2). Among these, we identified multiple transcription factors or regulators of transcriptional activation. The latter included multiple components of RNA pol II machinery (POLR2G, RTF1) and multiple subunits of Mediator (MED12, MED30, MED21, MED11), a complex that regulates RNA pol II activity and has been shown to modulate super-enhancer-associated genes in AML cells. To validate select hits, we transduced MOLM-14 and MV411 CRISPRi cells with a tetracycline-inducible sgRNA expression vector. Using this system, we found that conditional knockdown of MED12, the top scoring Mediator subunit in our screen, significantly sensitized MOLM-14 (FgH1) cells to gilteritinib while modestly augmenting the cytotoxicity of gilteritinib in MV411 (FgH1) cells when compared to a non-targeting sgRNA. Functionally, MED12 associates with MED13, Cyclin C, and CDK8 to form the CDK8 kinase module of Mediator. MED12 knockdown, as expected, led to suppression of STAT1 S7272 and STAT5 S726 phosphorylation, known targets of CDK8. Based on these results, we hypothesized that CDK8 inhibition would augment apoptosis induced by gilteritinib in HS5 conditioned media. Using SEL120, a novel CDK8 inhibitor already in early phase AML clinical trials, we performed an 8 x 8 dose matrix drug synergy analysis of gilteritinib and SEL120 in multiple FLT3-mutant AML cell lines using Bliss independence modeling. We found that SEL120 was synergistic with gilteritinib in inducing apoptosis in MOLM-14 and MV411 cells in HS5 conditioned media (Bliss synergy scores of 2.44 and 11.45 with most synergistic area scores of 10.91 and 26.85, respectively). We also found combinatorial activity against MOLM-14 cells harboring secondary NRAS activating mutations (G12C and Q61K), suggesting the therapeutic combination could potentially overcome cell intrinsic and extrinsic MAPK-activating resistance mechanisms. Lastly, we found that gilteritinib and SEL120 combined to impart greater cytotoxicity than either drug alone in a primary sample (AML #1) from a patient with newly diagnosed AML possessing a FLT3-ITD mutation at high mutant allele ratio.Conclusions: The results and validation of our CRISPRi screen suggest that combined CDK8 and FLT3 inhibition is a novel strategy for augmenting gilteritinib cytotoxicity. Assessment of the activity of the combination in additional primary AML samples and in vivo murine models of AML is planned. Additional candidate targets already described and other Mediator and RNA pol II subunits from our screen are also being further evaluated to precisely define the transcriptional programs that influence FLT3 inhibitor resistance. DisclosuresLogan: Pharmacyclics, Astellas, Jazz, Kite, Kadmon, Autolus, Amphivena: Research Funding; Amgen, Pfizer, AbbVie: Consultancy. Gilbert: Denali Therapeutics: Ended employment in the past 24 months, Other: Spouse/Significant Other's Employment; GSK: Consultancy, Research Funding; AstraZeneca: Research Funding; Chroma Medicine: Consultancy, Other: Co-founder. Smith: Revolutions Medicine: Research Funding; AbbVie: Research Funding; Daiichi Sankyo: Consultancy; Amgen: Honoraria; FUJIFILM: Research Funding; Astellas Pharma: Consultancy, Research Funding.

Landscape and Clonal Dominance of Co-occurring Genomic Alterations in Non–Small-Cell Lung Cancer Harboring MET Exon 14 Skipping

PURPOSEMET exon 14 skipping alterations (METex14) comprise a diverse set of actionable oncogene drivers in non–small-cell lung cancer (NSCLC). Recent studies have established the efficacy of tyrosine kinase inhibitors for this patient population. The landscape of co-occurring genetic alterations in METex14 NSCLC and their potential impact to therapeutic sensitivities has not yet been fully described.MATERIALS AND METHODSMETex14 NSCLC cases were collected from three cohorts: the VISION trial, and data sets from Guardant360 and GenePlus. Clinicopathologic characteristics and METex14 mutation sites were analyzed and compared across data sets. Co-occurring genetic alterations and the clonality relationships to METex14 were evaluated.RESULTSOf 40,824 NSCLCs, 692 METex14 cases (1.7%) were identified, including 332 in Guardant360, 188 in VISION, and 172 in GenePlus. The demographics and mutation type and/or sites were similar in the Asian versus Western cohorts. MET amplification, which were found to be associated with sensitivity to MET kinase inhibitors, co-occurs in 7.6%-13.8% of cases, whereas kinase domain secondary mutation of MET co-occurs in 5%-6%. When co-occurring with METex14, EGFR mutations were often identified as the dominant clone (78%, 7 of 9), whereas when co-occurring, METex14 (39%, 7 of 18) and KRAS (44%, 8 of 18) had similar rates of clonal dominance. PIK3CA and PTEN mutations were almost always subclones (89%, 16 of 18) to METex14. Moreover, RET-CCDC6 fusion and EGFR mutation were detected following crizotinib treatment in two patients, suggesting novel mechanisms of resistance.CONCLUSIONMETex14 mutations frequently co-occur with other potential driver oncogenes with differing patterns of clonal dominance observed among the drivers. This cellular context can provide insights into whether METex14 is acting as a primary oncogenic driver or resistance mechanism and help guide treatment choices.

Effect of Epigallocatechin-3-Gallate on EGFR Signaling and Migration in Non-Small Cell Lung Cancer.

The epidermal growth factor receptor (EGFR) is one of the most well-studied molecular targets in non-small cell lung cancer (NSCLC) and tyrosine kinase inhibitors have been shown to be effective in the treatment of advanced NSCLC. Nevertheless, the efficacy of tyrosine kinase inhibitors could be compromised by additional mutations in EGFR and compensatory activations of other pathways. Epigallocatechin-3-gallate (EGCG), the main bioactive molecule in green tea, acts as a tyrosine kinase inhibitor toward cancer cells overexpressing EGFR (wild-type). However, little information has been reported on the effect of EGCG on EGFR with activating mutations. In this study, we evaluated the ability of EGCG to inhibit EGFR signaling activation in three different NSCLC cell lines containing wild-type EGFR or EGFR with additional mutations. The effect on proliferation, apoptosis, migration, and vinculin expression was then studied. Overall, our results demonstrate that EGCG polyphenol inhibits cell proliferation and migration in NSCLC cell lines, although with different efficacy and mechanisms. These data may be of interest for an evaluation of the use of EGCG as an adjunct to NSCLC therapies.

Recent advances and new insights in the management of early-stage epidermal growth factor receptor-mutated non-small-cell lung cancer.

Patients with early-stage non-small-cell lung cancer (NSCLC) are candidates for curative surgery; however, despite multiple advances in lung cancer management, recurrence rates remain high. Adjuvant chemotherapy has been demonstrated to significantly prolong overall survival (OS), but this benefit is modest and there is an urgent need for effective new therapies to provide a cure for more patients. The high efficacy of tyrosine kinase inhibitors (TKIs) against epidermal growth factor receptor-mutated (EGFR) in patients with advanced EGFR-mutated NSCLC has led to the evaluation of these agents in early stages of the disease. Multiple clinical trials have evaluated the safety and efficacy of EGFR TKIs as an adjuvant treatment, in patients with resected EGFR-mutated NSCLC, and shown that they significantly prolong disease-free survival (DFS), but this benefit does not translate to OS. Recently, an interim analysis of the ADAURA trial demonstrated that, surprisingly, osimertinib improved DFS. This led to the study being stopped early, leaving many unanswered questions about its potential effect on OS and its incorporation as a standard adjuvant treatment in this patient subgroup. These targeted agents are also being evaluated in locally-advanced disease, with promising results, although prospective studies with larger sample sizes are needed to confirm these results. In this article, we review the most relevant studies on the role of EGFR TKIs in the management of early-stage EGFR-mutated NSCLC.

EGFR Exon 20 Insertion in Metastatic Non-Small-Cell Lung Cancer: Survival and Clinical Efficacy of EGFR Tyrosine-Kinase Inhibitor and Chemotherapy.

Simple SummaryEGFR exon 20 insertions are rare genetic alterations in non-small-cell lung cancers (NSCLCs) that are usually unresponsive to approved EGFR tyrosine kinase inhibitors (TKIs), but data is limited about this population. We aim to describe clinical features, survival, and response to chemotherapy and TKIs in this patient population.EGFR exon 20 insertions are rare genetic alterations in non-small-cell lung cancers (NSCLCs) that are usually unresponsive to approved EGFR tyrosine kinase inhibitors (TKIs). In this paper, we describe the clinical characteristics, efficacy of EFGR TKIs and chemotherapy, and resulting survival in this population. We retrospectively collected patients with EGFR exon 20 insertions (Exon20ins) from 11 French genetic platforms and paired them (1:2 ratio) with classic Exon 19/21 EGFR mutation patients (controls). Between 2012 and 2017, 35 Exon20ins patients were included. These patients were younger at diagnosis than the controls. All Exon20ins patients who were treated with first-line EGFR TKIs (n = 6) showed progressive disease as the best tumor response. There was no significant difference in the tumor response or the disease control rate with first-line platinum-based chemotherapy between the two groups. A trend towards shorter overall survival was observed in Exon20ins vs. controls (17 months (14—not reach(NR) 95% confidence interval(CI) vs. 29 months (17–NR 95%CI), p = 0.09), respectively. A significant heterogeneity in amino acid insertion in EGFR exon 20 was observed. EGFR exon 20 insertions are heterogeneous molecular alterations in NSCLC that are resistant to classic EGFR TKIs, which contraindicates their use as a first-line treatment.

MiR-125a-3p and MiR-320b Differentially Expressed in Patients with Chronic Myeloid Leukemia Treated with Allogeneic Hematopoietic Stem Cell Transplantation and Imatinib Mesylate.

Chronic myeloid leukemia (CML), a hematopoietic neoplasm arising from the fusion of BCR (breakpoint cluster region) gene on chromosome 22 to the ABL (Abelson leukemia virus) gene on chromosome 9 (BCR-ABL1 oncogene), originates from a small population of leukemic stem cells with extensive capacity for self-renewal and an inflammatory microenvironment. Currently, CML treatment is based on tyrosine kinase inhibitors (TKIs). However, allogeneic hematopoietic stem cell transplantation (HSCT-allo) is currently the only effective treatment of CML. The difficulty of finding a compatible donor and high rates of morbidity and mortality limit transplantation treatment. Despite the safety and efficacy of TKIs, patients can develop resistance. Thus, microRNAs (miRNAs) play a prominent role as biomarkers and post-transcriptional regulators of gene expression. The aim of this study was to analyze the miRNA profile in CML patients who achieved cytogenetic remission after treatment with both HSCT-allo and TKI. Expression analyses of the 758 miRNAs were performed using reverse transcription quantitative polymerase chain reaction (RT-qPCR). Bioinformatics tools were used for data analysis. We detected miRNA profiles using their possible target genes and target pathways. MiR-125a-3p stood out among the downregulated miRNAs, showing an interaction network with 52 target genes. MiR-320b was the only upregulated miRNA, with an interaction network of 26 genes. The results are expected to aid future studies of miRNAs, residual leukemic cells, and prognosis in CML.

Use of tyrosine kinase inhibitors during pregnancy for oncogenic-driven advanced non-small cell lung carcinoma

IntroductionLung cancer associated with pregnancy is rare but on the increase. The use of tyrosine kinase inhibitor (TKI) therapy for advanced oncogenic-driven non-small cell lung carcinoma (NSCLC) has improved overall survival. Oncological and obstetric outcomes of patients diagnosed with NSCLC and treated by TKIs during pregnancy have been poorly evaluated. MethodsThree cases of NSCLC treated by TKIs during pregnancy were collected from the prospective database of the Cancer Associé à La Grossesse (CALG) network (France) in addition to eight cases identified by a systematic review performed between 2000 and 2021. ResultsAmong the eleven reported patients, six received an EGFR- and five an ALK-TKI. All patients were young nonsmokers and four had brain metastases at diagnosis. TKI treatment was initiated during the first trimester for three patients. Premature delivery was induced in 10/11 patients. Anamnios occurred in one patient treated by osimertinib and trastuzumab. Five newborns were hypotrophic. No newborn malformations were observed. Diffusion of the TKIs, confirmed by blood cord sampling, represented about 1/3 (EGFR-TKI) and 1/8 (ALK-TKI) of the maternal concentration. No developmental abnormalities were observed in the children (follow-up 30 months). The anti-tumor efficacy and tolerance of TKIs, when reported, appears similar to that described in the general population. ConclusionsOur results support the rationale for using TKIs during pregnancy, both in terms of maternal NSCLC disease control and the relatively mild effects on the fetus. Our data will serve to better inform patients about the risks associated with TKIs used during pregnancy, contributing to shared decision making.

The thermogenic activity of adjacent adipocytes fuels the progression of ccRCC and compromises anti-tumor therapeutic efficacy

Clear cell renal cell carcinoma (ccRCC) preferentially invades into perinephric adipose tissue (PAT), a process associated with poor prognosis. However, the detailed mechanisms underlying this interaction remain elusive. Here, we describe a bi-directional communication between ccRCC cells and the PAT. We found that ccRCC cells secrete parathyroid-hormone-related protein (PTHrP) to promote the browning of PAT by PKA activation, while PAT-mediated thermogenesis results in the release of excess lactate to enhance ccRCC growth, invasion, and metastasis. Further, tyrosine kinase inhibitors (TKIs) extensively used in the treatment of ccRCC enhanced this vicious cycle of ccRCC-PAT communication by promoting the browning of PAT. However, if this cross-communication was short circuited by the pharmacological suppression of adipocyte browning via H89 or KT5720, the anti-tumor efficacy of the TKI, sunitinib, was enhanced. These results suggest that ccRCC-PAT cross-communication has important clinical relevance, and use of combined therapy holds great promise in enhancing the efficacy of TKIs.

Prognostic and predictive impact of creatine kinase level in non-small cell lung cancer treated with tyrosine kinase inhibitors.

BackgroundThe use of tyrosine kinase inhibitors (TKIs) is associated with incident creatine kinase (CK) elevation in the treatment of advanced non-small cell lung cancer (NSCLC) patients. However, whether higher CK levels are associated with better antitumor responses or survival remains to be explored. We intend to investigate the clinical correlation between CK levels and TKI efficacy in advanced NSCLC.MethodsIn this retrospective study, we enrolled 135 patients with stage IV NSCLC receiving TKI-based therapy in our center between June 2012 to July 2020. CK levels were monitored from the initiation of TKI medication and during the administration period. An X-tile analysis provided the optimal cutoff point for higher baseline CK. Patients were identified and grouped according to their baseline CK level and fold changes during TKI therapy. The primary endpoints included progression-free survival (PFS) and overall survival (OS), and the objective response rate (ORR) was calculated as the secondary endpoint.ResultsAmong the 135 patients included in our study, those with higher baseline CK levels (≥70 U/L) had favorable PFS (15.2 vs. 8.8 months; P=0.028), while patients with significantly elevated CK (the highest CK value/baseline CK value ≥2 times) appeared to gain better PFS (14.6 vs. 10.0 months; P=0.139). The overall ORR was 67.4%. Patients with higher baseline CK levels had numerically higher ORR (74.6% vs. 60.3%; P=0.076). Similarly, patients with significant CK elevation had a superior 4-month PFS rate (77.6% vs. 59.7%; P=0.029). Results from the subgroup analyses were identical to the overall ones. For patients with higher baseline CK levels, those experiencing significant CK elevation had prolonged PFS (17.2 vs. 14.2 months; P=0.038); a same trend was obtained from the lower baseline CK group (<70 U/L) (9.4 vs. 7.9 months; P=0.038). In multivariable analysis, higher baseline CK level and significant CK elevation remained statistically associated with PFS, with hazard ratios of 0.48 and 0.59, respectively.ConclusionsBoth higher baseline CK levels and significant CK elevation after treatment were correlated with prolonged PFS in NSCLC treated with TKIs, suggesting the potential prognostic and predictive impact of CK level on these patients.

1226P Efficacy and safety of Anti-EGFR TKIs combined with bevacizumab or ramucirumab in the first-line treatment of non-small cell lung cancer: Meta-analysis of randomized controlled trials

Anti-EGFR tyrosine kinase inhibitors (TKIs) are the standard therapy in the first-line treatment of EGFR mutant non-small cell lung cancer (NSCLC). It was aimed to increase the efficacy by adding anti-angiogenic antibodies to these agents, and several randomized controlled trials (RCTs)have been conducted in this area in recent years. Here, we performed an efficacy and safety analysis of RCTs investigating the addition of bevacizumab or ramucirumab to EGFR-TKIs in EGFR mutant advanced NSCLC.

MP14-04 ADJUVANT THERAPY WITH TYROSINE KINASE INHIBITORS FOR RENAL CELL CARCINOMA: AN UPDATED SYSTEMATIC REVIEW AND META-ANALYSIS

You have accessJournal of UrologyKidney Cancer: Advanced (including Drug Therapy) I (MP14)1 Sep 2021MP14-04 ADJUVANT THERAPY WITH TYROSINE KINASE INHIBITORS FOR RENAL CELL CARCINOMA: AN UPDATED SYSTEMATIC REVIEW AND META-ANALYSIS Ekaterina Laukhtina, Fahad Quhal, Keiichiro Mori, Dmitry Enikeev, Pierre I. Karakiewicz, Manuela Schmidinger, and Shahrokh F. Shariat Ekaterina LaukhtinaEkaterina Laukhtina More articles by this author , Fahad QuhalFahad Quhal More articles by this author , Keiichiro MoriKeiichiro Mori More articles by this author , Dmitry EnikeevDmitry Enikeev More articles by this author , Pierre I. KarakiewiczPierre I. Karakiewicz More articles by this author , Manuela SchmidingerManuela Schmidinger More articles by this author , and Shahrokh F. ShariatShahrokh F. Shariat More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001995.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Tyrosine kinase inhibitors (TKIs) have been widely used in the management of patients with metastatic renal cell carcinoma (RCC). However, the use of systemic therapies in the adjuvant setting of localized and locally advanced RCC has shown conflicting results across the literature. Therefore, we aimed to conduct an updated systematic review and meta-analysis comparing the efficacy and safety of TKIs in the adjuvant setting for patients with localized and locally advanced RCC. METHODS: The MEDLINE and EMBASE databases were searched in December 2020 to identify phase III randomized controlled trials (RCT) of patients receiving adjuvant therapies with TKI for RCC. Disease-free survival (DFS) and overall survival (OS) were the primary endpoints. The secondary endpoints included treatment-related adverse events (TRAEs) of high and any grade. Forest plots were used to describe the relationships between treatment and survival outcomes as well as TRAEs (TKI therapy versus placebo). RESULTS: Five trials (S-TRAC, ASSURE, PROTECT, ATLAS, and SORCE) were included in our meta-analysis comprising 6,531 patients. The forest plot revealed that TKI therapy was associated with a significantly longer DFS compared to placebo (pooled HR:0.88, 95%CI: 0.81–0.96, p=0.004). The Cochrane’s Q test (p=0.51) and I2 test (I2=0%) revealed no significant heterogeneity. Adjuvant TKI was not associated with improved OS compared to placebo (pooled HR:0.93, 95%CI: 0.83–1.04, p=0.23). The Cochrane’s Q test (p=0.74) and I2 test (I2=0%) revealed no significant heterogeneity.The forest plot revealed that TKI therapy, compared to placebo, was associated with higher rates of high grade TRAEs (OR:5.20, 95%CI: 4.10–6.59, p<0.00001) as well as any grade TRAEs (OR:3.85, 95%CI: 1.22–12.17, p=0.02). The Cochrane’s Q tests (P<0.0001 and p<0.00001, respectively) and I2 tests (I2=79% and I2=90%, respectively) revealed significant heterogeneity. CONCLUSIONS: The findings of our analyses suggest an improved DFS in patients with localized and locally advanced RCC receiving adjuvant TKI as compared to placebo; however, this did not translate into any significant OS benefit. Additionally, TKI therapy led to significant toxicity. Adjuvant TKI does not seem to offer a satisfactory risk/ benefit balance for all patients. Select patients with very poor prognosis may be considered in a shared decision-making process with the patient. With the successful arrival of immune-based therapies in RCC, these may allow a more favorable risk/benefit profile. Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e253-e253 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ekaterina Laukhtina More articles by this author Fahad Quhal More articles by this author Keiichiro Mori More articles by this author Dmitry Enikeev More articles by this author Pierre I. Karakiewicz More articles by this author Manuela Schmidinger More articles by this author Shahrokh F. Shariat More articles by this author Expand All Advertisement Loading ...

CML-479: Systematic Literature Review of Treatment Patterns, Long-Term Efficacy, and Safety of Dasatinib Therapy for Patients with Chronic Myeloid Leukemia

Objectives: The tyrosine kinase inhibitors (TKIs) imatinib, dasatinib, and nilotinib are approved for the treatment of chronic myeloid leukemia (CML). It is important to evaluate differences in efficacy and safety of TKIs to help guide first-line (1L) treatment decisions. The objective of this review was to assess the treatment patterns, long-term efficacy, and safety of dasatinib compared with imatinib and nilotinib in CML. Methods: A systematic literature review (SLR) was conducted by searching Embase®, MEDLINE®, and Cochrane databases (Jan 2010 – Jul 2020). Searches of key congress abstracts (2017–2020) were performed using PRISMA guidelines and the Population, Intervention, Comparator, Outcome (PICO) criteria. Eligible interventional and real-world evidence (RWE) studies describing the treatment and switching patterns, efficacy, and safety were selected. Results: Of 224 records identified, 119 reported switching or discontinuation in ≥1L settings, and 128 reported the safety and efficacy of 1L dasatinib. Discontinuation rates for dasatinib were lower than those for imatinib and nilotinib (17/22 studies). Dasatinib elicited a faster, deeper molecular response than imatinib (3/3 randomized clinical trial studies) but a similar response to nilotinib (6/6 RWE studies). Achieving an early molecular response at 3 months (n=6) or a major molecular response (MMR) at 12 months (n=7) correlated with increased 5-year overall survival (R2=0.5946 and 0.8415, respectively). Sustained use of 1L dasatinib led to improved MMR and survival. Hematologic adverse events (AEs) were similar between dasatinib and imatinib in RWE studies (n=4; 15%–50% vs 15%–40% grade 3 AEs, respectively), but certain hematologic AEs (e.g., thrombocytopenia) were higher in clinical trials (n=4). Across all studies, cardiovascular and gastrointestinal AEs were higher in patients receiving nilotinib than dasatinib. Conclusions: This SLR demonstrates that dasatinib remains an effective long-term option for 1L treatment of patients with CML, with a lower incidence of non-hematologic AEs compared with imatinib or nilotinib. Moreover, patients were more likely to remain on dasatinib, leading to improved outcomes. Funding: Funded by Bristol Myers Squibb, Princeton, NJ, USA. Previous presentation: Reprinted from Harricharan S et al. Value Health 2021;24(suppl 1):S23. Copyright 2021, with permission from Elsevier.

Genomic Landscape and Tumor Mutational Burden Determination of Circulating Tumor DNA in Over 5,000 Chinese Patients with Lung Cancer.

Having emerged as a noninvasive and clinically applicable approach for molecular determination of lung cancer, a genomic overview of circulating tumor DNA (ctDNA) of large-scale cohort may be helpful in novel biomarker development and therapeutic innovation. Primary cohort encompasses 5,671 blood samples from 4,892 patients with lung cancer. Pair-wise tissue samples from 579 patients and additional 358 sample pairs were collected to evaluate the correlation between blood and tissue tumor mutational burden (TMB). Parallel sequencing with plasma/tissue and white blood cells was performed using a 1,021-gene panel. Histologic subtyping was the most relevant to ctDNA detectability independent of other demographic characteristics, with small cell lung cancer showing the highest detectability, ctDNA abundance, and blood TMB (bTMB). Mutational landscape demonstrated significant differences, and integrated clonality analysis highlighted distinct driver-pattern and functional pathway interaction among various subtypes. The clonality and concurrent genes of EGFR mutations could predict the therapeutic efficacy of tyrosine kinase inhibitors (TKI), and RB1 mutations in non-small cell lung cancer characterized a subset with high bTMB, elevated ctDNA level, and potential small cell transformation. Most importantly, we developed an adjusted algorithm for bTMB in samples with extremely low ctDNA level and validated its correlation with tissue TMB in an independent cohort. ctDNA could serve as a promising alternative in genomic profiling for lung cancer. The novel identification of ctDNA clonality and adjusted bTMB might improve therapeutic and prognostic evaluation. This dataset was also a valuable resource for the development of new therapeutic targets and new genomically guided clinical trials.