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Entrectinib is a potent inhibitor of tropomyosin receptor kinase (TRK) A, B, and C, which has been shown to have anti-tumour activity against NTRK gene fusion-positive solid tumours, including CNS activity due to its ability to penetrate the blood–brain barrier. We present an integrated efficacy and safety analysis of patients with metastatic or locally advanced solid tumours harbouring oncogenic NTRK1, NTRK2, and NTRK3 gene fusions treated in three ongoing, early-phase trials. An integrated database comprised the pivotal datasets of three, ongoing phase 1 or 2 clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2), which enrolled patients aged 18 years or older with metastatic or locally advanced NTRK fusion-positive solid tumours who received entrectinib orally at a dose of at least 600 mg once per day in a capsule. All patients had an Eastern Cooperative Oncology Group performance status of 0–2 and could have received previous anti-cancer therapy (except previous TRK inhibitors). The primary endpoints, the proportion of patients with an objective response and median duration of response, were evaluated by blinded independent central review in the efficacy-evaluable population (ie, patients with NTRK fusion-positive solid tumours who were TRK inhibitor-naive and had received at least one dose of entrectinib). Overall safety evaluable population included patients from STARTRK-1, STARTRK-2, ALKA-372-001, and STARTRK-NG (NCT02650401; treating young adult and paediatric patients [aged ≤21 years]), who received at least one dose of entrectinib, regardless of tumour type or gene rearrangement. NTRK fusion-positive safety evaluable population comprised all patients who have received at least one dose of entrectinib regardless of dose or follow-up. These ongoing studies are registered with ClinicalTrials.gov, NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012–000148–88 (ALKA-372-001). Patients were enrolled in ALKA-372–001 from Oct 26, 2012, to March 27, 2018; in STARTRK-1 from Aug 7, 2014, to May 10, 2018; and in STARTRK-2 from Nov 19, 2015 (enrolment is ongoing). At the data cutoff date for this analysis (May 31, 2018) the efficacy-evaluable population comprised 54 adults with advanced or metastatic NTRK fusion-positive solid tumours comprising ten different tumour types and 19 different histologies. Median follow-up was 12.9 months (IQR 8·77–18·76). 31 (57%; 95% CI 43·2–70·8) of 54 patients had an objective response, of which four (7%) were complete responses and 27 (50%) partial reponses. Median duration of response was 10 months (95% CI 7·1 to not estimable). The most common grade 3 or 4 treatment-related adverse events in both safety populations were increased weight (seven [10%] of 68 patients in the NTRK fusion-positive safety population and in 18 [5%] of 355 patients in the overall safety-evaluable population) and anaemia (8 [12%] and 16 [5%]). The most common serious treatment-related adverse events were nervous system disorders (three [4%] of 68 patients and ten [3%] of 355 patients). No treatment-related deaths occurred. Entrectinib induced durable and clinically meaningful responses in patients with NTRK fusion-positive solid tumours, and was well tolerated with a manageable safety profile. These results show that entrectinib is a safe and active treatment option for patients with NTRK fusion-positive solid tumours. These data highlight the need to routinely test for NTRK fusions to broaden the therapeutic options available for patients with NTRK fusion-positive solid tumours. Ignyta/F Hoffmann-La Roche.

In pancreatic ductal adenocarcinoma (PDAC), the dense stroma rich in cancer-associated fibroblasts (CAFs) and the immunosuppressive microenvironment confer resistance to treatments. To overcome such resistance, we tested the combination of FOLFIRINOX (DNA damage-inducing chemotherapy drugs) with VE-822 (an ataxia-telangiectasia and RAD3-related inhibitor that targets DNA damage repair). PDAC spheroid models and organoids were used to assess the combination effects. Tumour growth and the immune and fibrotic microenvironment were evaluated by immunohistochemistry, single-cell analysis and spatial proteomics in patient-derived xenograft (PDX) and orthotopic immunocompetent KPC mouse models. The FOLFIRINOX and VE-822 combination had a strong synergistic effect in several PDAC cell lines, whatever their BRCA1, BRCA2 and ATM mutation status and resistance to standard chemotherapy agents. This was associated with high DNA damage and inhibition of DNA repair signalling pathways, leading to increased apoptosis. In immunocompetent and PDX mouse models of PDAC, the combination inhibited tumour growth more effectively than FOLFIRINOX alone. This was associated with tumour microenvironment remodelling, particularly decreased proportion of fibroblast activated protein-positive CAFs and increased anti-tumorigenic immune cell infiltration and interaction. The FOLFIRINOX and VE-822 combination is a promising strategy to improve FOLFIRINOX efficacy and overcome drug resistance in PDAC.

Recently, nanomedicine has made significant advancements, opening exciting new possibilities for treating a wide range of diseases. In this field, novel drug delivery systems (DDSs) are among the most noteworthy developments. The primary objective of DDSs is to ensure that treatments reach the intended targets while minimising adverse effects. In this context, nanoparticle (NP)-based DDSs have shown remarkable potential in oncology, particularly for ovarian cancer (OC), the deadliest type of gynecological cancer due to its mortality rate and the occurrence of treatment resistance. In this review, we provide a comprehensive description of the different types of NPs being explored for OC treatment, with a special emphasis on their involvement in delivering small interfering RNA (siRNA) treatments. We review various NP platforms shedding light on how they enhance drug stability, enable controlled release, and reduce toxicity. We also explore the techniques used to synthesise these NPs, emphasizing how modifying their physical and chemical properties can improve their ability to target cancer cells effectively. We also discuss the importance of 3D-tumor models, which more accurately replicate the complexity of real tumors. This enables us to examine the ability of NPs to penetrate tumors and consequently therapies are delivered in a setting that really resembles real-life situations. Recent advances in RNA-based therapeutics through DDS offer a highly targeted approach to shutting down oncogenes and drug resistance mechanisms, making them a powerful strategy to complement conventional treatments. The analysis of clinical trials results indicate a requirement for further studies in order to refine the clinical applications of drugs based on siRNAs. Despite the ongoing challenges, NP-based DDSs are paving the way for more precise and personalized OC treatments.Graphical abstract

YAP and TAZ, the Hippo pathway terminal transcriptional activators, are frequently upregulated in cancers. In tumor cells, they have been mainly associated with increased tumorigenesis controlling different aspects from cell cycle regulation, stemness, or resistance to chemotherapies. In fewer cases, they have also been shown to oppose cancer progression, including by promoting cell death through the action of the p73/YAP transcriptional complex, in particular after chemotherapeutic drug exposure. Using HCT116 cells, we show here that oxaliplatin treatment led to core Hippo pathway down-regulation and nuclear accumulation of TAZ. We further show that TAZ was required for the increased sensitivity of HCT116 cells to oxaliplatin, an effect that appeared independent of p73, but which required the nuclear relocalization of TAZ. Accordingly, Verteporfin and CA3, two drugs affecting the activity of YAP and TAZ, showed antagonistic effects with oxaliplatin in co-treatments. Importantly, using several colorectal cell lines, we show that the sensitizing action of TAZ to oxaliplatin is dependent on the p53 status of the cells. Our results support thus an early action of TAZ to sensitize cells to oxaliplatin, consistent with a model in which nuclear TAZ in the context of DNA damage and p53 activity pushes cells towards apoptosis.

The Imiqualines family is an original group of small heterocyclic compounds, diversely substituted around different scaffolds. Among these compounds, the lead EAPB02303 displays outstanding cytotoxic activity at nanomolar concentrations comparable to those of standard-of-care chemotherapy drugs in different cancer cell lines, including Pancreatic Ductal AdenoCarcinoma (PDAC) cell lines. Due to its high aggressiveness and resistance to therapies, PDAC has an extremely poor prognosis with limited treatment options. Here, we demonstrated the cytotoxic activities of EAPB02303 alone or combined with standard chemotherapy drugs in several PDAC cell lines and confirmed these results in patient-derived xenograft mouse models. EAPB02303 potently induced cell cycle arrest in the G2/M phase and in mitosis followed by apoptosis. Then, using a combination of transcriptomic, proteomic, biochemical and cellular assay, we found that EAPB02303 mechanism of action relies on its bioactivation by catechol-O-methyltransferase, resulting in the production of a methylated compound that effectively inhibits microtubule polymerization. Moreover, EAPB02303 had a synergistic effect when combined with paclitaxel (the standard-of-care agent in PDAC) providing the rationale to continue the development of EAPB02303 combination strategies for the treatment of catechol-O-methyltransferase-overexpressing PDAC.

Background:Our previous survey on first-in-human trials (FIHT) of monoclonal antibodies (mAbs) showed that, due to their limited toxicity, the recommended phase II dose (RP2D) was only tentatively defined.Methods:We identified, by MEDLINE search, articles on single-agent trials of mAbs with an FIHT included in our previous survey. For each mAb, we examined tested dose(s) and dose selection rationale in non-FIHTs (NFIHTs). We also assessed the correlation between doses tested in the registration trials (RTs) of all FDA-approved mAbs and the corresponding FIHT results.Results:In the 37 dose-escalation NFIHTs, the RP2D indication was still poorly defined. In phase II-III NFIHTs (n=103 on 37 mAbs), the FIHT RP2D was the only dose tested for five mAbs. For 16 mAbs, only doses different from the FIHT RP2D or the maximum administered dose (MAD) were tested and the dose selection rationale infrequently indicated. In the 60 RTs on 27 FDA-approved mAbs with available FIHT, the FIHT RP2D was tested only for two mAbs, and RT doses were much lower than the FIHT MAD.Conclusions:The rationale beyond dose selection in phase II and III trials of mAbs is often unclear in published articles and not based on FIHT data.

Background The irinotecan-induced phosphokinome changes in colorectal cancer (CRC) cells were used to guide the selection of targeted agents to be tested in combination with irinotecan. Methods Phosphokinome profiling with peptide arrays of tumour samples from nude mice xenografted with HT29 cells and treated or not with an effective dose of irinotecan was used to identify signalling pathways activated by irinotecan treatment. Then, drugs targeting these pathways were combined in vitro with irinotecan to test potential synergistic effect. The interactions between these drug combinations were assessed by a dose matrix approach. Confirmation of the most potential combination has been confirmed in vivo in xenografted mice. Results Irinotecan induced in vivo the activation of AKT and MEK1 phosphorylation. The dose matrix approach showed that BKM120 (PI3K inhibitor) and MEK162 (MEK inhibitor) are synergistic in vitro and in vivo with a cytostatic and cytotoxic effect, while combination of BKM120 and irinotecan or MEK162 and irinotecan are only additive or even antagonistic. However, the triple combination of SN38, BKM120 and MEK162 showed a better synergistic effect that BKM120 and MEK162, indicating that the cells need to inhibit both AKT and ERK pathways to become more sensitive to irinotecan-based chemotherapies. Conclusion Analysis of chemotherapy-induced phosphokinome changes helps to elucidate the mechanisms of drug resistance and to guide the selection of targets for combination therapies with synergistic activity.

BackgroundColorectal cancer (CRC) is the third most common cancer type and one of the leading causes of cancer-related death worldwide. The treatment of advanced metastatic CRC relies on classical chemotherapy combinations (5-fluorouracil, oxaliplatin or irinotecan). However, their use is limited by the emergence of resistance mechanisms, including to oxaliplatin. In this context, we recently showed that the combination of oxaliplatin and ataxia telangiectasia and Rad3-related protein inhibition (VE-822) is synergistic and may have a potential therapeutic effect in metastatic CRC management.MethodsIn this study, we investigated the role of the VE-822+oxaliplatin (Vox) combination on the immune response and its potential synergy with an anti-programmed-cell Death receptor-1 (PD-1) antibody. We used cell lines and organoids from metastatic CRC to investigate in vitro Vox efficacy and orthotopic syngeneic mouse models of metastatic CRC to assess the efficacy of Vox+anti-PD-1 antibody and identify the involved immune cells.ResultsThe Vox+anti-PD-1 antibody combination completely cured tumor-bearing mice and protected them from a rechallenge. Vox was associated with a reduction of tumor-infiltrated neutrophils, CD206+ macrophages and regulatory T cells. Vox also induced a deep depletion of blood neutrophils. The increased bone marrow granulopoiesis failed to compensate for the Vox-mediated mature neutrophil depletion. Neutrophil depletion using a mouse recombinant anti-Ly6G antibody partially mimicked the Vox effect on the tumor microenvironment, but to a lower extent compared with the Vox+anti-PD-1 antibody combination. Vox, but not neutrophil depletion, led to the emergence of an Ly6C+ PD-1+ CD8+ T-cell population in the blood and spleen of tumor-harboring mice. These cells were proliferating, and expressed IFN-γ, CD62L, CXCR3 and Eomes. Moreover, the proportion of tumor antigen-specific T cells and of CD122+ BCL6+ T cells, which shared phenotypic characteristics with stem-like CD8+ T cells, was increased in treated mice.ConclusionsOur work strongly suggests that the Vox+anti-PD-1 antibody combination might significantly improve survival in patients with metastatic and treatment-refractory CRC by acting both on cancer cells and CD8+ T cells.

BackgroundImmune checkpoint inhibitors (ICI) have transformed cancer treatment over the last decade. Alongside this therapeutic improvement, a new variety of side effects has emerged, called immune-related adverse events (irAEs), potentially affecting any organ. Among these irAEs, myocarditis is rare but life-threatening.MethodsWe conducted a multicenter cross-sectional retrospective study with the aim of better characterizing ICI-related myocarditis. Myocarditis diagnosis was based on the recent consensus statement of the International Cardio-Oncology Society.ResultsTwenty-nine patients were identified, from six different referral centers. Most patients (55%) were treated using anti-programmed-death 1, rather than ICI combination (35%) or anti-programmed-death-ligand 1 (10%). Transthoracic echocardiography was abnormal in 52% of them, and cardiac magnetic resonance showed abnormal features in 14/24 patients (58%). Eleven patients (38%) were classified as severe. Compared with other patients, they had more frequently pre-existing systemic autoimmune disease (45% vs 6%, p=0.018), higher troponin level on admission (42-fold the upper limit vs 3.55-fold, p=0.001), and exhibited anti-acetylcholine receptor autoantibodies (p=0.001). Seven patients (24%) had myocarditis-related death, and eight more patients died from cancer progression during follow-up. Twenty-eight patients received glucocorticoids, 10 underwent plasma exchanges, 8 received intravenous immunoglobulins, and 5 other immunosuppressants. ICI rechallenge was performed in six patients, with only one myocarditis relapse.DiscussionThe management of ICI-related myocarditis may be challenging and requires a multidisciplinary approach. Prognostic features are herein described and may help to allow ICI rechallenge for some patients with smoldering presentation, after an accurate evaluation of benefit–risk balance.

Background Immune checkpoint inhibitors (ICIs) improved survival in patients with locally advanced or metastatic urothelial carcinoma (la/mUC). Patient‐reported symptoms in this context were poorly studied. The study aimed to compare symptom severity between patients and clinicians. Methodology The secondary analysis of the AMI clinical trial comparing changes in the gut microbiota in patients with la/mUC treated with pembrolizumab was conducted in nine French centers. Secondary endpoints were expected in this prospective study. Patient‐Reported Outcome‐Common Terminology Criteria for Adverse Events (PRO‐CTCAE) and CTCAE were assessed respectively by patients and clinicians before pembrolizumab initiation, and at each treatment visit until treatment cycle 12. Agreement in severity between clinicians and patients for grade ≥ 3 symptoms was calculated with Cohen's kappa coefficient. The toxicity index was generated for CTCAE and PRO‐CTCAE to assess discordance in a longitudinal manner. The Wilcoxon test was used to compare clinicians' and patients' toxicity index and symptom severity frequencies. Results Thirty‐nine patients were included (M/F sex ratio: 2.5) from December 2020 to March 2022. PRO‐CTCAE baseline completion rate was 77.5%. Cohen's kappa coefficient ranged from −0.017 (95% confidence interval (CI), [−0.039, 0.005]) for numbness/tingling to 0.161 (95% CI, [0.045, 0.276]) for fatigue. The patient self‐rated symptom toxicity index was > 2 for all symptoms compared to ≤ 0.62 (fatigue) when assessed by clinicians in longitudinal reporting of symptom frequency and severity with a p value < 0.001. The three most commonly reported symptoms by patients and clinicians, respectively, were: Fatigue 53.3% versus 23.4%, generalized pain 42.4% versus 16.5%, and insomnia 41.1% versus 9.5%. Symptom frequency reports between clinicians and patients were statistically different (p < 0.009). Conclusions Symptom severity assessment showed discordance between patients and physicians. Clinicians reported fewer symptoms and graded them less severely than patients. PROs should be used to accurately reflect patient experience. Trial Registration ClinicalTrials.gov identifier: NCT04566029