MYC targeting by OMO-103 in solid tumors: a phase 1 trial.

Among the 'most wanted' targets in cancer therapy is the oncogene MYC, which coordinates key transcriptional programs in tumor development and maintenance. It has, however, long been considered undruggable. OMO-103 is a MYC inhibitor consisting of a 91-amino acid miniprotein. Here we present results from a phase 1 study of OMO-103 in advanced solid tumors, established to examine safety and tolerability as primary outcomes and pharmacokinetics, recommended phase 2 dose and preliminary signs of activity as secondary ones. A classical 3 + 3 design was used for dose escalation of weekly intravenous, single-agent OMO-103 administration in 21-day cycles, encompassing six dose levels (DLs). A total of 22 patients were enrolled, with treatment maintained until disease progression. The most common adverse events were grade 1 infusion-related reactions, occurring in ten patients. One dose-limiting toxicity occurred at DL5. Pharmacokinetics showed nonlinearity, with tissue saturation signs at DL5 and a terminal half-life in serum of 40 h. Of the 19 patients evaluable for response, 12 reached the predefined 9-week time point for assessment of drug antitumor activity, eight of those showing stable disease by computed tomography. One patient defined as stable disease by response evaluation criteria in solid tumors showed a 49% reduction in total tumor volume at best response. Transcriptomic analysis supported target engagement in tumor biopsies. In addition, we identified soluble factors that are potential pharmacodynamic and predictive response markers. Based on all these data, the recommended phase 2 dose was determined as DL5 (6.48 mg kg-1).ClinicalTrials.gov identifier: NCT04808362 .

Phase 1 first-in-human dose-escalation study of ANV419 in patients with relapsed/refractory advanced solid tumors.

BACKGROUND: ANV419 is a stable antibody-cytokine fusion protein consisting of interleukin-2 (IL-2) fused to an anti-IL-2 monoclonal antibody that sterically hinders binding of IL-2 to the α subunit of its receptor but has selective affinity for the receptor ßγ subunits. Thus, ANV419 preferentially stimulates CD8+ effector T cells and natural killer cells which are associated with tumor killing, while minimizing the activation of immunosuppressive regulatory T cells. METHODS: ANV419-001 is an open-label, multicenter, phase 1 study to evaluate the safety, tolerability, maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ANV419. Secondary objectives were to characterize the pharmacokinetics, pharmacodynamics and tumor response. Adult patients with advanced solid tumors and disease progression after ≥1 previous line of systemic therapy were enrolled. ANV419 was administered by intravenous infusion once every 2 weeks, with a planned treatment duration of 12 months. The dose escalation part of the study explored doses 3, 6 and 12 µg/kg as single patient cohorts followed by 24-364 µg/kg in a 3+3 design. Interim results are reported here (data cut-off: March 22, 2023). RESULTS: Forty patients were enrolled and received at least one dose of ANV419. The MTD and RP2D were determined to be 243 µg/kg. The most common ANV419-related treatment-emergent adverse events were Grade 1 and 2 fever (31 (77.5%)), chills (23 (57.5%), vomiting (14 (35.0%)), cytokine release syndrome and nausea (12 (30.0%) each). Transient and self-limiting lymphopenia due to lymphocyte redistribution was observed in all patients. In the RP2D cohort, Grade ≥3 thrombocytopenia and fever were reported by one patient (12.5%) each. All events were manageable with standard supportive care. At doses of 243 µg/kg (RP2D/MTD), the estimated T1/2 was approximately 12 hours. At ANV419 doses ≥108 µg/kg, 64% of patients had a best response of at least SD (15 SD and 1 confirmed PR). CONCLUSIONS: ANV419 at doses up to 243 µg/kg (the RP2D) was well tolerated and showed signs of antitumor activity in a heavily pretreated patient population with advanced solid tumors. TRIAL REGISTRATION NUMBER: NCT04855929.

Anti-Zic4 paraneoplastic cerebellar degeneration in a patient with EGFR-mutated NSCLC: a case report.

Paraneoplastic cerebellar degeneration (PCD) is one of the most prevalent neurological paraneoplastic syndromes, typically associated with small cell lung cancer (SCLC). PCD is thought to be caused by proteins expressed by tumor cells which trigger an antibody-mediated immune response. Despite PCD being commonly associated with anti-Yo, anti-Hu and anti-Tr/DNER antibodies, PCD is the most prevalent paraneoplastic syndrome in patients harboring anti-Zic4 antibodies. We report what, to our knowledge, is the first known case of anti-Zic4 mediated PCD in a patient with EGFR-mutated metastatic non-small cell lung cancer (NSCLC). Our patient was in complete response (CR) to targeted therapy and presented to the emergency room with drowsiness, unsteady gait and memory lapses. The diagnostic work-up revealed a diffuse cerebellar atrophy in the MRI, ruling out brain metastasis and leptomeningeal carcinomatosis. A body-CT scan showed no signs of recurrent disease. The cerebrospinal fluid (CSF) was within normal parameters. An onconeural antibody panel was conducted in a peripheral blood sample, detecting high levels of anti-Zic4 antibody by indirect immunofluorescence (IFI), results later confirmed by immunoblot testing. With the suspected diagnosis of an anti-Zic4 PCD, the case was discussed with the neurology department and treatment with high dose methylprednisolone was initiated. Considering the lack of substantial clinical benefit, the patient was then treated with intravenous immunoglobulins (IVIG) for 5 days, showing modest improvement. At this time, the patient presented minor disease relapse in the form of a sub-centimetric pulmonary nodule. Despite one cycle of chemotherapy, the patient's neurological condition deteriorated leading to fatal pneumonia secondary to progressive dysphagia. There is scarce evidence of paraneoplastic syndromes in EGFR-mutated NSCLC. Further research is warranted to stablish a possible association between anti-Zic4 and the EGFR molecular pathway.

New horizons for uncommon mutations in non-small cell lung cancer: BRAF, KRAS, RET, MET, NTRK, HER2.

The 2004 discovery of EGFR mutations, followed by ALK rearrangements, ushered in a targeted therapy era for advanced non-small cell lung cancer (NSCLC). Tyrosine kinase inhibitors targeting gene alterations have substantially improved survival and quality of life for patients with NSCLC. In the last decade, rearrangements of the ROS1 oncogene have been incorporated into healthcare practice that are applicable to another small subgroup of patients who benefit from similar targeted strategies. Recent genome studies of lung adenocarcinoma have identified other possible therapeutic targets, including RET, NTRK fusions, c-MET alterations, and activating mutations in KRAS, BRAF, and HER2, all with frequencies greater than 1%. Lung cancers harbouring these genome changes can potentially be treated with agents approved for other indications or under clinical development. This review updates the therapeutic arsenal that especially targets those genes.

Analysis of adverse drug events as a way to improve cancer patient care.

PURPOSE: To define the signals that a new artificial intelligence (AI) system must emit to improve adverse drug events (ADEs) management in oral antineoplastic agents (OAA). METHODS: A multidisciplinary group of experts in patient safety was set up to define what signals the new AI system must emit to improve ADEs management in OAAs. The baseline data for the new AI system were generated through an observational and ambispective study carried out in a university hospital. All patients who met the inclusion criteria were selected consecutively every working day for 6 months. The ADEs were collected by interview and by the review of health records. The ADEs were categorised according to how they could be detected: patient, analysis, examination. RESULTS: The group defined what signals the AI system must emit to improve ADEs management in OAAs: a signal to educate the patient when the possible ADEs were categorised as patient, a signal as a reminder to request a blood test or a microbiological culture when the possible ADEs were categorised as analysis, and a signal as a reminder for the necessity of a clinical examination when the possible ADEs were categorised as examination. A total of 1652 ADEs were reported in the interviews (ADE-interview) with the pharmacist, and doctors noted 1989 ADEs in the health record (ADE-HR). The most frequent ADEs were identified in the patient category. CONCLUSION: This study opens a new way for better management of ADEs and is the first step in the development of a future technology, which will improve the quality of life of patients.

Prolonged Responses With Trastuzumab Emtasine Treatment of Human Epidermal Growth Factor Receptor 2-positive Metastatic Breast Cancer Refractory to Trastuzumab and Pertuzumab: Systematic Review of Evidence.

Amplification of human epidermal growth factor receptor 2 (HER2) occurs in around 25% of breast cancers and has been associated with aggressive disease. Here, we summarize published evidence on efficacy and prolonged responses with trastuzumab emtansine (T-DM1) after first-line trastuzumab plus pertuzumab and provide possible factors related to prolonged responses to T-DM1. We conducted a literature search using PubMed, and articles that were published in English between July 1, 2012 and December 31, 2019 were included. A review of the bibliography included in the articles found was made. Nine articles were eligible; 2 were case reports, and the remaining 7 were nonexperimental studies, all retrospective. Five were multi-center works. The total number of patients was 796 (276 received pertuzumab). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was used for this systematic review. The population included was heterogeneous among studies according to hormone receptor status, de novo metastatic disease, number of metastatic sites, visceral involvement, brain metastasis, previous neoadjuvant or adjuvant trastuzumab, and line of therapy in which T-DM1 was administered. Less efficacy in terms of responses (overall response rate, 18%-33%) and progression-free survival (4-6 months) with second-line T-DM1, in patients pretreated with pertuzumab, was shown (if compared with the EMILIA trial). The results are more similar to those of the TH3RESA trial (very pretreated population). Prolonged treatments (6 months or more) were observed in at least 17% of cases. The efficacy of T-DM1 after a previous pertuzumab treatment is lower than if pertuzumab is not given, although prolonged responses are observed in this setting.

Targeting KRAS in Non-Small Cell Lung Cancer.

Kirsten Rat Sarcoma viral oncogene homolog (KRAS) is the most frequently altered oncogene in Non-Small Cell Lung Cancer (NSCLC). KRAS mutant tumors constitute a heterogeneous group of diseases, different from other oncogene-derived tumors in terms of biology and response to treatment, which hinders the development of effective drugs against KRAS. Therefore, for decades, despite enormous efforts invested in the development of drugs aimed at inhibiting KRAS or its signaling pathways, KRAS was considered to be undruggable. Recently, the discovery of a new pocket under the effector binding switch II region of KRAS G12C has allowed the development of direct KRAS inhibitors such as sotorasib, the first FDA-approved drug targeting KRAS G12C, or adagrasib, initiating a new exciting era. However, treatment with targeted KRAS G12C inhibitors also leads to resistance, and understanding the possible mechanisms of resistance and which drugs could be useful to overcome it is key. Among others, KRAS G12C (ON) tricomplex inhibitors and different combination therapy strategies are being analyzed in clinical trials. Another area of interest is the potential role of co-mutations in treatment selection, particularly immunotherapy. The best first-line strategy remains to be determined and, due to the heterogeneity of KRAS, is likely to be based on combination therapies.

Albumin-bound paclitaxel as new treatment for metastatic cholangiocarcinoma: A case report.

BACKGROUND: Cholangiocarcinomas are rare and very aggressive tumors. Most patients have advanced-stage or unresectable disease at presentation, and the systemic therapies have limited efficacy. Albumin-bound paclitaxel (nab-paclitaxel) is a solvent-free taxane that has been approved for the treatment of some cancers such as breast, non-small cell lung and pancreatic cancer, however it has not been applied to treat cholangiocarcinoma. We have both preclinical and clinical evidence of the efficacy of nab-paclitaxel in cholangiocarcinoma, yet no phase 3 trials have been made. CASE SUMMARY: A 63-year-old man was diagnosed in December 2016 with stage III B intrahepatic cholangiocarcinoma. Surgery was performed, followed by adjuvant chemotherapy treatment with capecitabine and gemcitabine; although, the gemcitabine was suspended due to allergic reaction after two cycles. In April 2019, metastatic cholangiocarcinoma relapse was diagnosed, and a first-line treatment with FOLFOX scheme was started. Eight cycles were administered, producing an initial clinical improvement and decrease in blood tumor marker levels. Radiological and serological progression was noted in September 2019. As a second-line treatment, FOLFIRI was not recommended due to risk of worsening the patient's tumor-related diarrhea. A combination therapy with gemcitabine was not feasible, as the patient had previously suffered from an allergic reaction to this treatment. We decided to use nab-paclitaxel as a second-line treatment, and four cycles were administered. Both clinical and serological responses were observed, and a radiological mixed response was also noted. CONCLUSION: Advanced cholangiocarcinoma could be treated with nab-paclitaxel monotherapy, which should be studied in combination with other types of treatment (chemotherapy, fibroblast growth factor receptor inhibitors).

Myocarditis and carotidynia caused by Granulocyte-Colony stimulating factor administration.

A 59 year-old woman was treated with adjuvant chemotherapy for triple negative breast cancer (TNBC) stage IB. She received pegfilgrastrim as secondary prophylaxis of neutropenia. After administration of pegfilgrastrim on day 11, she was hospitalised because of carotidynia and myocarditis that improved with antibiotics and steroids as an infection was suspected. Once she was recovered, another cycle of chemotherapy with pegfilgrastrim was administrated. At this time, the patient presented to our hospital with fever, odynophagia and chest pain, with diagnosis of myocarditis coupled with cardiogenic shock. She received antibiotics and steroids, advanced life support and also a pericardial window was done, with recovery of her condition. After a complete evaluation and exclusion of other possible aetiologies, we concluded that pegfilgrastrim was responsible for inducing carotidynia and myocarditis. Few cases have been published about Granulocyte-Colony stimulating factor (G-CSF) induced carotidynia and aortitis. However, this is the first reported case about G-CSF induced myocarditis and carotidynia.