Management of Trastuzumab Deruxtecan-related nausea and vomiting in real-world practice.

Background: Nausea and vomiting are common side effects of Trastuzumab Deruxtecan (T-DXd), but guidelines for optimal management were not initially available. This retrospective single-center study aimed at evaluating the efficacy of two antiemetic regimens in patients receiving T-DXd. Methods: Data from metastatic breast cancer patients receiving T-DXd were collected. Two groups were defined: patients treated with 5-HT3 receptor antagonists (RA) ± dexamethasone (5-HT3-group) and patients treated with a fixed oral combination of netupitant (NK1RA) and palonosetron ± dexamethasone (NK1 group). Physicians preferentially offered the NK1 regimen to patients at higher risk of nausea and vomiting based on internal recommendations. Only nausea and vomiting during cycles 1 and 2 were considered. Comparisons of nausea and vomiting by the antiemetic prophylaxis group were assessed using chi-square. Results: A total of 53 patients were included in the analysis. At cycle 1, 72% and 28% of patients received the 5-HT3 and NK1 prophylaxis, respectively. Overall, 58% reported nausea, with no differences between groups (58% vs. 60%; p = 0.832), but with a trend for lower grade in the NK1 group (33.3% G1; 26.7% G2) compared to the 5-HT3 group (23.7% G1; 31.6% G2; 2.6% G3). Vomiting was reported by 21% and 0% of patients in the 5-HT3 and the NK1 group, respectively (p = 0.054). Among the 15 patients in the 5-HT3 group with nausea at cycle 1 who escalated to NK1 at cycle 2, nausea decreased from 100% to 53% (p = 0.022) and vomiting decreased from 47% to 13% (p = 0.046). Conclusions: The NK1 regimen improved vomiting control at cycle 1 and, when introduced at cycle 2, significantly improved both nausea and vomiting. The biased NK1 selection for higher-risk patients may have dampened the differences between groups at cycle 1. These findings support enhanced control of T-DXd-related nausea and vomiting with NK1RA.

Pan-cancer analysis of antibody-drug conjugate targets and putative predictors of treatment response.

BACKGROUND: Antibody-drug conjugates (ADCs) are a rapidly expanding class of compounds in oncology. Our goal was to assess the expression of ADC targets and potential downstream determining factors of activity across pan-cancer and normal tissues. MATERIALS AND METHODS: ADCs in clinical trials (n = 121) were identified through ClinicalTrials.gov, corresponding to 54 targets. Genes potentially implicated in treatment response were identified in the literature. Gene expression from The Cancer Genome Atlas (9000+ cancers of 31 cancer types), the Genotype-Tissue Expression database (n = 19,000 samples from 31 normal tissue types), and the TNMplot.com (n = 12,494 unmatched primary and metastatic samples) were used in this analysis. To compare relative expression across and within tumour types we used pooled normal tissues as reference. RESULTS: For most ADC targets, mRNA levels correlated with protein expression. Pan-cancer target expression distributions identified appealing cancer types for each ADC development. Co-expression of multiple targets was common and suggested opportunities for ADC combinations. Expression levels of genes potentially implicated in ADC response downstream of the target might provide additional information (e.g. TOP1 was highly expressed in many tumour types, including breast and lung cancers). Metastatic compared to primary tissues overexpressed some ADCs targets. Single sample "targetgram" plots were generated to visualise the expression of potentially competing ADC targets and resistance/sensitivity markers highlighting high inter-patient heterogeneity. Off-cancer target expression only partially explains adverse events, while expression of determinants of payload activity explained more of the observed toxicities. CONCLUSION: Our findings draw attention to new therapeutic opportunities for ADCs that can be tested in the clinic and our web platform (https://tnmplot.com) can assist in prioritising upcoming ADC targets for clinical development.

Tissue- and liquid biopsy-based biomarkers for immunotherapy in breast cancer.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy and now represent the mainstay of treatment for many tumor types, including triple-negative breast cancer and two agnostic registrations. However, despite impressive durable responses suggestive of an even curative potential in some cases, most patients receiving ICIs do not derive a substantial benefit, highlighting the need for more precise patient selection and stratification. The identification of predictive biomarkers of response to ICIs may play a pivotal role in optimizing the therapeutic use of such compounds. In this Review, we describe the current landscape of tissue and blood biomarkers that could serve as predictive factors for ICI treatment in breast cancer. The integration of these biomarkers in a "holistic" perspective aimed at developing comprehensive panels of multiple predictive factors will be a major step forward towards precision immune-oncology.

Understanding the causes of recurrent HCC after liver resection and radiofrequency ablation.

INTRODUCTION: Surgical resection and radiofrequency ablation are preferred options for early-stage disease. With the increasing availability of therapeutic options understanding the causes of recurrence and identifying its predictors should be priorities in the hepatocellular carcinoma (HCC) research agenda. AREAS COVERED: Current knowledge of HCC predictors of recurrence is reviewed, and recent insights about their underlying mechanisms are presented. In addition, results from recent clinical trials investigating treatment combinations are critically appraised. EXPERT OPINION: HCC recurrence is either due to the progressive growth of microscopic residual disease or to de novo cancer development in the context of a diseased liver, each occurring in an early (<2 years) vs. late (≥2 years) fashion. Collectively, morphological, proteomic, and transcriptomic data suggest vascular invasion and angiogenesis as key drivers of HCC recurrence. Agents aimed at blocking either of these two hallmarks should be prioritized at the moment of early-stage HCC clinical trial design. Emerging results from clinical trials testing ICI in early-stage HCC underscore the importance of defining the best treatment sequence and the most appropriate combination strategies.Finally,as different responses to systemic therapies are increasingly defined according to the HCC etiology, patient enrollment into clinical trials should take into account the biological characteristics of their inherent disease.

Interferon ß-1a (IFNß-1a) in COVID-19 patients (INTERCOP): study protocol for a randomized controlled trial.

BACKGROUND: Pharmacological therapies of proven efficacy in coronavirus disease 2019 (COVID-19) are still lacking. We have identified IFNß-1a as the most promising drug to be repurposed for COVID-19. The rationale relies on the evidence of IFNß anti-viral activity in vitro against SARS-CoV-2 and animal models resembling SARS-CoV-2 infection and on a recent clinical trial where IFNß was indicated as the key component of a successful therapeutic combination. METHODS: This is a randomized, controlled, open-label, monocentric, phase II trial (INTERCOP trial). One hundred twenty-six patients with positive swab detection of SARS-CoV-2, radiological signs of pneumonia, and mild-to-moderate disease will be randomized 2:1 to IFNß-1a in addition to standard of care vs standard of care alone. No other anti-viral drugs will be used as part of the regimens, both in the control and the intervention arms. IFNß-1a will be administered subcutaneously at the dose of 44 mcg (equivalent to 12 million international units) three times per week, at least 48 h apart, for a total of 2 weeks. The primary outcome is the time to negative conversion of SARS-CoV-2 nasopharyngeal swabs. Secondary outcomes include improvement or worsening in a clinical severity score measured on a 7-point ordinal scale (including transfer to intensive care unit and death), oxygen- and ventilator-free days, mortality, changes in pulmonary computed tomography severity score, hospital stay duration, reduction of viral load measured on nasopharyngeal swabs, number of serious adverse events, and changes in biochemical markers of organ dysfunction. Exploratory outcomes include blood cell counts, cytokine and inflammatory profile, peripheral mRNA expression profiles of interferon-stimulated genes, and antibodies to SARS-CoV-2 and to IFNß-1a. INTERCOP is the first study to specifically investigate the clinical benefits of IFNß-1a in COVID-19 patients. DISCUSSION: Potential implications of this trial are multifaceted: should the primary outcome be fulfilled and the treatment be safe, one may envisage that IFNß-1a be used to reduce the infectivity of patients with mild-to moderate disease. In case IFNß-1a reduced the duration of hospital stay and/or ameliorated the clinical status, it may become a cornerstone of COVID-19 treatment. TRIAL REGISTRATION: EudraCT 2020-002458-25. Registered on May 11, 2020 ClinicalTrials.gov Identifier: NCT04449380.

Molecular Profile of Advanced Non-Small Cell Lung Cancers in Octogenarians: The Door to Precision Medicine in Elderly Patients.

BACKGROUND: There is a pressing need to expand the evidence base in geriatric lung oncology. Most non-small cell lung cancers (NSCLCs) are diagnosed in the elderly, with approximately 15% of cases affecting octogenarians. Treatment-related decisions are challenging in this population, and the role of biologically driven therapies is still underrated. METHODS: A single-institution cohort of 76 NSCLCs from octogenarian patients was submitted to molecular analysis using a next-generation sequencing (NGS) multigene panel, fluorescence in situ hybridization (FISH) analyses, and immunohistochemistry for PD-L1 assessment. Treatment and clinical outcome data were available for 33 patients. RESULTS: Most cases (n = 66, 87%) harbored at least one genomic alteration. EGFR and KRAS mutations were detected in 18 (24%) and 20 (26%) patients, respectively. No ALK alterations were found, but in two patients ROS1 translocation was identified. Of 22 cases tested, 17 were positive for PD-L1 staining. Octogenarian patients who received tyrosine kinase inhibitors (TKIs) based on molecular analysis showed clinical benefits, with long progression-free survival as expected in TKI-treated younger cohorts. CONCLUSIONS: This study highlights the utility of molecular profiling in all advanced-stage NSCLCs, regardless of the age at diagnosis, to drive personalized treatment. The prevalence of druggable alterations and the clinical benefits obtained by biologically-driven therapies in octogenarians were comparable to those of the younger NSCLC population.