Search

Markus Joerger,1 Kira-Lee Koster,1 Tomas Janik,2 Floris A de Jong3,4 1Department of Medical Oncology and Hematology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland; 2Research & Development Department, Mundipharma Research Limited, Cambridge, UK; 3Global Medical Affairs Department, Mundipharma Research Limited, Cambridge, UK; 4Medical Affairs Department, Exact Sciences International GmbH, Baar, SwitzerlandCorrespondence: Tomas Janik, Mundipharma Research Limited, Cambridge Science Park, Milton Road, Cambridge, UK, Email tomas.janik@mundipharma.czPurpose: Immune checkpoint inhibitors (CPIs) have been widely adopted in a number of early and advanced malignancies. Histone deacetylase inhibitors (HDACis) and alkylating agents (AAs) have been suggested to potentiate the actions of CPIs on tumor cells. We conducted a comprehensive literature review to explore the potential synergistic activity between CPIs, AAs, and HDACis.Patients and Methods: Clinical and non-clinical studies describing outcomes in patients with cancer receiving CPIs and either concomitant or sequential (pre- or post-CPI) AAs or HDACis were identified in PubMed using pre-defined search strings. Manual searches of key oncology congresses were similarly performed. All relevant articles and abstracts were manually screened for relevance, classified according to the specific anticancer agents used (CPIs, AAs, or HDACis), tumor entity, and whether treatment was concomitant or sequential.Results: Overall, 227 unique clinical studies across a range of tumor types, both solid tumors and hematological malignancies, were identified. One hundred and fifty-nine publications on Phase I and II clinical studies together with 41 publications on Phase III studies were examined. The most commonly investigated tumor types were melanoma, triple-negative breast cancer, non-small cell lung cancer, and Hodgkin lymphoma. The randomized clinical studies identified, all of which reported on the combination of a CPI with an AA, demonstrated superior outcomes in the combination arm compared with CPI or AA monotherapy. Similarly, combination therapy with CPIs and HDACis demonstrated promising activity.Conclusion: Sequential or concomitant administration of a CPI with an AA or an HDACi may improve outcomes for patients with a range of tumor types. There is a rationale to support further investigation into the potential for synergy between CPIs, alkylating agents and/or HDACis in both the non-clinical and clinical settings.Plain Language Summary: People being treated for cancer will often receive more than one drug at a time, and the concept of combining cancer drugs is frequently investigated as a potential opportunity to improve outcomes for patients. We reviewed the published literature for clinical trials and work undertaken in laboratories to explore whether combining targeted agents that stop cancer cells from multiplying (known as checkpoint inhibitors) with traditional chemotherapy that kills cancer cells could be a useful approach. We looked at evidence in publications where checkpoint inhibitors were used at the same time as chemotherapy, or given immediately before or after chemotherapy. The most important evidence came from clinical trials where outcomes for patients receiving combinations of treatment were directly compared with those from patients receiving a single treatment. These studies showed superior outcomes for patients who were treated with a combination of cancer drugs compared with patients receiving monotherapy. We also found evidence that adding another class of cancer drug, called histone deacetylase inhibitors, might sensitize tumors to checkpoint inhibitors. These findings provide a rationale for examining alkylating agents and/or histone deacetylase inhibitors combined with checkpoint inhibitors.Keywords: histone deacetylase inhibitor, checkpoint inhibitor, alkylating agents, synergy, hematological malignancies, solid tumors

We present the case of a 70-year-old never-smoking female patient with epidermal growth factor receptor ( EGFR ) p.L858R-mutated metastatic non-small cell lung cancer (NSCLC). After three months of first-line treatment with erlotinib, progression occurred and platinum/pemetrexed was initiated, followed by a response for more than two years. After the progression, the molecular testing of a vertebral metastasis revealed a ROS proto-oncogene 1 ( ROS1 ) translocation and a human epidermal growth factor receptor 2 ( HER 2) p.S310F mutation, in addition to the known EGFR p.L858R mutation. Crizotinib then led to a durable response of 17 months. The molecular retesting of the tumour cells obtained from the recurrent pleural effusion revealed the absence of the ROS1 translocation, whereas the EGFR and HER2 mutations were still present. Afatinib was added to the crizotinib, and the combination treatment resulted in another durable response of more than two years. The patient died more than 7 years after the initial diagnosis of metastatic NSCLC. This case demonstrates that the repeated molecular testing of metastatic NSCLC may identify new druggable genomic alterations that can impact the patient management and improve the patient outcome.

Background: Immune checkpoint inhibitors (ICIs) improve overall survival (OS) in advanced/metastatic urothelial cancer (a/mUC) patients. Preliminary evidence suggests a prognostic role of inflammatory biomarkers in this setting. We aimed to develop a disease-specific prognostic inflammatory index for a/mUC patients on ICIs., Methods: Fifteen variables were retrospectively correlated with OS and progression-free survival (PFS) in a development (D, n = 264) and a validation (V, n = 132) cohort of platinum-pretreated a/mUC pts receiving ICIs at L2 or further line. A nomogram and inflammatory prognostic index (U-IPI) were developed. The index was also tested in a control cohort of patients treated with chemotherapy only (C, n = 114)., Results: The strongest predictors of OS were baseline platelet/lymphocyte (PLR) and neutrophil/lymphocyte (NLR) ratios, and lactate dehydrogenase (LDH), NLR, and albumin changes at 4 weeks. These were used to build the U-IPI, which can distinctly classify patients into good or poor response groups. The nomogram scoring is significant for PFS and OS ( p < 0.001 in the D, V, and combined cohorts) for the immunotherapy (IO) cohort, but not for the control cohort., Conclusions: The lack of a baseline systemic inflammatory profile and the absence of early serum inflammatory biomarker changes are associated with significantly better outcomes on ICIs in a/mUC pts. The U-IPI is an easily applicable dynamic prognostic tool for PFS and OS, allowing for the early identification of a sub-group with dismal outcomes that would not benefit from ICIs, while distinguishing another that draws an important benefit.

Background: TLD-1 is a novel liposomal doxorubicin that compared favorably to conventional doxorubicin liposomal formulations in preclinical models. This phase I first-in-human study aimed to define the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety and preliminary activity of TLD-1 in patients with advanced solid tumors., Patients and Methods: We recruited patients with advanced solid tumors who failed standard therapy and received up to 3 prior lines of palliative systemic chemotherapy. TLD-1 was administered intravenously every 3 weeks up to a maximum of 9 cycles (6 for patients with prior anthracyclines) from a starting dose of 10 mg/m 2 , according to an accelerated titration design followed by a modified continual reassessment method., Results: 30 patients were enrolled between November 2018 and May 2021. No dose-limiting toxicities (DLT) were observed. Maximum administered dose of TLD-1 was 45 mg/m 2 , RP2D was defined at 40 mg/m 2 . Most frequent treatment-related adverse events (TRAE) of any grade included palmar-plantar erythrodysesthesia (PPE) (50% of patients), oral mucositis (50%), fatigue (30%) and skin rash (26.7%). Most common G3 TRAE included PPE in 4 patients (13.3%) and oral mucositis in 2 (6.7%). Overall objective response rate was 10% in the whole population and 23.1% among 13 patients with breast cancer; median time-to-treatment failure was 2.7 months. TLD-1 exhibit linear pharmacokinetics, with a median terminal half-life of 95 h., Conclusions: The new liposomal doxorubicin formulation TLD-1 showed a favourable safety profile and antitumor activity, particularly in breast cancer. RP2D was defined at 40 mg/m 2 administered every 3 weeks. (NCT03387917)., Competing Interests: Declaration of Competing Interest Ilaria Colombo: Travel grants: Tesaro, Janssen, AZ, GSK. Honoraria for consultancy or expert opinion: AZ, GSK, Novartis, MSD, BionTech. Institutional grants for clinical trials (PI): MSD, Bayer, Vivesto, Incyte, AZ, Orion. Kira-Lee Koster: Travel grants for congress visits from Takeda Pharma AG und Janssen-Cilag AG (paid to institution). Lisa Holer: no conflict of interest. Simon Haefliger: no conflict of interest. Manuela Rabaglio: no conflict of interest. Sara Bastian: no conflict of interest. Michael Schwitter: no conflict of interest. Katrin Eckhardt: no conflict of interest. Stefanie Hayoz: no conflict of interest. Anna M. Mc Laughlin: current employee of Pharmetheus AB and a paid consultant to multiple pharmaceutical companies. Charlotte Kloft: no conflict of interest. Marian Klose: no conflict of interest. Stefan Halbherr: Stefan Halbherr owns shares of InnoMedica Holding AG and functions as part of the executive management of the firm. Christian Baumgartner: Christian Baumgartner hold shares of Innomedica and is a former employee of the firm. He has received advisory fees from Boehringer Ingelheim. Cristiana Sessa: no conflict of interest. Anastasios Stathis: Institutional funding for clinical trials: Innomedica, Abbvie; ADC Therapeutics; Amgen, Astra Zeneca; Bayer; Cellestia; Incyte, Loxo Oncology; Merck MSD; Novartis; Pfizer; Philogen; Roche. Consultant/expert testimony/advisory board (institutional): Debiopharm, Janssen, AstraZeneca, Incyte, Eli Lilly, Novartis, Roche, Loxo Oncology. Travel grant: Incyte; Astra Zeneca. Dagmar Hess: no conflict of interest. Markus Joerger: Advisory role (institutional): Novartis, Astra Zeneca, Basilea Pharmaceutica, Bayer, BMS, Debiopharm, MSD, Roche, Sanofi; research funding: Swiss Cancer Research; travel grants: Roche, Sanofi, Takeda., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)