Search

Bispecific antibodies (bsAbs) are engineered molecules designed to target two different epitopes or antigens. The mechanism of action is determined by the bsAb molecular targets and structure (or format), which can be manipulated to create variable and novel functionalities, including linking immune cells with tumor cells, or dual signaling pathway blockade. Several bsAbs have already changed the treatment landscape of hematological malignancies and select solid cancers. However, the mechanisms of resistance to these agents are understudied and the management of toxicities remains challenging. Herein, we review the principles in bsAb engineering, current understanding of mechanisms of action and resistance, data for clinical application, and provide a perspective on ongoing challenges and future developments in this field., Competing Interests: Declaration of interests None declared by authors., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Antibody-drug conjugates (ADCs) have emerged as a promising class of anticancer agents. Currently, the Food and Drug Administration has granted approval to 12 compounds, with 2 later undergoing withdrawal. Moreover, several other compounds are currently under clinical development at different stages. Despite substantial antitumoral activity observed among different tumor types, adverse events and the development of resistance represent significant challenges in their use. Over the last years, an increasing number of clinical trials have been testing these drugs in different combinations with other anticancer agents, such as traditional chemotherapy, immune checkpoint inhibitors, monoclonal antibodies, and small targeted agents, reporting promising results based on possible synergistic effects and a potential for improved treatment outcomes among different tumor types. Here we will review combinations of ADCs with other antitumor agents aiming at describing the current state of the art and future directions., Competing Interests: Anastasios Stathis: research grants (institutional): Astra Zeneca, Bayer, Eli Lilly, Incyte, Janssen, Roche, Abbvie, ADC Therapeutics, Amgen, Merck MSD, Novartis, Pfizer, Philogen, and Cellestina; travel grants: Astra Zeneca, Incyte; expert testimony (institutional): Bayer, Eli Lilly; advisory board (institutional): Roche, Jannsen. Anastasios Stathis, who is the Guest Editor of Exploration of Targeted Anti-tumor Therapy, had no involvement in the decision-making or the review process of this manuscript. All the other authors declare that they have no conflicts of interest., (© The Author(s) 2024.)

In recent years, we have seen the development and approval for clinical use of an increasing number of therapeutic agents against actionable oncogenic drivers in metastatic non-small cell lung cancer (NSCLC). Among them, selective inhibitors, including tyrosine kinase inhibitors (TKIs) and monoclonal antibodies targeting the mesenchymal-epithelial transition (MET) receptor, have been studied in patients with advanced NSCLC with MET deregulation, primarily due to exon 14 skipping mutations or MET amplification. Some MET TKIs, including capmatinib and tepotinib, have proven to be highly effective in this molecularly defined subgroup of patients and are already approved for clinical use. Other similar agents are being tested in early-stage clinical trials with promising antitumor activity. The purpose of this review is to provide an overview of MET signaling pathways, MET oncogenic alterations primarily focusing on exon 14 skipping mutations, and the laboratory techniques used to detect MET alterations. Furthermore, we will summarize the currently available clinical data and ongoing studies on MET inhibitors, as well as the mechanisms of resistance to MET TKIs and new potential strategies, including combinatorial approaches, to improve the clinical outcomes of MET exon 14-altered NSCLC patients.

The majority of epidermal growth factor receptor (EGFR) mutations (85-90%) are exon 19 deletions and L858R point mutations of exon 21, characterized by high sensitivity to EGFR-tyrosine kinase inhibitors (TKIs). Less is known about uncommon mutations (10-15% of EGFR mutations). The predominant mutation types in this category include exon 18 point mutations, exon 21 L861X, exon 20 insertions, and exon 20 S768I. This group shows a heterogeneous prevalence, partly due to different testing methods and to the presence of compound mutations, which in some cases can lead to shorter overall survival and different sensitivity to different TKIs compared to simple mutations. Additionally, EGFR-TKI sensitivity may also vary depending on the specific mutation and the tertiary structure of the protein. The best strategy remains uncertain, and the data of EGFR-TKIs efficacy are based on few prospective and some retrospective series. Newer investigational agents are still under study, and there are no other approved specific treatments targeting uncommon EGFR mutations. Defining the best treatment option for this patient population remains an unmet medical need. The objective of this review is to evaluate existing data on the outcomes, epidemiology, and clinical characteristics of lung cancer patients with rare EGFR mutations, with a focus on intracranial activity and response to immunotherapy.

Background: Osimertinib is considered the standard-of-care for previously-untreated EGFR mutant advanced non-small cell lung cancer (NSCLC). Oncogene driver screening in early NSCLC is not standard practice. A real-world study has been designed in order to investigate the optimal testing frequency and timing for EGFR mutations in early NSCLC in clinical practice., Patients and Methods: The present observational, retrospective study evaluated the real-world diagnostic-therapeutic pathway and clinical outcomes of 225 patients with stage I-III NSCLC, with particular reference to the EGFR -mutant subgroup., Results: Prior to surgery, 101 patients had undergone a diagnostic biopsy; EGFR mutational analysis was available in 56 (55%) patients and 12 patients (21%) had a cancer harboring an EGFR mutation. Among surgical specimens, reflex EGFR test was performed in 181 (80%) of 225 and 35 cases (19%) were EGFR mutant. The majority of patients had not received adjuvant chemotherapy ( N =174, 77%) or adjuvant radiotherapy (N=201, 89%). Of 49 (22%) patients experiencing disease relapse, 26 (53%) received first-line systemic treatment. All EGFR -mutant relapsed patients (N=6, 12.2%) received an EGFR-TKI. Median overall survival (OS) and relapse-free survival for the entire population were not reached. Multivariate analysis for OS confirmed a significant correlation with age, female gender, EGFR status, necrosis score, perineural invasion, and relapsed disease. EGFR test costs represented 1.6-2.4% of the total costs of management per patient (€34,340)., Conclusions: Our results suggest that the frequency of EGFR mutations in early stage (I-III) NSCLC is similar to that of advanced stages. Reflex EGFR testing in all early-stage NSCLC at diagnosis or after surgery appears to be a valid tool to give patients the chance to benefit from targeted adjuvant treatment., Competing Interests: GPa: Advisory Boards/Honoraria/Speakers’ fee/Consultant for: AstraZeneca, BMS, Boehringer Ing., Eli Lilly; MSD, Novartis, Pfizer, Roche, Takeda; VG: personal fees from Eli Lilly, Roche, Novartis, MSD, GSK, Gilead, outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pasello, Lorenzi, Pretelli, Comacchio, Pezzuto, Schiavon, Buja, Frega, Bonanno, Guarneri, Calabrese and Rea.)