Top advances of the year: Precision oncology

Abstract

The advent of precision medicine has changed the landscape of oncologic biomarkers, drug discovery, drug development, and, more importantly, outcomes for patients with cancer. Precision oncology entails the genomic profiling of tumors to detect actionable aberrations. The advances in clinical next-generation sequencing from both tumor tissue and liquid biopsy and availability of targeted therapies has rapidly entered mainstream clinical practice. In this review, recent major developments in precision oncology that have affected outcomes for patients with cancer are discussed. Rapid clinical development was seen of targeted agents across various mutational profiles such as KRASG12C (which was considered "undruggable" for almost 4 decades), Exon 20 insertions, and RET mutations. Approaches to precision chemotherapy delivery by the introduction of antibody drug conjugates in the armamentarium against lung cancer has been appreciated. K E Y W O R D Santibody drug conjugates, cancer, oncogenic driver, precision oncology, targeted therapy Lung cancer is one of the most aggressive tumor types, with 131,880 estimated deaths from this disease in 2021. 1 Targeted therapies stratified by oncogenic drivers have substantially improved therapeutic outcomes in patients with non-small cell lung cancer (NSCLC). 2 However, such oncogenic drivers are not found in 25% to 40% of cases of lung adenocarcinoma. Identifying new therapeutic targets is imperative to improve outcomes in NSCLC 3 (Table 1). Izumi et al. recently reported a novel fusion transcript ofCLIP1 and LTK using whole-transcriptome sequencing in a multiinstitutional genome screening platform. 4 The CLIP1-LTK fusion was present in 0.4% of NSCLCs and was mutually exclusive to other known oncogenic drivers. The authors demonstrated that kinase activity of the CLIP1-LTK fusion protein is constitutively activated and that it has transformation potential. Furthermore, there was preclinical evidence of inhibition of CLIP1-LTK kinase with lorlatinib with good clinical response in an n-of-1 study. This novel fusion target may be another target for routine screening. Clinical development of therapeutic agents for this new oncogenic driver is now warranted. KRAS G12CActivating mutations in Kirsten rat sarcoma viral oncogene homologue (KRAS) are found in 25% to 30% of nonsquamous cell NSCLCs, representing the most prevalent genomic driver event in NSCLC. 5 Aakash Desai and Neha K. Reddy contributed equally.

Revolutionizing cancer drug development: Harnessing the potential of basket trials

“…There have been several notable examples of basket trials conducted in oncology that have led to US Food and Drug Administration (FDA) approval. 19 Interestingly, each trial design and drug approval has been unique. The success of basket trials depends on various factors, such as the specific molecular alteration, clinical response rates, safety profile, and the strength of the overall evidence generated through the trial.…”

“…Basket trials continue to evolve and play a critical role in advancing precision oncology and beyond by providing valuable insights into the efficacy of targeted therapies in specific molecularly defined patient populations, regardless of tumor histology or anatomic location. There have been several notable examples of basket trials conducted in oncology that have led to US Food and Drug Administration (FDA) approval 19 . Interestingly, each trial design and drug approval has been unique.…”

Neoantigen therapeutic cancer vaccines: a promising approach to personalized immunotherapy

“…Personalized therapy, also known as precision or targeted therapy, aims to provide patients with optimal treatment based on their unique case [13]. This requires the examination of the tumour to detect characteristic genetic mutations and peptides that would serve as points of intervention for the applied therapy [14]. In the case of targeted immunotherapy, immune system cells are directed against the identified molecules, leading to an attack on tumour cells and ultimately achieving a therapeutic effect [15].…”