Neoadjuvant Oncogene-Targeted Therapy in Early Stage Non–Small-Cell Lung Cancer as a Strategy to Improve Clinical Outcome and Identify Early Mechanisms of Resistance

Abstract

Evaluations of resistance mechanisms to targeted treatments in non-small cell lung cancer (NSCLC) are necessary for development of improved treatment after progression and to help delay progression. Populations of cells that survive after initial treatment form the basis of resistance via outgrowth of resistant clones or activation of alternative signaling pathways. Here we describe a clinical trial approach in which patients with EGFR, ALK, ROS1 and MET exon 14 alterations and early stage (IA–IIIA) NSCLC will be treated with induction epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) or crizotinib, a TKI which inhibits anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 (ROS1) and hepatocyte growth factor receptor (MET). We will evaluate resected tumor samples for pathologic response to induction therapy, overall response rate and disease free survival. Additionally, we will assess patients for early evidence of resistance to targeted therapy in terms of activation of alternative signaling pathways and for identification of resistance clones in remnant cell populations.

Off-Label Use of Crizotinib as a Neoadjuvant Treatment for a Young Patient When Conventional Chemotherapy Gave No Benefits in Stage IIIA Non-Small Cell Lung Cancer

“…We think that crizotinib, as with other targeted therapies, can be an option in neoadjuvant schemes, especially when conventional chemotherapy gives no benefits. Controlled studies are needed to establish the role of crizotinib in patients with locally advanced disease, and work is already ongoing to identify early mechanisms of resistance [ 15 ].…”

Expanding anaplastic lymphoma kinase therapeutic indication to early stage non-small cell lung cancer

“…Extended follow-up, prospective and wider validation analyses, including different oncogene-addicted subgroups, could corroborate the evidence of a negative clinical impact of ALK gene translocations. Nevertheless, the undoubted higher number of disease recurrences in this patients' subgroup spurs scientific community to implement peri-operative strategies aiming to a better disease control (9,30).…”

“…Unfortunately, little is known about underpinning molecular events driving this "persistent" phenotype and whether ALKtargeting adjuvant therapies may cause accumulation of this cancer cells subset, altering biological history of the disease, is still to be defined. Relevant insights will be gained through clinical trials, ongoing or planned (i.e., NCT03088930 and PROMISE trials), in the neo-adjuvant setting, taking advantage of the opportunity to analyze residual tumor tissues after TKI exposure (8,30,54). A deep characterization of residual tumor cells and associated tumor microenvironment represents a unique chance to deeply study TKI-induced early molecular alterations driving future resistance to targeted therapies.…”

Neoadjuvant Crizotinib for ALK Re-arranged NSCLC?

“…Moderate yet well-established effect of targeted therapy witnessed in the advanced-stage NSCLC aroused the idea of usage of the drug in earlier stages. 15 The 72% to 74% response rate posed a challenge to secure and establish the supposedly stabilized tumor-body relation: eliminating the primary focus. 16 A promising scenario, a room for neoadjuvant setting was spontaneously generated for selected cases.…”

“…One might question the value of anecdotic reports or retrospective case series, in particular, because there are highly sophisticated trials underway such as the ALCHEMIST, the Swiss SAKK 16-14, and the NCTO 1857271, 2201992, and 2347839 trials among others. 15,23,24 Indisputably, a trilogy that resonates includes the epistemological, the evidence-seeking statistical, and the moral issues. Building knowledge requires the first bricks, even in our current litigation-infested, risk-averse age.…”