New systemic strategies for overcoming resistance to targeted therapies in non-small cell lung cancer

ABSTRACT

Introduction: Although the achievements in the treatment of advanced non-small cell lung cancer (NSCLC) have been translated in improved disease control, response rate and survival, especially in the case of patients with targetable oncogenic drivers, acquired resistance is common after initial benefit; furthermore, primary resistance can occasionally be observed. Due to its clinical implications, the management of treatment-resistant NSCLC is a top topic of the current research, and many efforts are being put in the study of the mechanisms at the base of resistance and in the development of effective therapeutic countermeasures.

Areas covered: This review aims at identifying the most relevant novel chemical therapies designed to overcome resistance in NSCLC, including recently approved agents, as well as compounds in clinical development.

Expert opinion: An improved knowledge of the mechanisms causing resistance to treatments in NSCLC translates into effective innovative chemical therapies able to overcome such occurrence, and the paradigms of this progress are represented by novel inhibitors of the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK); however, the study of novel systemic therapies in this setting is challenging, and further efforts in this setting are highly needed.

KEYWORDS:

• EGFR
• ALK
• resistance
• non-small cell lung cancer
• T790M

Article highlights

• The availability of targeted therapies has dramatically modified the management of advanced non-small cell lung cancer (NSCLC).

• Different mechanisms of resistance to targeted agents have been identified and described; some of these mechanisms involve alterations within the therapeutic targets (such as ALK or EGFR), while others involve the activation of other signaling pathways.

• Novel approaches, including combination strategies, third-generation EGFR inhibitors, and new ALK inhibitors are being explored in the management of resistant NSCLC.

• In the case of EGFR TKI resistance, the identification of a secondary mutation (T790M) is critical in order to prescribe a third-generation inhibitor; therefore, significant efforts are being put in strategies designed to improve the ability to detect this mutation.

• In spite of the promising effects of novel inhibitors, additional mechanisms of resistance (including tertiary mutations) have been observed; additional studies designed to overcome this new occurrence are ongoing.

This box summarizes key points contained in the article.

Declaration of interest

C Genova has received honoraria/speakers’ bureaus from Bristol-Myers Squibb, Boehringer Ingelheim, and Astra Zeneca; E Rijavec has received honoraria/speakers’ bureaus from Bristol-Myers Squibb, Boehringer Ingelheim, and Astra Zeneca; G Biello has received speakers’ bureaus from Astra Zeneca; F Grossi has received honoraria/speakers’ bureaus from Bristol-Myers Squibb, Boehringer Ingelheim, and Astra Zeneca. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded