Identification of drug combinations for lung cancer patients whose tumors are unresponsive to targeted therapy: clinical bases and future directions

ABSTRACT

Introduction

Targeted therapies have granted unprecedented results in terms of survival and safety to oncogene-addicted advanced NSCLC patients. However, these patients eventually become unresponsive to such treatments due to several different resistance mechanisms. Moreover, the current lack of subsequent-line treatments forces these patients to receive less tolerable and less effective chemotherapy regimens.

Areas covered

Thus, this paper aims to review the current state of the art with respect to targeted therapies for the treatment of oncogene-addicted advanced NSCLC patients, focusing on resistance mechanisms and on drug combinations to overcome them.

Expert opinion

We strongly believe that a personalized sequential treatment approach based on resistance mutations will become the standard of care for oncogene-addicted advance NSCLC patients. Furthermore, we believe that TKI combination regimens will play a key role. In the same vein, ICI-containing regimens will play a part both in patients without druggable resistance mutations and in patients progressing on TKI therapies.

KEYWORDS:

• ALK
• BRAF
• combination treatments
• EGFR
• HER-2
• MET
• NTRK
• RET
• ROS1
• TKI

Article highlights

• Targeted therapies have granted unprecedented results in terms of survival and safety to oncogene-addicted advanced NSCLC patients.

• However, oncogene-addicted advanced NSCLC patients eventually become unresponsive to TKI treatments due to several different resistance mechanisms.

• In order to develop and employ better drugs to treat oncogene-addicted advanced NSCLC patients progressing on targeted therapies, it is of paramount importance to understand the acquired resistance mechanisms developing in these patients.

• A personalized sequential treatment approach based on resistance mutations will become the standard of care for oncogene-addicted advance NSCLC patients and TKI combination regimens will play a key role.

• ICI-containing regimens will play a part both in patients without druggable resistance mutations and in patients progressing on TKI therapies.

Disclosure statement

Dr. Gridelli received honoraria as speaker bureau and advisory board member from: AstraZeneca, BMS, MSD and Roche. All the other authors have no conflicts of interest to declare.