Immunotherapy in Non-Small-Cell Lung Cancer Patients with Driver Alterations: A New Strategy?

Abstract

For many years, researchers have been trying to develop the most effective ways to fight lung cancer, which is the cause of the largest number of cancer-related deaths among men and women worldwide. The most advanced treatments for nearly all non-small-cell lung cancer (NSCLC) types include immunotherapy with immune checkpoint inhibitors (ICIs), mainly anti-programmed death 1/anti-programmed death ligand 1 monoclonal antibodies (anti-PD-1/PD-L1 mAbs) in monotherapy or in combination with other strategies. Despite significant advances, long survival is not achievable in most cases, so new solutions are constantly being sought. One of the questions raised by oncologists is the efficacy of ICIs in patients with molecular driver alterations, especially when the possibilities of using molecularly targeted therapies are exhausted (e.g., due to resistance to tyrosine kinase inhibitors). There are studies investigating this problem, but it is still poorly described. Among probable immunotherapy’ failures reasons, low immunogenicity of tumors with one driver mutation is listed. Nevertheless, in some cases, the therapy is efficient, and more research is required to establish the management of NSCLC patients with oncogenic driver abnormalities. The aim of this article is to review current discoveries in this matter.

BRAF-AXL-PD-L1 Signaling Axis as a Possible Biological Marker for RAI Treatment in the Thyroid Cancer ATA Intermediate Risk Category

“…Our results are reinforced by other studies that have reported that BRAF mutations are associated with higher expression of the PD-L1 protein in thyroid cancer, and that increased PD-L1 expression is significantly associated with disease recurrence and poor survival [ 19 , 20 ]. The direct and significant association between BRAF mutations and a higher level of PD-L1 expression in thyroid cancer, as also described in other human cancers, such as NSCLC, is probably due to a relatively higher TMB level [ 21 , 22 ] or the induction of epithelial/mesenchymal (EM) transition with subsequent greater tumor immune evasion, as a consequence of AXL-PI3Kinase-PD-L1 signaling axis activation, a mechanism recently described in head and neck and lung cancer [ 23 , 24 ]. Nonetheless, the presence of higher levels of CD8+ in the tumor microenvironment could be an index of a patient’s better immune response, and, consequently, of the higher PD-L1 expression, indicating the higher intrinsic immune escape capability of the tumor [ 25 ].…”

Optimizing treatment strategies for a MET exon 14 skipping mutation in non-small-cell lung cancer: a case report of sequential immunotherapy and targeted therapy and literature review

“…Sabari et al [25] researched the response to ICIs in a group of 24 NSCLC patients with the MET exon 14 skipping mutation. They reported an ORR of 17% and PFS of 1.9 months [25,26].…”

Efficacy of chemoimmunotherapy in a lung adenocarcinoma patient with mutations in the KRAS and STK11

“…Differences in response are probably related to tumor microenvironment (TME) characteristics that are diverse, depending on the alterations occurring. STK11-mutated tumors exhibit lower lymphocyte infiltration and lower PD-L1 expression, compared to TP53-mutated ones [2].…”

“…However, the coexistence of KRAS mutations and mutations in suppressor genes, such as STK11 (Serine/Threonine Kinase 11 also called Liver Kinase B1, LKB1), may result in the lack of response to immunotherapy. Contrarily, the coexistence of mutations in the KRAS and TP53 (tumor protein p53) genes may increase the effectiveness of immunotherapy [2].…”