Developments in pharmacotherapy for treating metastatic non-small cell lung cancer

ABSTRACT

Introduction: Most patients with non-small cell lung (NSCLC), including squamous cell carcinoma, adenocarcinoma and large cell carcinoma, have advanced disease at diagnosis and systemic therapy is the standard-of-care. About 20% of Caucasian patients are affected by an oncogene-addicted advanced NSCLC for which correspondent inhibitors are available.

Areas covered: The main state-of-the-art synthetic anticancer drugs in the groups of chemotherapeutics, epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors for NSCLC treatment, are reviewed and discussed from phase III randomized practice-changing trials onwards. A structured search of bibliographic databases for peer-reviewed research literature and of main meetings using a focused review question was undertaken.

Expert opinion: The survival of NSCLC patients is increasing, regardless of the presence or not of a specific target, due to the availability of new generation drugs. The continuous deep knowledge of the mechanisms of NSCLC development and the constant research into new drugs should lead to the discovery of new potential targets and the synthesis of corresponding inhibitors to improve the outcomes of each subgroup of patients in order to control the disease in a constantly growing percentage of patients.

KEYWORDS:

• ALK
• chemotherapy
• EGFR
• NSCLC
• pemetrexed
• tyrosine kinase inhibitor

Article highlights

• Most of patients with non-small cell lung (NSCLC) had advanced disease at diagnosis and systemic therapy is the standard-of-care. About 20% of Caucasian patients are affected by an oncogene-addicted advanced NSCLC for which correspondent inhibitors are available.

• In the last decades, in the area of cancer therapy, about 75% of molecules approved are other than synthetic, with most of them actually being either natural products or directly derived therefrom.

• The main synthetic anticancer drugs in the groups of chemotherapeutics, epidermal growth factor receptor (EGFR)- and anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors (TKIs) introduced in the clinical practice for the treatment of advanced NSCLC, are discussed from phase III randomized practice-changing trials onwards.

• Among chemotherapeutics, pemetrexed showing activity against non-squamous NSCLC, in any type of strategic approach (second-, first-line, maintenance), can be considered as a sort of targeted chemotherapy due to its inhibition of thymidylate synthase (TS) whose expression is lower in non-squamous NSCLC.

• First- (gefitinib, erlotinib), second- (afatinib), and third-generation (osimertinib) EGFR-TKIs, are effectiveness in the management of EGFR-addicted NSCLC differing mainly for the toxicity profile. Osimertinib is able to overcome the resistance due to the onset of a further EGFR exon 20 mutation, the T790M, during the treatment with first- or second-generation EGFR-TKIs.

• The ALK-TKI crizotinib showed effectiveness in ALK-rearranged NSCLC patients. Second-generation (ceritinib, alectinib) ALK-TKIs are already available in the clinical practice for the management of ALK-rearranged crizotinib-resistant NSCLC patients.

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Declaration of interest

A Rossi declared a role as Speaker Bureau for Roche, Boehringer Ingelheim, advisory boards’ participation for Eli-Lilly, AstraZeneca and Roche. P Maione declared a role as advisory boards’ participation for Roche, Eli-Lilly. C Gridelli declared a role as Speaker Bureau and advisory boards’ participation for Roche, Boehringer Ingelheim and Eli-Lilly. 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 is not funded.