Emerging new treatments with targeted therapies in lung cancer

As you could read in the previous step, over the last two decades a lot has changed in the treatment of lung cancer. Nowadays all patients with advanced lung cancer should be tested for driver mutations of their tumour, for whom only palliative treatments are available.

Depending from the geographical regions the incidence of these mutations differ. For example the most prevalent mutation (EGFR exon 19 and exon 21) has an incidence of around 50% in Asia whereas the incidence in Europe is around 10%. Treatment for this mutation became available after the landmark study by Tony Mok in 2009.

Tyrosine Kinase Inhibitors

This was the first study to show that patients with a driver mutation had benefit from targeted treatment (gefitinib) over chemotherapy, whereas patients that did not have the specific mutation did very poor on that treatment. These targeted agents are often referred to as Tyrosine Kinase Inhibitors (TKI). TKI come in the formulation of a pill that have to be taken daily for as long as it they are effective and side effects are doable for the patient. The TKI for a specific mutation are generally improved over time. The first available TKI is called a first generation inhibitor, the next a second generation and so on.

EGFR mutations

For EGFR mutations the first generation TKI’s were gefitinib and erlotinib, both targeting the epidermal growth factor mutation (EGFR), especially the exon 19 deletion known as the p.(E746_A750del) deletion and the point mutation in exon 21 also known as the L858R mutation (these two mutations makeup around 90% of all targetable EGFR mutations).

Osimertinib

In 2018 the Flaura study showed that first line treatment with osimertinib (a 3rd generation EGFR inhibitor) resulted in an improvement of more than 8 month in progression free survival (PFS) over gefitinib or erlotinib. Another advantage of Osimertinib is that it passes the blood-brain barrier much better than the first generation EGGFR inhibitors, making it an effective drug for brain metastasis in these patients as well. The median PFS with Osimertinib is 38.6 month. Progression occurs due to the development or emergence of resistant clones. Sometimes these clones can be targeted as well. In such an instance treatment with eg Osimertinib is continued and another drug is given as well for the other driver (eg in case of a MET amplification or BRAF V600E mutation).

Targeting KRAS mutation

Another relevant mutation is the KRAS mutation. KRAS mutations are the most prevalent mutation in the Western hemisphere, accounting for approximately 30% of mutations found in lung cancer. This mutation was long considered undruggable, due to the high affinity between KRAS and GTP. However recently this has become a druggable target as well. Small molecules that irreversibly bind to and inactivate a common oncogenic mutated KRASG12C shed new light on targeting KRAS. These compounds selectively bind to the mutated cysteine residue of KRASG12C via a covalent bond and disrupt both switch-I and switch-II pocket, subverting the native nucleotide preference to GTP over GDP. Thereby they impair the binding of KRAS to RAF proto-oncogene serine/threonine-protein kinase, preventing signalling downstream that results in the survival/growth of the KRAS dependent tumour. Sotorasib was the first KRASG12C inhibitor to show activity against KRAS. Multiple trials are currently ongoing with 2nd generation KRAS inhibitors showing even more promise.

Targeting ALK

ALK is a next druggable target. In 2007 it was described first as a somatic oncogenic gene translocation in lung cancer, involving fusion of two genes, EML4 (echinoderm microtubule associated protein-like 4) and ALK (anaplastic lymphoma kinase). The mechanism here is not a mutation but rather a translocation. This means that a part of a different gene is fused to the ALK gene, promoting its activation. The most prevalent translocation is the aforementioned ALK-EML4 translocation, whereby EML4 is placed in front of ALK. ALK activation is driven by the trimerization domain of EML4, which drives self-association of the kinase domains, thereby driving the disease. It is prevalent in around 3-6% of lung cancers. In 2011 crizotinib was approved by the FDA for the first-line treatment of advanced NSCLC in patients with ALK+ tumours. Nowadays this treatment is replaced by the more effective 3rd generation TKI alectinib and lorlatinib showing median PFS of more than 34 month for both these drugs.

BRAF mutations

BRAFV600E BRAF mutations are reported across many types of cancers, including melanoma, colorectal cancer, thyroid cancer and NSCLC. BRAF is a serine/threonine protein kinase belonging to the RAF kinase family. Upon activation by RAS, these proteins play a pivotal role in cell growth, proliferation, migration and survival by the activation of the MAPK–ERK pathway. BRAF mutations are classified into three classes according to their dimerization status, their kinase activity, and RAS dependence for activation. Here only class 1 mutations, also known as BRAFV600E, that are characterized by RAS-independent, high BRAF kinase activity in a monomeric status are discussed. In lung cancer this mutation is prevalent around 1-3% and another target. First a RAF inhibitor dabrafenib showed activity in first trials 2016. However, in the same year the combination of both a BRAF and MEK inhibitor (dabrafenib and trametinib) was shown to be more effective and resulted in less side effects, was better tolerated.

MET amplifications and MET mutations

Both MET amplifications and MET mutations (also known as the MET exon 14 skipping mutation) appear to be relevant in lung cancer as well. Also this mutation is found in around 1-3%. Additionally it is also a resistance mechanism, especially in EGFR TKI treated patients. Upon resistance to osimertinib this aberration accounts for 7-15% of cases. MET exon 14 contains a binding site for CBL, thereby CBL-mediated MET protein degradation is impaired, leading to the accumulation of MET receptors and the aberrant activation of MET oncogenic signalling. Tepotinib is available for treatment of MET exon 14 skipping lung cancer in the Netherlands since 2023.

RET and ROS1 fusions

RET fusions are mainly seen in non-small-cell lung cancer (1-3%), thyroid cancer (up to 70%), and breast cancer (30-70%), whereas RET-mutations are found in medullary thyroid cancer. For lung cancer for this fusion selpercatinib was approved in 2020 by the FDA. ROS fusions account for around 1% of lung cancers. Crizotinib is the only registered drug at this time.

Most relevant driver mutations in the Netherlands in 2022 (Courtesy Anthonie van der Wekken)

Timeline of FDA-approved targeted therapies for NSCLC. First-line therapies depicted (Source: Mitchell et al. 2023)

References

• Mok T, Wu Y, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. The New England Journal of Medicine 2009;361:947-957.
• Mitchell CL, Zhang AL, Bruno DS, et al. NSCLC in the era of targeted and immunotherapy: What every pulmonologist must know. Diagnostics (Basel) 2023;13:1117. doi: 10.3390/diagnostics13061117.