New-Generation Drugs Are Promising for ROS1 Mutation-Positive Stage 4 Lung Cancer

This year, on 23-26 September 2018, Toronto, Canada, hosted the 19th World Conference on Lung Cancer, where, in ROS1 mutation-positive patients with stage 4 lung cancer, entrectinib, lorlatinib and repotrectinib were among the new-generation drugs reported to provide high response rates and longer survival.

As is known, lung cancer is divided into two main groups: small cell and non-small cell lung cancer , and non-small cell lung cancer accounts for most lung cancers (%80-85). Mutations and similar genetic changes are targets for targeted drugs , which so far have shown efficacy and received approval only in non-small cell lung cancer. The figure below shows genetic changes associated with lung cancer for which targeted drugs are available:

One of these genetic changes is a ROS1 fusion mutation. ROS1 genetic changes are estimated to account for approximately %1 of all lung adenocarcinomas . ROS1 is a gene encoding a cell-surface protein that is a tyrosine kinase receptor. This receptorcan activate various signaling pathways involved in cell growth and mitosis (proliferation), differentiation and survival. The figure below shows the intracellular signaling pathways activated by the tyrosine kinase receptor encoded by the ROS1 gene in its role in cell growth and proliferation.

Changes in the ROS1 gene have been linked to non-small cell lung cancer and the rapidly growing brain tumor glioblastoma multiforme (GBM) . These changes result from rearrangement of the chromosome containing the gene.

The importance of ROS1 in lung cancer

In lung cancers, ROS1 translocations / gene fusions occur at a rate of %1. Translocations occur when a piece of a gene separates from the rest of the gene and enters another gene in the DNA, creating a fusion gene and consequently a fusion protein. In lung cancer-associated ROS1 fusion, the separated fragment enters another part of the same gene. When a fusion occurs in the ROS1 gene, the resulting fusion protein, a tyrosine kinase receptor, becomes continuously active and generates signals for the cancer cell's continuous growth and proliferation.

A new-generation ROS1-targeted drug in lung cancer: Entrectinib

Taken orally (as a pill), with activity against mutations such as ROS1 / NTRK / ALK shown in preclinical studies, entrectinibwas evaluated in patients with ROS1 mutations in pooled efficacy analyses from the STARTRK-2, STARTRK-1 and ALKA-372-001 studies presented at this congress.

One of the most important problems in patients with a ROS1 mutation is the higher frequency of brain metastasis; (brain metastases are detected at diagnosis in %36 of patients). Entrectinib's ability to cross the blood-brain barrier is thought to allow better disease control particularly in this patient group.

Study results

• Entrectinib was shown to cause disease regression in %74 of patients with brain metastases, compared with %80 in patients without brain metastases. 
• Time to progression with entrectinib was 13.6 months in patients with brain metastases at baseline versus 26.3 months in those without brain metastases.
• Entrectinib, which has fewer side effects than chemotherapy, was shown to be an effective and safe treatment agent in patients with a ROS1 mutation.

Other ROS1-targeted drugs: Lorlatinib and Repotrectinib

In patients with ROS1 mutation-positive stage 4 lung cancer, two other drugs whose efficacy results were presented were lorlatinib and repotrectinib .

• Lorlatinib was used in a phase 2 clinical trialin which the objective response rate was reported as %62 in all patients and %67 in patients with brain metastases. Time to progression in these patients was reported as 21 months.
• With another molecule, repotrectinib, the objective response rate was %80 in all patients and %100 when assessed for brain metastases. Time to progression was not reported because median survival had not yet been reached. Repotrectinib was also reported to be the most effective treatment agent in patients with a ROS1 mutation treated with crizotinib (Xalkori) who had the G2032R mutation, the most common mutation responsible for crizotinib resistance.

These 3 treatment agents are promising because they achieve better survival outcomes in patients with ROS1 mutations by crossing the blood-brain barrier effectively and exerting substantial effects on brain metastases, particularly in lung cancer patients in whom brain metastases are associated with shorter survival.