Overview of Rare Driver Alterations in NSCLC

Lyudmila A. Bazhenova, MD: Lung cancer has enjoyed tremendous progress in understanding oncogenic-driven subsets. We used to pay attention only to histology in treatment selection. Now we have 7 oncogenic drivers, all associated with FDA-approved targeted therapies. Those are the EGFR, ALK, ROS, BRAF V600E, NTRK, RET, and MET exon 14 skipping mutations.

In addition, we have 3 other abnormalities such as KRAS G12C mutations, EGFR, and HER2 [human epidermal growth factor receptor 2] exon 20 insertions, which have compounds in clinical trials with preliminary evidence of efficacy. With novel targeted therapies, we see unprecedented survival with some of the drivers. Take, for example, recent update of the ALEX trial for ALK-rearranged lung cancer. The alectinib arm in this trial showed a 5-year survival of 67%, and this data set is only 37% mature.

The median survival has not been reached, and the median follow-up is already 48 months. We also have learned in the past 10 years that the CNS [central nervous system] is currently a battleground for many of oncogenic-driven patients. In response to that, all novel targeted therapies are being developed with CNS coverage in mind.

Jonathan W. Riess, MD: In terms of how the approach of ALK-rearranged and ROS1-rearranged non–small cell lung cancer has evolved recently, there have been a lot of exciting developments. For the past several years, crizotinib, which is both an ALK and ROS1 inhibitor in addition to be initially developed as a MET inhibitor, has had potent activity in ALK and ROS1.

That was the first-generation ALK inhibitor, and it was compared with next-generation ALK inhibitors, alectinib and brigatinib, in the ALEX and J-ALEX trials for alectinib and in the ALTA-1L trial with brigatinib as first-line therapy. There was a substantial improvement in progression-free survival with bringing these next-generation ALK inhibitors, such as alectinib and brigatinib, up front. Alectinib had a median progression-free survival of about 3 years, and brigatinib median progression-free survival was about 2 years.

This really changed the landscape of how we treat ALK-positive non–small cell lung cancer. When we talk about ROS1 non–small cell lung cancer, crizotinib is a really good ROS1 inhibitor. Its approval was based on a study of about 50 patients. It was published in the New England Journal of Medicine in 2014. The median progression-free survival was a bit over 19 months, so really effective response rates at around 70%. Lately, there’s a new approved ROS1 inhibitor, entrectinib, which also appears quite active and has CNS penetration as well. It’s a bit better than crizotinib, which is also an advantage.

It’s been great that we’ve had these new ALK and ROS1 inhibitors to bring to the clinic. Also in development is lorlatinib, which is approved for ALK non–small cell lung cancer after progression on a prior ALK TKI [tyrosine kinase inhibitor] and also has activity in ROS1 non–small cell lung cancer, although it’s not approved for that indication.

Lyudmila A. Bazhenova, MD: NTRK fusions are oncogenic and lead to downstream activation of signaling pathways. In lung cancer, NTRK fusions are found in approximately 1% of patients. The incidence is slightly higher in a subset of lung cancer called lung neuroendocrine carcinomas. We have 2 FDA-approved histology-agnostic NTRK-fusion agents, such as larotrectinib and entrectinib. Those drugs have remarkable activity with a response rate of approximately 60% to 70%. Responses appear to be durable, and CNS activity has been reported with both larotrectinib and entrectinib. We definitely need to be testing for NTRK fusions in our lung cancer patients.

Transcript Edited for Clarity