Alexander E. Drilon, MD, discusses developing markers in the non–small cell lung cancer paradigm.
Alexander Drilon, MD
Markers beyond ALK, ROS1, and EGFR are slowly becoming well-known in the treatment landscape of non—small cell lung cancer (NSCLC), offering an opportunity for patients with rarer alterations to undergo a more targeted treatment approach.
Some targeted agents are already moving through the pipeline, such as crizotinib (Xalkori), which was granted a breakthrough therapy designation by the FDA in May 2018 for the treatment of patients with metastatic NSCLC who harbor MET exon 14 alterations.
More agents are being evaluated in clinical trials, including poziotinib. In a study presented at the 19th World Conference on Lung Cancer, high antitumor activity was demonstrated with the oral quinazoline-based TKI poziotinib in patients with metastatic, heavily pretreated EGFR and HER2 exon 20 mutant NSCLC. In evaluable patients with EGFR exon 20 mutant NSCLC, poziotinib induced a best response rate of 55%, including a 43% confirmed objective response rate.
Additionally, patients with NSCLC who harbor HER2 mutations were included on a basket trial of ado-trastuzumab emtansine (T-DM1; Kadcyla), noted Drilon. Trials of antibody-drug conjugates (ADCs) also look hopeful for these patients.
Alexander E. Drilon, MD, will be presenting on emerging targeted biomarkers during the 2018 New York Lung Cancers Symposium on November 10, 2018.
In an interview with OncLive ahead of this year’s symposium, Drilon, a medical oncologist at Memorial Sloan Kettering Cancer Center, discussed these developing markers in the NSCLC paradigm.Drilon: At the 2018 New York Lung Cancers Symposium, I will be talking about emerging biomarkers beyond EGFR, ALK, and ROS1. These include recurrent gene rearrangements or fusions like RET and NTRK, for which there are exciting new targeted therapies that are currently in development. Some of these targeted therapies might be approved soon by the FDA.
I am also going to talk about HER2 mutations, which occur in about 2% of lung cancers. We are seeing activity with newer agents, not just TKIs, but also ADCs. That may be a path forward for the development of targeted therapies for this genomic subset.
There are also MET exon 14 alterations, which occur in about 4% of all NSCLCs. Many different MET inhibitors are currently in development and being tested. One of these, crizotinib, has been granted breakthrough designation by the FDA.HER2 activation in lung cancer is different than what we are used to seeing in breast cancer, where you are seeing HER2 activated because of copy number changes or amplification. In lung cancer, we are seeing activation via mutation. Interestingly, that can occur by insertions or deletions that are, in a way, similar to the EGFR exon 20 insertions. There are a lot of TKIs that can target HER2; however, with the older drugs, we have only seen response rates up to about 12%.
Thankfully, there are newer agents that are being tested like poziotinib, which also has activity against EGFR exon 20. In the recent presentation of poziotinib, the response rate was in excess of 40%. At our center, we have also tested the ADC T-DM1. The response rate in that phase II basket trial for HER2-mutant lung was in the excess of 40%. Finally, building on the successes of T-DM1, there are companies like Daiichi Sankyo, for example, who have new ADCs with very exciting activity in HER2-positive breast cancer, as well as lung cancer. We are seeing a response rate in excess of 70% for HER2-mutant lung cancer. For this subset, my hope is that we will see a nod from one or more regulatory agencies sometime soon, given that we are seeing higher response rates than we did in the past. There is a lot of movement in the targeted therapy field beyond the drivers that we are used to seeing in lung cancer in 2004 and 2007. The take-home message here is that we make sure to think about the best tests to sequence your patients' cancers on. I would recommend doing a comprehensive next-generation sequencing (NGS) assay that is not only able to detect EGFR, ALK, ROS1, and BRAF V600E, but all of these other [abnormalities]. In patients for whom a biopsy might be challenging, then use something like a plasma genomic profiling assay as a complementary test to a tumor-based NGS.
Heymach J, Negrao M, Robichaux J, et al. A phase II trial of poziotinib in EGFR and HER2 exon 20 mutant non-small cell lung cancer (NSCLC). In: Proceedings from the IASLC 19th World Conference on Lung Cancer; September 23-26, 2018; Toronto, Canada. Abstract OA02.06.