Emerging Biomarkers in NSCLC

Alexander Drilon, MD

Alexander Drilon, MD

The treatment landscape of non—small cell lung cancer (NSCLC) is developing to include additional biomarkers beyond ALK, ROS1,andEGFR,allowing patients with rarer alterations the possibility of a more targeted treatment approach.

One of the targeted agents already moving through the pipeline is crizotinib (Xalkori), which was granted a breakthrough therapy designation by the FDA in May 2018 for the treatment of patients with metastatic NSCLC who harborMETexon 14 alterations.

Ongoing clinical trials are evaluating additional agents, including poziotinib, which demonstrated high antitumor activity in patients with metastatic, heavily pretreatedEGFRandHER2exon 20 mutant NSCLC. In results presented at the 19th World Conference on Lung Cancer, the oral quinazoline-based TKI induced a best response rate of 55%, including a 43% confirmed objective response rate in evaluable patients with EGFRexon 20 mutant NSCLC.

Additionally, patients with NSCLC who harborHER2mutations 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.

In an interview withTargeted Oncologyahead of this year’s New York Lung Cancers Symposium, where he presented on emerging targeted biomarkers, Alexander E. Drilon, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, discussed these developing markers in the NSCLC paradigm.

TARGETED ONCOLOGY:Could you please provide an overview of your lecture this year?

Drilon: At the 2018 New York Lung Cancers Symposium, I will be talking about emerging biomarkers beyondEGFR, ALK,andROS1.These include recurrent gene rearrangements or fusions likeRETandNTRK, 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 aboutHER2mutations, 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 alsoMETexon 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.

TARGETED ONCOLOGY:How should a clinician treat a patient with a rare alteration, such as HER2?

Drilon: HER2activation in lung cancer is different than what we are used to seeing in breast cancer, where you are seeingHER2activated 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 targetHER2;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 againstEGFRexon 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 forHER2-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% forHER2-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. 

TARGETED ONCOLOGY:What do you hope attendees take away from your lecture?

Drilon: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,andBRAFV600E, 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.

Reference:

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.