Update on Newer Non–EGFR-Targeted Agents in Non–Small-Cell Lung Cancer

We spoke with Dr. Alexander Drilon, MD, a medical oncologist who specializes in the care and treatment of patients with lung cancer, about targeting non-EGFR mutations in non–small-cell lung cancer. Dr. Drilon is a medical oncologist at the Memorial Sloan Kettering Cancer Center in New York City, where he serves as the clinical director of the Early Drug Development Service.

-Interviewed by Anna Azvolinsky

Cancer Network: There are at least four oral, targeted agents against epidermal growth factor receptor, which is overexpressed in some non–small-cell lung cancer tumors. This is probably the most known alteration in lung cancer. Can you talk about some of the other known alterations that are also being targeted or being used as biomarkers in non–small-cell lung cancer, including the frequencies of these mutations?

Dr. Drilon: For EGFR, the classic biomarker is a mutation and that either involves L858R or exon 19 deletions. But since the discovery of these driver mutations in 2003 and 2004, there has been an explosion of driver discoveries in non–small-cell lung cancer. And beyond EGFR mutations, there are several gene rearrangements or fusions involving the genes ALK, ROS1, and RET. There are mutations involving BRAF, specifically BRAF V600E. There are also HER2 mutations. Lastly, there are splicing site alterations that involve MET exon 14 that lead to oncogenesis. The frequency of these alterations varies. For ALK rearrangements and MET exon 14 alterations, the frequency is on the order of 3% to 4%. For ROS1 and RET alterations, the frequency is about 1% to 2%.

Cancer Network: As far as targeting the ALK alterations, there are now several ALK inhibitors that are approved for treatment by the FDA. Do non–small-cell lung cancer tumors with ALK alterations tend not to also harbor EGFR mutations or the other mutations you just mentioned, and how does that affect treatment?

Dr. Drilon: That is correct. For the most part, these driver mutations are what we call mutually exclusive, meaning that they sit by themselves within a cancer and are the major drivers of growth. There are rare instances where you might see two driver mutations within one tumor, but by and large when we find something like an ALK rearrangement it is usually the primary driver of a cancer and exclusively there [while] other drivers are not.

Cancer Network: You mentioned RET-rearranged lung cancer mutations. Are there drugs in development that are targeting these RET rearrangements or drugs that are approved?

Dr. Drilon: There are no approved agents targeting RET-rearranged lung cancers. There are older drugs that are in the NCCN [National Comprehensive Cancer Network] guidelines, such as cabozantinib and vandetanib. These are multikinase inhibitors that have a likelihood of achieving a response in these tumors of about 30%. However, the limitation of these older agents is that because they are multikinase inhibitors and they target other proteins in addition to RET, hitting these proteins strongly, including VEGFR2, results in some strong side effects in patients, resulting in the need for dose modifications. Thankfully, we now have a new wave of selective RET inhibitors. These are BLU-667 from Blueprint Medicines and LOXO-292 from Loxo Oncology. As opposed to the older drugs, these are cleaner agents that selectively inhibit RET and are designed to avoid non-RET targets. And the preliminary data presented so far have been encouraging. We have seen higher response rates with these drugs compared to the multikinase inhibitors, and certainly because they are cleaner and only target RET we are seeing a much more favorable safety profile compared to the older drugs.

Cancer Network: What about HER2 mutations in non–small-cell lung cancer? Are there drugs in development for that, and do some of these include the HER2-targeted therapies approved for breast cancer?

Dr. Drilon: In the targeted [therapy] space for HER2-targeted lung cancer, the field has borrowed a lot from the therapies that have been developed in the HER2-positive breast cancer space. Initially, tyrosine kinase inhibitors were investigated in HER2-mutated lung cancers-like dacomitinib, which does have activity against HER2. But the response rate for that drug and [for] afatinib, another pan-ERBB inhibitor, ‎were low as single-agent therapies. However, there have been more encouraging data, this time with the use of ado trastuzumab emtansine or TDM1, that were recently presented at the ASCO 2018 meeting, showing an approximately 40% response rate when this antibody-drug conjugate was used. Ultimately, we might need to look for better drugs in this space to get up to a response rate of 60% or 80%, as we have for drugs that target some of the other driver mutations. Or like in the breast cancer space, we might want to look into the utility of combination therapy.

Cancer Network: Lastly, are you and your colleagues working on whole genome sequencing or other large-scale data mining, to identify additional driver mutations or other important mutations in non–small-cell lung cancers?

Dr. Drilon: Yes, those efforts are ongoing and they have really driven the identification of new biomarkers, not just for lung cancer but for other tumors. Part of this effort is to increase comprehensive sequencing not just on a research front but in the clinic, where we have good, much more focused targeted exome panels. And this has led to the discovery of newer biomarkers, such as NTRK fusions, for example. Those fusions have been specifically identified not just in lung cancer but in many other solid tumors. Recent data on an NTRK inhibitor, larotrectinib, shows a very high response rate of 75% to 80% in tumors of any kind that harbor an NTRK fusion, and among these were lung cancers. So I think that looking at the genome much more carefully and doing these analyses on the clinical front is hopefully going to increase the number of biomarkers associated with matched therapies that are able to help a larger proportion of patients..