TKIs Set the Stage for Treatment in HER2-Mutant Lung Cancer, But May Be Eclipsed by ADCs

Poziotinib, mobocertinib (TAK-788), and fam-trastuzumab deruxtecan-nxki (Enhertu) are among some of the agents that have positioned HER2 as a must-test alteration in newly diagnosed advanced lung cancer, explained Lecia V. Sequist, MD, MPH, who added that the specificity of antibody-drug conjugates (ADCs) could challenge the broad activity of TKIs as a frontline standard in the near future.

“In the EGFR space where there are such established TKIs, ADCs are being thought of as salvage therapy, but if an ADC gets approved first for a certain indication, like HER2 for example, then we’re really looking at a different paradigm where TKIs are then going up against ADCs. As a field, we could learn a lot by comparing and contrasting these different types of therapeutic approaches,” said Sequist.

In an interview with OncLive^®, Sequist, the Landry Family Associate Professor of Medicine at Harvard Medical School, and director, Center for Innovation in Early Cancer Detection, Massachusetts General Hospital, discussed some of the advances that bore out in 2020 in HER2-mutant lung cancer and previewed anticipated developments in 2021.

OncLive^®: Has HER2 joined the roster of genes to test for in advanced lung cancer? 

Sequist: HER2 has really become a much more widely recognized subset of lung cancer that we need to test for. One big lesson is that for patients with newly diagnosed advanced lung cancer, in particular advanced lung adenocarcinoma, we really need to do broad testing for a number of different mutations that have therapeutic implications, not just EGFR and ALK anymore. We really need to test for ROS, RET, MET, and BRAF, and HER2 is now in that list as well. 

HER2 mutations tend to [reside] in the exon 20 section of HER2, and HER2 is very analogous in its protein structure to EGFR. HER2 mutations are therapeutically often treated with the same types of approaches as EGFR exon 20 mutations, which is nice because a lot of the drugs do have activity in both genotypes. Some of the oral TKIs that work for EGFR exon 20 insertions might also work for HER2 exon 20 insertions like poziotinib and TAK-788. 

The most exciting thing we saw in 2020 for [patients with] HER2 [mutations] was probably the results of the DESTINY-Lung01 study at the 2020 ASCO Virtual Scientific Program looking at an ADC. This [agent], trastuzumab deruxtecan, works just for [patients with a] HER2 [mutation]; it’s not appropriate for [an] EGFR exon 20 [mutation]. The ADC has a very high response rate of about 60% in the frontline setting. For patients with this particular mutation, that’s a very exciting therapy, especially since it’s already FDA approved for patients with breast cancer.

What were your initial thoughts regarding the data with poziotinib and TAK-788? 

Poziotinib and TAK-788 are similar in that they have broad activity, not only over EGFR and HER2, but importantly, wild-type EGFR too, and that leads to a lot of side effects like rash and diarrhea. The experience for patients with these drugs is similar to what we’ve seen in the past with the second-generation EGFR inhibitors, like afatinib [Gilotrif] and dacomitinib [Vizimpro], where you tend to get a good amount of rash and diarrhea and other skin and nail side effects, as well as oral side effects, that can be bothersome for patients. If that’s the only possible therapeutic approach, then there are ways to mitigate these side effects. However, if there are approaches that are more specific, more potent to just the mutant form of the proteins, and not the wild-type, or a totally different approach like an ADC that may have less toxicity, that’s really great for patients. 

The good thing about poziotinib and TAK-788 is they have really opened the door to treating new subsets of patients, which previously hadn’t been targeted specifically in clinical trials. I’m glad that there are now several companies and stakeholders going after this space, because there are a lot of patients with these mutations. If you test, you’ll find more and more [abnormalities], and having a personalized treatment option available is always a good thing.

How does trastuzumab deruxtecan stack up against these TKIs? 

For any genetically defined subgroup of lung cancer, if there is an approved therapy, that kind of catapults that to the head of the list. If [trastuzumab deruxtecan] does receive FDA approval, which I hope it does in the coming months, it’s certainly something that I would think about using in the frontline setting for patients with [a] HER2 [mutation]. I have used the agent in some patients in the frontline setting as part of a clinical trial. It’s a great opportunity for these patients, and it really drives home the point that we need to test at the time of diagnosis, so that we are aware of which patients have this mutation.

What do you anticipate coming down the pipeline in 2021 in the HER2 space?

Novel TKIs are being developed that we haven’t seen results of. Some new TKIs, such as CLN-081, are being studied that we haven’t seen mature results on. For many of the genotypes, whether it’s EGFR or HER2, a space where there happens to be TKIs that can be effective and also ADCs that can be effective, we really aren’t sure how to sequence them. There have been few, if any, head-to-head studies of these two very different strategies.