Targeted Therapies Continue to Make Strides in Oncogene-Driven NSCLC

Andreas Saltos, MD

Patients with oncogene-driven non–small cell lung cancer (NSCLC) stand to benefit from the availability of targeted therapy in the clinic, but also in clinical trials, explained Andreas Saltos, MD, making broad molecular testing all the more essential to lung cancer care.

“These are very effective new drugs that were not available a couple of years ago for mutations that may not have been considered standard to test for a couple of years ago. [The availability of these drugs] highlights the importance of broad genomic profiling for every patient with advanced NSCLC,” said Saltos. “It’s always important to know the full genetic makeup of your patient’s cancer, because there really are a lot of new targeted treatments that are being worked on beyond [those for mutations in], ALK, EGFR and ROS1, and it’s really exciting to see that these drugs are effective in the populations that they’re targeted for.”

In an interview with OncLive^® during an Institutional Perspectives in Cancer webinar on lung cancer, Saltos, a medical oncologist and Clinical Research Medical Director in the Department of Thoracic Oncology at Moffitt Cancer Center, provided perspective on the use of targeted therapy across EGFR-, RET-, and MET-positive NSCLC.

OncLive^®: With regard to the ADAURA trial, is it necessary to wait to see an overall survival (OS) benefit with adjuvant osimertinib (Tagrisso) before you start recommending it to your patients with early-stage EGFR-mutant NSCLC?

Saltos: It’s a key first step to wait for the long-term data, but it’s always going to come down to a patient and physician discussion. As far as the risks and benefits go, it’s very true that OS is not necessarily always found to be significant in a study where [disease]-free survival [DFS] was significant. There are examples with other EGFR-targeted therapies, such as erlotinib [Tarceva], where that was true.

On the other hand, the hazard ratio [for DFS] is very striking. There’s also something to be said of having a markedly improved DFS. Some patients who progress may have brain metastases or very symptomatic events, so sometimes if the therapy can forestall progression, it may have some merits on its own in that context, especially if the therapy is tolerable.

That’s where the tolerability of osimertinib really comes into play. Certainly, there are patients who have a lot of adverse effects [AEs] with osimertinib, but there are some who don’t, and individualization of a plan and careful monitoring are going to be a key part of that anyway.

In a bigger context, when we’re designing these adjuvant therapy clinical trials, we know there’s a tradeoff between having a more readily available outcome for quick readout like DFS vs the gold standard of OS.

What research is being done to build off of the benefit achieved with osimertinib in the advanced EGFR-mutant setting?

The big ones are the combination of osimertinib and chemotherapy and the combination of osimertinib with anti-VEGF therapy, both of which have some have some pretty good clinical backgrounds to support the hypothesis that those combinations might be of benefit to patients.

The FLAURA 2 study is looking at randomization of osimertinib with or without platinum-based chemotherapy in the first-line setting. Hopefully that trial will answer the question about the chemotherapy combination. As far as the combination in the RELAY trial, which was conducted with erlotinib plus the VEGF inhibitor ramucirumab [Cyramza], this was positive and led to the FDA approval of the combination. Where that exactly fits into first-line therapy compared with osimertinib is not completely clear.

We’re also running a clinical trial at Moffitt Cancer Center looking at combining ramucirumab with osimertinib, taking the next logical step. Hopefully, we’ll have information on whether those [combinations] work [soon].

Poziotinib showed encouraging data in patients with EGFR- or HER2-exon 20 mutant NSCLC in the ZENITH20 trial. What are your thoughts on the doses that are being tested?

The tolerability of EGFR TKIs has been kind of a concern, especially in the early days with some of the earlier agents that had more wild-type EGFR inhibition. Some of those same toxicities are emerging with drugs like poziotinib. A lot of clinical experience with these agents and knowing what supportive care to institute and when can maximize the ability to tolerate the drug for many patients. Early institution of things like topical steroids, topical antibiotics, or oral antibiotics for dermatologic toxicities [can help]. I even often institute things like oral non-absorbable steroids, such as budesonide, for patients who have severe diarrhea. There are a lot of different tricks that can help.

EGFR exon 20 mutations, historically, have been very difficult to target, but there are a few drugs [in development]. There’s also amivantamab, which is a bispecific antibody targeting MET and EGFR, that the FDA is looking at.

Shifting to RET fusions, how do the data seen with pralsetinib (Gavreto) and selpercatinib (Retevmo) stack up against the data with next-generation EGFR and ALK inhibitors?

RET fusions are proving to be like a true driver mutation that is highly targetable, much in the same way of ALK or EGFR. The clinical benefit rates and response rates to both of these drugs, from the LIBRETTO[-001] and ARROW studies, are phenomenal. Patients who had no prior therapy on the selpercatinib trial had an 85% response rate, and only 3% of patients had confirmed progression of disease on the drug. That’s pretty much in line with what we see with the ALK and EGFR next-generation TKIs. It’s a very similar story with pralsetinib. The treatment-naïve patients had about a 75% response rate, but these are small trials.

It’s difficult to do cross-trial comparison, but clearly, most of these drugs are highly effective and fairly well tolerated. The incidence of grade 3 toxicity with both of these drugs is very acceptable. With both drugs, a majority of patients with central nervous system (CNS) metastases had a significant response, which means that patients with asymptomatic brain metastases, who have historically been treated with whole brain radiation, can maybe be spared that [approach] up front, which can be very meaningful for quality of life.

For patients with MET amplification, how have capmatinib (Tabrecta) and tepotinib (Tepmetko) affected the paradigm? Where do you see research headed?

MET amplification is its own entity in lung cancer, and sometimes it goes hand in hand with exon 14 skipping, but clearly the patients who are more sensitive to these drugs are the ones who have the exon 14 skipping mutations.

The response rates are not quite as high as what we see with the EGFR, ALK, and RET inhibitors, but still a majority of patients have a response to both of these drugs in the frontline setting, somewhere in the 50% to 60% range. Both agents are quite well tolerated and also have good CNS activity.

We know how to target patients who have these high-level MET amplifications. Both of these drugs do show activity in that amplification setting. There certainly are some patients who have MET amplification, independent of any driver mutations, but there are also some patients with EGFR-mutant lung cancer who progress on osimertinib. It’s a very common scenario where they become resistant to osimertinib through MET amplification. Many clinical trials are looking at these drugs in combination with EGFR inhibitors for those patients, as well as those who have MET amplification alone.

The second area of important research will be novel drugs to target MET and what the resistance mechanisms might end up being for patients who progress on these drugs. Some patients may progress through resistance mutations within the MET gene, but a lot of patients may progress through alternate pathways, which is what we see with the other driver mutations in NSCLC. Being able to characterize and develop more targeted strategies beyond the first line will be important, but for now, these 2 new drug approvals represent a nice milestone for those patients.