Treatment Landscape Expands for EGFR-Mutated Non–Small Cell Lung Cancer

Balazs Halmos, MD, MS

EGFR mutations are observed in about 10% to 15% of all advanced cases of non–small cell lung cancer (NSCLC), and these mutations can also appear in earlier stages of disease. A number of FDA approvals are contributing to the expanding treatment landscape for these patients.

Due to the number of available treatment options for this patient population and the clinical benefit they may provide, it is important to be conducting testing on patients with NSCLC to identify those harboring EGFR mutations that may benefit from targeted treatment. At the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program, many clinical trials were presented that evaluated different targeted agents to treat patients with EGFR-mutant NSCLC.

In an interview with Targeted Oncology, Balazs Halmos, MD, MS, director of the Multidisciplinary Thoracic Oncology Program and director of the Section of Thoracic Medical Oncology for Montefiore Health Systems, and first director of Clinical Cancer Genetics and professor of clinical medicine at the Albert Einstein College of Medicine, discussed the current treatment landscape of EGFR-mutant NSCLC and how this space is evolving based on recent clinical trials.

TARGETED ONCOLOGY: Could you provide an overview of the EGFR-mutant NSCLC treatment landscape?

Halmos: EGFR mutations make up about 10% to 15% of all advanced NSCLCs. They tend to happen in a more enriched fashion in women, adenocarcinomas, younger age, and nonsmokers. Now, out of the range of EGFR mutations, the common ones are L858R and exon 19 deletions. These are very responsive to first-, second-, and third-generation agents, but there's a small subset of EGFR mutations called EGFR exon 20 insertions that seem to be highly refractory to the classes of agents that we've had in the clinic, like the first- and second-generation drugs [that have been available] for a long time.

Lately, science has moved along advances to the point that we understand the reason for this resistance and as related to the ATP binding, the drug binding packet of this molecule is being more restricted, so all the smaller molecules fit in, and this has led to the development of a number of compounds, [and some of these] exciting advances were presented at ASCO. There's EGFR exon 20–directed inhibitors, such as poziotinib and TAK-788. These have shown significant responses but also suffered a little bit from significant toxicity. Between the 2 agents, TAK-788 seems to have more of the real parameters to reaching FDA approval. We've also seen a nice study from ECOG focusing on a higher dose of the third-generation drug, osimertinib (Tagrisso), which, biochemically speaking, is not the perfect fit for this particular insertion. At the same time, it's a very nontoxic molecule, so in a way, the therapeutic window is quite favorable. The study showed the small but reasonable response rate to say that maybe there's some room here for osimertinib to have some value.

Lastly, a novel bispecific antibody directed at EGFR and MET has also been developed, and that has shown a very nice response rate, about 60% in this particular context, with reasonable toxicities, but with some questions about the central nervous system activity of this agent. I think we need a little bit more data and a little bit more work on this particular molecule, but very interesting initial data, that's for sure.

TARGETED ONCOLOGY: What about the early-stage treatment landscape?

Halmos: We've seen 2 major presentations at ASCO [on early stage lung cancer]. First is a follow-up on the very important CTONG1104 study, using adjuvant gefitinib (Iressa) versus chemotherapy in patients with resected EGFR-mutant lung cancer, which showed a nice improvement in disease-free survival (DFS) but actually didn't show an ultimate improvement in overall survival (OS) in this particular pivotal phase 3 study.

Now we've seen even more exciting data from the ADAURA study. This study is using the third-generation drug osimertinib in a randomized fashion after the delivery of appropriate adjuvant chemotherapy for resected stage IB to IIIA patients. This study was unblinded early in April by the Independent Data Monitoring Committee based on the exceedingly improved DFS with a hazard ratio of 0.7 seen for the primary end point of stage II and stage IIIA patients favoring osimertinib. Now this is a dramatic improvement in DFS which translates to an OS benefit. We do not know, but at the same time, the degree of benefit made it important for us to be able to see these data. I'm hopeful that we'll be able to discuss it with patients with an FDA approval to see if maybe some patients could benefit from this approach. Now we're awaiting maturation of the OS data.

TARGETED ONCOLOGY: Were there any other trials that you were particularly excited about in this space?

Halmos: It's very hard to pick and choose just 1 of them because there are so many ongoing studies that are so important. We certainly have to continue to focus on the targeted subpopulations. It might be small numbers of patients but still critically important to focus on. I'm very happy with seeing improvement in the early-stage space, which will call for incorporation of molecular testing for early-stage patients. We haven't even discussed circulating tumor DNA, which doesn't have great value [in this setting yet], but it already does in the metastatic setting and maybe can be brought [into play for] a minimal residual disease question after resection, picking out the highest-risk patients. Overall, these are very valuable but very costly agents that should be used in the most cost-efficient fashion.

TARGETED ONCOLOGY: Where do you see the future of lung cancer treatment headed?

Halmos: We've accomplished a lot over the last few years. I want to see cementing of all that we've accomplished. What was disappointing is that with all this excitement and all these events, we still do not see this being integrated into the community setting at the rate that we should see it. I think it's very important to continue this educational effort to make sure the information is actually being advanced to the actual patient in the field and the community that will be seen. I think it's implementation that we've accomplished, and then of course, we will have to start focusing on the next generation of studies. For example, with no checkpoint inhibition, we've achieved a lot, but still for the large majority of our patients with advanced cancer, we're not curing them, so we need to improve upon what we've accomplished. There are a lot of different approaches, and this can be an individualized tailored approach, such as vaccine approaches, CAR T-cell approaches, etc.

We don't know exactly which one will be the winner out of the number of strategies we're looking at, so we need to invest in a number of them. We need to keep a lot of balls up in the air to make sure that we're allowing our patients to have even more hope in the future.

TARGETED ONCOLOGY: Are there any other challenges that remain in this space?

Halmos: We covered many of them. In terms of molecular testing, I think 1 major area of focus is the liquid biopsy–based approach where the current platforms are exciting, but they need to be improved for us to be able to move them into an earlier-stage setting to be able to detect the minimal residual disease setting. However, there's also an extra layer of improvement that we haven't even spoken about to use them in the early-stage diagnostic settings, such as the lung cancer screening setting, for example. The technology is advancing at such a rapid rate that the hope is actually that with greater investment into those approaches, you'll be able to utilize this technology to benefit earlier-stage patients. That's the most important, that's when your chance is the highest to cure patients.