Therapeutic Advances Promote Personalized Medicine in Advanced NSCLC

Significant research advances in targeted therapy and immunotherapy within the past years have created a more personalized approach to treatment for patients with advanced non–small cell lung cancer.

Heather Wakelee, MD

Significant research advances in targeted therapy and immunotherapy within the past few years have created a more personalized approach to treatment for patients with advanced non—small cell lung cancer (NSCLC), depending on whether they harbor driver mutations or have high PD-L1 expression, explained Heather Wakelee, MD.

“When you think about the recent advances in the setting of lung cancer, there are many of them. A lot of the things we're learning in metastatic lung cancer are brought into earlier stage disease,” said Wakelee. “There were great advances with targeted therapy with immunotherapy, but a lot [more is] to come.”

Though comprehensive molecular testing provides critical information for treatment decisions, results take around 1 to 3 weeks to arrive. For patients who require immediate treatment, there are little data to support a concrete next step. In these scenarios, Wakelee said she recommends chemotherapy, which, while not the optimal option, likely will not cause harm to the patient.

In an interview with OncLive during the 2020 Winter Lung Conference, Wakelee, a professor of medicine at Stanford University Medical Center, discussed treatment advances in advanced NSCLC and recommendations for specific clinical scenarios.

OncLive: Could you provide an overview of the current metastatic lung cancer landscape?

Wakelee: If I have a patient coming into my office, and they have just been diagnosed, what do I do? I talk to them about the 3 pillars of therapy: chemotherapy, targeted therapy, and immunotherapy. I always talk about chemotherapy because it’s still important, though it's not an “advance.” We never completely moved away from [chemotherapy] but a lot of patients say, "Oh, I don't want it." However, they don't have a reason for saying that other than they just think they don't want it.

What are some recent advances in targeted therapy?

Many advances have happened in targeted therapy in a targeted revolution. [Targeted therapy has been around] almost been 20 years now. I don't think most people can imagine treating a patient with advanced lung cancer without knowing their driver mutations. For a while, we have known to look for EGFR [mutations] and to treat these patients with EGFR TKIs instead of chemotherapy. More recently, the FLAURA data showed us that osimertinib (Tagrisso) is perhaps a better EGFR TKI to start with because of the longer duration of response, as well as the improved overall survival compared with some of the other EGFR TKIs. In general, for the patients, [osimertinib is] better tolerated, although we do need to be mindful about cardiac and some other [toxicities].

The EGFR story set the paradigm. We have 5 drugs approved for ALK-positive NSCLC, which is really exciting. There has been faster development with many other targets. We have drugs for BRAF, ROS1, NTRK, RET, MET exon 14 skipping mutation, and now KRAS is being developed; the list can keep going. The idea is the more we look, the more we find these actionable driver mutations. When we find them, we can impact patients’ lives with many drugs. If you don't look, you don't know. If you look, you are going to find these driver mutations in the patient's tumors. There are so many different medications available, [and ongoing] clinical trials for the rarer subset so we can better understand [these patients]. That's a big development.

What are some recent advances in immunotherapy?

When I think about lung cancer education conferences—I've been doing them for a long time—and it used to be that we would spend hours debating how to best treat patients with stage III lung cancer because we didn't have much else to talk about. Then, we started just talking about EGFR and then started to talk about all the other drivers.

Now, when you go to conferences, [we discuss] immunotherapy for 2 days and then a half day on other things. That speaks to the importance of [immuno]therapy, and also how much we still don't understand. In a patient who has newly diagnosed disease, with no driver mutation, and they have high PD-L1 status, we can just give single-agent immunotherapy. If they have a high disease burden, we can give [immunotherapy] with chemotherapy if we want them to have a response [quick]. If they have any level of PD-L1 expression and no driver mutation, we know they can get chemotherapy plus immunotherapy. There are multiple drugs now that we have as options in that setting, and that has been really exciting.

Outside of the PD-L1 levels in the first-line setting, we don't have great biomarkers. There has been a lot of discussions around tumor mutational burden (TMB). Debates go back and forth between TMB being great and not so good; we don't really know. We also know that, despite having high PD-L1 expression, single-agent pembrolizumab (Keytruda) doesn't work for about half the patients. We don't know why. Some of it has to do with the driver mutations, which is another reason those are so important to know, but that's just a piece of it. There has to be something about the neoantigen and what the immune system recognizes about the tumor. However, we don't know how to figure that out other than TMB, which isn't great.

There is a lot [to consider] about the host, the host immunity, the microbiome, and so many other factors, but we're just starting to understand it. We talk about it so much because, as much as it's tremendously helped a good percentage of patients, there's another huge percentage of patients who are not necessarily helped with the checkpoint inhibitors. We need to understand that better.

What are your recommendations for patients who require immediate treatment but are waiting for their molecular testing results?

When they're newly diagnosed, there are 2 factors that you have to take into account: physical and psychological factors of the patients. Some patients, by the time they present, are quite ill. They have a high tumor burden and might have painful bone metastases, liver metastases, or have difficulty breathing. In this case, you cannot wait 2 more weeks [to administer therapy] because they won’t be well enough to even get treatment.

Then, you are forced to start and pick a treatment. That's where you have to be a little bit less evidence based. If you have a high suspicion that they have a driver mutation, those are the patients I'm going to treat with chemotherapy—maybe with bevacizumab (Avastin)—but not with immunotherapy. I don't want to give them immunotherapy and then find out 3 weeks later that they actually have an ALK translocation. I'm going to be limited in which ALK-targeted drug I can use, because of the reaction to the immunotherapy that's already in their system. The same applies with EGFR. In that setting, I'll wait.

With someone who is very unlikely to have a driver mutation, then I might think about giving chemotherapy plus immunotherapy, because I cannot wait to start. Occasionally, you can't even do that because, sometimes, the payers are going to say, "I'm not giving chemotherapy plus immunotherapy unless I know there's no driver." Then, you're a little bit stuck. You can always give chemotherapy. Chemotherapy is never a wrong choice. It may be not the best choice, but if you don't know then it's an OK choice. For patients who physically need to get started on therapy, that's how I think about it.

For patients who psychologically need to get started on therapy, which is a much bigger group, we spend the time talking with patients about the fact that I could start doing chemotherapy today, which is an OK choice. However, if I understand the whole tumor by getting those driver mutations, I can perhaps pick a better therapy, or at least not be worried that I'm picking a not as good one. Most people are OK with that, but you need to see them at least once a week in clinic and keep coaching them and check in on them.

Most of the tissue testing can still take 2 to 3 weeks to come back. People are working on making it faster, but it's still slow. Many of the liquid biopsies looking at circulating tumor DNA have results that come back faster, but they are not always being covered by the payers. It's going to depend on the patient as to whether they're willing to take a gamble of potentially spending several thousand dollars. It's complicated because sometimes those costs will be covered in different ways.

In general, those are the conversations that we have to have. I would like to get to a point where we can do both the tissue testing and the plasma testing simultaneously, knowing that some of the time we will get redundant information. However, sometimes we will get a much better story about the whole issue with the tumor and how much it is shedding, or whether we happened to biopsy 1 portion that didn't have the whole story about the mutations. That's my ideal world, but I don't always get to do that for my patients.

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