Wakelee Praises Progress, Points to Next Steps in NSCLC

Heather A. Wakelee, MD

Understanding the molecular basis of lung cancer has allowed researchers to personalize patient treatment, but improving early detection methods and continuing to enhance the reach of immunotherapy will be crucial to further progress, said Heather Wakelee, MD.

In recent years, checkpoint inhibitors transformed the treatment landscape of metastatic non—small cell lung cancer (NSCLC) as they moved into the frontline setting. The PD-1 inhibitor pembrolizumab (Keytruda), for example, demonstrated an overall survival (OS) advantage in 3 phase III clinical trials as a single agent and in combination with chemotherapy across squamous and nonsquamous histologies.

In August 2018, the FDA granted a full approval to pembrolizumab for use in combination with either carboplatin or cisplatin and pemetrexed in the treatment of patients with nonsquamous metastatic NSCLC, based on positive data from the KEYNOTE-189 trial. In the study, combination immunotherapy and chemotherapy reduced the risk of death by 51% versus standard chemotherapy alone. One-year OS rates were 69.2% in the pembrolizumab arm compared with 49.4% in the control arm.

In addition, the number of treatment options available for patients with oncogene-driven NSCLC has increased exponentially. In ALK-positive NSCLC, alectinib (Alecensa) is still considered the frontline standard of care, but other ALK TKIs are coming to the forefront. For instance, brigatinib (Alunbrig) and lorlatinib (Lorbrena) have shown promise in recent clinical trials in the frontline and second-line settings, respectively.

While the future looks promising, Wakelee, an associate professor of medicine at Stanford University Medical Center, called for more extensive research to further extend survival for these patients.

OncLive: What does a diagnosis of lung cancer mean today versus 5 years ago?

In an interview with OncLive, Wakelee shared insight on the current landscape of lung cancer and discussed how immunotherapy and targeted therapy can be improved for patients with NSCLC.Wakelee: We have a lot of other treatment options than we used to have. When I started treating patients with lung cancer, we really just had chemotherapy. Starting about 15 years ago, we started to understand the molecular basis of lung cancer in a way that we could actually change treatment. In the past 5 years, the number of targeted agents for EGFR- and ALK-positive NSCLC—as well as the rare mutations like ROS1 and BRAF—gives us a lot of flexibility and options for patients in that setting.

Is there a subset of patients, for whom immunotherapy has not yet had a role, who could benefit from this treatment?

But where things have changed the most is with the development of immunotherapy. Five years ago, we were just starting to hear about immunotherapeutics, and there was some single-agent activity in the second line. Then, immunotherapy completely changed the frontline treatment options where we are now giving combination immunotherapy and chemotherapy as the standard of care for almost all patients, unless they have a contraindication or driver mutation. We also have the option of single-agent pembrolizumab for the frontline treatment of patients with high PD-L1 status.At this time, when you look at the chemotherapy plus immunotherapy data in metastatic disease, there is no group for which it clearly [was ineffective] other than in patients with specific driver mutations. We are still challenged in the oncogene-driven setting where we have other good options, but the immunotherapy agents have not worked yet. We are trying to figure out where immunotherapy fits into this space, but we know it is not in combination with TKIs because that has not gone well.

The toxicity [with that kind of combination] has been significant, and when there was not much toxicity the increase in efficacy, if any, was very low. The chemotherapy and immunotherapy combination might be working in the driver mutation subsets, but we do not know enough about it yet, and the early data have not been too promising. There is still a lot to explore there.

Now that we have effective therapies for patients with driver mutations, what is the importance of performing next-generation sequencing (NGS) testing?

The other area where immunotherapy may not reach, at least with the drugs we have now, is in patients with underlying autoimmunity or those who have had organ transplants. However, the underlying autoimmunity is definitely an issue and it is one we are trying to figure out. It is this question of, how much do we risk with the harm of causing a bad flare but make sure we are giving the best treatment? This is an ongoing area of research.The use of NGS is critical for patients with advanced-stage NSCLC—especially those with adenocarcinoma. There are also patients with squamous cell disease, especially if they are never-smokers, who can develop driver mutations. We think that the classic patient with a driver mutation is going to be a never-smoker who gets adenocarcinoma, but you can absolutely see a patient with a smoking history develop driver mutations. You could have patients from every ethnic background present with driver mutations.

Are we getting to a point in any subset of lung cancer that can be managed as a chronic disease?

In a practice where you do not have to worry about the resources in the same way, we just perform NGS on everyone. As you get more resource-limited, you have to ask those questions in a different way. At the same time, if you miss a patient with a driver mutation, you are essentially missing out on giving them therapy that they will not only tolerate well, but that may give them years of extra life. It is a travesty when that happens, so that is why it is important to do NGS.For patients with specific driver mutations, it is more often a chronic disease than other forms of lung cancer. If you look especially at ALK-driven NSCLC, the survival has been extended beyond 5 years—10 years for some patients. We do not see this level of benefit in everyone, but it is certainly enough to have that conversation with patients. With EGFR-positive disease, it is a little less common—but as new [agents] are being developed, it is more likely to be the case.

What is the biggest area of unmet need in lung cancer?

There are also certain patients where immunotherapy works for a very long time. The percentage of patients who have these phenomenal responses to immunotherapy is not that high, but those are the settings where we can think about the disease that way.There are many different areas that need more research. We need to still be working on finding lung cancer early—that is not what I focus on as much, but it is something we need to get better at. We have got to continue screening and to find lung cancer early. Obviously, stopping the disease and preventing it are important, but trying to understand why it is happening in patients who do not smoke is an unanswered question.

Working on improving cure rates for early-stage patients is another area. We are getting some hints of bringing in immunotherapy and targeted drugs, but that is an unclear area right now. There are ongoing studies here, but we have not seen any data. Also, in metastatic disease, what is next after our targeted agents? These drugs are effective, but they are not working forever. As much as we would like to view it as a chronic disease, it is only a chronic disease for a temporary period of time.

Then, of course, if we can get the immune system to recognize cancer, that is always going to be the path forward. As smart as we are in developing targeted drugs, the tumors are always going to be smarter in figuring out resistance pathways. We need to get the immune system to do that job of surveillance.

Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non—small-cell lung cancer. N Engl J Med. 2018;378(22):2078-2092. doi: 10.1056/NEJMoa1801005.