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Wakelee Praises Progress, Points to Next Steps in NSCLC

Brandon Scalea
Published: Tuesday, Feb 12, 2019

Heather A. Wakelee, MD
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.

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.

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

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.

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.

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

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.


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