Immunotherapy and EGFR, ALK Inhibitors Deliver Precision Medicine in NSCLC

Edward S. Kim, MD

It has been a year of therapeutic advancements in the field of non—small cell lung cancer (NSCLC), most notably with 2 targeted agents that significantly improved progression-free survival (PFS) outcomes in differing subgroups of patients.

First, the long-awaited findings of the double-blind, phase III FLAURA trial demonstrated that frontline treatment with the third-generation irreversible EGFR inhibitor osimertinib (Tagrisso) was associated with a 54% reduction in the risk of progression or death compared with standard therapy—a first-generation agent, gefitinib (Iressa) or erlotinib (Tarceva)—in patients with EGFR-mutant disease.

In October, the FDA granted a breakthrough therapy designation to osimertinib for the first-line treatment of patients with metastatic EGFR mutation—positive NSCLC based on these results.¹

In November, the FDA approved alectinib (Alecensa) for the frontline treatment of patients with ALK-positive metastatic NSCLC, primarily based on findings from the phase III ALEX study. Here, alectinib improved PFS versus standard crizotinib (Xalkori) by 47% (HR, 0.53; 95% CI, 0.38-0.73; P <.0001).² Immunotherapy has not gone unnoticed either, with the May 2017 approval of pembrolizumab (Keytruda) in combination with carboplatin/pemetrexed for the frontline treatment of patients with metastatic or advanced nonsquamous NSCLC regardless of PD-L1 expression. “It is great that lung cancer has actually become the face of precision medicine, because we have so many patients that we touch with lung cancer,” said Edward S. Kim, MD. “Even a 1% or 2% marker touches thousands of patients, so its impact is huge. It has been fun to watch the evolution of this occur over the last 2 decades.”

OncLive: You chaired this State of the Science SummitTM. Can you share some of the overall advancements we have witnessed in this field?

In an interview during the 2017 OncLive^® State of the Science Summit^TM on Advanced Non—Small Cell Lung Cancer, Kim, chair, Solid Tumor Oncology and Investigational Therapeutics, Donald S. Kim Distinguished Chair for Cancer Research, Levine Cancer Institute, Carolinas HealthCare System, spoke to the advancements in lung cancer in 2017, specifically in EGFR- and ALK-positive patients and those with PD-L1 expression.Kim: The landscape in lung cancer has changed so much in the last 6 months to 1 year—you can really put any time stamp on it over the last 5 years. We had a lot of interest [at the meeting] because people need to catch up. There seems to [constantly] be emails coming from the FDA or ASCO [with updates on] a new drug, new biomarker, or another indication. That is exciting for patients; this has happened with tyrosine kinase inhibitors (TKIs), biomarkers, and immunotherapy.

Let's dive in to some of the updates as of late. Can you comment on osimertinib and how the FLAURA findings have impacted practice for EGFR-mutated NSCLC?

It confuses a lot of clinicians out there because they thought they knew how to use a drug and in what setting, and then they see you can use it in a different setting. Or, perhaps you shouldn’t use that drug anymore or there is [news about] a different or better drug. Perhaps you have to test a certain marker. We had a nice summary of these topics. When one sees a patient with lung cancer, we don’t want a diagnosis anymore. We want tissue. We will get a diagnosis if we have enough tissue but, more importantly, we’ll get the requisite markers that we need. We absolutely must have them in order to make informed decisions to stage the patient and pick the right drug. You’ll have situations where you’ll get a diagnosis and it will be based on cytology or brushings—we don’t care. We don’t want to [just] know that its NSCLC or adenocarcinoma.

You absolutely have to [test] these biomarkers—EGFR mutation, ALK translocation, ROS1, BRAF, and PD-L1—because any one of these markers could be present and almost 50% of patients with NSCLC may have one of them. That means you don’t use chemotherapy. When we see a patient with breast cancer, do we start treating without knowing the hormone receptor status or the HER2 status? Absolutely not. Some might say that’s unethical. I am trying to implore people that this is just as important in lung cancer.

What are your thoughts on PD-L1 as a prognostic biomarker?

Now, we know that not only should you start with an EGFR TKI if a patient has an EGFR mutation present, but there are actually better EGFR TKIs out there in situations. Osimertinib brings the latest data set that shows an improved PFS over the traditional erlotinib or gefitinib drugs. There is still that small segment of uncommon mutations in which afatinib (Gilotrif) may be more appropriate for. Right now, osimertinib is rising to the top as far as the frontline choice.There are [a lot] immunotherapies that are FDA approved out there. Several of them are in lung cancer, but most are in bladder cancer. Only one of them uses PD-L1 expression as a marker to determine treatment. There had been some criticisms about this marker. We are not crazy about expression or immunohistochemistry, especially as biomarkers, but we still use HER2 in that manner. I wish there was a better marker, but I am okay that we have PD-L1 as a biomarker, because it does tell us who should be treated in the first-line setting. No other drug has been able to demonstrate with PD-L1 expression or not that there is benefit in the frontline setting. Pembrolizumab does this with a PD-L1 score greater than 50%.

For ALK-positive NSCLC, alectinib has now been approved in the first-line setting. What is the impact of this approval?

Now, again, you have a situation where you don’t have to use chemotherapy; that is a big deal for patients. Certainly, if you don’t have high expression, you can use chemotherapy—sometimes in combination with antiangiogenesis drugs, and then in the second-line setting you can use one of several approved drugs, including atezolizumab (Tecentriq) or nivolumab (Opdivo). ALK NSCLC is another area that has transformed patient care. If you find an ALK translocation present, you can substitute a pill instead of chemotherapy. It is a smaller population of patients—4% to 6%. We have had several drugs, but we are now also seeing emerging, newer-generation drugs—alectinib in particular—that has shown a tremendously large PFS versus earlier traditional drugs like crizotinib (Xalkori).

Precision medicine is a term thrown around frequently in lung cancer. How should community oncologists be thinking about and using it in their practice?

Alectinib has really changed the standard of care in ALK-positive patients. Now, everyone is asking the question, "What do you do after alectinib?" There are some drugs out there being tested [such as] brigatinib (Alunbrig), and lorlatinib is coming. Perhaps you can resort back to the first-generation drugs, but alectinib is clearly one of the new super drugs like osimertinib. They both have characteristics where they have better PFS than traditional agents, they both penetrate the CNS reliably, and they both [have] less [severe] side effect profiles, which is, again, the whole package there. Precision medicine is a label that has evolved over time. When we practiced 20 years ago, precision wasn’t getting the exact histologic diagnosis. It was non—small disease versus small cell disease, or adenocarcinoma versus squamous versus non–small cell disease. We have evolved from superficial terminology, but we were still trying to be precise based on what the technology was.

Now, we have gone past just the histology. We have gone into, “What does the genomic signature say?” What are those markers telling us that is unique about these cancer cells? That is what has helped us stratify into whether you’re going to give somebody chemotherapy and you’re not sure what the benefit is—versus giving them a targeted agent where we have a very reliable and predictable benefit and more efficacy.

References

1. Ramalingam S, Reungwetwattana T, Chewaskulyong B, et al. Osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFRm advanced NSCLC: FLAURA. Presented at: 2017 ESMO Congress; Madrid, Spain; September 9-12, 2017. Abstract LBA2_PR.2.
2. FDA Approves Genentech’s Alecensa (Alectinib) as First-Line Treatment for People with Specific Type of Lung Cancer. Genentech. Available at: http://bit.ly/2zmLda7. Accessed November 6, 2017.