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Despite Success With Targeted Therapies in NSCLC, Drug Resistance Remains Issue

Caroline Seymour
Published: Wednesday, Dec 12, 2018

Stephen L. Graziano, MD

Stephen L. Graziano, MD

Targeted therapies are extending progression-free survival (PFS) and overall survival (OS) in patients with oncogene-driven non–small cell lung cancer (NSCLC), although they are not curative agents, said Stephen L. Graziano, MD.

“These oral targeted therapies have dramatically altered the natural history of adenocarcinoma of the lung. You don’t want to miss those patients, because they can really benefit from those therapies,” said Graziano, professor of medicine, division chief of medicine, and division chief of Upstate Cancer Center Adult Hematology/Oncology at the Upstate University Hospital.

Data from the phase III FLAURA trial secured osimertinib (Tagrisso) as a frontline therapy for patients with EGFR-mutated NSCLC. With the April 2018 FDA approval, the third-generation tyrosine kinase inhibitor (TKI) became the fifth targeted therapy to join the treatment armamentarium for EGFR-positive patients with NSCLC.

For ALK-positive NSCLC treatment, alectinib (Alecensa) has sustained its role as the standard frontline therapy following its FDA approval in November 2017. However, in November 2018, lorlatinib (Lorbrena) became the most recent ALK inhibitor to be approved for second-line treatment after progression on 1 or more ALK TKIs. Although the majority of patients with a driver mutation present with either EGFR or ALK, more therapies are emerging for patients who harbor abnormalities in BRAF, RET, NTRK, ROS1, MET, and HER2.

In an interview during the 2018 OncLive® State of the Science Summit™ on Advanced Non–Small Cell Lung Cancer, Graziano discussed available and emerging targeted therapies for common driver mutations in patients with NSCLC and the sequencing strategies beyond frontline treatment.

OncLive: What are the available targeted therapies for patients with EGFR and ALK abnormalities?

Graziano: Targeted therapy is becoming established as the standard of care in most oncology practices. When a patient is diagnosed with adenocarcinoma of the lung, it’s standard practice to do at least a limited panel of markers that include EGFR, ALK, ROS1, and BRAF. We’re testing for PD-L1, as well. Generally, we do the panel so that we can choose initial therapy for the patient. If patients are positive for EGFR mutations— either deletion 19 or exon 21—we generally will start with osimertinib as the first-line therapy; that has been established based on data in recent publications.

For patients with ALK mutations, we generally will choose alectinib as the first-line therapy, although there are several first-line indications; these include ceritinib (Zykadia), crizotinib (Xalkori), and brigatinib (Alunbrig). ROS1-positive tumors are rare, but they can dramatically respond to crizotinib, so that’s generally our first drug of choice. For patients with BRAF mutations, it’s double oral therapy with dabrafenib (Tafinlar) and trametinib (Mekinist), which is similar to how we treat [patients with] melanoma.

Are there any particularly compelling data for patients with these alterations?

For EGFR, osimertinib has been established as the drug of choice for first-line therapy, but it may be a little controversial. A general principle in oncology is to use your best drug first. Most oncologists would go right to osimertinib. If the patient progresses after osimertinib, then the next line of therapy is similar to that of other patients: chemotherapy with or without immunotherapy.

Are any new agents on the horizon for these targets?

New agents are coming [through the pipeline] every month or so. Lorlatinib was just approved by the FDA for ALK-positive patients. Second-line drugs for ALK-positive patients include ceritinib, alectinib, brigatinib, and lorlatinib—so there are many options.

We’ll be using next-generation sequencing either as a blood test or tissue test to see which specific mutations there are. Then you can tailor the specific ALK inhibitor to that mutation or rearrangement. For ROS1 patients, there are a number of other drugs besides crizotinib. Ceritinib is active, and lorlatinib is coming along. Cabozantinib (Cabometyx) is probably active in that group of patients, too.

How should a clinician go about choosing a therapy?

The next steps for research that need to be done include determining the optimal sequencing. We usually start with the best agent, and then, based on the specific molecular abnormalities, we try to choose the next agent; that’s coming along very nicely.


View Conference Coverage
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TitleExpiration DateCME Credits
Community Practice Connections™: Addressing Post-Transplant Obstacles: Current and Emerging Strategies to Evolve the Standard of Care for Patients With Graft-Versus-Host DiseaseMar 28, 20192.0
2017 Year in Review™: Clinical Impact of Immunotherapies in the Treatment of CancerMar 30, 20191.75
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