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

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.

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

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.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.

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

Are any new agents on the horizon for these targets?

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.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.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.

How should a clinician go about choosing a therapy?

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.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.

How are emerging biomarkers being used to guide treatment in this space?

One other principle that’s a little different from chemotherapy is if a patient has localized progression, you can sometimes continue with the same targeted agent and then treat locally with local radiation and, occasionally, surgery. A good example would be a patient with lung cancer who has multiple pulmonary nodules who is treated with a targeted agent. If the nodules stay stable, except for 1 that may be growing, you can treat with localized radiation and continue with your targeted agent.This is an area of active research. We have the upfront panel that you want to do in every patient. When patients become refractory to their treatment, that’s the time to do NGS to try to determine which molecular abnormalities are driving the tumor. A good example is EGFR patients who progress. A fairly high percentage of these patients will have MET amplification and you can treat that with crizotinib. Patients with MET exon 14 splicing abnormalities are also very responsive to crizotinib; this may be the next major molecular abnormality that we’ll have a good targeted therapy for. Studies are in progress.

How are PD-L1 and TMB being used to select immunotherapy?

What is an unmet need that you would like to see addressed?

If a patient has a HER2 mutation, they can respond very well to trastuzumab (Herceptin). The drugs that we use in breast cancer for HER2-mutated disease often induce very dramatic responses [in these patients]. The other major marker that’s coming down the pike is tumor mutation burden (TMB). We don’t currently have that in our panel. The advantage of using NGS is you get TMB. Many times, you can use immune therapy for those patients. You can forego chemotherapy altogether and use an immune agent and ipilimumab (Yervoy) as primary treatment. That’s an exciting area, as well.We’re still learning. They seem to be independent biomarkers. If [a patient has] high TMB, they are more likely to respond to immunotherapy. For PD-L1, if [a patient has expression] ≥50%, [physicians should] go right to pembrolizumab (Keytruda) as the initial agent. If the patient expresses less than 50%, the standard of care usually consists of a combination of chemotherapy and pembrolizumab.Whenever you have new treatments, you’re always looking to the next step. All these targeted therapies are wonderful; they prolong PFS and OS, but they’re not curative. Therefore, we have to keep in mind localized therapies. I have a patient right now who has had a virtual complete remission (CR) with crizotinib for ROS1-positive lung cancer. She’s in a CR, but the median PFS is about 20 months; therefore, she’s probably going to become resistant at some point. When do you use local therapy? Do you treat until maximum response and then use local radiation therapy? Those are the types of questions that we need to answer going forward.

Going back to immune therapy, we’ve made advances, but most patients will progress at some point. We need to find out how to enhance the efficacy of drugs such as nivolumab (Opdivo), atezolizumab (Tecentriq), durvalumab (Imfinzi), and pembrolizumab. The whole host of NGS research studies are going to be adding agonists to those checkpoint inhibitors.