Newer ALK+ NSCLC Options Focus on Targeting Acquired Resistance

Anne Chiang, MD, PhD

With a handful of agents available to treat patients with ALK-positive non—small cell lung cancer (NSCLC), the next step of research is to evaluate how to treat patients who become resistant to ALK-targeted therapies, explained Anne Chiang, MD, PhD.

“Think about this paradigm of sequential treatment with various ALK inhibitors,” said Chiang. “Recognize that many patients with stage IV ALK-mutated disease may not have curative treatment, but you want to be able to develop tools that will sequentially treat their disease over the course of many years.”

In an interview with OncLive, Chiang, an associate professor at Yale School of Medicine and chief network officer and deputy chief medical officer at Smilow Cancer Network, discussed the currently available treatments and ongoing research in ALK-positive NSCLC.

OncLive: Could you discuss the current state of treatment for patients with ALK-positive NSCLC?

Chiang: Targeted therapy has been incredibly effective for patients. I've had many patients who have done very well and are excited that they can avoid the toxicities of chemotherapy or other types of therapy. However, with targeted therapy, you can develop resistance to these agents. One of the very important areas of focus is how to treat those patients. How do we understand what's happening with resistance? One of the approaches that has been incredibly effective is to biopsy areas that are growing resistant; we identify additional mutations or pathways that are involved in developing resistance. By understanding those pathways, we can then develop new targeted agents that address those specific resistance mutations. That has been a very important area of research for EGFR-targeted therapy.

Similarly, ALK-targeted therapy has provided the basis and rationale for developing many of the second- and third-generation agents. [There are] clinical scenarios in which a patient is previously treated with crizotinib (Xalkori), a first-generation agent, and then acquires resistance. In the past 10 years, second- and third-generation agents have emerged, including ceritinib (Zykadia), brigatinib (Alunbrig), and alectinib (Alecensa), which are FDA approved for patients who have disease that develop resistance to crizotinib. Two of these agents, alectinib and ceritinib, are second-generation agents that have also been approved in the first-line setting. Right now, alectinib is the preferred agent for treating first-line patients with ALK-mutated lung adenocarcinoma.

There is also the third-generation ALK inhibitor called lorlatinib (Lorbrena). The patterns of resistance that developed in patients who are taking a first-generation drug, such as crizotinib, are different than the mutations you see when patients are taking ceritinib or alectinib. Lorlatinib is incredibly potent because it attacks and is effective against the G1202R mutation, which confers resistance to many of the ALK inhibitors—with lorlatinib being an exception.

Over the course of natural history of disease in a patient with ALK-mutated lung cancer, you can treat these patients sequentially with different drugs. You may start with crizotinib and then may be able to administer crizotinib later. By targeting resistance mutations, [researchers] have been able to follow the course of 1 patient over 4 years. [In a trial], while a patient was on lorlatinib and developed resistance, the re-biopsy showed that the patient developed a resistance mutation that crizotinib could target. The patient was treated and had a good effect with crizotinib.

Two new TKIs, ensartinib and entrectinib (Rozlytrek), are also promising for treating patients with ALK-positive disease.

Another option for patients who are slowly developing resistance with growth of 1 or 2 lesions that are isolated is to combine a local therapy, such as stereotactic body radiation therapy or fractionated [therapy] and be able to continue the same drug. That's been effective in many patients, as well.

What are the current sequencing techniques for this patient population?

Right now, the optimal sequence of agents is that you start out with alectinib on the basis of the ALEX study, which compared patients treated with first-line alectinib versus crizotinib. Results showed that there was a pretty significant benefit for alectinib over crizotinib in terms of PFS, as well as the efficacy of intracranial [activity]. Many of these new-generation ALK inhibitors are more effective, cross the blood—brain barrier, and are more effective in the brain. That's one of the reasons why alectinib is preferred for frontline treatment. For patients who progress on alectinib, the recommendation is to treat with lorlatinib.

For patients who originally were on crizotinib and progress, many of those patients will be treated with another option that is very effective in the brain. If patients develop resistance on ceritinib or brigatinib, or alectinib again, lorlatinib would be a good treatment option for them. If your patient then develops resistance to lorlatinib, you start to think about systemic therapy with either chemotherapy. There are some data for chemotherapy combined with immunotherapy, as seen with the IMpower150 regimen with platinum-doublet, atezolizumab (Tecentriq), and bevacizumab (Avastin).

What is the benefit of testing when a patient becomes resistant to therapy?

With more information on what kind of resistance mutation is present, you can dial in the therapy and use the precise therapy for that mutation. Sometimes there aren't mutations. For example, there may be a mutation in G1202R, which is more difficult to treat. In that case, you would want to treat with lorlatinib. If you have a patient who doesn't have that mutation, you might want to reserve lorlatinib for a later-line therapy and then treat them with one of the other ALK inhibitors.

What does testing for ALK resistance entail?

With testing for ALK resistance, the gold standard has always been doing a tissue biopsy, but there are more interesting data about utilizing liquid biopsies, which involves drawing a peripheral blood specimen and then doing a mutational analysis of that. More studies show that plasma biopsies may be equally effective in identifying resistance mutations and are more easily obtained. Patients choose to have a blood draw versus undergo a bronchoscopy or a CT-guided biopsy. It's very promising.

More studies show that mutational analysis is feasible with peripheral blood draws, and then you have the ability to follow what's happening with the mutational profile of the patients. If there is a mutation that can be targeted by specific agent, you have a great rationale for treating the patient with that agent.

We still have much to learn around the optimal dosing and sequencing of these agents, but being able to put patients on clinical trials and the ability to rebiopsy them, whether with their tissue or through liquid biopsy, is really important in understanding the pattern and treating this disease.

What other drugs are in the pipeline for ALK-positive disease?

There are a lot of really exciting drugs coming forward. Ensartinib is a novel ALK TKI that inhibits many of the mutations that have been identified. The preclinical data are very promising. It shows more potency than crizotinib and some of the other second-generation TKIs. Entrectinib is already FDA approved for ROS1-mutated NSCLC, but it also has very good blood—brain barrier penetration and may also be very attractive for ALK-positive disease.