Aggarwal Lends Insight on the Use of TKIs and Liquid Biopsies in ALK+ NSCLC

Charu Aggarwal, MD, MPH

The emergence of second-generation TKIs has reshaped the treatment paradigm of ALK-positive non–small cell lung cancer (NSCLC), according to Charu Aggarwal, MD, MPH.

“Treatment options for NSCLC are numerous, and we are blessed to be able to have so many active agents available to us,” said Aggarwal, who gave a presentation on this lung cancer subtype during the 21st Annual International Lung Cancer Congress (ILCC), a program developed by Physicians’ Education Resource® (PER®), LLC. “At the ILCC meeting, I will be speaking about ALK-rearranged NSCLC, including the current state of [treatment], as well as the future landscape for this rare, but very treatable, subgroup of patients with metastatic NSCLC.”

In November 2017, the FDA approved alectinib (Alecensa) for the frontline treatment of patients with ALK-positive metastatic NSCLC.

During the 2020 ASCO Virtual Scientific Program, updated data from the phase 3 ALEX trial for which the approval of alectinib was based demonstrated continued clinically meaningful improvement in overall survival (OS) with the second-generation TKI compared with crizotinib (Xalkori).¹ At 5-years, the OS rates were 62.5% with alectinib versus 45.5% with crizotinib.

Since the approval of alectinib, the field also received data from the phase 3 ALTA-1L trial. Findings from the study, which showed a 51% reduction in the risk of disease progression or death with brigatinib compared with crizotinib,² served as the basis for the May 2020 approval of the agent as frontline therapy in this patient population.

As the armamentarium in this space continues to grow, so too will the use of liquid biopsy for serial monitoring of minimal residual disease (MRD) and mechanisms of resistance, said Aggarwal.

In the interview, Aggarwal, the Leslye Heisler Assistant Professor of Medicine in the Hematology-Oncology Division at the University of Pennsylvania’s Perelman School of Medicine, discussed the current state of treatment for patients with ALK-positive NSCLC, the utility of liquid biopsy, and remaining questions that need to be addressed in the space.

OncLive: What are some of the latest developments that have been made in the treatment of patients with ALK-positive NSCLC?

Aggarwal: We have been using alectinib, but we are also extremely glad to see the approval of brigatinib and lorlatinib (Lorbrena). These are 2 more drugs that have been added to the armamentarium for patients with this malignancy.

The use of these agents varies slightly at the hands of the practicing individual, but it is safe to say that lorlatinib is being used upon progression following the use of a second-generation ALK TKI.

I look forward to discussing more data as it relates to the clinical trials that led to these individual approvals, as well as [how] the future landscape [may] incorporate some of these agents into the first-line setting.

What key data have shaped the treatment landscape in ALK-positive NSCLC?

There’s the ALEX trial, which led to the approval of alectinib in the first-line setting. I’m also interested in giving the audience an update of the ALTA-1L trial, which looked at brigatinib compared with crizotinib in the first-line setting, as well as data regarding the use of lorlatinib primarily in the second- or third-line setting for patients who previously received a second-generation TKI. There’s also some data, albeit not clinical trial-based and not prospective, looking at the emergence of resistance mutations after treatment with TKIs.

What emerging therapeutic approaches are important to highlight?

There are many emerging approaches in the management of ALK-rearranged NSCLC. One of these approaches is based on finding a resistance mutation. Going after that clinically and practically has not been feasible in the clinic. However, we are now able to use lorlatinib which covers many of the mutations that can emerge after a patient has been treated with a second-generation TKI.

The question of what to do after patients progress on lorlatinib remains unanswered. Is there value in using chemotherapy? Should we move lorlatinib into the first-line setting? There are clinical trials evaluating both of these topics.

What factors are important to consider when selecting between therapies for patients?

During my presentation at the 2020 ILCC meeting, I will talk about our treatment strategies before the approval of alectinib and brigatinib, what we used to use, and how our treatment options have evolved with the availability of these new agents that also have excellent central nervous system (CNS) penetration. That is one of the points that I always stress to my patients. We need to consider agents that are efficacious and safe, but we also have to look at CNS penetration.

Liquid biopsies have grown dramatically in this space. Could you shed light on their utility?

Liquid biopsies have become an integral component of how we manage and diagnose our patients with NSCLC. I am a big proponent of using liquid biopsies in parallel with tissue sequencing to increase our ability to detect and direct therapeutic decisions for patients with nonsquamous NSCLC. A lot of approaches with the use of liquid biopsy are currently under

investigation. These will likely be useful in the future, including the use of MRD techniques and serial monitoring to detect mutations that emerge after treatment with a particular TKI.

What are some of the challenges with liquid biopsies? How do those challenges compare with those of tissue biopsies?

While liquid biopsies are easy, fast, and minimally invasive, there are certain downfalls and limitations that exist with their use. These include the fact that our ability to detect a mutation on a liquid biopsy directly correlates with the amount of [circulating] tumor DNA shed in the patient’s bloodstream.

For patients who primarily have intrathoracic disease or an overall low burden of disease, our ability to detect a mutation decreases significantly. A negative result on a liquid biopsy may be misconstrued as a negative result overall. However, [negative results on a liquid biopsy] need to be taken with a grain of salt and need to be looked at carefully. If a patient only has intrathoracic metastatic disease, we must rely on tissue biopsy, which remains our gold standard.

There are also other mutations, such as clonal hematopoiesis of indeterminate potential or CHIP mutations, that may mislead us to direct treatment. Those mutations should be interpreted cautiously.

Looking to the future, what challenges need to be addressed in the lung cancer space? Are there any promising opportunities on the horizon that may address some of those challenges?

We’ve come a long way in treating patients with lung cancer compared with even 5 years ago. We have many immunotherapeutic regimens and combinations, as well as numerous targeted therapy approaches that continue to help our patients.

The greatest challenges lie in the application of these therapies in a sequential fashion for our patients without overlapping toxicities, as well as coming in with our best drug first.

References:

1. Peters S, Mok TS, Gadgeel SM, et al. Updated overall survival (OS) and safety data from the randomized, phase III ALEX study of alectinib (ALC) versus crizotinib (CRZ) in untreated ALK+ NSCLC. J Clin Oncol. 2020;38(15 suppl):9518. doi:10.1200/JCO.2020.38.15_suppl.9518
2. Camidge R, Kim HR, Ahn M, et al. Brigatinib vs crizotinib in patients with ALK inhibitor-naive advanced ALK+ NSCLC: updated results from the phase III ALTA-1L trial. Ann Oncol. 2019;30(9 suppl):ix183-ix202. doi:10.1093/annonc/mdz446