New Treatments, Greater Grasp of Biology Advance ALK+ NSCLC Care

Vamsidhar Velcheti, MD

The development of treatments for patients with ALK-positive non—small cell lung cancer (NSCLC) continues to advance, especially in the frontline setting, according to Vamsidhar Velcheti, MD. Moreover, researchers are also investigating how to best sequence available agents in a patient population that varies greatly from those with EGFR mutations.

“One of the most important highlights from the 2016 ASCO Annual Meeting was the advancement in our understanding of the biology of ALK-positive lung cancer, and the role of newer and more important ALK inhibitors in patients who have ALK-positive lung cancer,” said Velcheti, an assistant professor of Medicine at Cleveland Clinic Lerner School of Medicine.

Velcheti lectured on existing and emerging treatment regimens for ALK-positive lung cancer during the 2016 OncLive State of the Science Summit on Metastatic Non—Small Cell Lung Cancer.

In an interview with OncLive during the meeting, Velcheti discussed the recent advancements in the ALK-positive landscape of NSCLC and key questions that still remain.

OncLive: What are some exciting highlights in the paradigm of ALK-positive NSCLC?

Velcheti: There is the J-ALEX study of alectinib, which is a newer generation and more potent ALK inhibitor in the first-line setting in patients who have metastatic lung cancer and ALK fusion. This study compared against the standard of care crizotinib (Xalkori) in patients who were previously untreated.

Results showed that there was a significant increase in the progression-free survival (PFS) of 66% with a hazard ratio of .34, and this is an incredible advance in treating patients with ALK-positive lung cancers. This demonstrates that use of more potent ALK inhibitors in the frontline setting offers a better progression-free control and could have a significant clinical benefit.

What should community oncologists take away from the latest advancements?

Community oncologists have to be aware of the various ALK inhibitors currently in development, and the differences between them. It is good to have more options for patients. For a disease such as ALK-, EGFR-, or ROS1-positive lung cancer, it is more rare and community oncologists are not very familiar with patients with ALK-positive tumors.

It is important for them to know that these patients have multiple ALK inhibitors and treatment options, and they should be aware of how to sequence these drugs, when to use these drugs, and what to do at the time of progression. It is an important area that needs to be addressed.

How has this field evolved over the last year alone?

One year ago, we still had a lot of ALK inhibitors that were still in clinical development. Over the past year, we have had 2 FDA approvals for ALK inhibitors. One of them is ceritinib (Zykadia) and the other drug is alectinib (Alecensa). Both of them have been approved in patients who have previously received an ALK inhibitor and for patients who have progressed on crizotinib. We are now seeing that these more potent agents could be used in the frontline setting, and it is yet to be seen if these drugs will have a greater impact on overall clinical benefit.

What are the biological differences between EGFR- and ALK-mutant NSCLC?

In terms of the biology and the natural history of the diseases, both EGFR and ALK have a very distinct natural history. At progression, patients with an EGFR mutation often have slightly slower progression compared with patients who have ALK rearrangement, and their disease generally tends to be more progressive. Patients with ALK-positive tumors tend to have more brain-associated failures versus EGFR. It is more important to monitor these patients more closely, especially around the time they are expected to progress on the first-line ALK inhibitor, which is about 1 year.

Looking ahead, what will the next couple of years look like for ALK-positive disease?

What are the biggest remaining questions about ALK mutations?

The biggest questions about patients who have ALK mutations are surrounding the mechanisms of resistance and how the resistance needs to be evaluated at the time of progression. When patients progress on ALK inhibitors, do we rebiopsy them? Do we evaluate using a liquid biopsy or circulating DNA assays, or do we just seek or use second-generation or third-generation ALK inhibitors at the time of progression?

Data from the earlier-mentioned trials are going to be very informative. What is most important is how does the evolution of the mutational landscape in ALK changes with using these more potent inhibitors in the frontline setting. Would they still respond to other ALK inhibitors after using a more potent ALK inhibitor in the frontline setting?

There are a lot of agents currently in clinical development. What we have focused on is to see what the right sequence of these ALK inhibitors is. At this point, we don’t have enough data about using these ALK inhibitors in sequence. We do know that these ALK inhibitors have varying degree of potency in various mutations in the ALK kinase domain, which are acquired events after treatment with ALK inhibitors. What is yet to be seen is, how do we sequence these drugs, how do we learn how these tumors become resistant to the ALK inhibitors, and how do we choose the subsequent line of ALK inhibitor more appropriately?