Therapeutic Additions Enhance ALK+ and ROS1+ Lung Cancer Paradigms

Gregory J. Riely, MD, PhD

Additional ALK inhibitors have come to the forefront since the 2011 FDA approval of crizotinib (Xalkori) for patients with ALK-positive non—small cell lung cancer (NSCLC), explained Gregory J. Riely, MD, PhD.

In 2017, both alectinib (Alecensa) and ceritinib (Zykadia) were granted approval for patients with previously untreated metastatic ALK-positive NSCLC. Also that year, brigatinib (Alunbrig) was approved for patients with metastatic ALK-positive NSCLC who are resistant to crizotinib.

Additionally, lorlatinib (Lorbrena) is available for ALK-positive patients who progressed on crizotinib and ≥1 other ALK inhibitor, or whose disease progressed on alectinib or ceritinib in the first-line setting.

For ROS1-positive NSCLC, further exploration of novel agents is underway. Most recently, in August 2019, entrectinib (Rozlytrek) was approved as a treatment for patients with ROS1-positive metastatic NSCLC, and also for the treatment of adult and pediatric patients ≥12 years of age with solid tumors that harbor an NTRK fusion.

“As we look for the next generation of inhibitors, we are probably going to see drugs that aren't necessarily ALK and ROS1 inhibitors,” said Riely. “We are going to see drugs that are more specific for ROS1.”

With the availability of these targeted agents, genetic testing is necessary, he added.

"We need to make sure all our patients have a full molecular evaluation," said Riely. "With the introduction of first-line immunotherapy, we have seen a somewhat loss of interest in testing. We know that if patients have EGFR mutations, they are less likely to derive benefit from immunotherapy approaches. The same story goes for ALK [and ROS1]."

In an interview during the 2019 OncLive^® State of the Science Summit™ on Non—Small Cell Lung Cancer, Riely, a medical oncologist, and vice chair of clinical research in the Department of Medicine at Memorial Sloan Kettering Cancer Center, discussed the current treatment landscape for ALK- and ROS1-positive NSCLC.

OncLive: What are the current treatment options for patients with ALK-positive disease?

Riely: ALK gene rearrangements happen in about 4% of patients with NSCLC. We see these rearrangements in a broad range of patients, perhaps more frequently in people who have never smoked and in younger men. However, we should test throughout our population of patients because we have new drugs that are targeted at ALK gene rearrangements.

There are 3 drugs currently FDA approved for the initial treatment of patients with ALK-positive NSCLC. We began understanding the targeting of ALK back in 2011 with crizotinib. Multiple new drugs have been developed and demonstrated superiority in comparison with crizotinib for initial therapy. Today, we have a number of FDA-approved drugs, including ceritinib, alectinib, brigatinib, and crizotinib as first-line therapy for patients with ALK-positive NSCLC.

Ceritinib was FDA approved based on a comparison with conventional chemotherapy, but alectinib and brigatinib are both FDA approved based on trials that showed superiority in terms of PFS compared with crizotinib for patients with ALK-positive NSCLC.

Do we have any data of alectinib compared with brigatinib?

We have no head-to-head data to compare alectinib with brigatinib in choosing first-line therapy. Both are reasonable, preferred choices. With the data that we have so far, they appear comparable in terms of their efficacy compared with crizotinib.

Does one agent have a greater central nervous system (CNS) benefit or an improved safety profile over the other?

Both alectinib and brigatinib have similar efficacy and have been shown to have excellent CNS activity in terms of prolonging disease-free time in the CNS compared with crizotinib. They both have tolerable safety profiles.

There are no data to tell you one way or another whether alectinib or brigatinib is a choice. They are both reasonable drugs, and most physicians have found one that they feel most comfortable with.

What does sequencing look like for patients once they progress on therapy?

When a patient progresses on a first-line, second-, or third-generation ALK inhibitor, such as alectinib or brigatinib, the data to tell us what to do next are relatively modest. There has been an approval of a third-generation drug called lorlatinib, which has demonstrated efficacy in patients who have had 1 or 2 prior ALK inhibitors. It tends to show activity in that context.

That said, the activity is not dramatic; response rates are less than 50%. There is definitely efficacy of conventional chemotherapy in that patient population, so it may be appropriate to consider conventional chemotherapy after a patient has progressed on first-line alectinib or brigatinib. Lorlatinib would also be up for consideration at that point.

Are we as familiar with resistance mutations in ALK as we are in the EGFR space?

We are not, and this is primarily because when we have sequenced, say after progression on crizotinib, we don't find a clear pattern of resistance. For instance, in EGFR-mutant lung cancer progressing on erlotinib (Tarceva), we saw 60% to 70% of patients had EGFR T790M. We don't see that same pattern in patients who progressed on crizotinib. We are beginning to understand alectinib and brigatinib more, but there isn't a clear resistance pattern and the data do not drive your decision-making quite as much.

What challenges remain in this space?

We have had great success with ALK inhibitors in patients with ALK-positive lung cancer. We see a median PFS of 2 years, which is a dramatic increase from where we were just a few years ago. Therefore, we are happy about that progress, but clearly, patients do begin to progress at a median of 2 years, so we need to do better for these patients.

Understanding mechanisms of resistance is crucial is going to help us guide the next generation of therapy development.

Are there any ongoing clinical trials that we should be keeping an eye out for?

With the recent introduction of lorlatinib as an FDA-approved agent, that agent has been the primary use in patients who had 1 or 2 prior ALK inhibitors. There are other ALK inhibitors currently in development, but we have to see how those pan out before we push forward.

Moving to the ROS1 space, what updates are we seeing for these patients?

ROS1 rearrangements were identified around the same time as ALK rearrangements. We saw data showing that ROS1 was active in patients with lung cancer. A few years after the FDA approval of crizotinib, a number of investigators identified ROS1 as another target for crizotinib as part of a phase I trial. This demonstrated efficacy of crizotinib in a small number of patients with ROS1-positive disease. Based on its efficacy in a single-arm phase II trial, or actually an expansion arm of a phase I trial, crizotinib received approval for treatment of patients with ROS1-positive lung cancer.

Other drugs have been explored in this context. Ceritinib has a relatively similar efficacy that has been published for patients with ROS1-positive NSCLC. We have also seen subsequent data that demonstrate the efficacy of crizotinib here.

More recently, we saw an FDA approval with the use of entrectinib for this population. Entrectinib was approved for the treatment of both patients with NTRK-positive lung cancer and ROS1-positive lung cancer. We don't have head-to-head data that compare entrectinib with crizotinib, but it is certainly another new option. There may be a hint that entrectinib has better CNS activity, but it hasn't been demonstrated prospectively in trials.

Upon progression, what options are available for ROS1-mutated disease?

At progression after crizotinib for patients with ROS1-positive NSCLC, we have relatively few targeted therapy options. We have seen some case reports demonstrating efficacy of cabozantinib (Cabometyx); there are ongoing trials to explore that. And, there are other newer ROS1 inhibitors, such as repotrectinib (TPX-0005), that are in clinical trials. There isn't anything that stands out as a clear next-generation ROS1 inhibitor, but this is certainly an area of investigation.

What about combination approaches?

Broadly, when we think about how we can improve upon outcomes for patients with oncogenic drivers, we begin to think about combining drugs, particularly kinase inhibitors that hit two different pathways. We are starting to explore this most thoroughly in patients with EGFR mutations, but it has potential in the full range of patients with oncogenic drivers.

We need to be smart about how we do it. Right now, I don't know that we have the right combinations to make, but this is something we are exploring as we go forward.