Targeting ROS1, TRK Can Have Meaningful Impact in Lung Cancer, Levy Says

Benjamin P. Levy, MD

Benjamin P. Levy, MD

There are many rare mutations in lung cancer that are highly actionable and can help guide treatment decisions, explains Benjamin P. Levy, MD. In addition to the more commonly tested mutations, such asEGFRandALK, physicians should also be looking for the rarer mutations, likeROS1andNTRK, for which there are drugs available that can make a meaningful impact.

More data is becoming available on agents targeting these rare mutations. Crizotinib (Xalkori) has already been approved by the FDA for patients withROS1rearrangements, while entrectinib is also showing exceptional activity in these patients. In an ongoing trial, larotrectinib (LOXO-101) is showing response rates close to 70% in patients with TRK fusions.

“We cannot just doEGFRandALKanymore,” Levy said. “We have too many good drugs for these rare mutations that are out there that are highly actionable in which we can make a meaningful impact.”

In a presentation during the 2018 Annual International Lung Cancer Congress, Levy also stressed the importance of reporting the new and varied immune-related adverse events (irAEs) that could arise with immunotherapy. While patients may not think it is necessary to report a rash or diarrhea, these can be symptoms of larger side effects to come, he said.

In an interview withTargeted Oncologyduring the meeting,Levy, clinical director of Medical Oncology at John Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital, discussed the agents currently being investigated for patients withROS1- orTRK-rearranged lung cancer. He also highlighted the challenges physicians will need to overcome to best treat their patients based on these new findings.

TARGETED ONCOLOGY:Can you begin by giving us an overview ofROS1andTRKrearrangements in lung cancer?

Levy:We’re in a new world of genotyping lung cancer. It started, of course, withEGFRandALK, thenROS1came around andBRAF, but we’re learning more and more about other rare, yet active mutations likeNTRK. My talk was on bothROS1andNTRK.

ROS1rearrangements are highly actionable. Crizotinib is the FDA-approved drug forROS1rearrangements, but we have new drugs coming down the pike that are exceptionally active, like entrectinib. With all these new drugs coming down the pike, we have to learn how to sequence these and to also understand mechanisms of resistance to ROS1. I think we’re in a new world with a crowded space with ROS1 and all these new drugs. It’ll be important to see which drug wins out, but for now, crizotinib is the standard. Whether entrectinib will also be considered, I think it should be, based on data we saw at the World Conference on Lung Cancer.

TRKfusions are a remarkable story. We have now a basket trial, a tissue agnostic basket trial, that included patients from age less than 2, all the way into the 50s and 60s. Who would have thought that was possible 5-10 years ago? Of course, all these patients had differentNTRKfusions identified and they were given a drug called larotrectinib (LOXO-101). The response rates were close to 70% and the median progression-free survival (PFS) has not been reached yet. The drug is exceptionally well tolerated. This is really the poster child for precision medicine. It speaks volumes to the need to comprehensive genomic profiling. It just has to happen.

We cannot just doEGFRandALKanymore. We have too many good drugs for these rare mutations that are out there that are highly actionable in which we can make a meaningful impact. At my center now, we do a 200 gene panel, so that we can understand all of these fusions and genetic aberrations that are important and can drive decision making.

TARGETED ONCOLOGY:In terms ofROS1-targeting strategies, are there other ALK inhibitors emerging that might also work?

Levy:Currently, crizotinib is the only FDA-approved drug, and most drugs that targetROS1also targetALK, because of the sequence homology in the receptors. The one drug that does not is alectinib (Alecensa). Alectinib is an ALK drug that does not have any ROS1 activity. The drugs that have come out recently have shown ALK drugs that also have ROS1 activity. Of course, ceritinib (Zykadia) is a drug that has recently been published on that shows a response rate north of 60%. It doesn’t work after crizotinib and, in fact, patients who are on crizotinib did not respond to ceritinib. Then, of course, [there is] entrectinib. This drug was presented at World Lung, showing very high response rates, durable responses, and a median PFS north of 25 months.

There are other drugs that are exciting. TPX001 is a license plate therapy. This is an opportunity again to targetROS1andNTRK. Cabozantinib may be a drug. It’s not an ALK drug, but it certainly has ROS1 activity. I think for now, if a patient who isROS1-positive is on crizotinib and they progress, [one option is a] clinical trial, of course, and then other opportunities include pemetrexed. That drug, like an ALK, has good activity, so I think we’re just at the tip of the iceberg with all of the drugs coming down the pike.

TARGETED ONCOLOGY:What are still the biggest challenges withROS1?

Levy:I think one of the biggest challenges forROS1is identifying it. There are still many centers that are not routinely testing forROS1.ROS1should be tested for by fluorescence in-situ hybridization (FISH) or next-generation sequencing. There’s even some immunohistochemistry panels that have high sensitivity and specificity when compared to FISH. I think the big gap is testing has not been routinely done, even though it’s considered to be the core testing and one of the molecular aberrations that we have to test for in all of our patients.

The other unmet need forROS1is what to do when patients progress. People see drugs like ceritinib and think okay, it’s also targetingROS1, so let’s use it after crizotinib. It doesn’t work. Entrectinib is another drug that is getting a lot of traction. That drug probably also doesn’t work for most patients who progress on crizotinib, so I think the initial diagnosis ofROS1rearrangement and how to sequence drugs [is an unmet need]. I think off of a clinical trial, if the patient is on crizotinib, I would offer them pemetrexed-based chemotherapy afterwards. Of course, many of these trials are trying to answer this question. These are the 2 real big challenges withROS1rearrangements.

TARGETED ONCOLOGY:You also gave a presentation on irAEs. What are the key takeaways from that presentation?

Levy:I think that we’ve entered a whole new realm with immunotherapy. They’ve altered the therapeutic algorithms or the paradigm on how we treat lung cancer, but these drugs come with a unique set of adverse events. They can affect any organ. I think we’ve ironed out some of the pathophysiology. Many of these side effects are T cell-mediated, but they also may be antibody-mediated and cytokine-mediated. I think it’s important that physicians who are treating patients with immunotherapy understand what those side effects could be, they understand how to educate patients, but also educate the multidisciplinary team that they work with. They need to collaborate with a multidisciplinary team and take a very proactive approach and have a very low threshold to consult with dermatology, endocrinology, gastroenterology, and pulmonary. I think that’s very important and I highlight this in my talk.

I do talk specifically about some adverse events of interest. Pneumonitis is one of those and is in less than 5% of patients. There’s been some nice work recently retrospectively looking at the overall incidence of pneumonitis in more than 400 patients treated with immunotherapy. Interestingly, these patients would look very different radiographically, they present very differently, and it could also look very different under the microscope. It could all be considered to be pneumonitis. It’s not like a bleomycin toxicity where you know the drug, you know what it looks like on a scan, and you know what it looks like under the microscope. It could appear many different ways.

What’s important is just the management of these adverse events, how to manage based on grading, so grades 1, 2, 3, or 4. There have been some recent NCCN guidelines on the management of irAEs, and I would point you toward those to be updated.

Finally, I talk about biomarkers, as well as rechallenging patients. For patients who have irAEs on an immunotherapy, you treat them with steroids, it resolves, but is it safe to retreat? We have some data to suggest it in small numbers. In biomarkers, we are finally trying to understand biomarkers that may predict efficacy to these drugs, but we are also trying to learn about biomarkers that predict adverse events. Many of these biomarkers may be housed in the gut, and [we are] trying to understand the milieu of the gut. It may be very important to understand which microbes are present and which are not. Believe it or not, the presence of some microbes can predict adverse events to immunotherapy.

TARGETED ONCOLOGY:Could you speak to the importance of community oncologists discussing these adverse events with their patients?

Levy: