Expert Perspectives on Trop-2 Biomarker Expression in Lung Cancer and the Potential Role of Dato-DXd

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In this expert interview, Jacob Sands, MD, shares key insights on unmet needs in the treatment of lung cancer, comments on the role of clinical trials investigating Trop-2-targeted therapy, and considers the potential impact of datopotamab deruxtecan (Dato-DXd) on the treatment landscape if it receives FDA approval for use in lung cancer.

OncLive®: Can you comment on current unmet treatment needs in patients with metastatic lung cancer?

SANDS: To address that question, we need to first talk about all the different populations of metastatic lung cancers, because a big thing that's happened in the last decade is the further subclassification of these tumors. Broadly speaking, small cell lung cancer (SCLC) continues to be its own separate group, but there is some work that will potentially help us subcategorize that.

Fortunately, we've had the benefit of immunotherapy, which has significantly improved outcomes related to first-line therapy. A subgroup of patients has had impressive durable responses to the inclusion of immunotherapy, but, in the second-line setting and beyond, we have a new drug in lurbinectedin. That's adding to the somewhat limited armamentarium of treatment options. There is a lot of work going on with some novel therapies in SCLC, and I'm excited for the future, but the advances thus far have been limited. Therefore, that is an area of real need.

In non–small cell lung cancer (NSCLC), we've had a tremendous subclassification, particularly related to nonsquamous NSCLC. Now, with nonsquamous NSCLC, getting genomic testing is really important, as there are multiple different actionable alterations with approved targeted therapies. When patients get beyond those targeted therapies, then beyond chemotherapy, and, in some cases, beyond immunotherapy, that's the next setting where we need a treatment option.

In patients without an actionable alteration who have a high PD-L1 expression, immunotherapy has been revolutionary. Even in those without high levels of PD-L1 expression, chemotherapy plus immunotherapy has improved outcomes, and we see some patients with years of ongoing durable control. These are some of the big wins that we've seen in the last 5 to 10 years, but once we get beyond any approved targeted therapies and first-line chemotherapy and immunotherapy, we're looking at the setting of second-line chemotherapy, and that's the setting where we really need more options.

It's interesting, because docetaxel was previously a standard second-line option, and we gave a lot of it. Now we have all of these other treatment options that are well-tolerated and, in many cases, quite effective. Docetaxel and other chemotherapy regimens continue to be important treatment options, but once we get to that point, there's a real opportunity for other advances, particularly in later lines of treatment.

OncLive®: What is the significance of Trop-2 biomarker expression in the prognosis and progression of lung cancers? How might Trop-2-targeted antibody-drug conjugates (ADCs) help address these unmet needs?

SANDS: There's still a lot for us to learn about Trop-2, and there are some different datasets suggesting that higher Trop-2 expression may indicate a likelihood of a worse prognosis. Not all datasets are completely consistent in that, but there is certainly a suggestion of that from some of the data that exist.

ADCs represent a very exciting new class of drugs that involves an antibody that binds to the cell receptor and then delivers the payload. When the antibody is specific to something that's on just the cancer cells, then this is a mechanism for delivering chemotherapy into cancer cells. This has the potential to substantially reduce toxicities as compared with just infusing the chemotherapy directly.

There have been a handful of different ADCs that have been studied, and there are at least a couple that are specific to Trop-2, so this is an exciting way of potentially delivering that chemotherapy directly to these cells that have Trop-2 expression.

OncLive®: What are your thoughts on the recent data presented on datopotamab deruxtecan (Dato-DXd) for patients with NSCLC who are enrolling in the ongoing TROPION-PanTumor01 trial? Could you comment on the safety and efficacy of this drug in patients with NSCLC who have actionable genomic alterations?

SANDS: I've been involved in this trial from very early on, so I've also had the opportunity to treat a number of patients with this drug. This has been exciting so far. There are a number of patients who have benefitted from the drug, and some of them that have gotten an impressive, durable response to treatment.

As far as outcomes, the drug has, fortunately, been very well-tolerated. The dose escalation went as high as 10 mg/kg, but, unfortunately, at that dose, patients did have mucositis and rash. When dropping the dose back down to 8 mg/kg and then even 6 mg/kg, the drug was more well-tolerated.

On top of that, we've seen some nice responses to therapy, as well. The TROPION-PanTumor01 study was looking at tolerability, but we do have some patients with durable responses, as well. I have a patient who has tolerated the drug for about 2 years. It is incredibly meaningful to have patients with early progression on first-line chemotherapy and immunotherapy go on to have such a durable response with a generally well-tolerated drug, where they can continue to work full time and carry on with their lives.

It's encouraging that we're seeing responses across all of these populations. Whether patients have an identified actionable genomic alteration or not, we're still seeing responses to therapy. Of course, that's the kind of thing we would expect with chemotherapy. When talking about these ADCs and Trop-2-directed ADCs in particular, it raises the question as to whether we might see difference within responses if there are differences in the availability of Trop-2. To see responses across them is encouraging as to the potential utility of these ADCs in the way that we would use next-line chemotherapy, which is across the whole population.

OncLive®: Regarding the TROPION-Lung02, TROPION-Lung04, and TROPION-Lung08 clinical trials, what impact do you think combination regimens may have on treatment selection and patient outcomes if they are FDA-approved?

SANDS: The first part in answering this is the speculation concerning these trials being done and leading to approval. Assuming that happens, then, of course, further evaluation of the details of those trials would be overwhelmingly important as far as determining potential clinical utility.

For the exercise of speculating on what would potentially be meaningful, each of these trials are looking at a combination of Dato-DXd, a Trop-2 ADC, plus checkpoint inhibitor immunotherapy. We've seen this have an impact on the standard of care when looking at chemotherapy plus immunotherapy vs chemotherapy alone.

In patients with a high PD-L1 expression, immunotherapy works well enough that, in many cases, immunotherapy is used alone in that population, so we tend to focus on patients with a PD-L1 expression below 50% when looking at chemotherapy plus immunotherapy. In the setting of Dato-DXd plus immunotherapy, broadly, if the outcomes of the study are better than immunotherapy alone in those with higher than 50% PD-L1 expression, that would be quite meaningful. The combination of chemotherapy plus immunotherapy is something that we certainly use, but if we can get away without using the chemotherapy, then that is preferable. One aspect of this combination study that's a bit different than what we would expect of chemotherapy plus immunotherapy is that Dato-DXd seems to be better tolerated. Broadly, if we're talking about the inclusion of a drug with substantial benefit and little toxicity, then that becomes quite compelling.

If Dato-DXd with immunotherapy ends up improving outcomes and continues to have a tolerable adverse effect profile, then it becomes more compelling to add that drug to immunotherapy. One aspect to Dato-DXd that would need to be taken into account is that some patients end up losing their hair, and some of them quite substantially, so this is part of the complex discussion of risk vs benefit. Sometimes, it's easy to talk about hair loss as not necessarily being important to the overall picture, but, for some patients, that's overwhelmingly meaningful. If the drug itself has tremendous efficacy and durability, then that tradeoff is different than if it adds some, but not overwhelming, durable benefit. This all just factors into that overall discussion with patients.

OncLive®: What other data from ongoing trials in Trop-2-targeted ADCs are you looking forward to seeing?

SANDS: There are a lot of studies currently underway looking at Dato-DXd, and there are also studies on sacituzumab govitecan. These are the 2 leading Trop-2 ADCs that are being studied. Fortunately, we’re seeing a suggestion that Trop-2 ADCs are well-tolerated and likely to have efficacy across a broad population of patients with NSCLC. They are being evaluated in other tumor types, as well. Of course, sacituzumab govitecan is being used with breast cancer, but this is something that will hopefully pan out across multiple tumor types

OncLive®: Regarding enrollment in clinical trials, what factors might you consider when recommending patients with lung cancer to take part? What kinds of challenges would you anticipate these patients to possibly encounter?

SANDS: Participation in clinical trials is extremely important for most patients, but, unfortunately, not all patients qualify for trials. There are some big misconceptions about clinical trials. Many patients believe clinical trials are something that they're doing for future populations, but they believe that they will not benefit from them. There is a broad belief that clinical trials are an option only for people who have no options. I hear people say they think of it as being a guinea pig, or there's this misconception that we're just throwing drugs in and seeing what sticks.

When I meet with patients early on, I speak to them about the value of clinical trials and focus on how best to treat them to help dispel some of these misunderstandings early on. In speaking with any patient who may qualify, and even more broadly … about a clinical trial or any treatment, our conversation is 100% around what is best for that individual. Any drug that gets to the point of even just a phase 1 study has to have tremendous justification based on earlier data, and that's after we see how it's tolerated. There needs to be some suggestion of this agent working in patients with that cancer to then expand that further and enroll patients in a phase 2 study. Individuals enrolling in a trial are essentially getting a potential future standard of care, and they're getting it today. I have had patients who are currently doing exceptionally well years after receiving a checkpoint inhibitor before that was available as a standard of care. That’s because they were on trials and, fortunately, did exceptionally well. Unfortunately, not every trial ends up having the exceptional outcomes we hope for, but these are … promising options that would be discussed. Any trial that I discuss with a patient would be because I think that that particular drug is a good option for that individual.

On top of that, I also make the point that anyone enrolling on a trial would get at least the best standard of care if there's a randomized trial. Broadly, patients often have the expectation that they're at risk of getting a placebo and, therefore, are essentially not getting any treatment but not knowing it. People are understandably quite afraid of that, so I also make a point to them very early on that nobody would enroll in a trial and get less than what is the current standard of care, and, in most cases, many trials now don't even have a placebo. If there's a placebo, patients on the study are getting the best-known standard of care plus either the experimental drug or placebo.

I try to allay patients' fears about this first by reassuring them that anything we do is about what's best for them. If they're on a trial and I think it's no longer the best for them, I would take them off of it. We're not bound to anything. We're not doing anything just for the future of science. This is all about their own treatment, and, hopefully, the treatment works well for them and goes on to help a lot of other people, as well. But the focus is around them and their care. Second, they would never end up on a placebo by itself; that's not how this works. Third, by going on clinical trials, we still have the standard-of-care options available. We're just adding in something else that might end up working for them. For all of these reasons, we use clinical trials to help out with an individual's care and, hopefully, get more out of treatment. This is not just a way of looking at drugs but rather of treating those individuals.

Clinical trials are another reason that it's important for patients to see an academic oncologist at one of the big centers. In some cases, clinical trials are available to the population in the first-line setting, where there still are plenty of treatment options and there's good proven therapy. But there's reason to believe that incorporating another drug in that first-line setting may help treatment options even more. One of the trials that you asked about earlier is first-line Dato-DXd plus pembrolizumab vs pembrolizumab alone in those with a high PD-L1 expression. Giving pembrolizumab alone in that population is approved, and it generally works well and is well-tolerated. The question is, does Dato-DXd add more in that setting? That's not something that would necessarily be known unless the oncologist has that trial open, so it's good for patients to get a second opinion just to have a sense of what other trials might be available.

Now, in some cases, I have patients who drive hours to come to see me. Although I may have a trial, it might not be worth the many hours of driving, particularly if its follow-up is once a week; in some cases, however, it is. For example, before the FDA approval of 2 different drugs for RET fusions, we had a trial open for RET fusion. When I saw patients who qualified but who had driven hours to see me, I told them, “I know this is an inconvenient journey, but, in this case, the drug itself is really worth it based upon the outcomes we're seeing. I fully expect this to be a drug that ultimately ends up being approved, because the responses are really pretty consistent, and the drug has been well-tolerated.”

In fact, I have 1 patient who drives about 45 minutes who has now continued to be on an initial trial for one of these RET fusion–targeted therapies. He's been on this for years. It's now an FDA-approved therapy. He saw me the day before he was to start chemotherapy as his first-line treatment; instead, he's been on a pill now for years with ongoing excellent control without adverse effects. We were only able to put him on that trial because he happened to come in for an opinion and hadn't yet started treatment. This is one of the reasons it's important to be seen at one of the big academic centers before starting therapy, because, sometimes, there are some compelling trials that might not be known unless the oncologist is well plugged in to some of these centers that have these options.

OncLive®: If Dato-DXd is approved for use in lung cancer, would you anticipate an issue with accessibility for use with patients?

SANDS: If it were approved, I would expect that there would be an effort to ramp up production to make sure that they're getting that to all cancer centers. This is a drug that has not been difficult to give to patients, so I would expect that to be widely available. Of course, that's pending full FDA approval.