Latest news with #MarkKris
Medscape
5 days ago
- Health
- Medscape
FDA Approves New ADC for Lung Cancer Treatment
This transcript has been edited for clarity. Hello. It's Mark Kris, from Memorial Sloan Kettering, talking about a birthday gift I received on June 23 when the FDA approved the indication of datopotamab deruxtecan for people with lung cancers. We have another drug, our third ADC (antibody-drug conjugate) to fight lung cancer, so that's a gift. Let's talk a little bit about that agent. It's an interesting twist in our practice patterns. What can the drug do? It had a response rate of 45%, which is really important in patients that had EGFR mutations with progression on osimertinib. We really need drugs in that space. The duration of response was about 7 months, which is significant. One interesting thing in the approval, [was] that the response rate of the blinded folks was greater than that in the investigator-assessed response by about 10%. It's very interesting. Clearly, we have another drug, and we have it in a space where we need it. Let's talk a bit about the toxicity. I'm going to focus more on the paper by Bardia et al that compared datopotamab deruxtecan to various chemo drugs in breast cancer, not in lung cancer. You can take this a little bit with a grain of salt. First, they saw a whole different array of side effects with datopotamab deruxtecan, things that we don't normally deal with here. Nausea, stomatitis, alopecia, dry eye, and vomiting. All of those were more than 10% more common in patients that received datopotamab deruxtecan compared to the control. The only things that were more common with the control were neutropenia, leukopenia, and hand-foot syndrome in patients that had capecitabine. One thing, though, is while you say, 'Oh, these weren't dangerous side effects,' they surely were lifestyle altering. Nobody wants to have these side effects on a daily basis. Again, there's an increasing awareness about these kinds of lower-grade but still lifestyle-disrupting side effects. When it goes on day after day, you really have to balance that into the benefit you're going to receive. I think the second important point is how, when we use this drug, we're going to have to go to another level to deal with the adverse effects that we are going to see. The first would be nausea and emesis. It is a highly emetogenic regimen based on the NCCN (National Comprehensive Cancer Network) guidelines, so you would need either three or four antiemetic drugs. That's number one. Number two, because of the potential eye problems, you need an eye exam before treatment — and the label says at least annually — with any symptoms. I think it's very important that you give the patients eyedrops, and in general, the preservative-free eyedrops are the ones that are most effective. Stomatitis is a very common side effect with that agent. It's really not seen with the other drugs that even contain the same warhead. There, dexamethasone rinses are important. Now, this is a compounded medicine so you need to be very careful in making sure that you identify pharmacies that will prepare this and will have it available for the patients that need it. Last, there is the risk of hypersensitivity reactions and there's a recommendation for premedication for that. As you think about using datopotamab deruxtecan, you need to have all your ducks in a row to treat side effects. You need prophylaxis for hypersensitivity reactions, nausea, and emesis. The patient will need an eye exam. You need to prepare the patient for possible dry eye and teach them which eyedrops are the best. You also need to ensure the availability of dexamethasone rinses and mouth washes. All that needs to be in place to make sure that the patient can safely use the drug. I think it's going to be a useful drug. We don't yet have a uniformly available way to select patients for its use other than EGFR . I should note that the approval is for EGFR -mutated lung cancers. It doesn't say which type of mutation, so that would give you some latitude in giving it for exon 20 atypicals as well as for the common sensitizing mutation. We have another drug. It's clearly going to be a useful one. It clearly comes with many adverse effects that we don't normally treat on an everyday basis, we're used to the diarrhea and skin changes that come on with the EGFR TKIs. This pattern of side effects is different and requires some additional attention, but with it, the drug can be useful. I'm glad that we have yet another way to fight this disease.
Medscape
6 days ago
- Health
- Medscape
New Tools for Lung Cancer, Harder Job for Clinicians
This transcript has been edited for clarity. Hello. It's Mark Kris, from Memorial Sloan Kettering, with a month-later review of the 2025 ASCO meeting in Chicago. I think everybody who was there and attended the lung cancer sessions left with the, I'll have to say, difficult time unpacking what we learned during that meeting. There was a dizzying array of trials presented and a huge amount of data, but sadly, there was no breakthrough. There was no one treatment or approach that told each of us we had to start doing this in every patient on Tuesday when we got home again. What it did was give us more tools and more ways we could fight cancers, but it really made our jobs much harder. I think that we need to spend some time thinking about how those data could be used, and I'll pick a couple of examples. I think one would be in the small cell lung cancer area. There was a large amount of attention to the use of tarlatamab as a treatment at relapse. It was a comparison trial to topotecan and lurbinectedin, and there was an improvement in outcomes in those groups. While that benefit was there, what was not addressed was the benefit of repeating standard therapy, which is what many of us do, particularly when there has been a longer time between the end of the induction treatment and recurrence. The second trial that I thought was useful in the small cell area was a randomized trial adding lurbinectedin to the checkpoint inhibitor after induction chemotherapy. There was an improvement in disease-free survival there also. Personally, I was more impressed by the latter trial, in that it gave our patients a longer time with disease control rather than focusing the time of relapse, where people may already have suffered symptoms brought on by the progressive lung cancer — which sadly is an all-too-common occurrence. In the perioperative space, my colleague Jamie Chaft reported on neoadjuvant osimertinib. In her trial of osimertinib alone, osimertinib plus chemotherapy, and osimertinib and chemotherapy alone, they showed a benefit for the osimertinib-containing arms but not a clear benefit of osimertinib alone versus osimertinib plus chemotherapy. What's the take-home message there? Well, again, it's not simple. I think that we need to give chemotherapy to every patient with stage IB disease and beyond, whether they have an EGFR mutation or not. Based on the fact that we can give chemotherapy more safelyand more completely in the neoadjuvant setting, I would tend to use osimertinib with chemotherapy upfront and then surgery. If you do go the other way and use osimertinib alone, you would need to give chemotherapy afterward, which is, frankly, tougher. I think my take-home message from that was osimertinib and chemotherapy, our standard of care for advanced disease, should also be our standard for neoadjuvant disease in patients with EGFR mutations. There was a fantastic lecture by Patricia LoRusso, from Yale, about antibody-drug conjugates (ADCs). I think that was the most confusing moment of all during the ASCO meeting — the number of ADCs under evaluation. Yet, as Dr LoRusso pointed out, despite the number, it's the same targets, largely the same warheads, and very often, antibodies without activity in and of themselves. When you look at the overall benefits of the group, there are none that truly stand out. We now have three available in the lung cancer arena. The benefit, side effects, and the whole field is really quite confusing. One other message was that, with the bispecific antibodies, the more targets you have, the more toxicity you're going to see. It's a real balance between benefit and risk. What are you going to do? Again, there was no breakthrough at ASCO this year. Clearly, there are more therapies and there are even more in the pipeline. I think what we need to do now is to learn more, and to — unfortunately — spend a large amount of time going through the data and see exactly the benefit versus risk ratio for each of the new therapies and for each of our patients deciding where that goes. For example, I would be a big fan of giving lurbinectedin because of its ability to improve disease-free survival, which is so important in small cell [lung cancer], where relapse is almost certain, and that disease-free time is the best time for our patients. For the neoadjuvant, it would be giving both chemotherapy and osimertinibpre-surgery, in that is better tolerated there and you can also assess benefit very well. For tarlatamab, it's a tough decision there. Again, it's the time of relapse. We have many choices at relapse, giving the same drugs again, giving another perhaps less toxic agent like temozolomide, giving tarlatamab and the standard drugs. Clearly, tarlatamab was better than some of the standard drugs, but they're not the ones that most of us use for the patients. We usually go with the same treatment by and large. Lastly, it's going to be incumbent on us to work harder to take that information we got at ASCO this year and make the best decisions for each patient. We have to focus on the nuance. We have to learn more, and there is no knee-jerk that every patient needs tarlatamab or every patient should get induction chemotherapy with the combination. We have to choose our patients wisely. You've heard me before, and I'll say it again. Our jobs are better, but they're harder.
Medscape
06-08-2025
- Health
- Medscape
Dato-DXd Shows Potential in Treating Lung Adenocarcinoma
This transcript has been edited for clarity. I'm Mark Kris, from Memorial Sloan Kettering, continuing a discussion about antibody-drug conjugates, or ADCs, and in this case, datopotamab deruxtecan, or Dato-DXd. This agent combines an anti-TROP2 antibody with a potent topoisomerase I inhibitor. It has had activity in a number of diseases, but the topic today is lung cancer. There has been a phase 3 randomized trial already. It's shown, compared to docetaxel, an improved rate of response by about 10% or so. It showed a small improvement in disease-free survival and about a 1-month improvement in overall survival over docetaxel. I think what this trial shows is that it clearly is an active agent, and I think it's useful to us for patients with adenocarcinoma, giving us an additional line of therapy. It would be a real judgment call when a patient needs a new line of therapy whether to give docetaxel or the Dato-DXd first. The drug is not yet approved for lung cancer but is obviously in the approval process now. The other thing noted in that phase 3 trial was that there was very limited activity. In fact, [there was] less activity than docetaxel in patients with squamous cell cancers. Clearly, that activity is largely limited to the adenocarcinoma patients, and I think that's where, if approved, it will finally be useful. The companion paper in the Journal of Clinical Oncology reports on the use of Dato-DXd in patients whose tumors have oncogenic drivers. They found a higher-than-expected response rate. It was in the twenties in an unselected population, but in the patients with EGFR mutations it was 36%, and in patients with ALK rearrangements in their tumors, it was 44%. I think this may be the place where it will be most useful. In 2025, we still don't have a therapy beyond standard chemotherapy after progression on osimertinib, and this may be a useful drug in that place. Again, it's useful in adenocarcinoma. To summarize, Dato-DXd is a drug in the regulatory approval process that clearly has activity in an unselected population of patients with adenocarcinoma. It's roughly comparable and slightly better than docetaxel. However, it's less effective than docetaxel in a squamous population. In addition, at least in other trials, it has shown some activity and perhaps even more activity in patients with drivers like EGFR or ALK .It may have some usefulness there. I think we're fortunate to have more new agents. We're fortunate to be able to make more choices to match drugs and side effects to specific patient characteristics and specific patient preferences. Once again, our job is better but it's hard. Clearly, the harder we work, the better we're going to make the course of illness for our patients.
Medscape
26-06-2025
- Health
- Medscape
It's Complicated: Surgery and Lung Cancer Care
This transcript has been edited for clarity. Hello. It's Mark Kris from Memorial Sloan Kettering, continuing my little series on the initial treatment of patients with lung cancers. In the earlier discussions, we talked about people with metastatic disease. I'd like to switch today to talking about people who are candidates for surgery. The two operant terms here are operable and resectable. Operable means that the patient is medically fit to have an operation and to undergo the extent of surgery needed for a complete resection. Resectable means that, in the opinion of the thoracic surgeon who will be performing the surgery, R0 resection is likely to be achieved. Again, these things are not perfect. Experience guides many of our decisions here, and the operative decision is made by many different folks. The surgery decision really needs to be made by a surgeon. The truth is that the question of resectability comes from the surgeon at your institution, in your multidisciplinary tumor board. What are the stages we're talking about? Looking at the trials of perioperative therapies, the stages looked at are IB (tumors greater than 4 cm, regardless of nodal status) up to IIIB (larger primary tumors with N2 nodes). N3 nodes are a different discussion, which we'll hopefully have later on. I think I personally am unbelievably struck by the amount of data and the absolute consistency of data about the use of neoadjuvant therapy in patients who do not have a driver. That's the first group I'd like to address. It is critical to get sufficient tissue to make sure that there are no drivers present. If you have a driver, particularly EGFR and ALK , it sends you in a different direction for decision making. Also, if you're following the package insert, for example, you need to show that the patients are EGFR and ALK negative. To do that, you really should do next-generation sequencing in 2025. It has to be done on tissue. The data from using blood in these situations show that less than [about] one in five of the mutations are detected in blood in these earlier-stage patients. You must have tissue. Obviously, if you have a positive blood test, that's great. You can use it. If it's negative, though, you must have tissue. You have to get the tissue, you have to get the answer, and you have to get it quickly. It's not an easy situation, and we can talk about that. I think the data are very, very clear in the nine trials now. There are nine randomized trials that have been reported, and every single one shows an improvement in disease-free survival by giving neoadjuvant therapy with chemotherapy and a checkpoint inhibitor. I'm struck by the consistency of the trials, by the huge amount of data, and I think that makes this the standard of care today in patients that are both operable and resectable. What about the discussions that go on at our tumor boards about the need for immediate surgery, particularly for sick patients with IB and II disease? Well, I have to say that there are virtually no data for the patient sitting in your office, saying that immediate surgery followed by adjuvant therapy is as good, or better than, the neoadjuvant approach. Frankly, there probably is never going to be a trial that answers that. When you look at the trials of where people have proposed to do adjuvant therapy, up to one-third of the patients, or more, never get the adjuvant therapy. It's really an apples-and-oranges comparison here. The data just do not exist and I think are unlikely to exist just by the nature of the problems. For people who have neoadjuvant therapy, there are two groups now as well. There are patients who have a major response, particularly a pathologic complete response or no pathologic response, and there are patients who don't. I think for those who don't, the way forward is clear. You need an alternative therapy. I personally would advise not to give a component of the neoadjuvant program that was truly unsuccessful, particularly for folks who have a large amount of remaining disease in the resection specimen. For people with no pathologic response or a pathologic complete response, the question there comes whether to give perioperative therapy, generally the checkpoint inhibitor, after or not. The data here are, again, not going to give you the answer. The trial of nivolumab — not followed by a year of nivolumab after surgery — showed very, very good results and really comparable to those results. The FDA has clearly pointed out that the data supporting the use of the additional year of therapy with the checkpoint inhibitor are not proven. There is toxicity. In adjuvant situations, the data are not particularly impressive. I do want to point out the need for consideration of postoperative therapy with radiation if you have N2 disease. When you look at the recurrences noted in the neoadjuvant and adjuvant trials, now with better systemic therapy, the recurrences are in the chest. We must think about improving control in the chest. Frankly, the only modality we have today to do that is radiation, and it's most proven for N2 disease. I do think it's very, very important for people with N2 disease to get a radiation oncologist in the treatment planning group to see if there is a role for radiation in those patients. To summarize, I think for patients who don't have a driver and are operable and resectable, neoadjuvant is the way to go. What you do afterward is difficult for people with a major pathologic response. You can make a good case for not giving any additional therapy. There are FDA-approved regimens to give additional therapy of the same drugs. For people who clearly progress, you need to think about what other alternatives there are, both local and systemic.
