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New Developments in Triple-Negative Breast Cancer Therapies

<ѻý class="mpt-content-deck">— Our expert roundtable discusses GeparNuevo and the future of treatments for TNBC
MedpageToday

The recent virtual featured several breast cancer clinical trials, including , which looked at the addition of durvalumab (Imfinzi) to anthracycline- and taxane-based chemotherapy as neoadjuvant therapy for triple-negative breast cancer (TNBC).

In this third of four exclusive episodes, ѻý brought together three expert leaders in the field. Moderator , of the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, is joined by , of the University of Texas MD Anderson Cancer Center in Houston, and , of Northwestern University Feinberg School of Medicine in Chicago, for a virtual roundtable discussion about GeparNuevo and the future of TNBC therapy.

Episode one: PARP Inhibitors for Early, BRCA-Mutant Breast Cancer

Episode two: New Data on Role of Gene Assays in Breast Cancer Treatment

Following is a transcript of their remarks:

Rugo: Hello, I'm Hope Rugo, a professor of medicine and director of breast oncology in clinical trials education at the University of California San Francisco's Comprehensive Cancer Center. We are going to talk about some interesting updates from ASCO 2021. With me today are my excellent colleagues, very knowledgeable and key opinion leaders in breast cancer: Dr. Jennifer Litton is professor of medicine and vice president of clinical research at MD Anderson's Comprehensive Cancer Center, and Dr. Bill Gradishar, who is professor of medicine and chief of hematology-oncology at Northwestern University.

Now, we are going to discuss some areas that were presented, some new areas that were presented, at ASCO this year that focused on triple-negative breast cancer. Again, this is an area that's such a challenge for us in trying to figure out the right way to treat patients with early-stage disease to try to improve outcomes, since we know that outcome is still poor in the metastatic setting. Then there were some additional data presented on new agents and some further subset analyses of already-presented data that I think are useful to discuss as well. But we'll start with the immunotherapy in the neoadjuvant setting.

We know that KEYNOTE-522 has had a press release very recently, noting that they met their event-free survival endpoint in patients who received a year of pembrolizumab versus those who received a placebo along with standard neoadjuvant chemotherapy. But we also know that there are some toxicities that continue in the post-neoadjuvant setting in patients who received checkpoint inhibitors, and occasionally those can even be fatal in certain situations. There is a lot of interest in what checkpoint inhibitors do.

There also was a little bit of data presented at the FDA's ODAC [Oncologic Drugs Advisory Committee] meeting from KEYNOTE-522 that suggested that giving pembrolizumab after surgery might have a positive impact even in patients who didn't achieve a PCR [pathologic complete response]. We learned something new from GeparNuevo, a phase II trial from the German Breast Group, about use of checkpoint inhibitors and these particular endpoints. Jennifer, can you tell us a little bit about what Sibylle Loibl presented?

Litton: Sure, absolutely. GeparNuevo was a study that was 174 patients who received nab-paclitaxel and durvalumab, followed by anthracycline-based chemotherapy with epirubicin and durvalumab, and then went to surgery. They already presented -- just like the IMpassion031 and the KEYNOTE-522 -- showing some improvement in PCR and that had been 44.2% to 53.4% improvement.

What this [study] did was actually look at median follow-up at 43.7 months and showed that question that everyone is asking for the use of immunotherapy, what about those longer-term survival curves? The 3-year invasive disease-free survival improved from 77.2% to 85.6%, the distant disease-free survival from 78.4% to 91.7%, and they are seeing a separation in the overall survival [curve] from 83.5% to 95.2%.

I think that this comes in to a lot of the questions that we really have around endpoints for preoperative chemotherapy or preoperative systemic therapy trials. What is the delta pathologic complete response that matters? I think that this also shows us that when we're thinking about immunotherapy, the delta and PCR isn't the whole story and seeing that bigger separation that we're seeing on the back end of it is something we're going to really need to think about as we're structuring these trials for these endpoints.

Rugo: Yeah, I thought this was really interesting. It's important to keep in mind that this is a phase II trial with less than 200 patients and 35% had stage I disease. In fact, although numerically as you nicely summarized, the PCR rate was higher, it didn't meet statistical significance in that trial, probably, I'm guessing, because there were a fair number of stage I patients who had no clinically known negative disease. But just with that treatment in the preoperative setting, they did show a big difference.

Now, we have seen in fact that phase II trials that show EFS [event-free survival] benefits don't necessarily translate into benefit in the phase III setting. But the big question, as you pointed out, is do you really need to give a checkpoint inhibitor for a whole year? We still haven't really figured that out for HER2-positive disease and trastuzumab, and never will. I think that's really the biggest issue. If you give a checkpoint inhibitor and somebody doesn't have a PCR, are you still really improving outcome in a clinically significant way? What was your take on that, Dr. Bill? How would that affect your use of checkpoint inhibitors if KEYNOTE-522 results in approval of pembrolizumab?

Gradishar: I think that all of this stuff is intriguing, but GeparNuevo falls in line with what the other trials showed with respect to PCR. But where it shines a bit is with the longer-term follow-up. Again, it's a smaller trial, but nonetheless, I think it's consistent in a sense with that.

Now are we using checkpoint inhibitors routinely preoperatively? We are not. I still agree that we should not be doing that routinely, but I think we will get there. We just need longer follow-up in some of these trials.

Rugo: If KEYNOTE-522 is an almost-1,200 patient study, it shows it's clinically important, not just statistically significant, but the P values are a lot to reach their significance. If it shows a clinically important difference in EFS, do you think then you'll be giving patients with triple-negative disease a year of pembrolizumab?

Gradishar: Yeah. I think we would consider it strongly in that setting. I don't know about you. I would.

Rugo: Yeah, I think we all will. Jen?

Litton: Yeah, I definitely would. I still am left with the same problem with triple-negative breast cancer where so many of the people will do so well with a full pathologic complete response with very little. I hoped that this is the end of the days of, let's throw all the patients with triple-negative breast cancer in the same study with one drug. It's one of the reasons ... I do love the I-SPY program and other kinds of platforms that try to individualize therapy here because I think that we could be minimizing a bigger effect for a group of people who really need this and that we're certainly going to be exposing a lot of people to the long-term toxicity of immunotherapy that can be lifelong, like the endocrinopathies, and they would have been cured completely with polychemotherapy alone and maybe even less of that. I think that, absolutely, if the KEYNOTE [study] is positive, we'll be doing it, but I really think we need to be more thoughtful of how we're going to figure out who really needs this or not.

Gradishar: I think, even though it's not directly germane, Leisha Emens's presentation about looking at the different markers really highlighted how early days we are in trying to figure this out. Because it was very interesting. But if I had to go explain it to somebody and how you're going to use it in clinic, you can't. I think we're really at early days about trying to distinguish these patients yet.

Rugo: Yeah, I think that it's going to be interesting. Clearly, the benefit was greater in node-positive versus node-negative disease. But I think the question for us, based on the combination of these datasets, is if somebody has a PCR, do you stop surgery and do you give this to node-negative disease? But we'll see.

Litton: We do have the SWOG 1418 that's rounding the corner of ending soon at some point, looking at just purely the year of pembrolizumab for high-risk patients with triple-negative breast cancer. I think that we'll get some more information there. The data of giving it during the adjuvant radiation is still, I think, multiple studies that are accruing and reporting, are going to give us more information on that. I think that we're still so early, like you said, Hope ... I don't think this is where we're going to end with this. I think we've got a lot of refining to do.

Rugo: Yes. I mean, the SWOG trial that Jennifer is mentioning looked at patients specifically who have residual disease after neoadjuvant therapy. Some will have received capecitabine, etc. I think that that will provide us with some really important data about whether or not you need to give this preoperatively. My bias is that you probably do because you need the chemotherapy interaction and that that's going to be really important, but we'll find out in, over time, a really important trial.

In just the last less than a minute or so, Jen, do you want to briefly talk about the antibody-drug conjugates we're using for metastatic triple-negative breast cancer? Sacituzumab govitecan had some updated data. Then there was an interesting, actually similar, Trop-2-targeted ADC [antibody-drug conjugate] that uses an exatecan derivative, deruxtecan, similar to trastuzumab deruxtecan, called Dato-DXd or datopotamab. It just presents some phase I data.

Litton: Yeah. I do think that the antibody-drug conjugates are such an exciting new group of drugs. Trastuzumab has now become a staple in my drug usage for patients with metastatic triple-negative breast cancer. I have definitely had patients have significant response in that third-line setting, which isn't something we've seen routinely for awhile.

Overall, Hope, I think that there are so many different drugs in development. I think they are getting smarter. I think they're getting more targeted. I'm very excited about them. I think that the dual antibody and the fusion proteins are also going to be where we're going in the next 5 years, so we can really look at multiple targets at the same time.

Rugo: Yeah, I agree. I think it's exciting and seeing that you can give sacituzumab in the second-line setting in older patients with similar results, seeing that there is a new ADC with the same antibody also is great. Maybe sequential therapy will be good. Of course, we're waiting for data using these agents in hormone receptor-positive disease. The TROPICS trial with sacituzumab has completed accrual, so hopefully we'll see that data next year, along with their trastuzumab deruxtecan and HER2-low. We just saw a press release for SYD985 meeting its endpoint in HER2-positive disease in the metastatic setting. I think that we have lots of new data to see in the near future. Thanks both of you for your excellent comments and discussion of this exciting area.

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    Greg Laub is the Senior Director of Video and currently leads the video and podcast production teams.