By: Danielle Ternyila
In an interview with Targeted Oncology, Julie R. Gralow, MD, discussed the findings from the KAITLIN study of T-DM1 in early-stage breast cancer
Over the last several years, there have been a plethora of new HER2 targeted agents that have been approved by the FDA. These therapies have made HER2-positive breast cancer highly survivable and highly curable, but unfortunately, some patients do still recur.
Among the many ongoing clinical trials evaluating the different treatment options in the HER2-positive setting, the KAITLIN study was recently presented at the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program. However, in the phase 3 KAITLIN study (NCT01966471) replacing adjuvant taxane therapy and trastuzumab (Herceptin) with trastuzumab emtansine (Kadcyla; T-DM1) in combination with pertuzumab (Perjeta) did not improve the overall survival in patients with HER2-positive breast cancer.
While the study failed to meet its primary end point, the T-DM1 appeared safe in this patient population. However, these findings may have helped demonstrate other patients in breast cancer who may benefit from T-DM1.
In an interview with Targeted Oncology, Julie R. Gralow, MD, the clinical director of Breast Medical Oncology at the Seattle Cancer Care Alliance, professor of Medical Oncology at the University of Washington School of Medicine, and professor of the Clinical Research Division at the Fred Hutchinson Cancer Research Center, discussed the findings from the KAILTIN study of T-DM1 in early-stage breast cancer.
TARGETED ONCOLOGY: Can you discuss the current treatment landscape for HER2-positive early breast cancer and what does the prognosis generally look like for these patients?
Gralow: In early-stage HER2-positive breast cancer, we’ve seen a real transition over the past couple of decades. This used to be an aggressive disease with high recurrence rates, but now with of these new targeted therapies, we now have seven FDA-approved HER2 targeted therapies. We’ve seen a real transition and HER2 positive early-stage breast cancers highly survivable and highly curable to the point where we’re looking at can we back off on our aggressive treatments. Can we give less chemotherapy? Which of these tumors respond to the HER2 agents alone or maybe to the antibody We’ve gotten such good results in so many patients, although sadly a few will still recur.
The KAITLIN trial was presented virtually at ASCO, and this was a trial that was looking at, could we use just T-DM1, the antibody-drug conjugate (ADC) that been FDA-approved for quite a while more recently moved into the early-stage setting if a patient has pre-op therapy and doesn’t have a complete resolution of the cancer, and so this was looking at could we just give T-DM1 with pertuzumab and we compared it to kind of a full-blown anthracycline, taxane, trastuzumab pertuzumab regimen. We looked at somewhat higher-risk patients because for the node-negative small tumors, I think we have good data that maybe a taxane and only trastuzumab does quite well. This was a population that wouldn’t qualify for what we call that HPT regimen of paclitaxel and trastuzumab alone but have somewhat higher risk. The hypothesis was that the T-DM1 with the producer map would do at least as well, if not better, and also have less toxicity.
What we saw and what was presented at ASCO 2020, was that there was no real difference. The T-DM1 and pertuzumab was not better. The group that had no kind of classic chemotherapy and during the chemotherapy phase, the side effects and the quality of life were better on the T-DM1 and the pertuzumab. However, once you got done with the chemotherapy, and you’re completing your whole year of treatment, then actually the T-DM1 and pertuzumab group had more dropouts, more patients who didn’t complete all of their therapy. They were allowed to transition over to trastuzumab alone or trastuzumab plus pertuzumab, and I think what that says is very interesting, which is that and of course, we should have expected it, but when you’re getting full blown chemotherapy, T-DM1 and pertuzumab is better, but when you’re just on the trastuzumab or pertuzumab of the year-long therapy, the T-DM1 has more side effects, so it didn’t play out to be a more favorable regimen in terms of either efficacy or side effects overall. It is certainly a reasonable regimen, but it didn’t meet its primary end points
TARGETED ONCOLOGY: What are the implications of these findings?
Gralow: I don’t think that the KAITLIN trial is going to change the standard of care. I think the regimen of T-DM1 and pertuzumab or T-DM1 alone is being investigated. It’s being compared to in the earliest stage patients to just the paclitaxel and trastuzumab regimen. I think we will find more of a role for the ADCs like T-DM1 in earlier stage breast cancer, but I don’t think this trial is going to change the treatment landscape very much. I think that patients can’t tolerate in early-stage breast cancer a full year of T-DM1 as well as just the 2 antibodies or 1 antibody all by itself. Now, if you did get preoperative chemotherapy, which is more commonly the standard in this group now, and you still had residual disease, I think we all have seen the data that shows that a switch of the antibodies to T-DM1 to follow. In that case, I think you’re really at high risk and that the tumor didn’t respond fully to the chemotherapy and the antibodies, and so I think you’d be more willing to put up with those toxicities, knowing that you have that highest risk. I think we’re pretty much giving preoperative therapy, and we’re using the responses at the time of surgery to determine what happens afterward. If you didn’t have a great response to the chemotherapy and the 2 antibodies, then you’d have the option of switching to T-DM1. We’ve shown in the KATHERINE study that this does change your outcome.
TARGETED ONCOLOGY: Are there any other next steps planned for this research?
Gralow: I think T-DM1 is an important drug in early-stage breast cancer. I’m not so sure we need to combine it with pertuzumab. I’m not sure we’ve ever really shown that it adds benefit in the metastatic setting or in the early-stage setting. I think what I’m interested to see is, as I mentioned that we have 7 FDA-approved HER2 positive drugs, could we combine T-DM1, for example, with 1 of the oral TKIs that targets HER2. Of course, we’re particularly excited about tucatinib now with the HER2 CLIMB data and brain metastases. We are worried about the brain being protected from these big antibodies when it’s intact, that blood brain barrier. While we know that the big antibodies can get into the brain when you’ve got visible symptomatic brain metastases, when the brain might have just been seeded a bit by a couple of cancer cells floating around early on, but the blood brain barrier is essentially still intact. [The question is,] would T-DM1 plus a drug like tucatinib, which would may kill off those few errant cells before we ever know about them, be of benefit? I think combining T-DM1 with other agents might be the way of the future and not so much with pertuzumab.
TARGETED ONCOLOGY: Can you elaborate on the safety profile of T-DM1?
Gralow: T-DM1 does have chemotherapy. It is an ADC, and the emtansine, which is the chemotherapy is cleaved and most of it stays inside the tumor cell. It doesn’t cause hair loss. It causes fatigue, a little bit of nausea. It certainly impacts the platelets which is very interesting. The platelets [are] out of proportion to any of the other blood cells. Very rarely, we’ve seen some liver toxicity of significance, so we have to watch out for it. And so overall, I think it’s fairly safe. If you compare it to, for example, trastuzumab deruxtecan (Enhertu), the other newly FDA-approved ADC, I think T-DM1 doesn’t cause hair loss as trastuzumab deruxtecan does. It doesn’t cause quite the cytopenia and all this a little bit gentler. It’s kind of maybe somewhere in between a full-blown classic chemotherapy and an antibody. It’s overall, even though patients fell off the T-DM1 arm in terms of toxicities, this is an early-stage group who may very well have been cured without that year of T-DM1, and I think they’re more likely to go off of it, but I think overall compared to other ADC, it’s fairly well tolerated.
TARGETED ONCOLOGY: What are your final thoughts on this study?
Gralow: I like the idea of de-escalating in HER2-positive breast cancer. That term de-escalation sometimes can be a bit scary, but what we know is we’re way overtreating a group of HER2 positive patients, and we may still be undertreating others. We’ve got multiple clinical trials going on now and again, using response to preoperative therapy, which can help tell us who needs more or something different and who doesn’t, I think is the way of the future.
Barbara Jacoby is an award winning blogger that has contributed her writings to multiple online publications that have touched readers worldwide.