Around the Practice: Updates in HER2+ Breast Cancer - Episode 2
Breast cancer experts review unmet needs in the management of HER2+ metastatic breast cancer and updates from the 2021 ASCO virtual meeting.
Vijayakrishna Gadi, MD, PhD: That sets the stage for Dr Kaklamani. With all these new agents, with all these drugs available to us, frankly I have had this expressed as HER2 envy by certain other kinds of patients. Can you share with me, do you think there are other challenges, unmet needs in this space still?
Virginia Kaklamani, MD: I think there are a lot of unmet needs. Look at for example, meningeal disease. We don’t have any clinical trials addressing that. The trial looking at tucatinib, HER2CLIMB, did not include patients with leptomeningeal disease. The more these patients live, the more the chance that they will develop leptomeningeal disease at some point. Another challenge, which is a great challenge to have, the patients who have a complete response, and we see these patients, not very often but we do see them, where 3 to 4 years later they are still on a dual combination of trastuzumab, pertuzumab disease free. They’re potentially ER/PR [estrogen receptor/progesterone receptor] negative, so you can’t really put them on endocrine therapy, and what do you do? How long do you continue this treatment? And again, we don’t have any data. Some people say, continue it for couple of years, but then you stop. I don’t know that I am brave enough to do that to my patients, unless they ask me for it, and then that’s wonderful. We do still have a lot of challenges, how can we prevent brain metastases? That is another issue that, with the KATHERINE trial, maybe T-DM1 [trastuzumab emtansine] is the right answer, but still patients develop brain metastasis. Can we avoid surgery altogether after neoadjuvant therapy, assuming that the patients have a complete response by imaging? We don’t know the answer to that, so there are a lot of questions that hopefully we will be addressing in the next several years.
Vijayakrishna Gadi, MD, PhD: I am getting a sense from you that so much of it is continuing to optimize. We’ve gone away from everybody gets everything all day long, to these are the right patients who need these drugs and don’t need these drugs. That’s always a challenge, but it’s a good one to have, like you said. Dr Isaacs, we just got through ASCO [American Society of Clinical Oncology annual meeting], it was virtual again. I am looking forward to seeing you all next year in person. But at this ASCO, I think we were commenting on it earlier, did you find anything in the HER2 MBC [metastatic breast cancer] space that was practice changing at this meeting for yourself?
Claudine Isaacs, MD: I think there were some interesting presentations. I think they help to support some of what we’d seen before. For instance, the HER2CLIMB study presented some updated data that showed continued benefit for the triplet of tucatinib, trastuzumab, and capecitabine versus the doublet with just capecitabine and trastuzumab. There were other interesting presentations. There were trials in progress that were presented that are looking at various combinations with T-DXd [trastuzumab deruxtecan], which I think are really interesting. There was a look at the DESTINY-Breast01 study, looking at the patients who had brain metastases at presentation, and suggesting that those patients also derive benefit from T-DXd. I think there were interesting things that will carry forward, and we will see there. I thought it was helpful as always. I too am really looking forward to seeing everyone in person again sometimes so we can chat in the hallways and get a sense of what we’re taking home from this. But I didn’t think there was anything that changed what we do.
The other thing to comment on in terms of presentations, I think there were some data from some larger trials. It didn’t make me quite ready to change what I do, but I think, adding on to what Dr Kaklamani said about what are some of the challenges. I always hesitate when I have a first-line patient with HER2-positive metastatic disease who is hormone receptor [HR]-positive. I always feel bad giving her—I too give paclitaxel more than docetaxel with it—but I always wish I could have data that would allow me to give her endocrine therapy and dual HER2-targeted therapy. There was a randomized phase 2 study from the group in China that looked at trastuzumab, chemotherapy versus endocrine therapy plus trastuzumab, and did not show a difference in outcome. The trial was small. It doesn’t reflect what we do as standard of care. We know the CLEOPATRA trial showed that incredible 16-month prolongation in overall survival. I am not quite brave enough to give up that possibility for my patient’s first line, but I look forward to the day when I will have more data and will feel more comfortable with it, so I can avoid giving chemotherapy to those patients. But I am not quite there yet.
Vijayakrishna Gadi, MD, PhD: I want to pick on that last one. We obviously will induce with chemotherapy and then pull back and give endocrine therapy with the trastuzumab, pertuzumab combination. There was a study a few years ago, it has been published in JCO [Journal of Clinical Oncology], called the PERTAIN trial, where a large fraction of the patients were treated exactly that way. I’ll share with you, in my personal practice, if I have an older patient who doesn’t want to go on chemotherapy, I feel pretty comfortable doing that. I see you’re nodding your head, but Dr Iyengar and Dr Kaklamani, do you ever do that, where you out of gate deescalate from the chemotherapy?
Neil Iyengar, MD: There are certainly situations as you outlined; that’s not the default for me. I have the sense that’s probably the same in your practice, but yes, I think there are individuals in whom chemotherapy may be contraindicated, or if we think about age or comorbidities, where it behooves us to avoid chemotherapy and combine hormone therapy. That approach is supported by PERTAIN, as you mentioned. What I strive to do is the approach we have all been talking about, to try to get in that initial chemotherapy. I have become a little more liberal now with withdrawing the chemotherapy and moving on with Herceptin, pertuzumab, and hormone therapy if they’re HR positive. But I think this is an incredible space for both biomarker and risk stratification development as well as novel agents that can be combined in that “maintenance” setting to try to prolong that chemotherapy-free interval.
Virginia Kaklamani, MD: I agree, and I think what seems to be important is the type of HER2-positive breast cancer that these patients have. We saw a glimpse of that in the PAMELA trial, and we saw again some data at ASCO, that based on PAM50 [tumor profiling test], there are subsets of breast cancer, they are all HER2-positive, but they could HER2-enriched versus other subsets. They will have different responses to anti-HER2 therapy and potentially also to endocrine therapy. It makes sense if they are luminal A or luminal B, again the minority, but still some of those, we might be able to start with endocrine therapy and then continue with anti-HER2 therapy upon progression. I haven’t been brave either. I haven’t done that as much, but I would love to because I don’t think we have definitive data that the combination of endocrine and anti-HER2 therapy is really better than anti-HER2 therapy by itself. Maybe we will just have more options by sequencing all these drugs, but in the right way.
Vijayakrishna Gadi, MD, PhD: Thank you for that. At this point, let’s go ahead and move on to the next polling question. This is question 3. Which of the studies listed below is most relevant to you? a. HER2CLIMB, b. DESTINY-Breast, c. pertuzumab, trastuzumab, nab-paclitaxel, d. neoadjuvant studies, or e. post-neoadjuvant studies. There are the results. It looks like DESTINY-Breast was very relevant to a lot of folks paying attention tonight, and then a lot of folks picked neoadjuvant trials as 40% each, and then the pertuzumab, trastuzumab, nab-paclitaxel study looked important to about a fifth of the users here tonight. Then one more update, it looks like equal percentage, 12.5% favoring the HER2CLIMB study.
Let’s go to the next question. Are the data from ASCO and the discussion you heard today likely to change your practice? Yes or no. It’s an easy one. We have the results here. It looks like most people were not moved so much by the data at ASCO this year, about a third of you were, but about two-thirds of you still are unlikely to change. There are more answers coming in, but it looks like it might be an even split, 50-50.
Transcript edited for clarity.