Sara Tolaney, MD, and Mark Pegram, MD, discuss their rationale for sequencing of most effective therapy in treatment of patients with metastatic breast cancer.
Sara Tolaney, MD: Usually, in the first-line setting for metastatic HER2-positive disease the current standard has been what we call the CLEOPATRA regimen. A combination of a taxane with dual HER2 [human epidermal growth factor receptor 2]-directed therapy with trastuzumab and pertuzumab. Most of us will give that THP [docetaxel, trastuzumab, pertuzumab] regimen upfront. We usually treat people until we see a maximal response or onset of toxicity that usually occurs after 6 or 8 cycles of the chemotherapy in which case we drop the chemotherapy and leave them on the trastuzumab and pertuzumab. Then, if they’re hormone receptor-positive, I’ll often add endocrine therapy to that HP [trastuzumab, pertuzumab] maintenance. When they progress on that, typically we had been using T-DM1 [trastuzumab emtansine] in the second-line setting. Sometimes we had been incorporating tucatinib with capecitabine and trastuzumab if someone had active brain metastases. In the third-line, we were thinking about trastuzumab deruxtecan [T-DXd]. However, I think that this sequencing strategy is now dramatically changed based on data from DESTINY-Breast03 [DB03] where we’re seeing that T-DXd is dramatically better than T-DM1. In my mind that makes T-DXd the new standard of care in the second-line setting. Which means that normally I would be giving THP in the first-line but then upon progression, I would really turn to T-DXd as my second-line standard of care. In the third-line, that then means that you have the choice of going to T-DM1 or to capecitabine/tucatinib/trastuzumab. I think most of us would make that decision based on whether or not there are brain metastases and in someone with active brain metastases would preferentially choose the tucatinib-based regimen. Then whatever you hadn’t given in the third-line setting you would then use in the fourth-line. Beyond that, there are certainly lots of other HER2-directed treatments. There’s the option of using margetuximab in combination with chemotherapy. There’s also the option of using neratinib, although that is in combination with capecitabine. Most of us are using capecitabine in combination with tucatinib and trastuzumab so that makes that a little bit harder to integrate along your treatment course. Beyond that, we’re really going to chemotherapy with trastuzumab for future lines of treatment. It does good to show that we do have a lot of options over someone’s time course, which is really nice to see.
Mark Pegram, MD: In the wake of ESMO [European Society for Medical Oncology meeting] 2021 and the presentation of the DB03 clinical trial data, I think there will likely be a change in clinical practice in the management of HER2-positive metastatic disease. In particular following progression on a CLEOPATRA-like regimen with taxane and dual antibody therapy. I think it’s very like the DB03 data will move up trastuzumab deruxtecan into consideration in the second-line setting, particularly for patients without brain metastasis or perhaps even with patients with stable brain metastasis which was allowed on the DB03 trial. That said, for patients with active CNS [central nervous system] disease we know that that group has level 1 evidence of an overall survival benefit with a tucatinib-based combination. That is the HER2CLIMB regimen, which is tucatinib, trastuzumab, and capecitabine. For active CNS disease, I think tucatinib will still carry the day. Tucatinib could also be a consideration for those patients with stable or previously treated brain metastasis based on the strength of the overall survival analysis of the CNS metastasis subset of the HER2CLIMB regimen. With that caveat, trastuzumab deruxtecan will likely move up from third-line into the second-line. Then, the third-line there will now be probably equipoise between T-DM1 versus tucatinib-based regimens. For HER2-positive breast cancer brain metastasis, tucatinib will be preferred over T-DM1 based on the strength of the HER2CLIMB overall survival analysis in the brain metastasis subset population. Whereas T-DM1 has a very high therapeutic index to be sure. In the case of either of those 2 drugs we don’t have any data yet about activity of these regimes after trastuzumab deruxtecan. That’s a weakness in an area where we’ll need to collect more data. Then in later lines after T-DM1, after tucatinib-based treatment then margetuximab plus chemotherapy in the United States would be a consideration. Then standard regimens such as chemotherapy plus trastuzumab that might also be a consideration in the late line salvage setting.
Sara Tolaney, MD: There has been some controversy about how to optimally sequence therapies. For the most part, in the oncology community, we want to give the most effective treatment in the earliest line of treatment because unfortunately there is some risk that patients may not get to their next line of treatment. If they develop disease progression and a complication you may not be able to get them to that subsequent treatment. In fact, there is data even in metastatic HER2-positive disease that about 20% of patients will drop out after second-line therapy and not be able to make it to third-line. Some of these cases are because patients unfortunately die of their metastatic disease before they’re able to get their third-line treatment. Knowing that, it makes it really critical to make sure that we do integrate the most efficacious treatment that we have in the earliest line setting because unfortunately we can’t guarantee if someone will make it to that subsequent line of therapy. The other thing you have to keep in the back of your mind is that unfortunately patient’s performance status can change over time, which can make it challenging to be able to integrate subsequent treatments if they’re not able to tolerate them. My general preference has been to use the most efficacious therapy in the earliest line of treatment.
Mark Pegram, MD: The question is, should we use our most active treatments in an earlier aligned setting or save them for later? Since for example the DESTINY-Breast01 data had such strengths even in heavily pretreated patients, some clinicians could say well maybe we could save it. There are mathematical modeling considerations in metastatic solid tumors suggesting that strategy is probably not correct. You probably don’t want to save your best agents for a rainy day. In fact, based on mathematic modeling the converse is true. You should always use your best regimens up front in order to capture the greatest clinical benefit in terms of not only response rate, but timed events outcomes as well, such as progression-free and overall survival. Moreover, if you look at all HER2-positive metastatic breast cancer data in the U.S., there’s a drop off with each subsequent line of patients who actually are still fit enough to receive salvaged treatment after first-line therapy. Between first- and second-line treatment there’s about a 20% drop out rate even in academic centers. In the community, it may even be a bit larger. Then about 10% per line thereafter, patients that are no longer eligible to receive treatment probably because decline of performance status and progressive disease or mortality events. In order to maximize the impact of a highly effective new agent, it’s best to consider it as an earlier line.
Transcript edited for clarity.