Remaining Unmet Needs in the Third-Line and Lessons from HER2CLIMB


Drs Tripathy and Kaklamani emphasize the most critical unmet needs for patients with HER2+ metastatic breast cancer in the third-line or higher settings and recap what the field previously learned from the HER2CLIMB trial of tucatinib/trastuzumab/capecitabine.


Sara Hurvitz, MD: Now we are going to wade into muddier waters. The third-line treatment and beyond in HER2-positive metastatic breast cancer is rapidly evolving. [There are] a lot of investigational agents in this area here. Debu, can you take us through the most critical unmet needs for patients who are in the third line and beyond? If you’re like me, I’ve got a ton of these patients in the clinic who are [on] seventh-, eighth-, and ninth-line [therapy]. So take us through what are the unmet needs.

Debu Tripathy, MD: The unmet needs for these patients include the ongoing risk of CNS [central nervous system] metastases, which we just discussed, so I won’t elaborate more on that. But the other thing is we start to see patients getting cumulative toxicities from the chemotherapy component, particularly neurotoxicity, and that limits the types of agents that we can use. Fortunately, cardiac toxicity is not one of the main ones because that seems to be an early event, and there’s probably a susceptible population such that in later lines we don’t see that many new cardiac events.

And with the tyrosine kinase inhibitors, I think toxicities of those drugs are a key issue. We forget that they’re a part of the landscape of treatment. Drugs like neratinib are approved. They do seem to be slightly better, for example, than lapatinib/capecitabine, but I think the side effect issues are a problem. And then the best way to assess a disease and have predictive factors that will point us in the right direction as to which of the options would be best. Should we be thinking about topoisomerase? Should we be thinking about other targets that are represented in our ADCs [antibody-drug conjugates]? Where does T-DM1 [trastuzumab emtansine] now fit? So a lot of issues of sequencing are problematic also.

Sara Hurvitz, MD: Absolutely. Understanding mechanisms of resistance for our patients and using that to inform sequencing is going to be really important as we go forward as well, playing into all of these things that you’ve brought up. Debu started to talk about the HER2CLIMB trial, but maybe take us through in a little more granularity, the findings from HER2CLIMB.

Virginia G. Kaklamani, MD, DSc: This was a trial that randomized patients with metastatic HER2-positive breast cancer to either trastuzumab and capecitabine, placebo, or the triple combination of tucatinib, trastuzumab, and capecitabine. The novelty of the trial was the active brain metastasis patients that were included, and 50% of the patients on the trial had some sort of brain metastasis, and many of them had active brain metastases. So that was a lot of good data that we finally were able to accumulate.

[There was] improvement in progression-free survival with tucatinib, I think most importantly, improvement in overall survival, 21.9 months vs 17.4 months with the placebo arm. Also, improvement in overall survival in patients with active brain metastases. To me the clinically useful end point was that there was a delay in between the first and second CNS progression with tucatinib. The number was 7.6 months vs 3.1 months with the placebo arm, which again, I think is very clinically useful. And so, as was mentioned before, when we have a patient that may have progression only in the brain, continuing a drug such as tucatinib may actually help delay the second CNS recurrence, which I think is critical for these patients.

Sara Hurvitz, MD: Absolutely. It’s a very important point that you’re making. And the tolerability, can you talk to me a little bit about that, what your experience has been with this regimen?

Virginia G. Kaklamani, MD. DSc: So it’s 2 diarrhea-causing drugs. You have capecitabine and tucatinib. Tucatinib, thankfully, is a lot more targeted as a tyrosine kinase inhibitor compared to others such as neratinib and lapatinib. It doesn’t target as much EGFR so the diarrhea rate is much lower [and] very manageable. We don’t really have to prophylax our patients like we do with neratinib, so it’s been manageable, and that’s the benefit of using this in second- or third-line setting, the metastatic disease.

Sara Hurvitz, MD: This was really important data. I think it was very practice changing and became sort of the standard of care after TDM-1.

Transcript edited for clarity.

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