Debu Tripathy, MD: Our next topic of discussion is a landslide of change, I guess we could say. I don’t want to be too dramatic, but these are practice-changing findings that are now in our population of patients with advanced HER2-positive (+) breast cancers (BCs). It’s gotten a long natural history. Ian, maybe you can start off with the key large randomized phase III trial data and then some of the other data that we have that gives us a lot of hope for effective new agents.

Ian E. Krop, MD, PhD: There was one session at San Antonio Breast Cancer Symposium [SABCS] 2019 for which there were 3 data sets for a similar patient population. These are patients with HER2+ advanced disease who had already, for the most part, progressed on trastuzumab-pertuzumab and T-DM1 [trastuzumab emtansine], so we’re talking third-line and later-line patients for whom there are treatments but the efficacy of those third-line and later-line treatments is not great. There’s no standard of care, and it probably represents the biggest unmet need in metastatic HER2+ disease right now. So, we had several data sets that I do think are practice-changing.

One was the HER2CLIMB study, a study that randomized patients who had already had T-DM1, pertuzumab, and trastuzumab to either a standard of capecitabine-trastuzumab with either placebo or this new HER2 kinase inhibitor, tucatinib. The interesting thing about tucatinib is, unlike lapatinib and neratinib, it does not block EGFR [epidermal growth factor receptor], so you don’t get nearly as much diarrhea and rash as you do with the other TKIs [tyrosine kinase inhibitors]. Tucatinib gets into the brain very well. The unique feature of this trial was that for the first time it allows those patients who not only…have stable brain metastases but also patients who have progressive brain metastases.

The data that were presented were unequivocally positive. For the primary endpoint of PFS [progression-free survival] in the entire population, the hazard ratio was 0.54. They even unexpectedly hit their overall survival cutoff for an interim analysis and hazard ratio, which was around 36%.

Adam M. Brufsky, MD, PhD: It was close to 0.5 in some of these studies.

Ian E. Krop, MD, PhD: I believe the survival was 0.64, so 36% benefit in that…we don’t typically see survival benefits so early. In the patient population that had brain metastases, both treated and untreated, the hazard ratio was 0.48. This is clearly beneficial. There is added toxicity with tucatinib, but it’s pretty mild. There was some increased diarrhea, there was some increased PPE [palmar-plantar erythrodysesthesia], but overall it was well tolerated and there was unequivocal benefit. That is definitely going to become a treatment option for these third-line and later-line patients, particularly those patients in whom brain metastases are a predominant problem.

Another data set that was presented was focused on a new antibody drug conjugate called trastuzumab deruxtecan. It differs from T-DM1 in the sense that its payload is a topoisomerase I inhibitor, which is not a chemotherapy we typically use in breast cancer. But that may mean that cancers are less resistant to this. Interestingly, this drug has a bystander effect, meaning that the payload, once it goes into a cell, can diffuse out of the cell and hit neighboring cells. This may help with this heterogeneity issue that we talked about.

Adam M. Brufsky, MD, PhD: Remember, that’s different from T-DM1.

Ian E. Krop, MD, PhD: Correct.

Adam M. Brufsky, MD, PhD: That’s the big key that people need to know: that T-DM1 does not have that bystander effect.

Ian E. Krop, MD, PhD: Correct, correct. So in the patient population that was heavily pretreated.… This was a single-arm, phase II study with 184 patients. All the patients had had prior trastuzumab and T-DM1. Two-thirds had had prior pertuzumab. Stable brain metastases were allowed but not progressive brain metastases. This study showed its primary end point, and the objective response was 60.9%. The PFS as a median was 16.4 months—both of those numbers are roughly double or triple what’s been seen in historical controls. So, this is clearly an effective agent.

The toxicity is interesting. In terms of common toxicities, GI [gastrointestinal] and hematologic were what was seen, but they’re almost low-grade, so that’s not an issue for most patients. But what was seen, and this was also seen in the previous trial, was that interstitial lung disease [ILD] or pneumonitis was present in about 13% of patients. Most of those were low-grade and manageable, but 4 patients out of 184 died, so 2% of patients had fatal ILD. Clearly, we’re going to have to learn how to manage ILD or pneumonitis with use of this drug. But its efficacy in a very pretreated population, I think, is going to be very welcome for patients who have refractory cancers.

Lastly, we heard updated…data from my neighbor here on the podium from margetuximab, which is a very interesting—yet a third—cool mechanism of action. All 3 of these drugs had different mechanisms of action. This one is a modified trastuzumab that is designed to interact better with natural killer cells to improve ADCC [antibody-dependent cell-mediated cytotoxicity] and other immune effects. We saw previous PFS data showing an improvement in PFS which was one of the primary endpoints. It was a modest difference but statistically significant, and now we saw some updated overall survival data. It’s not yet statistically significant, but it is trending in the right direction. What’s particularly interesting about this data set was that there are people who have 2 different types of Fc receptors based on genetic polymorphisms. One is a high-affinity receptor, and the majority of people have low-affinity receptors.

Based on preclinical data, it’s thought that this drug, which binds better to these Fc receptors, would have most of its benefit in patients who had the low-affinity receptors, which is 86% of patients. That does seem to be what’s borne out in this trial…, that the majority of the benefit was in the patients who had these low-affinity receptors. Somewhat surprising, it may actually look like trastuzumab was better than margetuximab in the 15% of patients who had the high-affinity receptors. But that could be a…

Hope S. Rugo, MD: There were 69 patients there.

Ian E. Krop, MD, PhD: Right, 69 patients so that could be…

Hope S. Rugo, MD: They had 3 times the number of brain metastases, liver metastases, and lung metastases. It wasn’t balanced.

Hope S. Rugo, MD: It wasn’t balanced.

Ian E. Krop, MD, PhD: Right, but clearly in those patients who have the low-affinity receptors, this does look like a potentially advantageous drug, and the toxicity is virtually the same as trastuzumab, other than some increased risk of low-grade infusion reaction. I think these are 3 very interesting drugs that should change the landscape of the third-line and later-line cancers. I think we, as a community, are going to have to figure out how to sequence these drugs. We have to figure out how to manage the pneumonitis that’s associated with trastuzumab deruxtecan, but overall, it’s a clear win for patients.

Transcript Edited for Clarity