™ presentation entitled “Expanding Options for Relapsed/Refractory 

[human epidermal growth factor receptor 2]–positive breast cancer has improved and patients live longer, some will experience metastatic recurrence after treatment with frontline 

-directed therapies. Today we are going to talk about the expanding role of recently FDA-approved novel options for these patients.

I am Dr Mark Pegram, the Susy Yuan-Huey Hung Professor of Medical Oncology, an associate director for clinical research, and an associate dean for clinical research quality at the Stanford School of Medicine in Stanford, California. Joining me today is Dr Julie Gralow, the Jill Bennett Endowed Professor of Breast Medical Oncology at the University of Washington School of Medicine in Seattle, Washington, and the clinical director of breast medical oncology at the Seattle Cancer Care Alliance. Julie, welcome.

 Thanks, Mark. Looking forward to a great discussion.

Thank you so much for joining us. Let’s begin, shall we? I’d like to begin, Julie, with a talk about the likelihood that a patient—let’s say, who’s finished all her 

-targeted neoadjuvant or adjuvant therapy or even extended adjuvant therapy—in this day and age, will develop a metastatic recurrence.

Well, Mark, I think you and I both started our careers before we had 

-targeted therapy, so we’ve seen a major change, a major improvement in the survival of early stage 

-positive breast cancer over the years. When we added trastuzumab to chemotherapy, we saw a dramatic reduction in recurrences and deaths. In looking at the 10-year follow-up for overall survival from the combined NSABP B31 trial with the NCCTG-N9831 trial, at 10 years about 10% of patients in the trastuzumab arm had died of breast cancer. That was a node-positive group, as you’ll recall, and everybody in that group got chemotherapy with trastuzumab.

That’s not our standard of care anymore, and it was great that 90% were still alive at 10 years compared with what it would have been without trastuzumab. But now we’ve got data on the benefit of adding pertuzumab, at least in a node-positive population. The benefit of using response to preoperative chemotherapy to decide what to give postoperatively, such as T-DM1 [trastuzumab emtansine] with residual disease, we’ve got the data from the ExteNET trial with the neratinib following the completion of trastuzumab.

Of course, in our small node-negative patients, we’ve got great data from what we call the APT trial, the adjuvant paclitaxel trastuzumab trial, where we saw recently reported 7-year follow-up for node-negative, up to 3 cm, 

-positive breast cancer. Where for just giving paclitaxel and trastuzumab alone, we saw a disease-free survival of 93% at 7 years but only 1% of the patients in that trial actually had a distant recurrence. Of the approximately 6% who had a recurrence or death, locoregional recurrence and contralateral recurrence accounted for about 3% of that 6%. Distant recurrence accounted for about 1% of the 6%, and deaths that weren’t related to breast cancer accounted for 2%. We also know that all 

-positive breast cancer isn’t the same. We get different responses with the ER [estrogen receptor]–positive and the ER-negative. We have different regimens and different outcomes in the node-positive and the node-negative groups as well.

Let’s talk for a minute about first-line regimens for 

-positive metastatic breast cancer. What would you consider in 2020 to be the gold standard in terms of first-line treatment for metastatic disease?

That’s shifting now that more patients are receiving pertuzumab, even T-DM1 [trastuzumab emtansine] and neratinib in the early line setting. We have to take into account what the patient did receive in the adjuvant setting and what the disease-free survival interval was from completing that therapy. We’ve used the CLEOPATRA trial regimen with taxane and trastuzumab and pertuzumab as our standard first-line regimen. That was a powerful study from combined 

 antibodies with the taxane. But now that more and more patients have received pertuzumab, even T-DM1 [trastuzumab emtansine] in the adjuvant setting, I’m not sure that data are quite as applicable. We have to look at what the patient has received. We have to look at how long they were disease-free. And the good news is we’ve got 7 FDA-approved agents for treating metastatic breast cancer right now.

What site of metastasis in particular is the most challenging for you, Julie?

Brain mets [metastases] of course are a devastating relapse, and we actually see those frequently because in part, we do a good job of controlling the disease below the neck with our antibodies, our big molecules. But in an intact blood-brain barrier, they don’t necessarily penetrate so well. We do see more brain mets as a site of first recurrence or a site of an eventual recurrence in our 

 population, in part because we’re doing such a good job of controlling the disease in the liver, lungs, and other sites, that the patients are living longer and have more time to develop the brain mets, sadly.

Treatment Options in HER2+ Metastatic Breast Cancer

Mark, let’s talk about the role of T-DM1, trastuzumab emtansine, in advanced 

 [human epidermal growth factor receptor 2]–positive breast cancer.

: It’s been quite awhile since the FDA approval of the EMILIA pivotal trial, the randomized phase 3 study comparing T-DM1 [trastuzumab emtansine] head-to-head against capecitabine and lapatinib in patients who had had prior taxane and trastuzumab. T-DM1 [trastuzumab emtansine] as a result of that published data has been considered the go-to second-line agent following a CLEOPATRA-like regimen now for the past several years. In the EMILIA trial, which was 991 patients, the objective response rate in the T-DM1 [trastuzumab emtansine] arm was about 43.6%, so that was higher than the control arm of about 31%. And the median duration of response was over a year in the T-DM1 [trastuzumab emtansine] arm versus about 6½ months in the control arm.

Moreover, in our final overall survival analysis that was published in 

 in 2017, the median overall survival was also longer with T-DM1 [trastuzumab emtansine] compared with control, 29.9 months versus 25.9 months. The hazard ratio was 0.75, and that’s despite the fact that 27% of the patients actually crossed over from the control CAPE [capecitabine]–lapatinib arm to T-DM1 [trastuzumab emtansine] during the course of their treatment.

The other data set, in terms of looking at expected response rates, is the TH3RESA trial. This is a phase 3 trial in more heavily pretreated 

-positive metastatic breast cancer patients who had had 2 or more prior lines of 

-targeted therapy as an eligibility criteria. In that study, there was a significant improvement in progression-free survival favoring T-DM1 [trastuzumab emtansine] as compared with a control arm that was treatment of physician’s choice, which was essentially chemotherapy du jour along with trastuzumab for most of the patients. The hazard ratio favoring T-DM1 [trastuzumab emtansine] was about half with high statistical confidence.

Overall survival was significantly longer with T-DM1 [trastuzumab emtansine] versus treatment of physician’s choice as well, over 22 months versus about 16 months for the control arm. That difference was statistically significant. The response rate in the case of T-DM1 [trastuzumab emtansine] in this more heavily pretreated population was 31.3% versus 8.6% for control. Both of these set the stage for the approval of T-DM1 [trastuzumab emtansine] and its place in the landscape of treating 

-positive in the second line following a CLEOPATRA-like regimen. That CLEOPATRA regimen has an extraordinary overall survival benefit that it remains entrenched as the first-line preferred option even in 2020, unless patients have recently been exposed to the dual-antibody combination, of course.

What about the toxicity of T-DM1 [trastuzumab emtansine] in comparison with some of the other regimens?

 Of course, with T-DM1 [trastuzumab emtansine], the most frequent adverse drug reactions are going to be fatigue, nausea, muscle pain, thrombocytopenia, transaminase elevation, headache, and constipation. All those have frequencies greater than 25% in the pivotal EMILIA clinical trial. One has to be mindful of those potential adverse events, and there are dose modifications available in the prescribing information, so clinicians should refer to those religiously to mitigate against these types of complications.

I want to add also that the response data that I mentioned from EMILIA and from the TH3RESA trial were in patients who had never had pertuzumab, for the most part, in those studies since these studies were done prior to the approval of pertuzumab in metastatic breast cancer. Consequently, there have been more recent updated data looking at a cohort of 77 patients published by our colleague from Italy, Dr Pierfranco Conte. That group was previously treated with pertuzumab, and the T-DM1 [trastuzumab emtansine] objective response rate in that cohort was 27%. Nearly 40% continued on treatment for at least 6 months with disease under control.

It’s nice that T-DM1 [trastuzumab emtansine] does not cause a lot of alopecia, as opposed to a couple of more recently approved antibody-drug conjugates in breast cancer that do. When we talk about options—and there are lots of options for patients who haven’t been head-on compared, so we don’t know the correct order—not losing your hair would be important for some of our patients. I have a patient who had a significant hepatotoxicity with T-DM1 [trastuzumab emtansine]. And I’ve used a lot of T-DM1 [trastuzumab emtansine]. This is rare, but it’s been reported. Have you had any experience with that?

I’ve seen 1 case, actually. When I was giving a lecture in Asia, they presented a case to me of a patient with a rather acute onset of signs and symptoms of portal hypertension, no transaminase elevation. This is 1 syndrome that clinicians must be mindful of because it’s so important and because it happens generally without transaminase elevation. This condition is called nodular regenerative hyperplasia. The diagnosis can be established only by biopsy of the liver, so it’s critical if you see a patient like that to get a liver biopsy, confirm the diagnosis, and then T-DM1 [trastuzumab emtansine] is contraindicated thereafter. It’s a very important point. These are really uncommon, even rare. It’s a rare syndrome, but if you see it you really need to act.

It’s serious, yeah. What excites you about some of the ongoing studies with T-DM1 [trastuzumab emtansine] in metastatic breast cancer?

The most interesting ongoing trial arguably is the combination with tucatinib, and this has already reached a phase 3 trial. It’s tucatinib versus placebo in combination with T-DM1 [trastuzumab emtansine] for patients with 

-positive advanced breast cancer; 460 patients will be enrolled. The study started in October 2019, and the estimated primary completion date will be in April 2024. There had been a prior phase 1b clinical trial of this combination, published by Virginia Borges, et al, and there was no PK [pharmacokinetic] interaction between these 2 drugs. The full dose with tucatinib was feasible, although higher doses was not. There was an expansion cohort of 50 patients, and 34 of those, that’s 68%, treated with the maximum tolerated dose had measurable disease and were evaluable for response, had objective responses, for a response rate of 47%. The median progression-free survival of that expansion cohort was about 8.2 months. That’s an interesting combination. If the pivotal trial is positive, and if it’s well tolerated, this could be a practice-changing result to look forward to in the future.

Trastuzumab Emtansine in HER2+ Breast Cancer

Next, let’s talk about what options there are for patients even after, let’s say, a dual-antibody combination and T-DM1 [trastuzumab emtansine]. What will be the traditional options prior to the recent FDA approvals? What kinds of outcomes would you have expected until recently?

Well, lapatinib with capecitabine received approval, although over time it’s been pushed back. Virtually all the recently approved drugs have proven to be better than lapatinib with capecitabine with or without trastuzumab. We also frequently reuse trastuzumab in combination with other chemotherapy agents and have shown if a patient has already had a taxane with 

 [human epidermal growth factor receptor 2] antibodies, that you can go third, fourth line with other chemotherapy agents that are proven to be safe and have synergy with trastuzumab. That was also commonly maybe a third-line approach after the combined TRASTUZ-PERTUZ [trastuzumab, pertuzumab] first line and then T-DM1 [trastuzumab emtansine]. Now we’ve got several new agents with efficacy and we don’t know which to use in what order. Are we going to move them up earlier?

There was an interesting abstract submitted to ASCO [American Society of Clinical Oncology] 2020 Annual Meeting, that came out of the Japanese group. It just looked, at after patients’ had progressed on T-DM1 [trastuzumab emtansine], what was being used in the real world. At that time, it was before the metastatic neratinib approval, tucatinib, or the trastuzumab deruxtecan approval. And it was a mishmash of everything: switching out the chemotherapy with trastuzumab, continuing pertuzumab sometimes beyond as well, adding lapatinib and capecitabine. But that’s already out of date. We’ve got a whole bunch of other active agents that are much more exciting than those choices. We’re starting to prescribe them and need more help in terms of knowing which tumors and which patients should get which of these drugs—that are very efficacious—in what order.

Options in Breast Cancer After HER2+ Targeted Therapy

Let’s move on to talk about some of these newer agents that have just recently been approved. I’ll lead off to talk a little about trastuzumab deruxtecan, also known as DS-8201a. This is a new antibody-drug conjugate, so it’s in the same family, the same drug class, as T-DM1 [trastuzumab emtansine], but it has some differences as compared with T-DM1 [trastuzumab emtansine]. It does have a trastuzumab biosimilar as its backbone, so the amino acid sequence is identical to trastuzumab and T-DM1 [trastuzumab emtansine]. It is humanized. It’s an IgG1 backbone antibody. The linker is different. Rather than the stable linker, this is a cleavable peptide-based linker. And the payload is unique. Rather than microtubule-interacting agent like derivative of maytansine 1, this payload is a TOP1 inhibitor, topoisomerase 1.

Moreover, the drug-to-antibody ratio is different from T-DM1 [trastuzumab emtansine]. In the case of T-DM [trastuzumab emtansine], it’s about 3 DM1 molecules per trastuzumab backbone. But in the case of trastuzumab deruxtecan, it’s about 8, so it has more of the TOP1 payload per antibody molecule as compared with T-DM1 [trastuzumab emtansine]. Finally the other interesting attribute about the TOP1 inhibitor payload of trastuzumab deruxtecan is that in contrast to T-DM1 [trastuzumab emtansine], where DM1 is insoluble and is incapable of killing any neighboring cells even after it’s released from dead or dying cells, it has no bystander effect. Whereas, the trastuzumab deruxtecan payload, TOP1 inhibitor, has a potent bystander effect and can kill adjacent tumor cells, even if they’re 

 [human epidermal growth factor receptor 2]–negative, at least in the laboratory for instance. It’s a really interesting molecule.

As you know, the results from the first nonrandomized phase 2 yet pivotal FDA registrational trial have recently been published this year by Shanu Modi and colleagues in the

. This is called the DESTINY-Breast01 trial, with 184 patients who had had a median of 6 previous treatments, received trastuzumab deruxtecan at the FDA-approved dosing schedule of 5.4 mg/kg every 3 weeks intravenously. In the intent-to-treat analysis, a response to therapy was reported in 112 of those patients. That’s about a 61% response rate from a single agent in heavily pretreated 

That was the most impressive waterfall plot I’ve ever seen in breast cancer anyway when that was presented on that phase 2 trial.

Absolutely right. This is the most active single-agent 

-targeted therapy developed. It’s the most incredible waterfall plot I’ve seen. I call it the waterfall plot that looks like Victoria Falls. The median response duration was about 15 months. I mean, that’s really also unparalleled in a heavily pretreated population like this. Remember, all these patients had prior T-DM1 [trastuzumab emtansine] and two-thirds had prior pertuzumab, 92% had visceral disease, 29% had bone metastasis, and 13% had brain metastasis. The sum of diameters of the target lesions was greater than or equal to 5 cm in half the patients. Yet we see these extraordinary results. I’d like to comment for a moment about those patients. There were 24 patients who had brain metastasis at baseline in this study. In that group, the overall response rate was similar to the intent-to-treat population; that is, 58.3% compared with about 61% for the population as a whole. Moreover, the duration of response was similar at about 17 months and the median PFS [progression-free survival] was also similar to the intent-to-treat in this case at 18.1 months.

We saw at ESMO [European Society for Medical Oncology] Breast [Cancer Congress] 2020 the data that you’re just describing with a CT [computed tomography] scan of 1 patient who had a dramatic response in the brain from trastuzumab deruxtecan. Do you think this antibody-drug conjugate is truly crossing the blood-brain barrier? These are disrupted blood-brain barriers in these patients. Or do you think this is because of the chemotherapy agent, what you’re calling the bystander effect, some of it getting back out into the blood and then getting into the brain? Or do you think it’s a combination of both?

We know, Julie, that the backbone antibody, trastuzumab, if you label that with a PET [positron emission tomography] label—like zirconium 89, for example—you can get very nice imaging of 

-positive brain metastasis in human subjects. And so we know that the antibody is able to get through these fenestrations of the disrupted endothelial barrier in the tumor microenvironment in a brain metastasis. Moreover, we have data from a phase 2 trial done in Italy in over 50 patients with 

-positive brain metastasis looking at T-DM1 [trastuzumab emtansine]. Ironically in that trial, the intracranial response rate, which was about 30%, was similar to the extracranial response rate, which was about 35% in that small phase 2 study. It’s evidence that these antibody-drug conjugates like T-DM1 [trastuzumab emtansine] can and do cross the blood-brain barrier and can even be associated with responses. I will bet that this agent, trastuzumab deruxtecan, will similarly be able to gain access to 

-positive brain metastasis and effect responses. But until we get larger numbers, we don’t have as much information as we’d like to have for this agent.

This drug is not without its toxicities. We know that we have a black box warning about interstitial lung disease and pneumonitis. We’ve had a lot of conversation about this. It’s rare. There are a handful of cases. We need to be really vigilant. What was very interesting was that because it was during the COVID-19 [coronavirus disease 2019] era that this drug was approved, there was some concern about if we would be able to distinguish if we were starting this drug in our patients between a COVID-related pneumonia and a toxicity from trastuzumab deruxtecan. I have yet to see a case of it at our site. It does get a black box warning, though. It seems to happen in less than 1% of patients, but we do need to be really alert because we’ve got to stop the drug quickly if it happens.

Regarding other common toxicities, we’ve talked about how, as opposed to T-DM1 [trastuzumab emtansine], it does cause some alopecia. We’ve got to warn our patients about that. The typical chemotherapy adverse effects, such as nausea, fatigue, neutropenia, all exist. Some diarrhea was also seen in these trials. I’ve talked with my patients about the adverse effects. Many of my patients who have been dealing with the 

 metastatic disease for years and years and years, they’ve had all the other drugs until these few recent approvals. We go over the adverse effects, and they say, “Well, they’re not any worse, for the most part, than anything else you’ve been giving me for the past 8 years.” If we put that in perspective with the balance of an extremely effective agent with tremendous response in very heavily pretreated patients, for the majority of our patients, the benefits will strongly outweigh the risks.

Trastuzumab Deruxtecan in HER2+ Breast Cancer

 Let’s move on to another combination that received recent FDA approval in the metastatic setting. Let’s talk a bit about neratinib and capecitabine in metastatic breast cancer. What is it? What’s neratinib? How does it differ from the other targeted therapies?

Neratinib is an orally bioavailable dual actually pan-

 [human epidermal growth factor] receptor kinase inhibitor, so it blocks 

 lacks a kinase active domain in the carboxy terminus of that protein, so it doesn’t hit the 3 per se. This agent has been tested in patients with 

 mutations in the kinase domain, has been shown to have activity in that setting, particularly when combined with antiestrogen such as fulvestrant. This combination of neratinib in combination with capecitabine was put to the test head-to-head against lapatinib plus capecitabine, which was approved by the FDA many years ago. This head-to-head trial was called the NALA trial.

It was presented first at ASCO [American Society of Clinical Oncology Annual Meeting] in 2019, and in that analysis the difference between the 2 arms in terms of the PFS [progression-free survival] was about 2.2 months. Oddly in that analysis, because the proportional hazard assumption did not hold, the separation between the curves didn’t occur until roughly after about 6 months. The statistical analysis plan for that trial prespecified that a restricted mean survival analysis at 24 months would be performed. In this prespecified analysis, the mean PFS for patients on the neratinib-plus-capecitabine arm was 8.8 months, and the mean PFS for patients treated with lapatinib-capecitabine was 6.6 months and that met statistical confidence.

Now the FDA has granted approval for neratinib in combination with capecitabine for 

-positive metastatic breast cancer patients who have received 2 or more prior anti–

-based regimens in the metastatic setting. It’s of note that when you use this combination, the drugs are to be taken orally once a day with food. The capecitabine is given on a 14-day on, 7-day off cycle—a 21-day cycle—while the neratinib is given continuously. Since neratinib blocks 

, it is associated with EGFR kinase inhibition adverse effects, particularly diarrhea. But it also can cause stomach upset, such as nausea, vomiting, anorexia, constipation, fatigue, weight loss, dizziness, back pain, arthralgia, and other troublesome adverse effects.

It’s of note that concomitant use with proton pump inhibitors is discouraged with this regimen. Patients requiring gastric acid–reducing agents are to use H2 receptor antagonists, but even then separated by at least 3 hours or so from the neratinib administration. Also remember neratinib is a 

-metabolized drug, so you’re to avoid strong CYP3A4 inhibitors. Because of the potential for this drug combination to cause diarrhea, it’s required to use a high-dosage loperamide prophylaxis starting at 12 mg per day for the first couple of weeks, then 4 mg twice a day from day 15 all the way to 56 and as needed thereafter. This can be a quite toxic regimen. There was no OS [overall survival] benefit—21 versus 18.7 months—and no statistically significant difference in response rate, about 33% versus 27% for the control arm.

Interestingly, the TBCRC [Translational Breast Cancer Research Consortium] has presented data on this regimen prior to the pivotal NALA trial, and it noted some CNS [central nervous system] responses. In about 49% of those patients without prior lapatinib exposure, they saw objective responses, and about a third even with prior lapatinib exposure had response to this regimen with median survivals in the range of 13 to 15 months, respectively. This regimen is available technically in as much as it’s approved by the FDA. In my opinion, given the challenging toxicities with lapatinib, I would argue that it has been trumped by the tucatinib HER2CLIMB trial regimen, which is tucatinib in combination with capecitabine and trastuzumab. I don’t currently use neratinib in the late-stage setting for 

-positive metastatic disease, because I don’t think the therapeutic index is there anymore compared with some of these more recently approved approaches.

Based on the control trial, which was in the extended adjuvant setting, our group has actually taken to starting colestipol with the loperamide as we initiate the drug, which seems to really help control the diarrhea early on. You can quickly get it off after a few cycles as you’re tapering the loperamide. While we learned how to help our patients manage the most significant adverse effect, I would agree with you that while neratinib has a role, it has some activity in the brain. The FDA gave it orphan drug status for 

-positive brain metastases, based on that TBCRC-022 trial that you described. But I do think that based on the adverse-effect profile, tucatinib probably wins out here, although the 2 haven’t been head-to-head compared in terms of efficacy.

Julie, there was a cohort 5 in the control trial, which was gradual escalation of the neratinib dose, first starting at about 120 mg/day. Have you ever used that either in the metastatic setting or in the extended adjuvant setting?

I’ve used it a couple of times in the metastatic setting when I’ve had frail patients who have had a lot of treatment, and I just wanted to slowly ease them into this. Have you had much experience with it?

 Yeah, I have tried it a few times since that cohort 5 was presented at a poster session. I forget which meeting, but it was about a year or so ago. It does seem to help. Most of the diarrhea from neratinib happens in the first 2 to 3 months, and consequently if you can just gradually escalate the dose during that interval, you can generally get by with it, albeit still with PRN [as-needed] loperamide and/or colestipol as you point out.

Neratinib + Capecitabine in HER2+ Breast Cancer

 Julie, what is the HER2CLIMB regimen, and what have we learned about it so far in terms of its role in the treatment of 

 [human epidermal growth factor receptor 2]–positive metastatic breast cancer?

Tucatinib is the new agent just approved by the FDA in April 2020 that was used in the HER2CLIMB study. It’s yet another oral small molecule tyrosine kinase inhibitor. But this one is really highly selective for the kinase domain of HER2, and it has a very minimal inhibition of EGFR, HER1.

The adverse effects are going to be different, and the diarrhea in particular is markedly less. The HER2CLIMB trial was a study in patients with 

-positive metastatic breast cancer who had prior trastuzumab, pertuzumab, and T-DM1 [trastuzumab emtansine]. That was required. A very fascinating addition was that active brain mets [metastases] were allowed. This trial specifically stated, as a lot of trials do, that treated and in-control brain mets could be included. But they also allowed the addition of patients with either treated brain mets that were progressing or untreated brain mets with any local treatment. That was about half—47% of the patients enrolled in the trial had a presence or a history of brain mets.

They disallowed any prior capecitabine or any recent lapatinib. In 600-some patients everybody got capecitabine and trastuzumab, and then patients were randomized to tucatinib or a placebo. The results were published in the

just this year for the primary end point, which was progression-free survival. We saw a difference of 7.8 versus 5.6 months for the intent-to-treat population, both the population with brain mets and without.

At the time of its publication it already had a positive overall survival benefit with a median overall survival for the intent-to-treat group of 21.9 months with tucatinib and 17.4 months without tucatinib. Two-year overall survival at the time of publication was 45% if you had tucatinib added to trastuzumab and capecitabine and 27% without the tucatinib, for a pretty powerful result.

We’ve separately looked at the brain mets cohort, both with the original publication, and then just updated it at the ASCO [American Society of Clinical Oncology] 2020 Annual Meeting with respect to survival in the brain mets cohort. That looked very powerful and very promising, and this is great news for our patients with 

Taking that 47% who had a history of either treated or active brain mets, the median progression-free survival was 7.6 versus 5.4 months. One-year progression-free survival in this brain mets group was 25%. A quarter had not progressed if they had tucatinib added. In the group that didn’t get tucatinib, 100% had actually progressed; so 0% had 1-year progression-free survival without the tucatinib. It’s updated at ASCO 2020. We saw that in the brain mets cohort the median overall survival was 18.1 months versus 12 months, with and without tucatinib with a 

 value of .005. These patients are living longer as well with the brain mets. The ASCO presentation looked at CNS [central nervous system] progression-free survival, which was also superior in the tucatinib arm, 9.9 versus 4.2 months. So there are really powerful data overall for managing disease unrelated to the brain but also within the brain; very exciting.

The presentation as ASCO by Dr Nancy Lin was just extraordinary. I’ve never seen that kind of efficacy data before for 

-positive brain metastasis. Is there any situation in 

-positive brain metastasis where you wouldn’t consider this regimen or actually just use it?

I can’t think of 1, although a question I would like to have answered with future trials is, do we really need to give tucatinib in this setting in combination with capecitabine and trastuzumab? There were early data that showed benefit and synergy, etc, that led to this being the regimen that was tested. Especially if our patient has seen a lot of prior trastuzumab or prior capecitabine. You know, what do we do? Would single-agent tucatinib work here? Do we need to add another 

 agent, such as trastuzumab? Are there other chemotherapy agents we could use in synergy? This is where future trials are going to help. You’ve already mentioned the T-DM1 [trastuzumab emtansine] trial with tucatinib that’s ongoing; that’s very interesting as well. But tucatinib, especially in the patients with brain metastases, is powerful, and here to stay, and it’s going to be a first-line choice, I think.

Understanding HER2CLIMB Clinical Trial

Mark, let’s talk about the adverse effects of the HER2CLIMB regimen with tucatinib, capecitabine, and trastuzumab. What did we see in these studies, and what should we be looking out for?

In the pivotal trial of HER2CLIMB, which won FDA approval, the most common adverse reactions occurring in at least 20% of the population or more were diarrhea, palmar-plantar erythrodysesthesia, from the capecitabine component obviously. Nausea, fatigue. There’s some hepatotoxicity. Stomatitis, anorexia, headache, anemia, and cutaneous rash were the most frequently reported.

Fortunately you know most of the time these can be mitigated by either dose modification or pill medication or both. You can also consider in some patients who may be, let’s say, more heavily pretreated in the metastatic setting or who aren’t able to tolerate capecitabine as well. In practice I’ve already considered the 1 week on, 1 week off schedule of capecitabine. That’s also another possibility to think about in case you’re getting any untoward toxicities with the FDA-prescribed

Using the combination of adjustment and schedule, adjustment and dose, or dose of either component drug and/or comedication will usually get you through this regimen safely and with a good tolerability. Therapeutic index with this regimen I judge to be quite high for a regimen in this setting in such heavily pretreated patients.

What we saw in HER2CLIMB with the diarrhea was, a lot of it, undoubtedly also related to capecitabine because it occurred in the other arm as well. Knowing the pure toxicity of tucatinib is not evident from this trial. But I agree with you: It appears to be well tolerated. The diarrhea seems less than with both lapatinib and neratinib. Who are you going to give this regimen to now that it’s FDA approved?

It’s an interesting question. The key question that keeps coming up in my practice are patients who have, let’s say, 1 or 2 new CNS [central nervous system] metastasis on whatever regimen they’re already on. In the old days, we would simply treat those with perhaps a cyber knife and then continue the systemic therapy if the extracranial disease had been under control. But given the extraordinary efficacy signals from the HER2CLIMB study, particularly in the 

 [human epidermal growth factor receptor 2]–positive brain metastasis subset, which was almost half the patients, and many of those patients had active brain metastasis or even untreated brain metastasis. I’ve been considering switching those patients to a tucatinib-based regimen just because we have evidence from a randomized phase 3 trial of a survival benefit.

Actually switching them before a progression.

 You could even do it before radiation and use it as a buffer to prolong the time needed prior to intervention with local control measures like neurosurgery radiation; that is also correct. For small occult metastasis in particular, treating them with the tucatinib-based regimen, our priority is a good strategy as long as you follow them closely, with serial MRI [magnetic resonance imaging], of course. That could also be an enhancement in quality of life metrics by postponing the need for radiation. Because even stereotactic approaches can be associated ultimately with cognitive decline, especially if you have to use it multiple times serially.

One thing I’ve done in a couple of cases, since you’ve got 2 oral drugs in this regimen—capecitabine and tucatinib—and then you have the intravenous trastuzumab, is I’ve offered patients subcutaneous trastuzumab just to keep their time in the infusion room as short as possible. We have a separate injection clinic where they can go. That also can add to the patient’s quality of life in terms of receiving this regimen; so minimize the time they need to spend in clinics.

 Absolutely. We made the same decision in our group at the beginning of the COVID-19 [coronavirus disease 2019] pandemic, that we would prefer subcutaneous routes of administration for 

 antibodies. We even started a trial of the fixed-dose combination of pertuzumab plus trastuzumab as a subcutaneous regimen, and that can be given at home by home-visiting nurses on that study protocol. That completely takes out of the loop their need to travel to a medical center, which would otherwise be considered a high-risk zone for a viral transmission.

Toxicity Management When Using HER2CLIMB Regimen

Next, let’s talk about new technologies for detection of the 

 [human epidermal growth factor receptor 2] gene alteration. I understand that at the ASCO [American Society of Clinical Oncology] 2020 Annual Meeting, there was some update at next-generation sequencing methodologies to detect 

. Can you comment on those abstracts, please?

There are a couple of abstracts looking at next-generation sequencing, trying to make the point that maybe we could more accurately assign 

 status based on next-generation sequencing. They found interesting cut points, but what we haven’t seen is would next-gen sequencing do any better at picking out a population who benefits from 

-targeted therapy? Maybe we can define levels of amplification and overexpression. But the real thing that matters is, are they going to respond to 

One of the most important things next-gen sequencing can do is to find an 

-activating mutation. As we know, that happens probably more commonly in the classic 

-negative population, yet we’ve seen responses and we’ve had trials with neratinib. In a classic 

-activating mutation, that tyrosine kinase inhibitor to HER2 can have efficacy.

From my perspective, right now where I would use next-gen sequencing is I’d be looking for an 

-activating mutation. I did have a recent case where it was present in a 

-positive early stage patient. She was enrolled in a clinical trial of trastuzumab and pertuzumab, a TBCRC [Translational Breast Cancer Research Consortium] trial, and had no response at all to TRASTUZ-PERTUZ [trastuzumab-pertuzumab]. It didn’t make any sense to me. Her tumor highly overexpressed 

. Then I added chemotherapy and had some response. At that point, at the time she went to surgery, we ran next-gen sequencing and found an 

 mutation, which I think explains why she hadn’t had a sense of response to the 

 antibodies. So this is something to look for.

A problem with next-gen sequencing is that we’re learning that 

 heterogeneity is important. In some recent trials that we’ve seen, populations where there’s a clear population of tumor cells that are 

 negative that’s 30% or greater don’t do so well with 

 2-plus and FISH [fluorescence in situ hybridization]–positive population might not be doing so well as the HER2 3-pluses when we look at the results of some recent trials.

So I think we have a lot of work to do. But as we define the way we are testing for 

, we have to remember that the bottom line is that we are doing it so we can assign treatment. There have been some exciting early data that maybe trastuzumab deruxtecan might work better in a 

-lower population. But we had the NSABP-B-47 trial that enrolled the 

, 1-plus and 2-plus FISH-negative population that showed that trastuzumab didn’t work there. Maybe we need to repeat that trial with trastuzumab deruxtecan as well.

Actually, we have a very interesting trial going on with our colleagues at the Uganda Cancer Institute looking at using a platform that’s commonly available in sub-Saharan Africa that they use in terms of TB [tuberculosis] and HIV analysis. The platform is there, and they’ve got cartridge that can do RT-PCR [reverse transcription–polymerase chain reaction] tumors for ER [estrogen receptor] and PR [progesterone receptor] 

, so you don’t need a complicated lab setup to do immunohistochemistry [IHC] or FISH. We’re comparing this African version, which is very practical, very doable with the gold standard that we do in Seattle right now, and we are finding a very tight correlation. For the rest of the world, which doesn’t have access to labs with not just next-gen sequencing but a lot of places they can’t do immunohistochemistry or fluorescence in situ hybridization, we might have some interesting new assays here as well.

That’s really interesting that you bring up the issue of this real-time PCR [polymerase chain reaction] cartridge that’s actually from some colleagues that are near us here in Northern California, in Sunnyvale, from Cepheid. And in a paper by Natalie Wu and Mike Press, who was a coauthor on that paper—it’s really interesting if you look at their 

-low subgroups. That is, for the patients who are 0 or 1-plus by IHC, if you look at their transcript level, it’s not dissimilar to 

 2-plus, FISH negative. In the development of trastuzumab deruxtecan—currently the 

-low definition is IHC1 or 2-plus, FISH-negative—I wonder whether we should also include 

 0 IHC based on these transcript levels that are about the same as 1 or 2-plus IHC. That could be a missed opportunity, and we should look into that in future clinical trials, indeed.

Next-Generation Sequencing in HER2+ Breast Cancer

Let’s sum this up, Mark, by talking about these brand-new agents that are FDA approved in metastatic 

 [human epidermal growth factor receptor 2]–positive breast cancer, in combination with those that were previously proven. How is the availability of these new agents going to impact the care of our patients with 

-positive metastatic breast cancer? How are we going to use these?

 To summarize the data, in conclusion, you know for the DESTINY-01 trastuzumab-deruxtecan trial the median prior lines of therapy for that cohort was 6. Whereas in the HER2CLIMB trial it was about 3. So that’s important if you’re going to be comparing these agents in clinical decision making.

Moreover, the median PFS [progression-free survival] was about 16½ months in the DESTINY-Breast01 trial, compared with almost 8 months in the HER2CLIMB trial in the experimental arm. Again, it’s a testament to the robust activity and extraordinary responses, and durability of response with the DS-8201 trastuzumab-deruxtecan.

The overall response rates are about 61% for the antibody-drug conjugate and about 41% for the HER2CLIMB regimen. The big difference, in my opinion, are the extraordinary data for the patients with brain metastasis that was shown at the ASCO [American Society of Clinical Oncology] 2020 Annual Meeting, by Dr Nancy Lin. Just the fact that you can get an OS [overall survival] signal with the HER2CLIMB tucatinib-based regimen in 

-positive brain mets [metastases], that carries the data for me. If a patient has brain mets, I’m going to use the tucatinib-based regimen. However, if they do not have known brain metastasis, I will probably use the trastuzumab-deruxtecan antibody-drug conjugate because of its very high response rate and long median PFS.

That summarizes my position in patients who have progressed after prior trastuzumab-pertuzumab, and T-DM1 [trastuzumab emtansine]. What do you think, Julie? Am I right on this notion?

My thoughts are similar to yours and also our community in general. If they’re brain mets, we prefer tucatinib. But without brain mets, the DESTINY-Breast01 is really impressive. We’re tending to favor the trastuzumab-deruxtecan.

What we’re all struggling with right now is that these drugs are approved after a couple of prior lines of therapy, and we want to use them in an earlier line. Of course, we are eager to start testing them even in the adjuvant setting, especially tucatinib—can we prevent brain mets? I’d rather prevent brain mets than treat brain mets.

What are you thinking about where these drugs are likely to go in the future, knowing we don’t have clinical trials data yet?

I think it’s fairly straightforward to move up the tucatinib regimen into second line if somebody has already had, let’s say, adjuvant or neoadjuvant pertuzumab-trastuzumab and maybe even postadjuvant T-DM1 [trastuzumab emtansine]. You can move into earlier lines because the FDA label says following 1 prior 

-targeted regimen for metastatic disease. Whereas the label language for the antibody-drug conjugate actually says for 2 or more prior lines than trastuzumab-deruxtecan is approved.

I think we will be doing some peer-to-peer calls, because as you rightly point out, it’s not that uncommon in 2020 to see patients who have already had dual-antibody therapy, and T-DM1 [trastuzumab emtansine], in the early stage disease setting. Therefore, all these new and exciting approaches are going to have graduate into earlier lines for metastatic disease. Moreover, as you rightly point out, there is a rich opportunity to use these agents in an earlier-stage disease, indeed—particularly, as you mentioned, tucatinib. I’d love to see that in an extended adjuvant setting to perhaps replace neratinib because of its higher therapeutic index, for instance. That would be 1 opportunity.

The antibody-drug conjugate is so impressive in terms of response with response duration, probably activity in the brain indeed based on retrospective subset analysis. That may play a role in early stage disease as well, although we’ll have to be very mindful of the risk of interstitial lung disease, as you mentioned in your remarks.

Where might you consider neratinib in the metastatic setting?

 kinase mutations, I use it regularly for that indication. Outside that, I could envision maybe somebody who’s had all the agents that we’ve already discussed in this program and still has good performance status and is, let’s say, progressing in the brain and have had whole-brain radiation already. You’re really at a loss for anything other than either best supportive care or even hospice considerations versus continuing therapy. In that setting, maybe. But those patients often are so heavily pretreated and are sick by the time they get to that phase, they may not tolerate the neratinib-capecitabine regimen well. I do worry about that, and I would use it cautiously, if at all, in that situation.

Do you think you’ll ever prescribe lapatinib again?

I can’t really imagine, in a tucatinib progressor, that lapatinib is going to have any activity. The KDs [kinase domains] for tucatinib are superior, even against 

 compared with lapatinib. I imagine that the mechanisms of resistance would be cross-resistant with 2 

 TKIs [tyrosine kinase inhibitors] like that. Lapatinib is going to be the lost stepchild in this situation. I can’t really imagine using it with much enthusiasm following tucatinib.

All right. Our time is up for this program. Thank you, Julie, for your insightful discussion. And thank you to our audience for watching this 

™ presentation on precision medicine. We hope you found this discussion to be useful and informative. Julie, any final remarks?

Thank you. As always, Mark, you have brought up a lot of great points and made me think. This is helpful, and I know we both want to use this information to get the best comes for our patients.

Expanding Options for Relapsed/Refractory HER2+ Metastatic Breast Cancer