Practicing Oncologists Debate New Tactics for Brain Metastases in HER2+ Breast Cancer

New approaches for treating patients with HER2-positive metastatic breast cancer are showing signs of efficacy against brain metastases, generating excitement about the potential to make critical advances and sparking questions about optimal sequencing. A panel of up-and-coming oncologists provided their key clinical takeaways about data from several practice-changing trials during The Talk, a new OncLive^® video program that features thought-provoking exchanges about practical oncology issues in a virtual format.

Moderator Sarah Sammons, MD, was joined for the roundtable by Julia M. Collins, MD, MPH; Kelly McCann, MD, PhD; and Laura Spring, MD. The conversation revolved around the primary and subgroup analysis of 3 studies, each of which included patients with brain metastases:

• HER2CLIMB (NCT02614794) evaluated tucatinib (Tukysa) in combination with trastuzumab (Herceptin) and capecitabine (Xeloda) for patients with advanced unresectable or metastatic HER2-positive breast cancer who have received 1 or more prior anti–HER2-based regimens in the metastatic setting.^1,2
• DESTINY-Breast01 (NCT03248492) assessed fam-trastuzumab deruxtecan-nxki (Enhertu) in patients with unresectable or metastatic HER2positive breast cancer who have received 2 or more prior anti–HER2-based regimens in the metastatic setting.^3,4
• NALA (NCT01808573) assessed neratinib (Nerlynx) plus capecitabine in patients with metastatic HER2-positive breast cancer who received 2 or more prior anti–HER2-based regimens in the metastatic setting.^5,6

Sammons: A very hot topic this year is metastatic HER2-positive breast cancer. It’s been a really exciting year in this field, both for clinicians and certainly for our patients. We have 3 approvals for drugs in the advanced setting, and we finally put the importance on brain metastasis that they deserve.

So we’re first going to get started with the 3 FDA approvals: tucatinib, added to trastuzumab and capecitabine; trastuzumab deruxtecan; and neratinib plus capecitabine. Kelly, could you talk to us a little bit about the HER2CLIMB trial?

HER2CLIMB

McCann: Sure. I think tucatinib is one of the most exciting drugs to get FDA approval in the past year, mostly because the HER2CLIMB trial enrolled patients who had brain metastases that had not been treated. And those patients are typically excluded from clinical trials. So about half of their patients actually had brain metastases.

In our practice, approximately half of our patients with metastatic HER2-positive disease will eventually go on to develop brain metastases. So we really need more drugs that cross the blood-brain barrier.

HER2CLIMB was a large phase 2 trial that enrolled more than 600 patients with metastatic HER2-positive breast cancer to either tucatinib plus intravenous trastuzumab plus capecitabine, versus placebo plus trastuzumab plus capecitabine. Because so many patients had brain metastases, they were able to conduct a subgroup analysis.

In the overall population, the response rate was approximately 40% for patients who received tucatinib versus 23% in the control arm. Median progression-free survival [PFS] in these patients, half of whom had brain metastases, was 7.8 months with tucatinib versus 5.6 months with placebo. Overall survival [OS] was also improved: almost 22 months versus 17.4 months, respectively.

As we know with all of the tyrosine kinase inhibitors [TKIs], such as neratinib and lapatinib [Tykerb], they all have the adverse effect of diarrhea, which was also common with tucatinib. And, of course, the patients are at risk for palmar-plantar erythrodysesthesia syndrome, so they should also be monitored for hepatic toxicity.

For my practice, when I’m trying to decide what the next line should be after a first-line therapy—usually a taxane plus trastuzumab or plus pertuzumab [Perjeta]—I might actually consider doing a brain MRI at that point to guide my decision on where to go next. This regimen has been approved for the second-line setting, even though patients enrolled in the trial needed to have already had trastuzumab, pertuzumab, and ado-trastuzumab emtansine [T-DM1; Kadcyla]. So it was a little bit of a surprise that they approved it in the second-line setting, but I think it’s great to have it available.

Sammons: That’s a really good point you bring up. I haven’t thought about doing a brain MRI on patients after they progress on the first-line setting. I think the most bang for the buck in this trial has certainly been looking at the CNS [central nervous system] end point and how the patients with brain metastases did. But I think, most importantly, is that the investigators in this trial showed us what we need to do with brain end points from now on in phase 3 randomized trials for HER2-positive advanced metastatic breast cancer. We just can’t plan a phase 3 trial without being really thoughtful about intracranial end points, and I think this will be an example for us moving forward.

DESTINY-Breast01

Sammons: So the next compound that I think blew everyone away is trastuzumab deruxtecan. Laura, would you mind telling us about the DESTINY- Breast01 study?

Spring: Trastuzumab deruxtecan is an antibody-drug conjugate composed of an anti-HER2 antibody trastuzumab as a cleavable linker that then has a cytotoxic payload, which in this case is a topoisomerase 1 inhibitor.

The agent was granted accelerated approval by the FDA in December 2019 based on the DESTINY-Breast01 trial, which enrolled patients with unresectable or metastatic HER2-positive breast cancer who had received 2 or more prior anti–HER2based regimens in the metastatic setting. All patients had received ado-trastuzumab emtansine [T-DM1; Kadcyla] as well.

Unlike the previous trial we spoke about, this was a single-arm phase 2 trial. The results demonstrated an impressive objective response rate of 60.9%, and the median PFS was 16.4 months. Notably, this was a very heavily pretreated population—the median number of prior therapies was 6. I think these results were quite remarkable given that.

It’s also important to note that the prescribing information for this drug does include a boxed warning for interstitial lung disease [ILD], and fatal outcomes from ILD occurred in 2.6% of patients. I do think interstitial lung disease is now better understood, and I think clinicians are certainly keeping their eye out for this, so hopefully it will be recognized earlier.

Results of this study were presented at the same time as the HER2CLIMB study at the San Antonio Breast Cancer Symposium [in 2019]. So with approval of both of these treatments, there’s been a lot of discussion in the breast cancer community about which regimen to favor and when.

Sammons: I know my jaw hit the floor when I saw the waterfall plot for this drug. I mean we just haven’t seen anything like this in a patient with a medium of 6 lines of therapy. I know we’re young-career oncologists, but I don’t ever remember a waterfall plot like that in advanced breast cancer.

The other thing I thought was interesting is a patient on that trial had 27 lines of therapies. And I was thinking, ‘What are the possible 27 lines of therapy that a patient could have had?’ That’s amazing.

McCann: I think what’s really interesting about the payload is that it is a topoisomerase 1 inhibitor, and we don’t usually give those to our patients; we’re not giving irinotecan to patients with breast cancer.

The other thing I consider when I’m talking to patients is the tolerability of T-DM1. With this drug [trastuzumab deruxtecan], they could have thinning and experience more of the adverse effects of a drug like irinotecan probably because the payload diffuses outside of the cell.

Spring: Yes, it almost makes it look like it’s more chemotherapy, and you see more of those adverse effects.

Sammons: Counseling patients on toxic death is hard to do. I know that all patients come in asking me about this drug, and we’re giving a lot of it. We have a registration-like protocol where we conduct CTs and PFTs [pulmonary function tests] at baseline and then repeat that if a patient has any pulmonary symptoms.

I am excited to see data from the phase 3 trials as well and see how toxicity will play out because I think we need more information on who’s at risk for pneumonitis. But trastuzumab deruxtecan is an excellent option for our patients. We’ve seen chest wall disease just melt away after 2 doses. It’s a great option.

Collins: If you’re talking to patients about these 2 options, are you sequencing the HER2CLIMB regimen prior to trastuzumab deruxtecan?

Sammons: I think the way that I’m sequencing is pretty solely dependent on whether or not they have brain metastasis right now and certainly what agents they’ve had previously. And everybody wants to know how we’re all sequencing them. And I think—does it really matter?

I think the median OS at this point for advanced HER2-positive disease is somewhere in the 7-year range. So hopefully at some point through their metastatic journey they’ll have the opportunity to get both therapies. But I think the way I’m sequencing at this point kind of depends on whether or not they have brain metastasis.

Spring: I’ve had some very astute patients who—and we don’t have these data yet—have asked me about the prevention of brain metastases. That’s 1 reason why they’re very interested in drugs like neratinib and tucatinib, even if they don’t have a history of CNS yet. Investigators are looking at the combination of tucatinib and T-DM1 in an ongoing study in the second line [NCT03975647], and I hope they are looking at ‘time to brain metastases’ as an outcome. I think that’s really one of the holy grails in HER2-positive metastatic breast cancer—preventing brain metastases in the first place.

NALA

Sammons: Absolutely right. That brings us to the NALA trial, a phase 3 randomized multicenter international trial of neratinib plus capecitabine versus lapatinib plus capecitabine in patients with metastatic HER2-positive breast cancer who have had at least 1 prior line of therapy.

Investigators randomized 621 patients 1:1, and the primary end point was investigator- assessed PFS with a coprimary end point of OS. The addition of neratinib to capecitabine did very modestly meet the primary end point of PFS but not of OS. The 6-month PFS rates were 47.2% versus 37.8% favoring neratinib versus lapatinib, and for 12 months they were 29% versus 15% favoring neratinib. Modest, but a small benefit to neratinib over lapatinib with capecitabine.

They also looked at an interesting end point, which was time to intervention for symptomatic CNS disease. And neratinib was slightly better, with an overall incidence of 22.8% versus 29%. The other very important thing to note is that neratinib with capecitabine had much higher grade 3 diarrhea than lapatinib plus capecitabine did at 24% versus 12%.

Kelly, you’re still using a decent amount of neratinib and capecitabine?

McCann: I am. And the way that I get patients adjusted to the drug is usually a dose escalation of neratinib instead of the heavy use of Imodium [for diarrhea]. I might start off with 120 mg for a week, and then go up to 160 mg, and then go to the full dose of 240 mg. And for whatever reason, that dose escalation ameliorates the diarrhea.

The same thing with capecitabine. That drug is difficult to tolerate and if somebody gets hand-foot syndrome early on, they’re probably going to quit the drug, so I start that at a lower dose and dose escalate as tolerated too.

Intracranial Impact

Sammons: Let’s dive into the specifics on intracranial efficacy of all these agents because I think that’s really how a lot of us are determining how we’re going to cycle them in the care of our patients. We’ll start with the HER2CLIMB study.⁷ Kelly, can you take us into that data?

McCann: In HER2CLIMB half the patients had brain metastases, and they were subcategorized as untreated or treated and stable, or treated and progressing. This was certainly a patient population that was at high risk for death. For patients with brain metastases, the median PFS was essentially the same as the overall population. Even though the median PFS and OS do not look like these giant numbers that are very impressive, the patient population was so high risk for bad outcomes that I think this is pretty impressive.

Investigators also analyzed median CNS PFS. In the tucatinib arm, the median CNS PFS is almost 10 months versus approximately 4 months in the control arm. The patients with brain metastases also had a better OS with tucatinib, 18 months versus 12 months.

Sammons: I think a 6-month improvement in terms of intracranial PFS is really significant. That’s where there is a lot of morbidity with brain metastasis, and so to be able to prolong their intracranial progression I think is really important—so much so that because the approved indication for tucatinib is after 1 line of therapy, a lot of patients with brain metastases are skipping T-DM1 and going to this regimen. What are your thoughts on that?

Collins: That’s been a hot topic at most institutions lately. I have trouble skipping the T-DM1 right now in that the data for these patients are post-THP [docetaxel, trastuzumab, and pertuzumab] and then T-DM1. I have been reserving this for third line based on the study. But since it has been approved in the second line, I wouldn’t say it’s wrong by any means, but I think it leaves us with a data-free zone to figure out when to sequence in the T-DM1.

Spring: That’s been a hot topic at most institutions lately. I have trouble skipping the T-DM1 right now in that the data for these patients are post-THP [docetaxel, trastuzumab, and pertuzumab] and then T-DM1. I have been reserving this for third line based on the study. But since it has been approved in the second line, I wouldn’t say it’s wrong by any means, but I think it leaves us with a data-free zone to figure out when to sequence in the T-DM1.

Sammons: I think the only patients at my institution for whom we consider skipping T-DM1 and going right to the HER2CLIMB regimen are those patients who have progressive brain metastases. These are patients who have had SRS or they’ve had a whole brain radiotherapy, and they had a progressive lesion. We have the best data to support this regimen for progressive brain metastases, which is not typically included in a phase 3 randomized design.

McCann: HER2CLIMB was an exciting trial for me at San Antonio Breast because these drugs are so desperately needed. It’s easy to also go directly to trastuzumab deruxtecan and say this is an excellent, excellent drug, but they didn’t have many patients with CNS.

Sammons: I think we all know that tucatinib with capecitabine and trastuzumab has very good intracranial efficacy and control. So the way we’re sequencing these drugs is kind of dependent on the brain metastasis.

What do we know about intracranial efficacy and the population with brain metastases from DESTINY-Breast01?⁸

Spring: There was a subgroup analysis of the DESTINY-Breast01 trial that looked at patients with CNS metastases at baseline as well as CNS status upon disease progression in the overall population. At the 5.4 mg/kg dose, only 24 of the 184 patients had CNS metastases at baseline.

It was good to see efficacy in the CNS subgroup. The direct-to-response rate was 58.3%, and the median PFS was 18.1 months, which was consistent with the overall population. But compared to something like a small molecule inhibitor like tucatinib, we know this is a much larger drug, an antibody-drug conjugate. And so, similar to T-DM1, trastuzumab deruxtecan likely cannot easily penetrate the CNS, and I don’t think we have a great understanding of why. In some cases we do see activity. I think this is another area that needs a lot more study.

Sammons: The data showed that patients with stable brain metastases did just as well extracranially as the patients who didn’t have known metastases, but DESTINY-Breast01 did not require a baseline MRI or serial MRIs.

Spring: Only a subset of patients had that follow-up MRI, and investigators reported data at a median follow-up of 11.1 months for progression involving the brain, which occurred in 4 of 48 patients assessed for that, including 2 of 8 who had the baseline CNS metastases. It’s Only a subset of patients had that follow-up MRI, and investigators reported data at a median follow-up of 11.1 months for progression involving the brain, which occurred in 4 of 48 patients assessed for that, including 2 of 8 who had the baseline CNS metastases. It’s hard to draw a lot of conclusions from this subgroup analysis.

Sammons: I would love to have some perspective or registrational studies on what the true intracranial efficacy is. I think at this point I certainly wouldn’t plan to put a patient with progressive brain metastases or patients who have brain metastases without local therapy, unless it was very tiny, on this compound.

An important thing to look for in future trials and the trials that we have is the differences between intracranial PFS and extracranial PFS, and how we manage both of them simultaneously and effectively. That’s always a challenge in designing trials for brain metastases and certainly in the clinic in treating these patients.

References

1. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382(7):597-609. doi:10.1056/NEJMoa1914609
2. FDA approves tucatinib for patients with HER2-positive metastatic breast cancer. FDA. Updated April 20, 2020. Accessed October 5, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tucatinib-patients-her2-positive-metastatic-breast-cancer
3. Modi S, Saura C, Yamashita T, et al; DESTINY-Breast01 Investigators. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382(7):610-621. doi:10.1056/NEJMoa1914510
4. FDA approves fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive breast cancer. FDA. Updated December 20, 2019. Accessed October 5, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-her2-positive-breast-cancer 
5. FDA approves neratinib for metastatic HER2-positive breast cancer. FDA. Updated February 26, 2020. Accessed October 5, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neratinib-metastatic-her2-positive-breast-cancer
6. Saura C, Oliveira M, Feng YH, et al; NALA Investigators. Neratinib plus capecitabine versus lapatinib plus capecitabine in HER2-positive metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: phase III NALA trial. J Clin Oncol. 2020;38(27):3138-3149. doi:10.1200/JCO.20.00147
7. Lin NU, Murthy RK, Anders CK, et al. Tucatinib versus placebo added to trastuzumab and capecitabine for patients with previously treated HER2+ metastatic breast cancer with brain metastases (HER2CLIMB). J Clin Oncol. 2020;38(suppl 15):1005. doi:10.1200/JCO.2020.38.15_suppl.1005
8. Jerusalem G, Park YH, Yamashita T, et al. CNS metastases in HER2-positive metastatic breast cancer treated with trastuzumab deruxtecan: DESTINY-Breast01 subgroup analyses. Ann Oncol. 2020;31(suppl 2):S63-S64. doi:10.1016/j.annonc.2020.03.239