Experts Take Stock of New CNS Data for HER2+ Metastatic Breast Cancer

March 18, 2021
Brittany Lovely
Brittany Lovely

Senior Editor, OncLive®
Brittany Lovely is a senior editor for the OncologyLive® print publication and editor of the Miami Breast Cancer Conference® and Chemotherapy Foundation Symposium® dailies. Email:

OncologyLive, Vol. 22/No. 5, Volume 22, Issue 05
Pages: 70

Findings from recent analyses have kindled hope that novel agents with manageable toxicity profiles may begin to bridge the gap for patients with HER2-positive metastatic breast cancer.

Although top-line data from clinical trials have fueled excitement across the therapeutic landscape for patients with HER2-positive metastatic breast cancer, disease progression and the development of central nervous system (CNS) metastases remain significant clinical challenges.1 Now, findings from recent analyses have kindled hope that novel agents with manageable toxicity profiles may begin to bridge the gap for this population.

Two tyrosine kinase inhibitors (TKIs), neratinib (Nerlynx) and tucatinib (Tukysa), have demonstrated efficacy against CNS metastases, according to findings presented at the 2020 San Antonio Breast Cancer Symposium (SABCS). Leading breast cancer investigators took a deep dive into these data during the OncLive® “HER2 Breast Cancer Talk” video program.

Neratinib, initially approved in 2017 as extended adjuvant therapy for early-stage, HER2-positive breast cancer, gained an expanded indication in February 2020 for use in combination with capecitabine (Xeloda) for patients with advanced or metastatic HER2positive disease who have received 2 or more prior anti-HER2–based regimens in the metastatic setting.2

The decision was based on data from the NALA trial (NCT01808573) in which the regimen showed a significant improvement in progression-free survival (PFS) versus lapatinib (Tykerb) plus capecitabine. The median PFS was 5.6 months (95% CI, 4.9-6.9) compared with 5.5 months (95% CI, 4.3-5.6), respectively (HR, 0.76; 95% CI, 0.63-0.93; P = .0059). Median overall survival (OS) was 21 months (95% CI, 17.7-23.8) and 18.7 months (95% CI, 15.5-21.2), respectively (HR, 0.88; 95% CI, 0.72-1.07; P = .2086).2

In April 2020, the FDA approved tucatinib in combination with trastuzumab (Herceptin) plus capecitabine for patients in the third-line setting based on results from the HER2CLIMB trial (NCT02614794). The median PFS in patients receiving tucatinib was 7.8 months (95% CI, 7.5-9.6) compared with 5.6 months (95% CI, 4.2-7.1) for patients receiving trastuzumab plus capecitabine alone (HR, 0.54; 95% CI, 0.42-0.71; P < .00001). The median OS in patients on the tucatinib arm was 21.9 months (95% CI, 18.3-31.0) compared with 17.4 months (95% CI, 13.6-19.9) for patients on the control arm (HR, 0.66; 95% CI, 0.50-0.87; P = .00480).3

Prospective trial analyses presented at 2020 SABCS showed that treatment with these TKIs has led to improved PFS, OS, and quality-of-life data for patients with HER2positive breast cancer with and without CNS metastases (TABLES 14 and 25).

“I think the follow-up that we’re getting from these studies, even though they don’t have the [same] limelight as the original findings, really are very helpful,” Debu Tripathy, MD, said during a discussion of the data. “It’s important to see how the data mature over time both in terms of safety and efficacy.”

Tripathy joined moderator Ruth M. O’Regan, MD, and fellow panelists Joyce A. O’Shaughnessy, MD, and Hope S. Rugo, MD, FASCO, to discuss the data as part of The Talk program.

Rugo: The analyses from the phase 3 NALA trial are important in that they led to regulatory approval of neratinib and capecitabine. [We saw] improved PFS compared with lapatinib and capecitabine in patients who had received at least 2 lines of prior therapy for metastatic HER2positive breast cancer.

Investigators allowed patients on the trial who had stable brain metastases, unlike HER2CLIMB, which enrolled patients who had untreated brain metastases [that] recurred after treatment. In this situation, patients had to have stable disease. What investigators saw, and had already presented and published, was that there were fewer CNS interventions required. [Data for the] 32 patients who had measurable CNS disease showed that the intracranial response went from 15.4% with [lapatinib plus capecitabine] to 26.3% with [neratinib plus capecitabine]. That’s a pretty impressive difference.

Investigators also were able to look at about 50 patients in each arm who had CNS metastases and saw an improvement in PFS. [Also,] in the overall intention-to-treat population, the OS was similar. They could not analyze that specifically in patients with CNS metastases, but if they looked at CNS-specific progression-free survival, in those 101 patients, the OS was 8.3 months for the patients receiving lapatinib and capecitabine versus 12.4 months in patients who were receiving neratinib and capecitabine, so that’s a pretty big difference of 4 months.

[These data are] very concordant with data from the NEFERTT [NCT00915018] trial as well as a small consortium trial called TBCRC 022 [NCT01494662] and, of course, the data from ExteNET [NCT00878709]. Another interesting part of that presentation is that 3 patients had leptomeningeal disease. I always wonder how they got onto the trial, but they had leptomeningeal disease and 2 of them who were enrolled on the neratinib arm had a long time to progressive disease. It was really interesting. [The results showed] 9.8 months to progression and the OS was 19.8 months; that was for 1 patient. The other patient had 5.6 months to progression and a 17.4 month OS.4 That’s really very impressive and we just don’t have a lot of data on leptomeningeal disease.

Subgroup data for patients on TBCRC 022, also appeared to have some efficacy, but that wasn’t a randomized trial. It’s fascinating to see this long duration of disease control and OS when neratinib was included. To me, I thought that the data in the CNS [subgroup] were impressive. [Although this was] not unexpected, the leptomeningeal disease, I think, was really important and contributory.

Another poster presentation looked at health-related quality of life [HRQOL] in the NALA trial, and that’s important when we start looking at a drug that we know causes diarrhea. How do people manage and how does their HRQOL pan out? Investigators looked at the QLQ-C30 [Quality of Life Questionnaire–C30], which is an EORTC [European Organisation for Research andTreatment of Cancer] measure, and also HRQOL. In the global evaluation, patients treated with neratinib had a sustained HRQOL and they maintained their QLQ-C30 scores, [which] also were not worse. The only place where patients felt worse was with diarrhea; there was obviously a little bit more diarrhea, as you would expect, so you see a slightly higher score [FIGURE 16].

Overall, that didn’t translate into anything different in terms of the global scores. I thought it was quite impressive that in the trial, patients had more diarrhea, they didn’t have worse constipation, and that neratinib resulted in sustained HRQOL on this scale as well, which is about overall functioning.

O'Regan: Where do you see using the NALA regimen in your sequencing for metastatic HER2-positive disease?

Tripathy: I think that I’d probably use this regimen in later lines, after potentially using tucatinib. Maybe I’d use it before trastuzumab deruxtecan [Enhertu] in someone who has low disease burden in whom I was concerned about toxicities. I definitely think that there is a time and place to use it. Someone with CNS disease, perhaps, might warrant getting it, or someone who maybe had cardiac issues in whom you want to use antibody-free therapy. I think that’s a situation in which this combination would [be effective], particu-larly in that group of patients.

Some of these patients are getting so many different treatments [in their sojourn] that we need a lot of options. Margetuximab [Margenza] is now going to be available. Although it’s a crowded space, we need these drugs because these patients are living longer and longer, and many patients are getting the later lines of therapy.

O'Shaughnessy: I totally agree with Dr Tripathy. I think the patients with brain metastases will be quite compelling. I’ll use the tucatinib first, but I’ll use the doublet as well in the patients that Dr Tripathy described. Patients need continued options and I think what we see from the NALA data is that these were very heavily pretreated patients, and they will get improvement in their PFS over what used to be our standard late-line treatment, lapati-nib and capecitabine. I will use neratinib/capecitabine instead.

O'Regan: Updates from the HER2CLIMB study [also looked at] the HRQOL effect on patients with brain metastases.

Rugo: The abstract that Erika P. Hamilton, MD, presented looked at the differential impact of tucatinib based on hormone-receptor status.5 [The data were] encouraging because we have wondered about how an oral TKI would work in hormone receptor–positive disease versus negative. However, the responses were almost identical [in the overall intention-to-treat population], and the study was not powered to look at P values. Investigators presented an objective response rate based on hormone-receptor status, and there appeared to be a greater differential, as you would expect, in overall response in patients who had hormone receptor–negative disease versus –positive. It was still pretty impressive, so it’s worth discussing the numbers: 15.6% [in those with hormone receptor–positive disease] versus 45.3% in hormone receptor–negative disease.

The difference in patients with hormone receptor–positive disease was still more than 10%—27.1% [with placebo], and 37.4% [with tucatinib]—but when you looked at the PFS and OS, the PFS differences looked to be fairly similar. The hazard ratios were almost identical regardless of whether you had hormone receptor–positive or –negative disease: 0.54 and 0.58 in negative and positive disease, respectively, for PFS.

Then if you looked at OS, it’s interesting because the patients with hormone receptorpositive disease had a narrower difference in OS—although again, [the trial was] not powered to look at that numerically. Their 2-year OS rate was almost 10% greater if they got tucatinib versus placebo, and numerically there was a slight increase in OS.

However, for the hormone receptor–negative group, who tend to have more resistant disease, there was a dramatic difference in 2-year OS rate—17.3% versus 51.3% [for placebo versus tucatinib, respectively]—and the median OS was 14.1 versus 31.1 months, respectively. These just continue to be just stellar and amazing data.

Investigators also looked at the PFS by hormone receptor status for patients with baseline brain metastases, and it didn’t make any difference. If a patient had brain metastases, they had a big improvement in PFS regardless of hormone receptor–negative or –positive status. That was encouraging. You see that same differential trend in OS, with less benefit in hormone receptorpositive versus hormone receptor–negative disease, probably because those patients have more treatment options overall. Even the control group does a little bit better than the hormone receptor–negative group.

I thought these data were really, really helpful in understanding the differences in hormone receptor–positive and –negative disease, and [in understanding] the lack of differences and looking at the natural history of these patients as well. It was nicely done and part of the spotlight on HER2-positive disease at San Antonio.

Another poster looked at HRQOL in patients being treated with tucatinib on HER2CLIMB who had brain metastases, which I think is a fascinating subset because it was such a big subset in this trial. They saw a markedly longer and clinically meaningful time to deterioration of HRQOL [FIGURE 27].

As you would expect, you live longer, you have less progression, you have better response in the brain, so your HRQOL follows along with that. It’s not that toxicity is making it worse. That was really nice to see, and patients treated with tucatinib maintained their HRQOL throughout the treatment—again, much longer than patients treated with trastuzumab and capecitabine.

I think that these are encouraging data [to see] when we add a novel agent to patients. Obviously, OS is our gold standard, but it’s nice to have people live longer and not feel miserable. In this situation, I think we saw great, great data.

Tripathy: The tucatinib story for CNS disease and its overall impact on survival is great to see. It’s [encouraging] to see that its impact is sustained, and to see it in both hormone receptor–positive and –negative disease.

O'Shaughnessy: That’s what I would highlight, too; with the tucatinib triplet, we finally have good agents [approved] or in progress for patients with brain metastasis. It’s quite outstanding. Additionally, the neratinib/capecitabine data [show that the regimen] also has salutary effects in the brain, so it’s a great advance for patients.

Rugo: So much excitement is going on in the whole field of HER2positive disease...You see all these subset analyses in the longer follow-up subset of HER2CLIMB, and the longer follow-up data from both trastuzumab deruxtecan and that of the NALA trial. Also, you look at the effect on CNS metastases, which has been such a big area of escape, even in patients who have early-stage, what appears to be curable disease. This is just, I think, a very exciting time in treating this disease.

I think a cool thing is that some of these agents are going to move into the treatment of patients who don’t have HER2-positive disease, which represents a much larger group of patients, so that’s also something we’re looking forward to.


  1. Pernas S, Tolaney SM. HER2-positive breast cancer: new therapeutic frontiers and overcoming resistance. Ther Adv Med Oncol. 2019;11:1758835919833519. doi:10.1177/1758835919833519
  2. FDA approves neratinib for metastatic HER2-positive breast cancer. FDA. Updated February 26, 2020. Accessed February 9, 2021.
  3. FDA approves tucatinib for patients with HER2-positive metastatic breast cancer. Updated April 20, 2020. Accessed February 9, 2021.
  4. Saura C, Ryvo L, Hurvitz S, et al. Impact of neratinib plus capecitabine on outcomes in HER2-positive metastatic breast cancer patients with central nervous system disease at baseline: findings from the phase 3 NALA trial. Poster presented at: 2020 San Antonio Breast Cancer Symposium. December 8-11, 2020; virtual. PD13-09.
  5. Hamilton E, Reinisch M, Loi S, et al. Tucatinib vs placebo in combination with trastuzumab and capecitabine for patients with locally advanced unresectable or HER2-positive metastatic breast cancer (HER2CLIMB): outcomes by hormone receptor status. Presented at: 2020 San Antonio Breast Cancer Symposium. December 8-11, 2020; virtual. Abstract PD3-08.
  6. Moy B, Oliveira M, Saura C, et al. Neratinib + capecitabine sustains health-related quality of life (HRQoL) while improving progression-free survival (PFS) in patients with HER2+ metastatic breast cancer and ≥2 prior HER2-directed regimens. Presented at: 2020 San Antonio Breast Cancer Symposium. December 8-11, 2020; virtual. Abstract PS9-02.
  7. Wardley A, Mueller V, Paplomata E, et al. Impact of tucatinib on health-related quality of life in patients with HER2+ metastatic breast cancer with brain metastases. Presented at: 2020 San Antonio Breast Cancer Symposium. December 8-11, 2020; virtual. Abstract PD13-04.