In an interview with Targeted Oncology following the SNO Brain Metastasis Meeting, Nancy Lin, MD, discussed the treatment of brain metastases in HER2-positive metastatic breast cancer in general, as well as the subgroup analysis of patients with brain metastases in the phase 2 HER2CLIMB clinical trial.
Tucatinib (Tukysa) added to trastuzumab (Herceptin) and capecitabine led to a 46% reduction in the risk of disease progression or death in heavily pretreated patients with unresectable, locally advanced, or metastatic HER2-positive breast cancer who were treated in the phase 2 HER2CLIMB clinical trial. The positive result ultimately led to the FDA approval of the triplet regimen as treatment of this patient population.
HER2CLIMB is an ongoing randomized, double-blind, controlled study assessing progression-free survival (PFS) as the primary end point and secondarily evaluating PFS in patients with brain metastasis, overall survival (OS), objective response rate, duration of response, and other outcomes.
In the trial, a subset of 291 patients had brain metastases, 174 of which were active and 117 that were stable. Notably, 66 patients enrolled in HER2CLIMB had never received treatment for brain metastases. According to Nancy Lin, MD, no other clinical trial has enrolled such a diverse group of patients with brain metastases, nor has any other trial treated these patients with systemic therapy in place of radiation.
Results from the 2020 American Society of Clinical Oncology (ASCO 2020) Virtual Scientific Program showed that in patients with brain metastases treated in HER2CLIMB, the risk of central nervous system (CNS) progression or death was reduced by 68% with a median CNS-PFS of 9.9 months (95% CI, 8.0-13.9) with the tucatinib triplet compared with only 4.2 months (95% CI, 3.6-5.7) in the control arm of placebo plus trastuzumab and capecitabine (HR, 0.32; 95% CI, 0.22-0.48; P <.00001). The overall CNS-PFS rate at 1 year was 40.2% with the HER2CLIMB regimen (95% CI, 29.5%-50.6%) compared with 0% in the doublet arm.
During a presentation at the 2020 Society for Neuro-Oncology (SNO) Conference on Brain Metastases, Lin presented the further from the subgroup analysis of patients with brain metastases treated with tucatinib plus trastuzumab and capecitabine in the HER2CLIMB study.
In an interview with Targeted Oncology following the meeting, Lin, associate chief, Division of Breast Oncology, Susan F. Smith Center for Women's Cancers; director, Metastatic Breast Cancer Program; senior physician, Dana-Farber Cancer Institute; and associate professor of medicine, Harvard Medical School, discussed the treatment of brain metastases in HER2-positive metastatic breast cancer in general, as well as the subgroup analysis of patients with brain metastases in HER2CLIMB.
TARGETED ONCOLOGY: What is most challenging about treating patients with HER2-positive metastatic breast cancer with brain metastasis?
Lin: HER2-positive metastatic breast cancer is a disease that has changed in terms of its natural history over the past decade with the advent of anti-HER2 therapies. Over time, what we've discovered is that approximately half of patients who have HER2-positive metastatic disease will eventually develop cancer in the brain. These patients can survive much longer than they had historically and what that means is that one course of radiation or one course of local treatment is often not enough, and patients have repetitive rounds of CNS progression. We struggle to determine what the best treatment options are.
TARGETED ONCOLOGY: Prior to tucatinib plus trastuzumab and capecitabine, how effective were the therapies available for treatment of this patient subgroup?
Lin: The standard treatment for most patients when they initially present with brain metastases is some form of radiation therapy, whether its stereotactic brain surgery or whole brain radiation treatment. Occasionally, there are patients for whom a surgical resection is appropriate.
In terms of systemic therapy, there are a number of regimens that have NCCN designations for the treatment of patients with brain metastases, and that includes lapatinib (Tykerb) in combination with capecitabine or neratinib (Nerlynx) in combination with capecitabine.
In the case of neratinib plus capecitabine, we showed in the TBCRC 022 trial that this leads to a small response rate in the brain of about 50%. This shows that there are data for response in the brain with systemic anti-HER2 therapies, but what has been missing is a clear demonstration in a randomized trial of whether systemic interventions can improve OS in patients with active brain metastases.
TARGETED ONCOLOGY: Can you discuss the importance of being able to cross the blood brain barrier?
Lin: There are many drugs that don’t cross the blood-brain barrier in preclinical animal models that look at an intact blood-brain barrier. That has been historically a barrier to including patients in clinical trials with the assumption that these drugs could not possibly work.
As it turns out, when patients have brain metastases, they tend to be leaky in term of the blood-brain barrier, and many drugs that we they might not get in actually dobrain metastases at a level sufficient enough to lead to CNS response.
What’s less clear is how much that CNS penetration is important in prevention of brain metastases. My hypothesis would be that the better the CNS penetration, the more that you might prevent the occurrence of brain metastases or delay the progression of brain metastases.
We can look at different examples of this in the adjuvant HER2 trial, which have largely looked at monoclonal antibodies such as trastuzumab deruxtecan (Enhertu) or T-DM1 (trastuzumab emtansine, Kadcyla), and we see no evidence of a CNS prevention effect of these medications.
TARGETED ONCOLOGY: Can you provide a recap of the HER2CLIMB data previously reported?
Lin: HER2CLIMB was a randomized trial that compared tucatinib in combination with trastuzumab and capecitabine versus trastuzumab and capecitabine alone. In the overall population of patients, which included patients with or without brain metastases, there was an improvement in OS among patients involved in trial.
TARGETED ONCOLOGY: What are the results you presented at the SNO Conference on Brain Metastases?
Lin: We reprise data that we have presented in part at ASCO 2020. I discussed a substudy that is looking at a subset of approximately 300 patients who had brain metastases and brain metastases at study baseline. The important distinction in these patients in addition to the high proportion within the trial overall is that 60% of the patients with brain metastases enrolled had active brain metastases. For the vast majority, if not in all registration trials in breast cancer, if they've included patients with brain metastases, they have only those with treated and stable brain metastases. This study is the first registration trial of breast cancer to include patients with active brain metastases.
Baseline and the top-line results of this exploratory analysis demonstrate that among the subset of patients with brain metastases enrolled in HER2CLIMB, there was a significant reduction by about two-thirds in time to CNS progression or death. There was also significant reduction in OS with a hazard ratio of 0.58, and this corresponded to a more than 6-month prolongation of median OS in this patient subset. This is the first study in a randomized fashion to demonstrate a survival benefit with systemic therapy in patients with brain metastases.
Finally, among the subset of patients with measurable, active brain metastases at baseline, the CNS objective response rate was 47%. That was versus 20% with trastuzumab and capecitabine alone.
All of these data put together suggest that the triplet of tucatinib plus trastuzumab and capecitabine not only leads to response and PFS advantages for patients with brain metastases, but also substantially improves OS.
TARGETED ONCOLOGY: What are the implications of these findings?
Lin: Given that the overall population of patients include those with and without brain metastases, I think that these findings overall firmly established the use of tucatinib in combination with trastuzumab and capecitabine for the treatment of HER2-positive metastatic breast cancer.
TARGETED ONCOLOGY: Are there any next steps with this subset analysis?
Lin: One of the questions that still remains is: What is the nature of CNS progression? Again, there was a prolongation in the time to CNS progression, but we are interested in understanding how many of the progression events were related to a worsening of existing CNS lesions versus the appearance of new lesions. That would indirectly get at this question of whether there is a CNS prevention effect. This is important as we think about moving tucatinib into early-stage adjuvant trails.
Another series of questions relates to the subset of patients who never had treatment for brain metastases. They went directly onto the trial and the study treatment was intended to treat brain metastases. This represents a different paradigm than our usual radiation-first paradigm. I think understanding the outcomes for those patients is important.
In terms of the overall drug development for tucatinib, there is an ongoing trial, HER2CLIMB 2, which is comparing the triplet versus T-DM1 in the second-line setting. This trial will also allow patients with or without brain metastases, and I think that trial will be very important to understand whether there's a role for tucatinib earlier in the line of treatment for metastatic breast cancer.
TARGETED ONCOLOGY: Now that this combination is FDA approved and you have efficacy results for the brain metastasis population, how would you advise community oncologists who are treating these patients in their clinics?
Lin: Thisis a very good option for patients and in the study, patients had to be in the third-line, and that’s where I would use it in the clinic. I would not use it as an eighth-or nineth-line regimen. I think you want to move up in therapy because of these potential benefits, including your survival benefit. And again, the benefit was not limited to patients with brain metastases, it was seen in the overall population.
As with all treatments, this combination can be a learning curve in terms of managing the toxicity profile. Fortunately, the toxicity profile here was quite manageable and much of the toxicity stemmed from known capecitabine toxicities, which I think oncologists are very well equipped to handle.
Trastuzumab is also something that most patients with have been exposed to already by the time they’re ready for the HER2CLIMB regimen. Then with tucatinib, there can be some diarrhea and rash, but these are less common than with some of the other tyrosine kinase inhibitors, which target EGFR more strongly. Finally, there can be some increases in liver function blood tests that oncologists should monitor very closely.
Overall, I think this regimen is manageable from a toxicity standpoint. Patients can have excellent quality of life while receiving this regimen; in fact, within the HER2CLIMB trial, there is a substudy. I think those results will provide further detail on how this regimen impacts patients who are treated with a triplet.
Having used this regimen myself, I can say the toxicities can be relatively straightforward to manage.
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