Nancy U. Lin, MD, discusses the updated data from the HER2CLIMB trial and underscored the need for future clinical trials that include patients with brain metastases to help fill the unmet need in the HER2-positive space.
The combination of tucatinib (Tukysa), trastuzumab (Herceptin), and capecitabine (Xeloda) showed significantly improved response rates and central nervous system (CNS) progression-free survival (PFS) in patients with HER2-positive metastatic breast cancer and brain metastases, as tested in the phase 2 HER2CLIMB trial, explained Nancy U. Lin, MD.
In April 2020, the FDA approved tucatinib for use in combination with trastuzumab and capecitabine in the treatment of patients with unresectable, locally advanced or metastatic HER2-positive breast cancer, including those with brain metastases, following at least 1 prior anti-HER2–based regimen in the metastatic setting. The decision was based on data from the HER2CLIMB trial, which showed that the tucatinib triplet reduced the risk of death by 34% versus trastuzumab and capecitabine alone in this patient population.
Updated findings on the subset of patients with brain metastases in the trial were presented at the 2020 ASCO Virtual Scientific Program. Results showed a 68% reduction in risk of CNS-PFS in the triplet arm (HR, 0.32; 95% CI, 0.22-0.48; P <.0001) at 1 year. The median CNS-PFS was 9.9 months versus 4.2 months in the triplet and doublet arms, respectively. In the overall brain metastases population, the triplet resulted in a 42% reduction in the risk of death (HR, 0.58; 95% CI, 0.40-0.85; P = .005). The median overall survival (OS) was 18.1 months in the triplet arm and 12 months in the doublet arm.
The confirmed intracranial objective response rate in patients who had measurable intracranial disease was 47% (95% CI, 33.7%-61.2%) in the triplet arm versus 20% (95% CI, 5.7%-43.7%) in the doublet arm (P = .03). Furthermore, the median duration of intracranial response was 6.8 months versus 3.0 months in the triplet and doublet arms, respectively.
“The importance of this study is that, for the first time, we are demonstrating an OS benefit that is both statistically significant and very clinically meaningful when it comes to our patients with brain metastases,” said Lin. “It shows us that it's possible to achieve these kinds of gains with improvements in systemic therapy. I hope it's just one in a long line of systemic therapies that we develop over the next few years to help patients who have brain metastases from HER2-positive disease.”
In an interview with OncLive, Lin, an associate professor of medicine at Harvard Medical School; associate chief of the Division of Breast Oncology at Susan F. Smith Center for Women’s Cancers; and director of the Metastatic Breast Cancer Program and senior physician at Dana-Farber Cancer Institute, discussed the updated data from the HER2CLIMB trial and underscored the need for future clinical trials that include patients with brain metastases to help fill the unmet need in the HER2-positive space.
OncLive: Could you discuss the pivotal HER2CLIMB study? What were the key findings were prior to the data reported at the 2020 ASCO Virtual Scientific Program?
Lin: HER2CLIMB was a randomized, double-blinded, placebo-controlled trial. It's a registration study that compared trastuzumab, capecitabine, and placebo versus trastuzumab, capecitabine, and the addition of the HER2 TKI, tucatinib. [We] enrolled patients with HER2-positive metastatic breast cancer who had received previous treatment with trastuzumab, pertuzumab (Perjeta), and ado-trastuzumab emtansine (T-DM1; Kadcyla). The study enrolled patients either with or without brain metastases. What was striking about the study enrollment is that it allowed patients with any status of brain metastases, including stable treated [metastases], which is traditional, as well as those patients with newly diagnosed, untreated brain metastases, and patients with progressive or active brain metastases on study entry.
What was seen in the overall study population and was published in the New England Journal of Medicine, was that HER2CLIMB met all of its primary efficacy analyses, including PFS as well as OS in the overall population, demonstrating statistically significant and clinically meaningful improvements with regard to both metrics.
How has the approval of tucatinib impacted the treatment paradigm?
Traditionally, we thought of trastuzumab, pertuzumab, and chemotherapy [as what should be used in] the first-line setting, and then [we would use] T-DM1 in the second-line setting. Many guideline committees, including the ASCO HER2 working group, have suggested that in the third-line setting, prior to the presentation of both HER2CLIMB as well as the DESTINY-Breast01 trial results, it was really kind of dealer's choice.
Patients and physicians could choose between a large variety of regimens, including lapatinib- (Tykerb) and neratinib (Nerlynx)-containing regimens, as well as regimens looking at trastuzumab with chemotherapy. What this study demonstrated is that for the third-line setting, it would certainly be reasonable to consider the HER2CLIMB regimen—that is, tucatinib, capecitabine, trastuzumab—given its superiority over trastuzumab chemotherapy. However, it doesn't really speak to how this would be placed relative to fam-trastuzumab deruxtecan-nxki (Enhertu; DS-8201) because [the drug was] not available simultaneously to patients outside of clinical trials when the studies enrolled.
What are these exploratory analyses evaluating? Could you elaborate on the patient population studied?
The HER2CLIMB trial, overall, enrolled approximately 600 patients; of these patients, 291 had brain metastases at study baseline. That's about half of the patients enrolled on the trial, which is, again, a very unique feature of HER2CLIMB. Of those patients, 60% actually had new or active brain metastases on study entry; that's very unique to this study. What we looked at in this analysis were the outcomes of patients with brain metastases enrolled on HER2CLIMB by randomized arm. We found that from the standpoint of intracranial response rate, it was higher with the triplet. Around half of the patients achieved a CNS partial response and [had a better prognosis] compared with patients who were receiving trastuzumab, capecitabine, and placebo.
More importantly, we found that there was a prolongation of an end point called CNS-PFS, which was defined as the time from randomization until CNS progression or death. We found this was significantly reduced by about two-thirds with the [addition of] tucatinib and this translated into about a 5-month absolute improvement in median time to CNS progression or death. Finally, we found that there was a significant improvement in OS with the use of the triplet in the brain metastases population; that corresponded to a hazard ratio of 0.58 and that translated into an approximately 6-month absolute improvement in median OS for this very difficult-to-treat patient population.
Patients with brain metastases continue to have an unmet need within this space. Could you speak to the significance of evaluating agents for this population?
In the case of HER2-positive metastatic breast cancer, at least half of patients will develop brain metastases over the course of their disease; this is not a rare occurrence. This is a very common occurrence in our patients who have HER2-positive advanced breast cancer. Until now, no drugs within FDA indication were available for the systemic treatment of patients with brain metastases. Although several single-arm, phase 2 trials [have examined] a number of other HER2 TKIs, such as lapatinib and neratinib, and they have shown CNS objective responses.
This is the first randomized trial to demonstrate an OS benefit for patients with brain metastases, which is very significant. It's also significant when we think about how we should consider patients with brain metastases for inclusion in clinical trials. This is an unmet medical need. The only way we can improve how patients with brain metastases do, is to allow them on clinical trials, even early-phase studies, to understand whether they would be appropriate to include in eventual registration trials. Again, this is really the only way that we can make any progress. This type of trial design, calls for including patients in the early-phase studies that were looking for a signal, and then, depending on those results, going ahead and potentially including those patients in larger phase 2 and then eventually phase 3 trials is something that is endorsed by ASCO and the Friends of Cancer Research, eligibility working groups, among other groups. In fact, the FDA has been very supportive of the inclusion of patients with brain metastases in a thoughtful way in trials.
What were the updated findings presented at this year’s virtual meeting?
In our abstract, we looked at the overall population of patients with brain metastases; however, in the ASCO presentation, we provided additional granular detail on how patients in the various brain metastases subgroups fared. For example, how did people with newly diagnosed brain metastases do on this trial? How did patients who had active or progressive brain metastases going into the trial do [on] the HER2CLIMB regimen?
The other interesting analysis that we will examine, that is sort of unique to HER2CLIMB, is on patients who developed isolated CNS progression when they were on randomized trial therapy. They were not immediately taken off protocol. They were allowed to stay on the study, receive stereotactic radiation or localized CNS-directed therapy, and then remain on the randomized blinded arm. We have data comparing the 2 arms as far as how long patients were able to continue on their treatment until the time of next progression.
Are there any unanswered questions with this combination that future research efforts should address?
Yes, one question is whether this regimen works in patients who have leptomeningeal disease because those patients were excluded from the HER2CLIMB study. In fact, a Translational Breast Cancer Research Consortium (TBCRC) study is asking this question now and is actively recruiting patients. Another question is whether there's value in moving tucatinib earlier up in the lines of therapy for patients with HER2-positive metastatic breast cancer. In fact, the HER2CLIMB-02 trial, which is randomizing patients to traditional second-line T-DM1 with or without tucatinib, will help to answer and clarify that question. The study, as with HER2CLIMB-01, includes patients with brain metastases as part of the eligibility criteria.
Then a final question that's really of interest and has yet to be answered is whether there is value in continuing HER2-based TKI therapy in conjunction with trastuzumab through multiple lines of therapy. For example, if a patient progresses on trastuzumab, capecitabine, and tucatinib, is there value when you normally would switch a patient to trastuzumab chemotherapy to continue that tucatinib along? That's a really interesting question that is, as of yet, unanswered.
Beyond this work, what are some of the other research efforts being made in this space that you’re excited about?
My colleague Rachel L. Friedman, MD, FACOG, of Concorde Medical Group, is leading a study that will combine T-DM1 with neratinib, the HER2 TKI, in patients with HER2-positive metastatic breast cancer. That study is interesting because it allows patients either with or without prior T-DM1 exposure, as preclinical data suggest that the addition of neratinib may actually reverse T-DM1 resistance. We're really excited about that study; it's going very well. We hope that we will complete accrual by the end of this year and potentially have results to present at next year's ASCO.
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