Novel Tucatinib-based Regimens Highlight Ongoing Research in HER2+ Breast Cancer

Ongoing studies are investigating tucatinib (Tukysa) in novel combinations, including with fam-trastuzumab deruxtecan-nxki (Enhertu) in the phase 2 HER2CLIMB-04 trial (NCT04539938), and with trastuzumab (Herceptin) and pertuzumab (Perjeta) in the phase 3 HER2CLIMB-05 trial (NCT05132582), building off the efficacy displayed by tucatinib in combination with trastuzumab and capecitabine (Xeloda) in the phase 2 HER2CLIMB trial (NCT02614794) in patients with HER2-positive breast cancer.

These novel regimens, along with other agents currently under development, highlight the ever-evolving treatment landscape in HER2-positive breast cancer, according to Jennifer M. Matro, MD.

“For HER2-positive breast cancer, the success story is the new drugs that have been approved. Right now, we are working on what is the optimal sequencing of the drugs that are available, and then [determining] where we can find a place for new drugs that are coming down the pike,” said Matro, who chaired an OncLive^® State of the Science Summit™ on breast cancer.

In an interview with OncLive, Matro discussed the real-world implications and uptake of the HER2CLIMB regimen, other trials investigating tucatinib-based regimens in HER2-positive metastatic breast cancer, how approaches differ between early-stage and metastatic hormone receptor (HR)–positive/HER2-negative breast cancer, and ongoing research at the University of California (UC) San Diego Health. Matro is a medical oncologist and an associate professor of medicine at the Moores Cancer Center of UC San Diego Health in California.

OncLive: How have real-world data for the use of tucatinib compared with what was observed in HER2CLIMB?

Matro: Essentially, the real-world data show that [this regimen] is being used commonly, particularly in patients who have central nervous system metastases. However, doctors are using different combinations of the medicines. It is not always tucatinib with capecitabine and trastuzumab. Sometimes they will drop the capecitabine or the trastuzumab. We cannot know this from the [real-world] data, but most likely, [agents are being dropped] to tailor the treatment for toxicities and adverse effects [AEs] for patients.

Could you provide some background on the HER2CLIMB study that led to the FDA approval of tucatinib plus trastuzumab and capecitabine in patients with HER2-postive breast cancer who have received at least 1 prior anti-HER2–based regimen in the metastatic setting?

The HER2CLIMB study looked at tucatinib plus capecitabine and trastuzumab vs capecitabine and trastuzumab alone. Most of the patients had at least 2 prior lines of treatment. They were required to have progressed on [trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1; Kadcyla)].

What was unique about that study was that not only was it done in heavily pretreated patients with HER2-positive positive breast cancer, but they enriched the population for patients with brain metastases, which was not something that was typically done up to that point. Usually, patients with brain metastases were excluded from clinical trials. However, HER2CLIMB allowed patients with previously treated brain metastases and active but asymptomatic brain metastases that did not require treatment.

They found that in both the patients who had brain metastases and those who did not that there was a significant benefit with the addition of tucatinib.

What treatment patterns were observed in HER2CLIMB? How do these data compare with real-world data on tucatinib-based treatment in clinical practice?

Patients stayed on the combination with tucatinib longer than they did in the control arm. There was more toxicity associated with tucatinib, although it is thought that this may have been from patients being on therapy longer, and most of the AEs could potentially be attributed to capecitabine, as well.

We are seeing a good uptake of the combination and comparable efficacy [in the real world vs] what was seen on the clinical trial. Patients are tolerating [the regimen] for meaningful periods of time.

Could you provide an overview of the ongoing, single-arm phase 2 HER2CLIMB-04 trial and the rationale for combining tucatinib with trastuzumab deruxtecan?

Trastuzumab deruxtecan has emerged as a game-changing anti-HER2 therapeutic. It is an antibody-drug conjugate and has been shown in the DESTINY-Breast trials to be effective for HER2-positive breast cancer in the second line [with superiority] to trastuzumab emtansine, which was previously the standard second-line [treatment]. [Trastuzumab deruxtecan] also has efficacy in HER2-low breast cancer.

In the HER2-positive space, we have seen trastuzumab deruxtecan replace trastuzumab emtansine as the standard second-line treatment after [the phase 3] CLEOPATRA trial [NCT00567190] regimen of a taxane, trastuzumab, and pertuzumab. The HER2CLIMB-04 study looked at tucatinib plus trastuzumab deruxtecan in a phase 2 setting,

Kay T. Yeung, MD, PhD, of Moores Cancer Center at UC San Diego Health, discussed HR-positive/HER2-negative breast cancer. Could you expand on the varying approaches between early-stage and metastatic disease?

For early-stage disease, we have data from the [phase 3] monarchE trial [NCT03155997] that showed that abemaciclib [Verzenio] in the adjuvant setting for 2 years in combination with hormone therapy provided a significant benefit for a selected high-risk patient population.

In metastatic [disease], we have 3 different CDK4/6 inhibitors that are approved. Ribociclib [Kisqali] and abemaciclib have both demonstrated overall survival [OS] benefits, whereas palbociclib [Ibrance] has not shown an OS benefit. That has led to more uptake of ribociclib and abemaciclib in combination with endocrine therapy in the treatment of [patients with] metastatic HR-positive breast cancer. Whether patients who have gotten abemaciclib in the adjuvant setting will still benefit from CDK4/6 inhibitors in the metastatic setting is unclear.

We now have data from a couple different studies—the phase 2 MAINTAIN [NCT02632045] and the PACE [NCT03147287] studies—[examining] the use of a CDK4/6 inhibitor beyond progression [on a prior CDK4/6 inhibitor]. In the case of ribociclib and the MAINTAIN study, [this approach] can provide benefit. In the PACE study, [most] patients continued palbociclib [from the first line], and the investigators did not see a significant benefit in combination with fulvestrant [Faslodex], although there was a signal of benefit with the addition of avelumab [Bavencio].

We do not have approval of CDK4/6 inhibitors beyond progression [on a prior CDK4/6 inhibitor] at this point. However, there is evidence now that switching from palbociclib to ribociclib can help or provide some additional benefit, as most of the patients in the MAINTAIN trial had received palbociclib [first]. As we transition to more use of ribociclib in the first line, whether we’re still going to see that benefit [with ribociclib after progression] is unclear.

Recently published were early results of the [phase 3] NATALEE trial [NCT03701334], which [evaluated] ribociclib [plus endocrine therapy] in the adjuvant setting. That [trial] looks like it met its primary end points in more of an average-risk population, [meaning] patients with stage II/III disease who did not need to have the high-risk features that were required [for enrollment] in the monarchE study. The full results still have to be presented, but it does look like we may soon have another option in the adjuvant setting.

Rebecca A. Shatsky, MD, of Moores Cancer Center UC San Diego Health, discussed oral selective estrogen receptor degraders (SERDs). With elacestrant (Orserdu) now approved for ER+/HER2–, ESR1-mutated advanced or metastatic breast cancer after at least 1 prior line of endocrine therapy, how could this agent and other oral SERDs affect the treatment landscape in ER-positive breast cancer?

This is a class of drugs that can provide benefit that will be easier to take and potentially easier to tolerate than something like fulvestrant, which requires patients to come in every month and get injections that can be painful. The underlying string that we have seen through these studies [of oral SERDs] is that it is not just all comers that are going to benefit after progression on initial hormone therapy. We are going to be using genomic sequencing to determine who is going to benefit the most. [In the evaluation of elacestrant] in the [phase 3] EMERALD study [NCT03778931], it was patients who had ESR1 mutations that seemed to benefit, and that is where the approval was geared toward.

We will see [how genomic sequencing will be needed] as some of these other agents and studies come out. We are also looking at combinations of oral SERDs with other drugs, such as targeted therapy or immunotherapy, for example.

Sara Grossi, MD, of Moores Cancer Center UC San Diego Health, discussed updates in local-regional treatment. What factors are important to consider when weighing breast conservation therapy with mastectomy?

The bottom line with breast conservation treatment vs mastectomy is that there is no survival advantage of having a mastectomy. More or bigger surgery does not mean less medicine or less medical treatments. What Dr Grossi’s presentation showed is that we are starting to be able to fine tune our radiation recommendations and our lymph node surgery recommendations so that we can minimize the morbidity of those procedures. We can better avoid axillary dissection when the benefit will not be there. We know when we can use radiation, either instead of axillary surgery or in addition to it, based on someone’s risk.

How are the various developments across different subsets of breast cancer affecting clinical practice?

We are seeing a lot of new developments in breast cancer, both in the early-stage and metastatic setting. In ER-positive breast cancer, we have new agents like elacestrant and new endocrine therapy agents. We are fine tuning our use of targeted therapies and extending our ability to give these treatments, improving outcomes in that way. We also know that new drugs that are still in the pipeline are not far out from potentially getting approval or having major data published.

Is there any ongoing research at Moores Cancer Center that you would like to highlight?

We have the HER2CLIMB-05 trial open for enrollment at UC San Diego Health, which is a randomized, double-blind study of tucatinib or placebo in combination with trastuzumab and pertuzumab as maintenance therapy for metastatic HER2-positive breast cancer.

This is going to be an interesting study. Right now, the standard first-line treatment for metastatic breast cancer is a taxane with trastuzumab and pertuzumab. Many of us, after 6 cycles, 6 months, or a certain period, will drop the chemotherapy because the toxicities start to build up, even though patients are continuing to respond, then continue them on the dual HER2 therapy as maintenance. Knowing whether tucatinib can prolong our ability to avoid chemotherapy or provide a chemotherapy holiday will be beneficial to patients.