Optimal Sequencing and Treatment Intensity Remain the Focus of Treatment in HER2+ Breast Cancer

G. Thomas Budd, MD

The integration of novel therapies, such as tucatinib (Tukysa) and fam-trastuzumab deruxtecan-nxki (Enhertu) into the treatment paradigm of metastatic HER2-positive breast cancer has eased the rigidity of treatment sequencing strategies, said G. Thomas Budd, MD, who added that additional new agents and tailored approaches with escalated or de-escalated therapy are positioned to further advance the field.

“We are not done developing new agents for HER2-positive breast cancer, but we will be sorting out [sequencing decisions] as time moves on. Although figuring out the [optimal] sequence is a [challenge], it is a good [challenge] to have several agents with activity,” said Budd, a staff physician in the Taussig Cancer Center at Cleveland Clinic, in an interview with OncLive^® during an Institutional Perspectives in Cancer (IPC) webinar on breast cancer.

Beyond the evolving HER2-positive paradigm, the virtual IPC meeting covered whether standards of care are changing in hormone receptor (HR)–positive, HER2-negative breast cancer, advances with short-course radiotherapy in breast cancer, and recent updates with immunotherapy and targeted therapy in triple-negative breast cancer (TNBC).

In the interview, Budd, who served as a cochair of the event, discussed the promise of tailored treatment approaches in HER2-positive breast cancer, the utility of the combination of fixed-dose trastuzumab (Herceptin), pertuzumab (Perjeta), and hyaluronidase-zzxf (Phesgo) via subcutaneous administration, and how sequencing could be further affected by drug development.

OncLive^®: How could treatment escalation and de-escalation techniques tailor neoadjuvant and adjuvant treatment for patients with HER2-positive breast cancer?

Budd: [Treatment escalation] is a very important new concept in the treatment of patients with early-stage breast cancer. In the past, the advantage of neoadjuvant chemotherapy was primarily as a research tool and to down-stage treatment to make surgery better. However, we were losing prognostic information in not knowing the pretreatment pathologic stage.

Now, we are gaining information in terms of response to treatment. It’s been demonstrated that we can use that information to modify treatment post-surgery to result in better outcomes. Specifically, patients who are not achieving pathologic complete responses [pCR] can be switched to treatment with ado-trastuzumab emtansine [Kadcyla; T-DM1] to have an improved outcome compared with continuing trastuzumab and pertuzumab. This approach is being advanced and alternative post-neoadjuvant agents are being studied to be compared with T-DM1.

Regarding treatment de-escalation, the knowledge that we can, in effect, salvage some of these patients makes it a safer approach to try treatment de-escalation in the neoadjuvant setting.

Data were presented during the 2021 ASCO Annual Meeting with trastuzumab, pertuzumab, and a taxane without more complicated treatment that showed very impressive pCR rates. The United States Intergroup is also looking at this approach.

Along the way, we may also be integrating other biomarkers in addition to pCR, such as circulating tumor DNA and circulating tumor cells. These [novel biomarkers] may augment this approach and allow us to better fine-tune therapy, perhaps even in the neoadjuvant setting.

What did the results of the phase 3 FeDeriCa trial [NCT03493854] demonstrate regarding the utility of trastuzumab, pertuzumab, and chemotherapy given in a subcutaneous injection? How are patients benefitting from this fixed-dose approach?

[FeDeriCa] was a neoadjuvant study looking at intravenous [IV] vs a subcutaneous fixed-dose combination of trastuzumab and pertuzumab. The [approaches] were found to be equally effective. The subcutaneous route is more convenient in some ways. It takes less chair time, so less time for the patient to spend in the clinic receiving treatment. It eliminates the need for continuing IV access through a port.

There was a 13% rate of some local reactions, so there is that downside. In most patients, the convenience will outweigh the small risk of local reaction or sometimes uncomfortable injection.

Obviously, it is the same treatment, so it isn’t an advance in terms of treatment effectiveness, but primarily treatment convenience. [Subcutaneous trastuzumab, pertuzumab, and hyaluronidase] is equivalent in efficacy [to the IV formulation] but is more convenient for patients. At our institution, [the subcutaneous formulation] does not seem to be more expensive than a biosimilar of trastuzumab plus pertuzumab.

How have the approvals of trastuzumab deruxtecan and tucatinib affected sequencing for patients with metastatic HER2-positive breast cancer?

The first 2 [lines of treatment] remain unchanged with [the combination of] a taxane, pertuzumab, and trastuzumab as first-line treatment, unless [a patient has] early recurrence after adjuvant therapy. [That combination is] followed by T-DM1.

Thereafter, the choices are tucatinib, trastuzumab, and capecitabine, or trastuzumab deruxtecan. We don’t have a head-to-head comparison of these approaches. The [NALA trial (NCT01808573)] with tucatinib has the advantage of being a phase 3 study with a survival advantage. Trastuzumab deruxtecan has very impressive phase 2 data and the clinical experience is basically supportive of the activity of this agent.

Tucatinib does have documented value in patients with central nervous system [CNS] metastases, so there is a tendency to use tucatinib in that setting. However, trastuzumab deruxtecan, as well as T-DM1, for that matter, can also produce responses in patients with CNS disease.

What treatment strategies are emerging that could further affect sequencing?

There are several newer antibody-drug conjugates [ADCs] under development, each of which have their own advantages in terms of targets, linkers, and chemotherapeutic partners. A number [of these agents] are under development that will find a role [in the treatment of patients with HER2-positive breast cancer]. Anti-HER3 agents are under development and could play a role as well.

Are there other research developments that you are eager to hear more about?

There was a [phase 3] Chinese trial [SYSUCC-002; NCT01950182] that looked at giving endocrine treatment with trastuzumab vs chemotherapy with trastuzumab in the frontline setting [for patients with HR-positive, HER2-positive breast cancer]. It was found that in estrogen receptor–positive patients, combining endocrine treatment with trastuzumab was noninferior.

This trial did not involve pertuzumab, so it may not be entirely applicable to the United States or other Western countries. However, [the results] suggest that for selected patients, this could be a good approach. It bodes well for future trials looking at combinations of anti-estrogen treatment and anti-HER2 treatment with the addition of CDK4/6 inhibitors. Trials looking at these combinations are underway.

Finally, during the IPC meeting, Megan Kruse, MD, a medical oncologist at Cleveland Clinic, discussed updates in TNBC. Could you speak to some of the key trends emerging in TNBC?

There are 2 major trends in TNBC. One is [in evaluating] newer ADCs to develop targeted treatments for TNBC. [These therapies could effectively make the disease] positive for something [instead of] being triple negative. Being able to target something [with agents is important, as was observed with] sacituzumab govitecan-hziy [Trodelvy]. Other monoclonal ADCs are under development that may target subsets of TNBC.

The other trend is with immunotherapy. Of course, we now have immunotherapeutic agents approved in metastatic TNBC. What has changed since Dr Kruse’s presentation is the approval of pembrolizumab [(Keytruda) in combination with chemotherapy] in the neoadjuvant setting [and as single-agent adjuvant treatment].