HR+/HER2– Metastatic Breast Cancer Treatment Developments Continue to Unfold

Alison K. Conlin, MD

The abundance of treatment options for patients with metastatic breast cancer continues to reframe the treatment paradigm, as the optimal sequencing of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) for patients with HER2-positive breast cancer becomes better defined and other therapies, such as capivasertib, enter the arena for those with hormone receptor (HR)–positive, HER2-negative disease, according to Alison K. Conlin, MD.

“In the HR-positive, HER2-negative arena, in terms of metastatic disease, there’s been an explosion of interesting, novel anti-estrogen agents,” Conlin said in an interview with OncLive^®.

In the interview, Conlin, a medical oncologist at Providence Cancer Institute Franz Clinic in Portland, Oregon, discussed patient characteristics that drive second-line treatment decisions for patients with HR-positive, HER2-negative metastatic breast cancer; remaining needs for patients with HR-positive, HER2-negative disease; and the evolving role of oral selective estrogen receptor degraders (SERDs) in patients with ESR1-mutated disease.

She also shared her insights on efficacy and safety data from the phase 3 CAPItello-291 trial (NCT04305496), which evaluated the AKT inhibitor capivasertib plus fulvestrant (Faslodex) vs placebo plus fulvestrant in patients with HR-positive, HER2-negative advanced breast cancer, noting the favorable safety profile observed with capivasertib. The most frequent adverse effects (AEs) in the capivasertib arm included rash (12.1%) and diarrhea (9.3%).¹

Additionally, Conlin highlighted the significance of the phase 3 SONIA trial (NCT03425838), in which patients with HR-positive, HER2-negative metastatic breast cancer who received a nonsteroidal aromatase inhibitor (AI) plus CDK4/6 inhibitor followed on progression by fulvestrant achieved a median time to second progression-free survival (PFS) of 31.0 months vs 26.8 months in those who received a nonsteroidal AI following progression by fulvestrant plus a CDK4/6 inhibitor (hazard ratio, 0.87; 95% CI, 0.74-1.03; P = .10).²

OncLive: What new data in HR-positive, HER2-negative metastatic breast cancer were you excited to see come out of the 2023 ASCO Annual Meeting?

Conlin: [ASCO] was an exciting meeting for patients with HR-positive, HER2-negative breast cancer. We’re always looking forward to new data in the adjuvant [setting], which were different [this year]. [It was] great to have a new trial supporting those patients. [Additionally, it was good to think] ahead about how to treat patients with metastatic disease.

What factors do you consider when selecting second-line treatment for patients with HR-positive, HER2-negative disease?

At [ASCO], there was a great study called SONIA, [which investigated] the timing of using CDK4/6 inhibitors in patients with HR-positive, HER2-negative metastatic disease. The [optimal] timing of [CDK4/6 inhibitors] has generally been well proven to be in the first line. This study allowed us to evaluate patients who happened to get [a CDK4/6 inhibitor] as a second-line treatment, and [data were] supportive of that.

These are great data to have. [In some] groups of patients, we feel that perhaps first-line, single-agent endocrine therapy is the right answer. Sometimes those are patients who are older, sicker, and frailer, who you’re concerned may not tolerate the toxicities of a CDK4/6 inhibitor. Sometimes it’s about accessibility and cost, [but] hopefully that’s not the reason. Hopefully we can provide these medicines to [all patients who are] the right patients for them. However, there are scenarios where patients will not be able to get [CDK4/6 inhibitors] in the first line. Now, I feel confident giving them as second-line treatment [because of] the results of the study. [The SONIA data are] supportive of some of the practices we’ve wanted to do and have been doing. I don’t think [the data] will make me always choose [CDK4/6 inhibitors in the] second line, but the data are supportive of that, which is a nice option for patients.

How have you begun to use trastuzumab deruxtecan in patients with HER2-positive or HR-positive/HER2-low metastatic disease, and is there still a role for ado-trastuzumab emtansine (T-DM1; Kadcyla) in the HER2-positive population?

In the HER2-positive paradigm, trastuzumab deruxtecan is such an incredible drug, and we’ve had great data with all the DESTINY-Breast studies. We are using trastuzumab deruxtecan in patients after [progression on] their first-line [phase 3 CLEOPATRA trial (NCT00567190)] regimen [of] a taxane, trastuzumab [Herceptin], and pertuzumab [Perjeta]. T-DM1 has moved further down the pathway because of that. Generally, in the HER2-positive arena, we are using trastuzumab deruxtecan. In patients with HR-positive and HER2-low disease, trastuzumab deruxtecan also has a good role after all endocrine therapy has been used.

How does the safety profile of trastuzumab deruxtecan compare with that of T-DM1?

Trastuzumab deruxtecan has a toxicity profile that’s more akin to traditional chemotherapy in many ways, [with AEs such as] nausea and appetite suppression. The general feeling, and the data from the [phase 3 DESTINY-Breast03 study (NCT03529110)] supported this, is that trastuzumab deruxtecan probably has more toxicity than T-DM1, so there may be patients who might be able to tolerate T-DM1 more than trastuzumab deruxtecan. That said, we have great antiemetic regimens. [Additionally], fatigue is [an AE that] we have many ideas and regimens [to manage]. The survival benefit and the response rate is so incredibly strong with trastuzumab deruxtecan that trying to support patients through toxicities, if we can, is important. [However, trastuzumab deruxtecan] is a harder regimen for many patients to be on for long periods.

What are the biggest unmet needs for patients with HR-positive, HER2-negative metastatic breast cancer?

For patients who still have hormone-sensitive disease, we’re continually trying to find new agents. That’s still a high-yield area. Trying to overcome resistance to hormonal suppression is always a goal with some of these targeted therapies, trying to understand those mechanisms better so we can target that [resistance]. Once patients have hormone-insensitive disease, we’re trying to offer them traditional cytotoxic chemotherapy and now, antibody-drug conjugates [ADCs] that may work well. Our challenges are always trying to figure out which patients still have hormone-sensitive disease; who may benefit from earlier, up-front, traditional chemotherapy or ADCs; and who may be able to have prolonged, good quality of life [QOL] with continued hormonal blockade.

How might capivasertib fit into the treatment paradigm for patients with HR-positive, HER2-negative disease, based on findings from the CAPItello-291 trial?

I was impressed by the CAPItello-291 study and look forward to using AKT inhibition in patients as a mechanism because the pathways involved seem important for hormonal blockade. It’s an interesting drug in that you dose it 4 days on and 3 days off. That will be an interesting challenge with patients, although not insurmountable; we give many different, harder treatments than that. However, I was impressed by the data. It will be a good offering for patients as soon as the FDA makes a decision.

What was the safety profile of capivasertib in CAPItello-291?

Overall, capivasertib looks like it will be a tolerable treatment. I think patients will be able to add it to fulvestrant to improve their time on the drug and their PFS. I didn’t find the toxicity to look too daunting for patients. When it’s available, I will find the appropriate patients to treat and offer this as a therapy.

How does AKT inhibition compare with PI3K inhibition?

[CAPItello-291 included] patients with mutations in different parts of the AKT/PI3K pathway. We currently have 1 approved PI3K inhibitor [alpelisib (Piqray)] that [is seemingly associated with] more toxicity than this AKT inhibitor [capivasertib]. I am hopeful, given that the CAPItello-291 trial included patients who had had a prior CDK4/6 inhibitor and still showed a benefit [with capivasertib], that patients will have a better response with this than we’ve traditionally seen with some PI3K inhibitors. However, cross-trial comparisons are hard to do, so real-world data will tell us how well these agents perform, although [they have] a similar setup regarding their partnership with endocrine therapy.

How do you approach sequencing with CDK4/6 inhibitors across different lines of therapy for patients with HR-positive breast cancer?

There are conflicting trial data on whether we should sequence back-to-back CDK4/6 inhibitors after progression on 1 initial CDK4/6 inhibitor. We’re opening a trial [at Providence Cancer Institute] to address that more systematically. I have used some continuation of CDK4/6 inhibitors, but not in every patient.

[We need to evaluate] what’s happening with the patient. How much progression is going on? How’s the tolerability? I want to wait for a good level of evidence, not an intriguing, phase 2, single-arm level of evidence, to make that a permanent practice pattern. It’s to be continued. Right now, most patients will receive their line of CDK4/6 inhibitor, hopefully have a long response to it, and then move on to some other targeted therapies that exist.

What does the future look like for oral SERDs in HR-positive breast cancer, and what agents in development might round out potential options in this setting?

Right now, there’s 1 approved oral SERD, elacestrant [Orserdu], which I’ve been using in patients in the appropriate setting: those who have developed ESR1 mutations. It has been great to have [an oral SERD] available for us to use. It’s a tolerable agent and has a nice safety profile.

However, we’re also looking forward to some other oral SERDs potentially coming out. Some of the trials that are designed are exciting, investigating [these agents] in some high-risk, adjuvant patients, the development of ESR1 mutations on an AI alone and changing to an oral SERD to prevent distant disease. I’m looking forward to getting that trial open because that’s where we’re trying to think ahead. Who can we use these agents for? [Oral SERDs may target a] common resistance pattern to standard therapy for high-risk patients. I’m looking forward to some of the data that are coming out, and I will stay tuned.

How do patient preference and QOL issues affect your breast cancer treatment selection?

QOL is supremely important to patients, and [we need to consider treatment] choices [based on] what patients are facing [and] their preferences. As oncologists, every day, we have these conversations with patients [to learn] what is important to them. Is coming in less often important because they live far away or have other responsibilities at home? Is nausea an AE they’re terrified of and have had bad experiences with? Will hair loss affect how their day-to-day life proceeds? Embedded into the work that we do as oncologists is considering what patients need to give up to do treatments to try to stay with us and stay healthier for longer if they can.

I love studies that look at [QOL], and we embed it into so many clinical trials. The [phase 2] X-7/7 trial [NCT02595320] evaluated a [capecitabine (Xeloda)] regimen we use often, [and although it did not] directly evaluate QOL, it’s much easier for patients to accomplish [QOL improvements] and potentially have less GI toxicity [with a dose-dense, fixed-dose regimen]. As oncologists, we’re considering QOL all the time, talking about it with patients, and making these choices. I appreciate the studies that include that.

References

1. Turner NC, Oliveira M, Howell SJ, et al. Capivasertib in hormone receptor-positive advanced breast cancer. N Engl J Med. 2023;388(22):2058-2070. doi:10.1056/NEJMoa2214131
2. Sonke GS, Van Ommen-Nijhof A, Wortelboer N, et al. Primary outcome analysis of the phase 3 SONIA trial (BOOG 2017-03) on selecting the optimal position of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors for patients with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC). J Clin Oncol. 2023;41(suppl_16). doi:10.1200/JCO.2023.41.17_suppl.LBA1000