Breast Cancer Research Breakthroughs Signal Paradigm Shifts Across Disease Subsets

Continued research efforts have solidified the use of targeted therapies in hormone receptor (HR)–positive breast cancer and indicate the importance of further research with novel agents, such as HER3-directed antibody-drug conjugates (ADCs) in metastatic disease, according to Maryam Lustberg, MD, MPH.

Among breast cancer data presented at the 2023 ASCO Annual Meeting were primary results from the phase 3 NATALEE trial (NCT03701334), in which adjuvant ribociclib (Kisqali) plus endocrine therapy generated a significantly longer invasive disease-free survival (IDFS) compared with endocrine therapy alone, with a hazard ratio of 0.748 (95% CI, 0.618-0.906; P = .0014). The 3-year IDFS rates were 90.4% with the combination vs 87.1% with endocrine therapy alone.¹

“The idea of adding a targeted agent after completion of primary adjuvant therapy in combination with endocrine therapy is an important finding,” Lustberg said of the NATALEE trial in an interview with OncLive® News Network: On Location during the 2023 ASCO Annual Meeting.

Additionally, Lustberg discussed findings from part A of a phase 2 study (NCT04699630) investigating patritumab deruxtecan (U3-1402) in patients with metastatic breast cancer, which led to an overall response rate (ORR) of 35% (95% CI, 23.1%-48.1%) in all patients, regardless of HER3 expression level. The ORRs were 33% and 46% in patients with at least 75% HER3 expression and 25% to 74% HER3 expression, respectively.²

In the interview, Lustberg also provided insights regarding other key breast cancer data presented at the 2023 ASCO Annual Meeting, including findings from the phase 3 BWEL trial (NCT02750826), updated data from the phase 2 ELAINE-2 trial (NCT04432454), and the final overall survival (OS) analysis of the phase 3 TROPiCS-02 trial (NCT03901339).

Lustberg is the director of the Center for Breast Cancer at Smilow Cancer Hospital and Yale Cancer Center, as well as chief of Breast Medical Oncology and an associate professor of internal medicine (medical oncology) at Yale Cancer Center in New Haven, Connecticut.

OncLive: What did findings from the BWEL trial reveal about the association between weight loss program participation and weight reduction in breast cancer survivors?

Lustberg: I’ve been anticipating the results of the BWEL trial. This was a large-scale, randomized study investigating telehealth coaching vs standard of care for breast cancer survivors with high-risk disease. The end points were recurrence and clinical outcomes, as well as weight reduction. At ASCO, the results of the weight reduction [portion] were formally presented, and they’re exciting, showing that additional support for breast cancer survivors can lead to significant reductions in weights that can be sustainable. We eagerly await continued follow-up of this trial [to see] how it may affect disease course, since obesity after breast cancer diagnosis is a significant risk factor for recurrence.

What telehealth methods did the BWEL trial use to achieve these outcomes?

One of the wonderful aspects of this study was it was done in diverse populations, and it was low technology. Telephones could be used to offer support to patients and guide them to make good diet and exercise choices. This highlights that, yes, technology is important, but more than anything, having frequent high touchpoints with patients can help them remember their personal health goals and achieve them.

How do the results of the NATALEE trial inform the potential future of ribociclib in HR-positive disease?

The results of the NATALEE trial are indeed promising and exciting. HR-positive breast cancer can have late recurrences, sometimes decades after initial diagnosis. This is a gap in the knowledge of how we treat these patients.

The NATALEE trial [investigated] the addition of a targeted therapy agent, ribociclib, for 3 years, in patients with some higher-risk features. Some patients with lower-risk [features than those] in the original monarchE trial with abemaciclib [Verzenio] still benefited from the addition of this targeted therapy approach. Potentially, we have the option of using [ribociclib] for more patients. The potential risk reduction and ultimate reduction in mortality, if it’s further confirmed, can drastically change and reduce overall breast cancer mortality, which is important.

With the FDA approval of elacestrant, where do longer follow-up data from the ELAINE-2 trial place the combination of lasofoxifene plus abemaciclib in the treatment sequence for patients with estrogen receptor–positive, HER2-negative metastatic breast cancer?

Elacestrant is 1 of the first novel endocrine therapy agents to be approved [in this setting]. That is a wonderful addition to the tools we have. It’s essential for us to know the ESR1 mutation status of patients with metastatic breast cancer, particularly after progression post–aromatase inhibitor therapy. I see elacestrant used as second- or third-line endocrine therapy unless there’s a clinical trial option available. 

What stood out to you from the TROPiCS-02 trial final OS data?

The TROPiCS-02 data are exciting and reconfirm how ADC therapies have revolutionized treatment options for patients with metastatic breast cancer. They’re now being further tested in the early-stage setting. Sacituzumab govitecan-hziy [Trodelvy] is an important option for both triple-negative breast cancer [TNBC] and HR-positive breast cancer. It needs to be used in earlier lines of treatment. TROPiCS-02 compared this agent with older chemotherapy agents.

Sacituzumab govitecan is helping patients live longer. There’s no question that this agent should be used over older agents such as gemcitabine and vinorelbine. I will continue to use it and recommend it be adopted for patients with HR-positive [breast cancer] and [those with] TNBC.

What did the phase 2 trial of patritumab deruxtecan in patients with metastatic breast cancer find, and what are the potential future implications of these results?

I was intrigued by these phase 2 trial results, which showed remarkable responses. Depending on how you classify HER3 status, 30% to 50% of patients responded to this HER3-directed ADC therapy, and the toxicity profile was reasonably acceptable. This was a heavily pretreated population that still responded to therapy.

I’m excited to see how these results will be further confirmed in the phase 3 setting. [These findings are] exciting and emphasize that ADCs will radically change how we treat patients, which is a good thing. How do we sequence these ADCs with other ADCs? That question still lingers.

In the phase 2 trial, how active was HER3-DXd according to HER3 expression level?

When the HER3 signal was higher, there was a higher association with response. However, even patients with lower HER3 levels had responses. [These findings] highlight 1 of the repeat principles we see with ADC therapy, which is that we [only] need low target levels to achieve responses. [Although] patients with higher [HER3] levels were more responsive, we still saw responses across the board.

What else were you excited to see at this year’s ASCO?

It was wonderful connecting with colleagues and patient advocates. [There have] been conversations, brainstorming, and thinking about future studies we could do together. These are all the things we missed out on during the pandemic. It’s wonderful to see it starting up again.

References

1. Slamon DJ, Stroyakovskiy D, Yardley DA, et al. Ribociclib and endocrine therapy as adjuvant treatment in patients with HR+/HER2- early breast cancer: primary results from the phase III NATALEE trial. J Clin Oncol. 2023;41(suppl 17):LBA500. doi:10.1200/JCO.2023.41.17_suppl.LBA500
2. Hamilton EP, Dosunmu O, Shastry M, et al. A phase 2 study of HER3-DXd in patients (pts) with metastatic breast cancer (MBC). J Clin Oncol. 2023;41(suppl 16):1004. doi:10.1200/JCO.2023.41.16_suppl.1004