ADC and CDK4/6 Inhibitor Decision-Making and Sequencing Questions Abound in Breast Cancer

Yuan Yuan, MD, PhD

The increased use of CDK4/6 inhibitors and antibody-drug conjugates (ADCs), which have gained a stronger foothold in the breast cancer treatment paradigm, has also highlighted additional areas of uncertainty regarding treatment eligibility, resistance mechanisms, and treatment sequencing, according to Yuan Yuan, MD, PhD.

In an interview with OncLive®, Yuan discussed emerging treatment options for patients with HR-positive breast cancer who have progressed on CDK4/6 inhibitors, the importance of individualized radiation therapy approaches, and where HER2-directed ADCs may fit into the breast cancer treatment paradigm to reflect recent expansions of the definition of HER2 expression.

She shared her perspectives on targeted lymph node dissection and the utility of circulating tumor DNA in breast cancer in another article.

Yuan is a professor of medicine, the director of Breast Oncology, and the medical director of the Breast Oncology Disease Research Group at Cedars-Sinai Medical Center in Los Angeles, California, as well as a health sciences clinical professor at the University of California, Los Angeles.

OncLive: What clinical trials have ushered in the current era of CDK4/6 inhibitors for patients with HR-positive, HER2-negative breast cancer, and what questions remain regarding the use of these agents in this population?

Yuan: [Several] large, phase 3 randomized trials [have been conducted in the] post-surgical breast cancer setting. One is monarchE [NCT03155997], which already led to the FDA approval of abemaciclib [(Verzenio) plus endocrine therapy for patients with hormone receptor (HR)–positive, HER2-negative early breast cancer].1 The second trial, results from which were presented 2 years in a row at the ASCO Annual Meeting, is the NATALEE trial [NCT03701334] evaluating a different CDK4/6 inhibitor, ribociclib [Kisqali], in the adjuvant setting.

[There were population] similarities and differences between the 2 trials. If a patient has clinically nodal-negative disease, we cannot apply the monarchE data, because [that trial] did not include that population. [For patients with] high-risk, nodal-negative, T2 [disease], we can use the NATALEE [regimen, which was approved in September 2024 for the treatment of patients with HR-positive, HER2-negative, stage II and III early breast cancer at high risk of recurrence].2 Moreover, the follow-up remains shorter for NATALEE [vs monarchE].

[Additionally], I would like to see [results from subset analyses with the NATALEE regimen in patients with] nodal-negative, high-risk, T2 [disease]. In the clinic, the NATALEE trial [findings have] increased the population [of patients eligible for CDK4/6 inhibition] and increased the number of discussions [regarding the use of ribociclib in this population]. In the past, those patients finished chemotherapy and then received endocrine therapy. Now we’re extending 3 more years of hair thinning and fatigue. The risk/benefit ratio [of CDK4/6 inhibition] is still unclear for the high-risk, nodal-negative patients. [Although these agents] have arrived [commercially], how much benefit and absolute gain patients are getting from those additional treatments remains to be teased out.

What treatment options exist for patients who have progressed on CDK4/6 inhibitors, and how do you decide between these approaches?

In the metastatic setting, [treatment includes] different lines of therapy. When patients have progressed beyond CDK4/6 inhibitors, what are the other options? The precision medicine approach has finally arrived in breast cancer. We’re considering [patients’] molecular features, for example, whether they have ESR1 mutations, PIK3CA mutations, AKT amplifications, BRCA mutations, or, extremely rarely, NTRK amplifications or translocations. [The presence or absence of these mutations] will define which [treatments] each patient will receive. Those are welcome data in the recent area of PIK3CA/AKT inhibition.

Now, we finally have [data with the phase 3] CAPItello-292 [trial (NCT04862663) regimen] providing a less toxic treatment option for patients with PIK3CA mutations. [Remaining questions include] the sequencing issue because this trial only included patients who had never received prior PIK3CA or AKT inhibition. What if a patient now recently progressed after alpelisib [Vijoice]? Then, the question would be: Would the continuation of AKT targeting even be valid? The CAPItello-292 patient population never received prior alpelisib. We continue to see this evolving paradigm. New questions arise and old questions [remain], and some of the questions will probably never have a randomized phase 3 trial address them. That’s our daily dilemma.

Extremely high-risk patients may [be eligible for agents beyond] CDK4/6 inhibitors. One of the novel PIK3CA inhibitors, inavolisib [GDC-0077], is [under evaluation] in combination with endocrine therapy plus a CDK4/6 inhibitor as a triplet regimen. Right now, the FDA [needs] to review the data [from the phase 3 INAVO120 trial (NCT04191499), which investigated that regimen in patients with PIK3CA-mutated, HR-positive, HER2-negative, locally advanced or metastatic breast cancer who have relapsed during or after endocrine therapy].

[This regimen is] not yet available, but it’s targeting those high-risk patients, who, for example, have a short disease-free period after they complete adjuvant endocrine treatment, have recurred within 1 year, or carry a PIK3CA mutation. [The INAVO120 regimen may] provide a future treatment option for extremely high-risk patients, [who are] distinctively different from all-comers with estrogen receptor–positive [disease, for whom] the current standard of care is endocrine therapy plus CDK4/6 inhibitors. [This population is] easy to address, but in the future, we will have more options.

Additionally, oral selective estrogen receptor degraders [SERDs], such as elacestrant [Orserdu], [are under investigation in] ongoing trials addressing their broader application. Perhaps in the meantime, we will see multiple oral SERDs become available in the paradigm.

How is breast cancer radiation therapy becoming more personalized?

Our old dogma was to give every patient, regardless of their disease type, 6 or 6 1/2 weeks of radiation. However, that’s largely changing. Now we have a smarter way to [administer radiation] treatment, and it can be delivered in a much shorter time. For example, we can have different schedules to fit 15 to 20 fractions into 3 to 4 weeks, or even 5 fractions within 1 week. [This is a] largely welcomed way to treat [patients with] low-risk disease. One size does not fit all, so it’s reassuring that our radiation oncology colleagues are working hard to try to minimize the toxicity [of radiation therapy] but maintain efficacy in early-stage patients.

What updates are on the horizon regarding ADCs in breast cancer?

ADCs, over the past 2 years, [have been one of the] most major breakthroughs in the breast cancer world. We have heard about HER2-low, and then at the 2024 ASCO Annual Meeting, we heard about HER2-ultralow. The question that stems from that is: Do we really care [about levels of] HER2 [expression]? [HER2] should be universally present on skin and in breast ducts. We have yet to understand [entirely] how to apply the data [with HER2-directed ADCs] to clinical practice.

Beyond HER2 and TROP2, there are many other drugs in development, [with different targets], including HER3, and also different payloads. We will have a crowded space with different ADCs. How can we leverage these drugs and try to organically put them together?

Additionally, there’s a huge need to understand drug resistance. When a patient has progressed on a HER2-targeted therapy, can we immediately give them another HER2-targeted therapy with a different payload? Or should we switch gears to use a TROP2-targeted agent [with a different] payload? We have a poor understanding of how ADCs work and how tumors outsmart ADCs. We need a huge amount of investment in research to try to understand what the future will be like. It’s an exciting field.

References

1. FDA approves abemaciclib with endocrine therapy for early breast cancer. FDA. October 12, 2021. Accessed October 7, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-abemaciclib-endocrine-therapy-early-breast-cancer
2. FDA approves Novartis Kisqali to reduce risk of recurrence in people with HR+/HER2- early breast cancer. News release. Novartis. September 17, 2024. Accessed September 17, 2024. https://www.novartis.com/news/media-releases/fda-approves-novartis-kisqali-reduce-risk-recurrence-people-hrher2-early-breast-cancer