CDK4/6 Inhibitors, ADCs, and PI3K Inhibitors Individualize HR+ Breast Cancer Management

The next wave of breast cancer research will build upon a foundation of increasingly personalized treatment strategies, due to approaches with CDK4/6 inhibitors, the broadening applicability of antibody-drug conjugates (ADCs), and reframed roles for chemotherapy, according to Shipra Gandhi, MD.

In an interview with OncLive®, Gandhi, an assistant professor of oncology in the Department of Medicine at Roswell Park Comprehensive Cancer Center in Buffalo, New York, discussed the various factors that influence treatment choices between available CDK4/6 inhibitors in the metastatic and adjuvant hormone receptor (HR)–positive breast cancer settings, as well as future directions for the development of ADCs within the breast cancer field.

Gandhi shared additional insights on treatment options for patients with HR-positive breast cancer who have progressed on CDK4/6 inhibitors in another article.

OncLive: What patient factors do you consider when choosing among CDK4/6 inhibitors therapies in HR-positive breast cancer?

Gandhi: When selecting CDK4/6 inhibitors, we have to talk about them in 2 settings: the metastatic setting and the adjuvant setting. In the metastatic setting, we have seen data from the phase 3 PALOMA-3 trial [NCT01942135] with palbociclib [Ibrance], the phase 3 MONALEESA-2 trial [NCT01958021] with ribociclib [Kisqali], and the phase 3 MONARCH 3 trial [NCT02246621] with abemaciclib [Verzenio]. In all these trials, we saw a progression-free survival [PFS] benefit [with the CDK4/6 inhibitors vs their respective control arms]. However, we saw that only ribociclib induced a statistically significant overall survival [OS] benefit. With abemaciclib, we saw a clinically relevant OS benefit, but it was not statistically significant. With palbociclib, we did not see an OS benefit. In real-world studies with palbociclib, there was a clinically relevant improvement in OS when the agent was added to abemaciclib.

How I view these data is that we have 3 options for patients in the metastatic setting, and there are patient-based and tumor-based factors we need to consider. For example, my go-to CDK4/6 inhibitor is ribociclib based on its statistically significant OS benefit. However, in a patient with cardiac issues or liver issues in whom I cannot use ribociclib because of the adverse effect profile, I might consider using abemaciclib. Although the OS benefit [with abemaciclib plus an aromatase inhibitor (AI)] was not statistically significant [in MONARCH 3], the delta was [clinically relevant].

In a patient who has problems with diarrhea, for example, when using abemaciclib, I might consider using palbociclib because it is well tolerated. Real-world studies have also shown that palbociclib has good efficacy in the metastatic setting. Abemaciclib monotherapy also has central nervous system [CNS] efficacy. If a patient has metastatic breast cancer and CNS disease, abemaciclib [would be] my go-to CDK4/6 inhibitor given its CNS penetration.

In the adjuvant setting, we have seen data with 2 CDK4/6 inhibitors that seem to be promising. One is abemaciclib based on findings from the phase 3 monarchE trial [NCT03155997], which only enrolled patients with lymph node–positive disease. Now, we have 5-year follow-up data showing an invasive disease–free survival [IDFS] benefit with abemaciclib [plus endocrine therapy vs endocrine therapy alone].

We’ve also seen data from the phase 3 NATALEE trial [NCT03701334], which investigated 3 years of ribociclib, [in which the agent plus an AI elicited an] IDFS benefit [vs an AI alone]. An additional point about NATALEE was that it enrolled patients with lymph node–negative disease who had high-risk features, such as those with grade 2 disease, a KI-67 proliferation of more than 20%, an Oncotype DX score higher than 26, or high-risk genomic profiling. These patients also had an IDFS benefit [with ribociclib plus an AI vs an AI alone].

The phase 3 PALLAS trial [NCT02513394] investigated palbociclib in the adjuvant setting, and we did not see an IDFS benefit [with palbociclib plus endocrine therapy vs endocrine therapy alone]. Based on that, we have 2 [adjuvant CDK4/6 inhibitor] options for patients. Given the robust follow-up of the monarchE trial, I would consider abemaciclib for patients with lymph node–positive disease. For patients with lymph node–negative disease but high-risk features, we have the option of giving ribociclib.

How might the continued development of ADCs shift treatment paradigms across breast cancer subtypes?

For both HR-positive and triple-negative breast cancer, sacituzumab govitecan-hziy [Trodelvy] and fam-trastuzumab deruxtecan-nxki [T-DXd; Enhertu] are approved. T-DXd was tested in the phase 3 DESTINY-Breast02 trial [NCT03523585], which enrolled a heavily pretreated population of patients with HER2-positive breast cancer. It showed a PFS and OS benefit [with T-DXd vs treatment of physician’s choice]. T-DXd then moved to the phase 3 DESTINY-Breast03 trial [NCT03529110], which was conducted more upfront in the second-line setting [in patients with HER2-positive metastatic disease following progression on a HER2-directed therapy plus a taxane]. In that trial, T-DXd beat ado-trastuzumab emtansine [Kadcyla], which was not surprising in that setting.

The indication for T-DXd also shifted from [exclusively] HER2-positive patients to [include] HER2-low patients based on results from the phase 3 DESTINY-Breast04 trial [NCT03734029], which enrolled a chemotherapy-pretreated population. In the phase 3 DESTINY-Breast06 trial [NCT04494425], T-DXd was moved even more frontline in a chemotherapy-naive population, where we saw a PFS delta of approximately 5 months [favoring T-DXd vs treatment of physician’s choice across the HER2-low and HER2-ultralow patient subgroups].

We’ve also seen data from the phase 3 TROPION-Breast01 trial [NCT05104866] with datopotamab deruxtecan [Dato-DXd], which had a PFS benefit [vs chemotherapy in previously treated patients with inoperable or metastatic HR-positive, HER2-negaive breast cancer]. We are moving these agents to the front line. We currently have 2 ADCs approved [for breast cancer], and Dato-DXd may also get approved. How will we sequence these ADCs? What about resistance mechanisms? Is it resistance to the target antigen? Is it resistance to the payload? These are some of the questions we don’t have answers to at this time. The TRADE-DXd trial is investigating the correct sequencing of Dato-DXd and T-DXd: Dato-DXd first and T-DXd after, or T-DXd first and Dato-DXd after. This will be an interesting trial to watch out for.

Additionally, as these agents are being developed in the metastatic setting, they are now moving into the neoadjuvant and adjuvant settings. What do we do when patients develop resistance and recur after receiving these agents in the neoadjuvant or adjuvant setting? What options do we have for patients in the metastatic setting? This is an interesting area that we will have to watch as time evolves.

What novel regimens and research are further expanding the HR-positive breast cancer armamentarium?

One interesting phase 2/3 trial, [(NCT04191499), which supported a FDA priority review of the investigational approach], investigated the combination of inavolisib [GDC-0077] with palbociclib and fulvestrant [Faslodex] in patients with metastatic HR-positive breast cancer with PIK3CA mutations who had progressed on or within 12 months of adjuvant endocrine therapy. These were patients with very high-risk disease. [This trial evaluated] a triplet regimen, so there are toxicities associated with it. However, despite the very high–risk nature of this disease, there was a PFS improvement from 7.3 [months in the placebo arm] to 15.0 months [in the inavolisib arm].

A lot of other interesting trials are ongoing. We have a trial asking: Can we avoid using chemotherapy in young patients with HR-positive, lymph node–positive disease? Other trials are evaluating avoiding chemotherapy in tumors that are at high anatomic risk but low genomic risk. Other trials are asking: What is the optimal minimal residual disease assay in the setting of high-risk, HR-positive disease, and how do we act on this?