Survival Advantages in Metastatic Breast Cancer Move the Needle Toward Curative-Intent Strategies

Improvements in progression-free survival (PFS) and overall survival (OS) observed with CDK4/6 inhibitors in hormone receptor (HR)–positive, HER2-negative breast cancer have paved the way for evaluation of these agents as potential curative-intent strategies, said Heather L. McArthur, MD, MPH.

“The whole body of hormone therapy with CDK4/6 inhibitors [in the metastatic or advanced setting regarding] the consistency and the magnitude of benefit all contributed to the development of curative-intent studies,” said McArthur, medical director of breast oncology at the Samuel Oschin Cancer Center of Cedars-Sinai, in an interview with OncLive® during an Institutional Perspectives in Cancer webinar on breast cancer. “Whenever we see innovation in the metastatic setting, we typically move those strategies earlier on in the course of disease to see if we can improve cure rates with those same strategies. That was a natural extension of the clear and consistent benefits in the metastatic setting.”

“It’s an incredibly exciting time to treat breast cancer and it’s incredibly exciting for our patients to have access to so many truly promising strategies,” McArthur added. “To see improvements in the thing we care about most in the advanced setting, which is OS [improvement], consistently reported across many of these studies is just incredibly exciting.”

The virtual meeting covered highlights from the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting in breast cancer as well as treatment considerations in HR-positive, HER2-negative breast cancer, HER2-positive breast cancer, and triple-negative breast cancer (TNBC).

In the interview, McArthur, who chaired the event, discussed key advances in breast cancer regarding CDK4/6 inhibitors, PI3K inhibitors, and subcutaneous formulations of standard treatments.

OncLive^®: What data from the MONALEESA-3 (NCT02422615) and MONALEESA-7 (NCT02278120) trials support the use of ribociclib (Kisqali) in metastatic HR-positive, HER2-negative breast cancer?

McArthur: The MONALEESA-3 study was a randomized phase 3 study of [726] women who had received 0 to 1 prior lines of therapy for advanced HR-positive breast cancer. Patients were randomized to receive fulvestrant [Faslodex] with the CDK4/6 inhibitor ribociclib or placebo. Previously, a response rate of 29% vs 49% in favor of the ribociclib arm was reported, with a [median] PFS almost doubling from 12.8 months to 20.5 months and a hazard ratio of 0.59. That’s really been a consistent effect across these clinical trials of hormone therapy with CDK4/6 inhibitors.

At the 2021 ASCO Annual Meeting, we saw an update from the [MONALEESA-3] study with a median follow-up of 56.3 months. At that time, the median OS [rate] reported was 44.5% [with placebo] vs 53.6% [with ribociclib]. Also reported was the time to chemotherapy, which is a very clinically important end point. The median time to chemotherapy was 28.8 months for the placebo arm vs 48.1 months for the ribociclib arm, [representing] a 20-month difference, which is really important to patients.

The MONALEESA-7 study is a first-line trial for premenopausal women. Patients received tamoxifen or an aromatase inhibitor [AI] plus ovarian suppression and placebo or ribociclib. With a median follow-up of 54 months, the median OS was 47.7 months [with placebo] vs 58.7 months [with ribociclib], translating to more than a 10-month improvement in OS. The time to chemotherapy was 36 months vs 50.9 months, [respectively], translating to a 14-month difference in time to chemotherapy. This is again, clinically [relevant]. The PFS was almost doubled from 13.8 months [with placebo] to 27.8 months [with ribociclib].

We see very consistent data, regardless of the hormone therapy backbone. The hazard ratios approach 0.5, so we essentially double the time that endocrine therapy is effective by adding a CDK4/6 inhibitor.

How have the findings from the MONALEESA studies paved the way for the monarchE trial (NCT03155997)?

The monarchE study took high-risk patients with HR-positive disease and randomized them to receive 2 years of the CDK4/6 inhibitor abemaciclib [Verzenio] or not with positive results. The 2-year disease-free survival [DFS] rate was 92.2% [with abemaciclib] vs 88.7% [with placebo, representing] a 3.5% delta in invasive DFS at 2 years, with only 15.5 months of follow-up reported. We are hoping that delta gets even longer with further follow-up.

What are the clinical implications of the monarchE trial? Are there any challenges to utilizing abemaciclib in the clinic that may impede its use in the adjuvant setting?

For selected patients with high-risk HR-positive disease, [CDK4/6 inhibitors] add another tool in our toolkit to treat patients and cure them of their disease. [The treatment] is biologically driven. Almost all of the women who participated in monarchE received chemotherapy, so this was already self-selected as a high-risk population. This is not a strategy for all patients, but for selected, high-risk patients.

There were a few interruptions or discontinuations [in the study]. The primary challenge with abemaciclib is the diarrhea that occurs, but it tends to occur early on in the first month or so of administration. If we are very proactive about [implementing] strategies to treat and prevent diarrhea, then [abemaciclib] can be very well tolerated. It’s terrific to have yet another strategy in our arsenal for the treatment of patients with HR-positive disease, which can have late recurrences beyond even 10 years.

What was unique about the findings of the PALOMA-3 trial (NCT01942135) in the context of those observed in the MONALEESA studies?

The PALOMA-3 study randomized postmenopausal women to fulvestrant with palbociclib [Ibrance] or placebo. We’ve seen many reports from that study in the past supporting the palbociclib combination. The study was just updated at [the 2021 ASCO Annual Meeting] with just over 73 months of follow-up [and showed] an improvement in PFS. [PFS] was the primary end point. [The median PFS at that time] was 34.8 months [with palbociclib] vs 28 months with the control, with a hazard ratio of 0.81. With further follow-up, [palbociclib] maintained PFS benefit.

There was a 10-month difference in OS at 39.3 months [with palbociclib] vs 29.7 months [with placebo]. That was very consistent with the MONALEESA data we discussed in terms of survival advantage. There was no benefit restricted to any particular subset; all subsets seemed to benefit from the addition of the CDK4/6 inhibitor.

Interestingly, patients harboring ESR1, TP53, and PIK3CA mutations appeared to do worse overall compared with non-mutation carriers. [Conversely], the addition of ribociclib seemed to benefit all of those patient populations. That was an exploratory subanalysis, but it was interesting and hypothesis-generating.

What efficacy has been observed with PI3K inhibitors in advanced HR-positive, HER2-negative breast cancer?

The SOLAR-1 study [NCT02437318] was a randomized phase 3 study of 572 patients with PIK3CA mutations. Patients were randomized to receive fulvestrant with alpelisib [Piqray] or placebo. They had to have had a recurrence or progression of disease on an AI to qualify for the study.

PFS in [the SOLAR-1] study was almost doubled from 5.7 months to 11 months with the addition of alpelisib. There was a non–statistically significant trend toward improvement in OS from 31.4 months to 39.3 months in favor of alpelisib. Also, an 8.5-month delta [was reported] in the time to chemotherapy. [Based on these results, alpelisib] became a standard of care.

One of the challenges in treating patients with alpelisib is the hyperglycemia that occurs. About a third of patients in SOLAR-1 experienced grade 3 hyperglycemia that required medical management, typically in the form of metformin. The associated symptoms of hyperglycemia can cause some dose interruptions or delays. The other [adverse] effect [associated with alpelisib] is rash, but that is typically low grade.

In HER2-positive breast cancer, how have the results of the FeDeriCa (NCT03493854) and PHranceSCa (NCT03674112) trials affected clinical practice?

The FeDeriCa trial looked at neoadjuvant dual HER2-directed therapy in the form of trastuzumab [Herceptin], pertuzumab [Perjeta], and [hyaluronidase-zzxf] vs that same HER2-directed therapy in a subcutaneous form [Phesgo]. The other study, PHranceSCa, was an adjuvant trial essentially [evaluating] the same idea [as FeDeriCa] and comparing trastuzumab plus pertuzumab vs [the subcutaneous formulation].

The subcutaneous [trastuzumab, pertuzumab, and hyaluronidase] is injected into the thigh. There is a lot of convenience associated with that. The intravenous [IV] and subcutaneous strategies appear to be similar; therefore, my own practice has been to concert patients to [the subcutaneous formulation] once the IV portion of their systemic therapy has been completed. For example, if I were giving AC-THP [doxorubicin and cyclophosphamide followed by paclitaxel, trastuzumab, and pertuzumab], I still give the IV trastuzumab and pertuzumab together with the taxane, but then when patients are switching to the dual core HER2 blockade alone, I try to access [the subcutaneous formulation] if insurance endorses that strategy.

What is your take-home message regarding the recent advances seen across the breast cancer paradigm?

It’s a very exciting time to be treating [patients with] breast cancer. If we look at drug development in the past few years, we have moved leaps and bounds. The future directions for breast cancer treatment will be escalation and de-escalation strategies, meaning giving more treatment to patients who need it and less to those who don’t.

That was a somewhat consistent theme that we saw at the 2021 ASCO Annual Meeting. Is there an opportunity to deescalate or optimize chemotherapy backbones by giving more rational biologic combinations? That is really encouraging to see.

I had read an article on TNBC, and I was struck by the fact that in 2018, the only drug we had available to treat patients was chemotherapy, which had really modest [efficacy]. In the past few years, we now have 3 different [types of] drugs—olaparib [Lynparza], sacituzumab govitecan-hziy [Trodelvy], and checkpoint inhibitors—for the treatment of [patients with] TNBC. That’s a tremendous amount of innovation in a relatively short period of time.