CDK4/6 Inhibitor Selection and Sequencing Continue to Evolve in HR+ Breast Cancer

Sarah Sammons, MD

Selection and sequencing of CDK4/6 inhibitors in patients with metastatic hormone receptor (HR)–positive, HER2-negative breast cancer hinge on the maturation of data in the first-line setting and beyond, and these decisions need to account for patient concerns and preferences, according to Sarah Sammons, MD.

Primary results from the phase 3 SONIA trial (NCT03425838) demonstrated that the use of the palbociclib (Ibrance), abemaciclib (Verzenio), or ribociclib (Kisqali) plus endocrine therapy in the first line prolonged the time on CDK4/6 inhibitors by 16.4 months compared with second-line use; however, first-line use did not generate a clinically meaningful or statistically significant progression-free survival (PFS) benefit compared with second-line use.¹

Regarding first-line use, ribociclib plus letrozole (Femara) demonstrated a statistically significant improvement in overall survival (OS) compared with letrozole alone in the phase 3 MONALEESA-2 trial (NCT01958021).² Notably, data from the phase 3 MONARCH 3 trial (NCT02246621) showed an OS trend favoring abemaciclib plus endocrine therapy vs endocrine therapy alone, but those data have not reached statistical significance.³ However, first-line palbociclib plus letrozole missed the OS end point vs letrozole alone in the phase 3 PALOMA-2 trial (NCT01740427).⁴

“Ribociclib is the only [CDK4/6 inhibitor with a] statistically significant OS advantage in the first-line setting. That’s what we can talk to patients about. It’s extremely important that we also talk to patients about the different adverse effect [AE] profiles, [discuss] the different monitoring required, and think about patient comorbidities. [We need to] have these discussions with patients because in the end, it’s their decision,” Sammons said in an interview with OncLive^® following an OncLive State of the Science Summit™ (SOSS) on breast cancer, which she cochaired.

In the interview, Sammons highlighted key discussion points from the SOSS, including the evolving role of CDK4/6 inhibitors in HR-positive breast cancer, the future of antibody-drug conjugates (ADCs) in triple-negative breast cancer (TNBC), and the importance of educating patients about their available treatment options so they can share in the decision-making process.

Sammons is associate director of the Metastatic Breast Cancer Program at Dana-Farber Cancer Institute – Chestnut Hill, in Newton, Massachusetts.

OncLive: Regarding your presentation on CDK4/6 inhibitors in metastatic HR-positive breast cancer, what controversies exist surrounding OS benefits with CDK4/6 inhibitors in the first-line setting?

Sammons: We have been debating CDK4/6 inhibitors for the past decade. Which one should we use? What are the differences? In terms of palbociclib, ribociclib, and abemaciclib, the PFS [data] in the first-line setting are numerically identical. We can tell from the registrational trials that the patient populations were similar because the control arms performed the same way.

However, we have seen differences emerge [regarding] OS and how long these patients on first-line CDK4/6 inhibition are living. We had been waiting for the first-line abemaciclib data from MONARCH 3. [Those data] showed a median OS of 67.1 months with first-line abemaciclib vs 54.5 months [with placebo]. We do await the final OS analysis. It’s trending toward positivity, but it’s not quite statistically significant.

We have already seen the OS data from the MONALEESA-2 trial, which, at the time, was the longest median OS for metastatic HR-positive breast cancer that we had seen at 63.9 months. Subsequently, we also saw a negative OS signal with the PALOMA-2 trial and the use of first-line palbociclib.

How do we reconcile that? [We saw] the same PFS with all 3 drugs but striking differences in OS. Many people have questioned issues such as trial design, missing data, and percentage of crossover, but there [is not striking evidence], at least across PALOMA-2 or MONALEESA-2, regarding those differences. Today, all we can do is take the data from each trial individually. It’s challenging to make cross-trial comparisons.

Should CDK4/6 inhibitors still be used as a standard first-line treatment?

This wasn’t even a question we were asking until the 2023 ASCO Annual Meeting. We had seen large OS improvements [and trends] in the first-line setting with ribociclib and abemaciclib. Most of us had moved toward offering a CDK4/6 inhibitor in the first-line setting.

However, at the 2023 ASCO Annual Meeting, we saw the results of SONIA, which was a practical and well-designed trial [that enrolled] patients in the first-line setting who had no prior therapy for advanced breast cancer. Those patients were randomly assigned 1:1 to either receive a nonsteroidal aromatase inhibitor [AI] plus a CDK4/6 inhibitor or a nonsteroidal AI [alone]. Upon progression, if they were randomly assigned to the CDK4/6 inhibitor, they went on to receive fulvestrant [Faslodex]. If they just received an AI, they went on to receive fulvestrant and a CDK4/6 inhibitor. Importantly, this was a palbociclib sequencing trial, because 91% of the patients received palbociclib.

The question here was: Are there differences between palbociclib plus AI followed by fulvestrant or AI followed by fulvestrant and palbociclib? Interestingly, there was a PFS advantage with the CDK4/6 inhibitor [in the first line]. They also investigated an interesting end point called time to second progression [PFS2]. There was no PFS2 difference between palbociclib in the first line vs the second line with an alternate endocrine therapy backbone. There was also no OS benefit whether you sequenced the CDK4/6 inhibitor in the first line or the second line.

However, [regarding] OS in SONIA, patients who received a first-line CDK4/6 inhibitor had an OS of 45.9 months. That’s [approximately] 20 months less than what we’ve seen with first-line ribociclib and abemaciclib. For me, this was not practice changing, but it showed that regarding palbociclib sequencing, the first line isn’t necessarily better than the second line, and for patients who are concerned with toxicity and AEs and are not [as concerned with] having the longest-term outcomes, starting with an AI [alone] could still be an option.

What is the significance of the findings from the phase 3 NATALEE trial (NCT03701334) for clinicians who are considering using adjuvant CDK4/6 inhibitors for patients with early-stage HR-positive/HER2-negative breast cancer?

CDK4/6 inhibitors have been successful in the metastatic setting and have changed the treatment landscape dramatically. Naturally, we wanted to move them into the early-stage, high-risk setting. We have already had the approval of abemaciclib in node-positive, high-risk patients for 2 years in the adjuvant setting. NATALEE was the large, phase 3, registrational trial evaluating 3 years of ribociclib added to endocrine therapy in the high-risk setting.

One of the differences between NATALEE and the [phase 3] monarchE trial [NCT03155997] was that NATALEE included a node-negative population, [meaning] a broader population. Another intriguing aspect of NATALEE was that they started the ribociclib dose at 400 mg, whereas in the metastatic setting, we start with a dose of 600 mg for most patients. This was an attempt to minimize toxicity.

At the second interim analysis, which had a median follow-up of 27.7 months, there was a statistically significant improvement in 3-year iDFS of 3.3% [with ribociclib plus endocrine therapy vs endocrine therapy alone]. Importantly, only 20.2% of patients had completed the 3 years of the recommended adjuvant ribociclib, so these are still early data. Additionally, the toxicity is not trivial. There was still an 8.3% rate of grade 3 [or higher liver-related AEs] even with the 400 mg dose.

It’s exciting to think about potentially offering an adjuvant CDK4/6 inhibitor to other high-risk patients beyond the extremely high-risk patients we saw in monarchE. However, before I prescribe this in my practice, I need to see further follow-up data. I need to see more patients complete 3 years of therapy, and I need to see those curves separate further so I can better understand the true risks and benefits of offering adjuvant ribociclib.

Nancy U. Lin, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts, who cochaired this SOSS event, discussed central nervous system (CNS) metastases treatment in patients with breast cancer. What considerations do you make for systemic treatment options for this population?

One of the most exciting developments in the treatment of brain metastasis is ADCs. Historically, we always thought the blood­–brain barrier would push out large molecules [such as] monoclonal antibodies and bulky ADCs with a monoclonal antibody, a linker, and a payload. However, what we’re beginning to see with the fam-trastuzumab deruxtecan-nxki [Enhertu] and sacituzumab govitecan-hziy [Trodelvy] data is that ADCs are able to penetrate the blood-brain barrier, especially a non-intact blood-brain barrier, which happens with active brain metastases.

We’ve seen excellent efficacy of trastuzumab deruxtecan in both stable and active HER2-positive brain metastases. In smaller studies, we’ve seen sacituzumab govitecan be able to get into the brain, which is also intriguing. I’m excited that these ADCs are having much extracranial [and intracranial] activity. This space is moving rapidly, and there is a lot coming down the pipeline. I’m excited to see that we can include patients with brain metastases in those trials, and that we can do other trials that include those patients and have hope for efficacy, because we certainly need new therapeutics in this setting.

Ana Garrido-Castro, MD, of Dana-Farber, discussed emerging ADCs in TNBC. What may be the potential future for ADCs in this population, and how might these agents affect the larger TNBC treatment landscape?

Trastuzumab deruxtecan has excellent activity in TNBC. There were a small but meaningful portion of patients in the [phase 3] DESTINY-Breast04 trial [NCT03734029] had HER2-low TNBC, and they did remarkably well with trastuzumab deruxtecan. That is an option for HER2-low TNBC.

Sacituzumab govitecan is in the clinic in the second line and beyond in TNBC. It is superior to physician’s choice of chemotherapy and is now [under investigation] in the phase 3 [ASCENT-03 trial (NCT05382299)] in the first-line setting. [Additionally], datopotamab deruxtecan [DS-1062a] is [under evaluation] in the [phase 3 TROPION-Breast02 trial (NCT05374512)] in the first-line, PD-L1–negative setting, and now the HER3[-targeted] ADC [patritumab deruxtecan (HER3-DXd)] is showing respectable response rates. It’s all promising and exciting.

The main question will be: How do we pick an antigen for these patients? How do we choose between ADCs that have similar payloads but different targets? This is what we need to tease out over the next few years.

Erica L. Mayer, MD, MPH, and Paolo Tarantino, MD, both of Dana-Farber, discussed treatment following CDK4/6 inhibitors. What challenges contribute to the unmet need for determining the optimal sequencing of endocrine therapy–based strategies after progression on CDK4/6 inhibitors?

For most patients, we’re still steadfast in using a CDK4/6 inhibitor in the first line. After that, we have an array of options, none of which have extremely meaningful PFS [data]. We need to keep many clinicopathological and genomic characteristics in mind.

The first thing I usually do when I have a patient who is progressing on a CDK4/6 inhibitor is send for circulating tumor DNA [testing]. I want to understand: Do they have an ESR1 mutation? Do they have a PI3K or AKT mutation? Do they have a high tumor mutational burden? Do they have a HER2 mutation? What is molecularly driving their breast cancer at this point? I also look at the length of time they spent on their first-line CDK4/6 inhibitor. Did they have a long interval, which would speak to a more endocrine-sensitive patient population?

If they had a long duration on a CDK4/6 inhibitor and they have an ESR1 mutation, [they may be in a] more endocrine-sensitive population and may continue to benefit from novel, endocrine therapy–based strategies. I’d be excited about a clinical trial with a novel selective estrogen receptor modulator, selective estrogen receptor degrader, or proteolysis-targeting chimera, either as single agents or in combinations, or I would consider elacestrant [Orserdu].

If they had a shorter-term duration [on a CDK4/6 inhibitor] and a PIK3CA or AKT mutation, then I would consider trials with targeted PI3K inhibitors. If they were fit and non-diabetic, I would consider alpelisib [Piqray]. We await the approval of capivasertib in this population, and that will be a great option as well.

Regarding the presentation by Adrienne G. Waks, MD, of Dana-Farber, on advances in metastatic HER2-positive breast cancer treatment, in what scenarios would you choose a tucatinib (Tukysa)-based regimen over trastuzumab deruxtecan or ado-trastuzumab emtansine (Kadcyla) in this population?

We’re most excited about tucatinib in [patients with] brain metastases. It has activity in [patients without] brain metastases. However, I would use a tucatinib-based regimen, maybe even in the second line, in a patient with intracranially predominant disease, maybe isolated brain relapse, or a short interval between their first and second brain metastases events. In a patient in whom I’m worried about CNS control, I would use tucatinib in the second-line setting.

For many other patients, given the [phase 3] DESTINY-Breast03 trial [NCT03529110] data comparing trastuzumab deruxtecan with trastuzumab emtansine, we’re considering trastuzumab deruxtecan in the second line. Some patients are incredibly concerned about toxicity, so it’s always a discussion with them. Regarding sequencing and OS, we don’t know if second-line trastuzumab deruxtecan is better than third-line trastuzumab deruxtecan. If a patient is concerned about toxicity, we should discuss trastuzumab emtansine in the second line. However, for most patients, we will move to trastuzumab deruxtecan in the second line.

Given the evolving treatment landscape for different populations of patients with breast cancer, how do discussions with patients factor into therapy decisions?

[The changing landscape] is exciting, and it is somewhat overwhelming as a clinician to keep up with it all. We don’t talk enough about patient-shared decision making. [We have the] ability to discuss these results with patients and discuss AEs, [including] what we know, what we don’t know, and the limitations of what we know. That’s incredibly important as well, because patients will always help us make the right decision when we have many options on the table.

Editor’s note: Dr Sammons reports research funding from AstraZeneca, AbbVie, Bristol Myers Squibb, Eli Lilly, Seagen, and Sermonix; and consulting roles with Foundation Medicine, AstraZeneca, Daiichi Sankyo, Eli Lilly, Incyclix Bio, Merck, Pfizer, Seagen, Sermonix, and Novartis.

References

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2. Hortobagyi GN, Stemmer SM, Burris HA, et al. Overall survival with ribociclib plus letrozole in advanced breast cancer. N Engl J Med. 2022;386(10):942-950. doi:10.1056/NEJMoa2114663
3. Goetz MP, Toi M, Huober J, et al. MONARCH 3: Interim overall survival (OS) results of abemaciclib plus a nonsteroidal aromatase inhibitor (NSAI) in patients (pts) with HR+, HER2- advanced breast cancer (ABC). Ann Oncol. 2022;33(suppl 7):S1384. doi:10.1016/j.annonc.2022.08.009
4. Finn RS, Rugo HS, Dieras VC, et al. Overall survival (OS) with first-line palbociclib plus letrozole (PAL+LET) versus placebo plus letrozole (PBO+LET) in women with estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer (ER+/HER2− ABC): Analyses from PALOMA-2. J Clin Oncol. 2022;40(suppl 17):LBA1003. doi:10.1200/JCO.2022.40.17_suppl.LBA1003