Treatment After Progression on CDK4/6 Inhibitors Requires Careful Consideration in HR+/HER2– mBC

Sarah Sammons, MD

Following disease progression on a CDK4/6 inhibitor, treatment options for patients with hormone receptor (HR)–positive, HER2-negative metastatic breast cancer depend on a variety of factors and decision making should be personalized for patients, according to Sarah Sammons, MD.

“It’s important to understand the biology of the tumor in a patient who progresses after CDK4/6 inhibition, understand the mutational status, understand the HER2-low status, [and] make sure that we know whether they have a somatic or germline BRCA mutation, because PARP inhibitors are excellent drugs in this space as well,” Sammons said in an interview with OncLive®. “Performing the right next-generation sequencing assay to understand what’s going on either by circulating tumor DNA [ctDNA] or biopsy is very important.”

In the interview, Sammons provided a detailed guide on how she treats patients who progressed on prior CDK4/6 inhibitors, diving into preferred treatment regimens. Sammons is a medical oncologist and associate director of the Metastatic Breast Cancer Program at Dana-Farber Cancer Institute in Boston, Massachusetts.

OncLive: What are treatment considerations for patients with HR-positive, HER2-negative metastatic breast cancer who experienced disease progression on a CDK4/6 inhibitor?

Sammons: [Regarding] where we are [for] patients with HR-positive, HER2-negative breast cancer after progression on CDK4/6 inhibitors, it is becoming a very crowded and exciting space. We have a lot of options, and it makes it a bit complex for patients and physicians to choose where to go after progression on a CDK4/6 inhibitor [occurs]. We need to look at a number of factors to truly personalize treatment for each patient.

After my patients progress on CDK4/6 inhibitors, I’m looking at the amount of time they were on the CDK4/6 inhibitor for. Was it a long time—more than 12 to 18 months—where I might still think they’re endocrine-sensitive? Or was it a short time—less than 6 months perhaps even less than 12 months—where I’m starting to worry that they’re not going to be endocrine responsive to subsequent strategies?

The second thing I’m going to think about is what their genomic alteration is. It’s pivotal to look at what’s going on genomically in the cancer after progression on CDK4/6 inhibitors. I personally like ctDNA. There are several assays that can be ordered, [but] ctDNA is more sensitive in picking up ESR1 mutations. We’re also interested in mutations in the PI3K/AKT/PTEN pathway and it’s important to know if the patient has a germline or somatic BRCA mutation.

Once we get all that information gathered and know the patient’s mutational status [and] have an idea of endocrine sensitivity based on their length of treatment with the prior CDK4/6 inhibitor, [we should ask] how symptomatic they are. Are they minimally symptomatic, asymptomatic from progression, or entering a [period where there is a] visceral problem? Once you get those ducks in a row, then you can make treatment decisions.

How do you treat patients who progressed following treatment with CDK4/6 inhibitors if they have a genetic alteration?

If I have a patient who is progressing on CDK4/6 inhibitors, and they had a respectable [response] of more than 12 to 18 months on first-line CDK4/6 inhibitor treatment, I’m going to look at their genomic [status, specifically to see] if they have a PIK3CA mutation, AKT or PTEN alteration, [or] ESR1 mutation.

If the patient has a PIK3CA mutation, then we have 2 options. We could treat them with fulvestrant [Faslodex] and capivasertib [Truqap] or fulvestrant and alpelisib [Piqray]. My choice between the two has to do with whether the patient has a hemoglobin A1C [level] higher than 6% or 6.5% and patient preference on adverse effects. If the patient has an AKT or PTEN alteration, then capivasertib/fulvestrant would be an option.

If a patient has an ESR1 mutation, and they’ve had a long degree of benefit on first-line CDK4/6 inhibitor therapy—ideally more than 18 months, perhaps more than 12 months—then elacestrant [Orserdu] is a nice endocrine monotherapy choice that has shown some benefit in terms of progression-free survival [PFS] compared with [other] endocrine monotherapies in that population. I would [consider elacestrant] for a patient with minimal progression [and] asymptomatic disease with ESR1-mutated disease [who] I thought would still benefit from endocrine therapy.

How do you treat patients who do not have a genetic alteration following progression on CDK4/6 inhibitors?

If I have a patient who doesn’t have any genomic alterations, then we have 2 nice options. We have the results of the phase 3 postMONARCH study [NCT05169567] which looked at abemaciclib [Verzenio] plus fulvestrant vs fulvestrant in patients who experienced prior progression on palbociclib [Ibrance] or ribociclib [Kisqali] and an aromatase inhibitor. This was a positive study, as there was an advantage with abemaciclib/fulvestrant in terms of PFS [observed], and overall [survival] data are immature. The benefit of abemaciclib seemed to be seen regardless of mutational status. That would be an option for a patient who has minimal progression, perhaps on an aromatase inhibitor [plus] palbociclib, without an alteration.

We also have everolimus [Afinitor] which can be used with either fulvestrant or tamoxifen. A single arm study of everolimus and fulvestrant post CDK4/6 inhibitor [treatment] was published this year that showed a respectable PFS of approximately 6 months. For my patients without mutations who I still think are endocrine sensitive in some way, either option with fulvestrant and abemaciclib or fulvestrant and everolimus are very reasonable.

Are there any other key considerations to keep in mind following CDK4/6 inhibitor progression?

[For] patients who we still want to give another line of endocrine therapy to—those who had a longer degree of benefit from their first-line treatment, who may have minimal progression, some visceral progression, but are asymptomatic—treatment with another line of endocrine therapy is very reasonable.

We do occasionally have a patient who has progression, for example within 6 months of starting a first-line CDK4/6 inhibitor, and that’s a patient who I’m worried about. I would want to know a couple of things about that patient—their genomic status but also estrogen status. Are they still estrogen-positive? [Is their disease] still estrogen-driven? There have been a variety of cases in patients like this who I’ve re-biopsied and found that they’re no longer estrogen-positive, so they are more of a triple negative phenotype. What is their HER2 status? Are they HER2-low? That is an important question as well.

If I have a patient who’s had rapid progression on CDK4/6 inhibitors or heavy symptomatic visceral progression, I’m probably not going to go to a second line of endocrine therapy and I’m most likely going to go to chemotherapy. The results of the phase 3 DESTINY-Breast06 trial [NCT04494425], which were published this year showed that first-line fam-trastuzumab deruxtecan-nxki [Enhertu] in patients with HER2-low [or -ultralow] HR-positive disease had benefits vs other chemotherapies, mostly capecitabine [Xeloda] and taxanes in terms of both PFS and overall response rate. [For] those patients who progress early who we worry about, I’m going to be thinking more about chemotherapy or antibody-drug conjugates [as treatment options].