Data Continue to Help Shape CDK4/6 Inhibitor Selection, Sequencing in HR+ Breast Cancer

Breast Cancer

Robust phase 3 trial data have led to the integration of CDK4/6 inhibitors into the hormone receptor–positive, HER2-negative breast cancer treatment paradigm, and the continued emergence of data have helped answer selection and sequencing questions about agents such as ribociclib (Kisqali), abemaciclib (Verzenio), and palbociclib (Ibrance), according to Lubna Naaz Chaudhary, MD, MS.

“In our first-line setting, we always want to try to use a CDK4/6 inhibitor with an aromatase inhibitor [AI], as supported by [data from] our phase 3 studies,” she explained in an interview with OncLive^®.

In the interview, following an OncLive State of the Science Summit^™ on breast cancer, Chaudhary, who serves as an associate professor of medicine at the Medical College of Wisconsin in Milwaukee, discussed factors she considers when selecting a CDK4/6 inhibitor, expanded sequencing decisions, as well as highlighted what the future looks like for these inhibitors.

OncLive: How are you selecting CDK4/6 inhibitors for the treatment of patients with breast cancer?

[In my presentation on CDK4/6 inhibitors], I went over the data on first-line and second-line for all 3 CDK4/6 inhibitors. We talked about the [data from the] phase 3 trials [that helped support the use of these agents], including [the first-line trials] PALOMA-2 [NCT01740427], MONARCH 3 [NCT02246621], and MONALEESA-2 [NCT01958021].

All 3 studies met the primary end point of progression-free survival [PFS]. However, the secondary end point of overall survival [OS], which is an important end point, was only met and statistically significant in the [MONALEESA-2 trial] of ribociclib. Abemaciclib did show an improvement in OS [in MONARCH 3], but it was not statistically significant. The [PALOMA-2 study] of palbociclib did not have a statistically significant OS [improvement]. Currently, unless contraindicated, the first-line therapy approach would be ribociclib [in combination] with an AI.

What other data help support ribociclib as a CDK4/6 inhibitor of choice in the first-line setting?

I went through data for all 3 CDK4/6 inhibitors in breast cancer. In the first-line setting, we want to use a CDK4/6 inhibitor; if not contraindicated, we use ribociclib. However, for an individual patient, abemaciclib and palbociclib are very good options. I feel comfortable with using any of those.

In the second-line setting, we have strong data on PFS and OS [for CDK4/6 inhibitors]. If we have a patient who received AI alone as first-line monotherapy, then we definitely want to use any [of the] available [CDK4/6 inhibitors] in the second line in combination with fulvestrant [Faslodex].

What are some of the contraindications to ribociclib that patients may have?

This is where our adverse effect [AE] profile comes in. Palbociclib and ribociclib [are associated with] more myelosuppression, whereas abemaciclib has more gastrointestinal [GI] toxicity and diarrhea concerns. There is also some cardiac and QTc monitoring required with ribociclib, and we have patients [who may be on] other medications that can cause a prolonged QTc interval. If a patient has a baseline cardiac or QTc issue, then that patient may not be a good candidate for ribociclib. [In that case], we are going to choose between abemaciclib and palbociclib.

Palbociclib was very well tolerated, so I would feel comfortable using that. Conversely, if we have a patient who started with abemaciclib, and they're having a lot of diarrhea and [other] AEs from a GI standpoint, then we can go to either ribociclib or palbociclib. [CDK4/6 inhibitor selection] depends on the potential AEs that may develop or baseline cardiac issues.

What are some of the treatment considerations for patients in the post-CDK4/6 inhibitor setting?

We have very good studies at this point in regard to the question of [using another] CDK4/6 inhibitor after [disease progression] on an initial CDK4/6 inhibitor. [During the State of the Science Summit, 3 trials were discussed: the phase 3 postMONARCH [NCT05169567], phase 2 MAINTAIN [NCT02632045], and the phase 2 PACE [NCT03147287] trials. With prior palbociclib use, we have strong data for switching [patients] to ribociclib or abemaciclib [after progression], based on the MAINTAIN and postMONARCH trials, respectively. There is a modest improvement in PFS. It's not a huge difference, but there is some improvement, including better tolerability and a delay in starting chemotherapy.

In patients with no targetable mutations [where the treatment] plan would be fulvestrant alone [after progression on an initial CDK4/6 inhibitor], switching the CDK4/6 [in the second-line setting] is a good option.

We always want to check for targetable alterations like an ESR1 mutation, an AKT pathway mutation, or a PIK3CA mutation. If any of those are present, then we want to combine fulvestrant with targeted agents like alpelisib [(Vijoice) for those with PIK3CA mutations] or capivasertib [(Truqap) for those with AKT pathway mutations]. We can also use elacestrant [Orserdu] for [patients with] an ESR1 mutation.

What have data shown for adjuvant CDK4/6 inhibitors?

We have 2 approved at this point, and we have been using [adjuvant] abemaciclib for the last couple years, based on data from the phase 3 monarchE trial [NCT03155997] that showed a reduced risk of recurrence with that addition of 2 years of abemaciclib compared with an AI alone in [patients with] high-risk, node-positive, estrogen receptor–positive breast cancer.

We also [recently] had the approval of adjuvant ribociclib per the phase 3 NATALEE trial [NCT03701334]; this indication [includes patients with] high-risk stage II or III HR-positive, HER2-negative breast cancer, [including those with node-negative disease]. Three years of treatment of [adjuvant] ribociclib plus an AI also reduced the risk of recurrence.

I believe we have enough CDK4/6 inhibitor data in the adjuvant setting. More options here are to [emerge here with] ongoing studies looking at selective estrogen receptor degraders in the adjuvant setting. We will see how that turns out.