Personalized Medicine Evolves With CDK4/6 Inhibitors, Immunotherapy, and ADCs in Breast Cancer

Hadeel Assad, MD

The CDK4/6 inhibitors ribociclib (Kisqali), palbociclib (Ibrance), and abemaciclib (Verzenio) have been integrated into clinical practice for patients with metastatic hormone receptor (HR)–positive breast cancer. Because all 3 agents have demonstrated progression-free survival (PFS) benefits in clinical trials, each has found a role in practice, according to Hadeel Assad, MD, who added adverse effects (AEs) such as QT prolongation, myelosuppression, and diarrhea, plus other patient factors, determine when to deploy each agent.

“Each [CDK4/6] inhibitor has a different [AE] profile. When we decide on a CDK4/6 inhibitor, it’s more based on AEs,” Assad said in an interview with OncLive® following an Institutional Perspectives in Cancer (IPC) webinar on breast cancer.

In the interview, Assad, the chair of the IPC meeting, discussed how CDK4/6 inhibitors have been implemented into practice and provided updates on key clinical trials in HER2-positive breast cancer and triple-negative breast cancer (TNBC). Assad is an assistant professor of oncology and a member of the Breast Cancer Program and the Phase I Clinical-Pharmacology Program at Barbara Ann Karmanos Cancer Institute, Wayne State University.

OncLive^®: How have CDK4/6 inhibitors been integrated into the treatment landscape for HR-positive breast cancer?

Assad: We have 3 [FDA-approved] CDK4/6 inhibitors: ribociclib, palbociclib, and abemaciclib. They were studied in the first- and second-line setting in metastatic HR-positive breast cancer. In the first- and second-line setting, [the agents] showed a doubling of PFS. We now have overall survival [OS] data from [ribociclib and abemaciclib from the phase 3 MONALEESA-2 (NCT01958021) and MONARCH 2 (NCT02107703) trials, respectively]. We are still waiting on the [OS] data [with palbociclib] from the phase 3 PALOMA-2 trial [NCT01740427].

In 2022, the standard of care for patients diagnosed with HR-positive metastatic breast cancer is to be treated with an aromatase inhibitor [AI] plus a CDK4/6 inhibitor in the frontline setting and fulvestrant [Faslodex] in the second-line setting.

Could you expand on treatment decisions regarding a CDK4/6 inhibitor as a single agent or in combination with other agents for HR-positive breast cancer?

[Treatment] depends on when the patient developed the metastasis and what [therapy] they were on when the recurrence or metastasis developed. If the patient was on adjuvant endocrine therapy with an AI and developed metastasis, I would switch them to fulvestrant with a CDK4/6 inhibitor. I typically use any of the 3 agents: [ribociclib, palbociclib, or abemaciclib]. I don’t have 1 favorite. We typically decide [which agent to use] based on AEs. The 3 inhibitors were never compared head-to-head, and cross-trial comparisons [create many] issues.

Although [ribociclib and abemaciclib] do have OS data, ribociclib is the only agent in the first-line setting with OS data. The MONALEESA-3 trial [NCT02422615] has OS data [for ribociclib] in the first and second line. [However, it is important to] check electrocardiograms because of the QT prolongation. If you don’t have the ability to do that in the clinic, I would advise against using [ribociclib].

Palbociclib has the most in the form of myelosuppression. If you run into issues with that, you can perhaps switch the patient to a different [CDK4/6 inhibitor]. Abemaciclib has the most [AE occurrences] in the form of diarrhea.

As for the companion endocrine therapy, it depends on what [a patient’s prior therapy was]. If patients were on an AI, put them on fulvestrant. If they were on tamoxifen, I put them on an AI, and if they were not on any endocrine therapy because they had de novo metastatic disease, or disease that happened 5 or 10 years after they were off endocrine therapy, then I would use an AI.

What updates in clinical trials have affected how oncologists utilize CDK4/6 inhibitors?

There were updated analyses of both the MONALEESA-2 and MONALEESA-3 trials [with ribociclib] at recent conferences, and they had updated survival data. Both studies showed that the OS benefit was maintained with additional follow-up, which is always reassuring to have. Moreover, most of the subgroup analysis also showed a benefit with [ribociclib] combination therapy compared with single-agent endocrine therapy.

There are some differences in the endocrine-sensitive and endocrine-resistant groups. We found that with the combination of fulvestrant and [ribociclib] there was no statistically significant benefit from the addition of the CDK4/6 inhibitor if [patients] were endocrine resistant. [Endocrine resistance was defined by] recurrence within 2 years of adjuvant endocrine therapy or progression within 6 months of first-line hormonal therapy.

[Moreover], if patients saw chemotherapy before they were placed on [ribociclib], we also saw that there seemed to be less of a benefit to the combination. It could be because the patients who required chemotherapy had very advanced disease, high-burden disease, or organ dysfunction that required the chemotherapy. You always have to take these subgroup analyses with a grain of salt, but those are things to keep in mind.

Lawrence Flaherty, MD, of Barbara Ann Karmanos Cancer Institute, discussed early and metastatic HER2-positive breast cancer. What recent trials have provided important updates in this space?

Metastatic HER2-positive breast cancer is where we apply the art of medicine because we have many options available. Deciding on how to sequence these options and the best regimen to give the patient is an art. [Dr Flaherty] touched on one of the most important studies that was recently published, which is the phase 3 DESTINY-Breast03 trial [NCT03529110]. That study [evaluated] fam-trastuzumab deruxtecan-nxki [Enhertu] vs ado-trastuzumab emtansine [Kadcyla; T-DM1] in the second-line setting for patients with HER2-positive metastatic disease.

Trastuzumab deruxtecan outperformed T-DM1 in terms of overall response rate [ORR], [which] was 79.7% compared with 34.2%, respectively. Median PFS was significantly better with trastuzumab deruxtecan at 25.1 months vs [7.2] months [with T-DM1]. That is more than 3.5 times higher for trastuzumab deruxtecan. The hazard ratio [for PFS] was [0.26], which is a [74%] reduction in the risk of progression [with trastuzumab deruxtecan] compared with T-DM1. This changed the standard of care for second-line therapy to trastuzumab deruxtecan for this disease.

Michael Simon, MD, of Barbara Ann Karmanos Cancer Institute, discussed the TNBC landscape. How has treatment evolved for these patients?

Dr Simon touched on the phase 3 ASCENT trial [NCT02574455]. That trial looked at sacituzumab govitecan-hziy [Trodelvy] vs physician’s choice chemotherapy for metastatic TNBC, which was looked at in the third line and beyond. Sacituzumab govitecan, which is the only antibody-drug conjugate [ADC] approved for TNBC, outperformed physician’s choice chemotherapy. The ORR was 35% compared with 5% in the control arm, and it is currently our standard-of-care therapy in the third-line setting for metastatic TNBC. 

[Dr Simon] also touched on immunotherapy in metastatic TNBC and all the nuances. Although atezolizumab [Tecentriq] was recently withdrawn [from the market] due to negative [results] from the phase IMpassion131 trial [NCT03125902], the phase 3 IMpassion130 trial [NCT02425891], in which [atezolizumab] was combined with nab-paclitaxel [Abraxane] was a positive study in terms of PFS. There was no OS data [suggesting a statistically significant improvement with atezolizumab in the intention-to-treat population].

He also touched on the phase 3 KEYNOTE-355 [NCT02819518], which is looking at pembrolizumab [Keytruda] in combination with chemotherapy for first-line treatment of metastatic TNBC. Pembrolizumab is currently our only checkpoint inhibitor that’s approved in the United States for metastatic, PD-L1–positive TNBC. PD-L1 positivity was defined as a PD-L1 [combined positive score] greater than 10. Immunotherapy is a huge area of research, especially in breast cancer. [Immunotherapy] is currently only approved in metastatic, PD-L1–positive TNBC in the first-line setting.

There’s still a lot of work to do in that area in terms of which patients are more likely to benefit. What is the best immune biomarker? Is it PD-L1, or is it microsatellite instability or tumor mutation burden? Or is it tumor infiltrating lymphocytes [TILs]? There is a lot of [research] looking at TILs.

There is also some work looking at checkpoint inhibitors in other receptor subtypes, such as the metastatic HER2-positive setting in combination with [HER2-targeted] monoclonal antibodies and chemotherapy.

Jailan Elayoubi, MD, of Barbara Ann Karmanos Cancer Institute, discussed emerging agents in breast cancer. Which key agents were discussed?

One of the most important novel agents that was highlighted is elacestrant, which is an oral selective estrogen receptor degrader [SERD]. It was studied in the phase 3 EMERALD trial [NCT03778931], which showed an improvement in PFS compared with fulvestrant. There are a lot of oral SERDS that are currently being studied in the metastatic setting, as well as in the adjuvant setting. It’s always nice to have options for patients, especially since the only [approved] SERD that we have is intramuscular. It requires 2 injections every month, the first 1 being a loading dose. When approved, oral SERDs would be a good option for patients in the metastatic setting, and I do anticipate that [oral SERDs] are going to be pushed into earlier breast cancer [settings].

How could emerging ADCs affect practice across breast cancer settings?

Oncologists that practice in the community and general oncologists that see more than one cancer [must] stay up to date, especially now with the ADCs that are coming in HER2-positive breast cancer and TNBC. We have new ADCs that are going to be coming out, and it’s important to stay on top of that, so that [oncologists] can always treat their patients with the best available therapy.