The Expanding Role of CDK 4/6 Inhibitors in Breast Cancer Treatment

Cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors are designed to arrest cancerous cell growth and have substantially changed the treatment landscape of metastatic and, more recently, early-stage breast cancer.^1,2 Originally studied for hormone-receptor positive (HR+)/HER2 negative (HER2–) metastatic breast cancer (MBC), CDK 4/6 inhibitors rapidly moved to earlier lines of treatment where they are currently approved as an adjuvant option for those with intermediate or high-risk early-stage breast cancer to minimize the risk of disease recurrence. Considering the effectiveness of CDK 4/6 inhibitors in HR+/HER2– metastatic and early-stage breast cancer, these drugs are now under investigation in various breast cancer subtypes and clinical scenarios. In this review, we will discuss the current FDA-approved indications for CDK 4/6 inhibitors, what is on the horizon, and the pharmacist’s role in managing patients on CDK 4/6 inhibitors.

Metastatic HR+/HER2– Breast Cancer

In the metastatic setting, CDK 4/6 inhibitors are used in the first-line treatment of HR+/HER2– locally advanced breast cancer or MBC. Currently, there are 3 FDA-approved CDK 4/6 inhibitors in this setting: palbociclib (Ibrance; Pfizer), abemaciclib (Verzenio; Eli Lilly), and ribociclib (Kisqali; Novartis). The addition of a CDK 4/6 inhibitor to endocrine therapy (ET) has shown improvement in progression-free survival (PFS) compared with ET alone. There is controversy on the choice of CDK 4/6 inhibitor as there are no head-to-head comparisons among these agents and there are some differences in study populations of the phase 3 randomized studies.² Overall survival benefit was demonstrated with ribociclib/ET and abemaciclib/fulvestrant (Faslodex; AstraZeneca) in phase 3 randomized clinical trials evaluating newly diagnosed patients. Data from the landmark trials are summarized in Table 1.³

Adjuvant HR+/HER2– Early-Stage Breast Cancer

Breast cancer cells. Image Credit: © Supithcha stock.adobe.com

With success observed in the metastatic setting, abemaciclib and ribociclib have both received FDA approval as adjuvant therapy in patients with high-risk HR+/HER2– early-stage breast cancer. The MONARCH-E trial (NCT03155997) evaluated abemaciclib in the adjuvant setting in patients with high-risk HR+/HER2–, lymph node-positive early-stage breast cancer.⁴ High risk was defined as 4 or more positive pathological axillary lymph nodes or between 1 and 3 positive axillary lymph nodes and at least 1 of the following additional high-risk features: tumor size 5 cm or larger or histological grade 3 disease. Additionally, patients were enrolled if they had 1 to 3 positive axillary lymph nodes and intermediate-risk clinicopathological features (tumor grade <3; tumor size <5 cm). A centrally determined high Ki-67 index (≥20%) was required as an additional risk feature. Participants received continuous abemaciclib 150 mg twice daily for 2 years in addition to ET vs endocrine therapy alone. At 54 months, an interim analysis conveyed a 32% reduction in invasive disease-free survival and a 32.5% reduction in recurrence-free survival with the addition of abemaciclib to ET.⁵

In September 2024, ribociclib received approval in the adjuvant setting based on data from the NATALEE trial (NCT03701334).⁶ Slamon et al enrolled patients with high-risk HR+/HER2– early-stage breast cancer to receive ribociclib 400 mg daily on days 1 through 21 every 28 days for 3 years in combination with ET. High risk was defined as stage IIA with nodal involvement, stage IIA with no nodal involvement and a grade 3 tumor, or stage IIA with no nodal involvement with a grade 2 tumor and a Ki-67 score 20% or higher considered to be in a high genomic risk group (Oncotype or MammaPrint). Patients with stage IIB or III disease were eligible irrespective of nodal status. The addition of ribociclib to ET in this patient population showed a 25.2% reduction in the risk of invasive disease, recurrence, or death compared with ET alone.

Medical oncologists will now have 2 options for CDK 4/6 inhibitors in the adjuvant setting. Table 2^4-6 highlights differences between the 2 CDK 4/6 inhibitors currently available. Having 2 FDA-approved CDK 4/6 inhibitors in this space is beneficial as it provides patients and providers with an alternative option when considering patient tolerability, preferences, and comorbidities.

Recent Combination Therapy Approvals

In October 2024, outcomes from the INAVO120 trial (NCT04191499) resulted in approval of the combination of inavolisib (Itovebi; Genentech), palbociclib, and fulvestrant in patients with HR+/HER2– MBC with PIK3CA mutations.⁷ INAVO120 compared safety and efficacy outcomes when adding inavolisib or placebo to fulvestrant and palbociclib. Participants were included if they had HR+/PIK3CA-mutated/HER2– breast cancer that progressed on or within 12 months of adjuvant ET completion. Patients with newly diagnosed breast cancer were excluded.

The addition of inavolisib to palbociclib and fulvestrant extended PFS to 15 months (vs 7.3 months in the placebo arm). Patients in the inavolisib-containing arm experienced more hyperglycemia, stomatitis, diarrhea, rash, decreased appetite, nausea, and fatigue. The INAVO120 trial produced the first triple-therapy combination for patients with HR+/HER2– MBC who are also PIK3CA mutated.

On the Horizon

With the current and previous successes of CDK 4/6 inhibitors in breast cancer, investigators continue to evaluate their use in alternative treatment settings including neoadjuvant treatment, aggressive disease (including visceral crisis), combination therapy with oral selective estrogen receptor degraders (SERDs), metastatic HER2+, and in combination with immunotherapy.

Neoadjuvant Treatment of HR+/HER2– Breast Cancer

Studies such as PALLET (NCT02296801) have attempted to demonstrate success of CDK 4/6 inhibitors in the neoadjuvant setting.⁸ The PALLET trial evaluated patients with HR+/HER2– breast cancer with tumors 2 cm or greater. Study participants received neoadjuvant letrozole and palbociclib for approximately 14 weeks and treatment response was determined based on change in Ki-67 score as well as clinical response. While a decreased tumor antiproliferative rate was observed, just 1.1% of patients achieved a pathological complete response following neoadjuvant therapy.

At the time of this article, incorporation of CDK 4/6 inhibitors in the neoadjuvant setting remains to be seen. Several clinical trials continue to investigate neoadjuvant CDK 4/6 inhibitor use to better understand the correct patient population for this setting.

HR+/HER2– MBC With Aggressive Disease

Medical oncologists tend to be more inclined to use cytotoxic chemotherapy for younger patients with aggressive breast cancer subtypes or for patients who are in visceral crisis from their disease. Using cytotoxic chemotherapy is challenging for various reasons including symptom management, logistics of treatment, and the potential for sustained myelosuppression for a period of time following chemotherapy cessation. For endocrine-susceptible breast cancers, the next line of treatment would frequently involve transitioning to ET in combination with a CDK 4/6 inhibitor, which can be a challenge for patients who are still experiencing residual myelosuppression from chemotherapy. The RIGHT Choice trial (NCT03839823) evaluated treatment with ribociclib and letrozole vs chemotherapy in premenopausal patients with HR+/ HER2‒ aggressive MBC, or patients who would have traditionally been considered for cytotoxic chemotherapy.⁹ PFS was notably longer (21.8 months) in the ribociclib and letrozole arm compared with the chemotherapy arm (12.8 months), raising the question of whether chemotherapy is an appropriate first-line treatment in all premenopausal patients with aggressive disease. It should be mentioned that 51% of patients in the RIGHT Choice trial were in visceral crisis, and while there was a slight trend favoring CDK 4/6 inhibitors and ET, there was not a statistically significant difference among outcomes for this subset of patients.

HR+/HER2– MBC in Combination With an Oral SERD

In January 2023, the first oral SERD, elacestrant (Orserdu; Stemline), was FDA approved for postmenopausal women or adult men with ER+/HER2–/ESR1-mutated MBC with disease progression following at least 1 line of ET based on results from the EMERALD trial (NCT03778931).¹⁰ Elacestrant provides another oral option for patients who have developed resistance to aromatase inhibitors through ESR1 mutation.

The ELEVATE trial (NCT05563220) is evaluating elacestrant in combination with everolimus (Afinitor; Novartis), alpelisib (Piqray; Novartis), ribociclib, palbociclib, or abemaciclib to address other mechanisms of resistance that may occur through PIK3, AKT, or mTOR pathways.¹¹ This trial is actively recruiting and results are expected in 2026.

The ELECTRA trial (NCT05386108) is also recruiting patients with HR+/HER2– MBC with brain metastases to receive abemaciclib with elacestrant, as both of these agents can cross the blood-brain barrier.¹² Results are expected in 2025. So far, the combination of CDK 4/6 inhibitors with elacestrant has shown promising results with a tolerable safety profile.

HR+/HER2+ MBC

HR+/HER2+ breast cancer represents an estimated 10% of all breast cancer subtypes in the United States. Recently, there have been several trials evaluating the role of CDK 4/6 inhibitors in this patient population.¹³ PATRICIA (NCT02536339) was a phase 2 trial that evaluated patients who previously received 2 to 4 lines of anti-HER2–based therapy for metastatic HR+/HER2+ breast cancer in Spain.¹⁴ Treatment consisted of palbociclib in combination with trastuzumab and letrozole. The PFS rate at 6 months was 46.4%, which showed benefit in patients with HR+/HER2+ pretreated disease.

MonarcHER (NCT02675231) was a phase 2 trial that evaluated abemaciclib, trastuzumab, and fulvestrant compared with chemotherapy and trastuzumab in patients with HR+/HER2+ MBC who previously received at least 2 HER2-targeted therapies for advanced disease.¹⁵PFS was 8.3 months in the abemaciclib group compared with 5.7 months in the chemotherapy group. This is a promising finding in pretreated HR+/HER2+ MBC.

Recently, the results of the PATINA trial (AFT-38/NCT02947685) were presented. PATINA is a phase 3 trial that enrolled participants with HR+/HER2+ MBC who had previously received 4 to 8 cycles of chemotherapy (paclitaxel or vinorelbine) with anti-HER2 treatment to receive anti-HER2 treatment (trastuzumab ± pertuzumab) in combination with ET with or without palbociclib until disease progression.^16,17 The addition of palbociclib significantly improved PFS with a hazard ratio of 0.74 (95% CI, 0.58-0.94; 1-sided P = .0074). Median PFS was 44.3 months (95% CI, 32.4-60.9) in the palbociclib arm compared with 29.1 months (95% CI, 23.3-38.6) in the control arm. These results demonstrate that the addition of palbociclib to standard of care shows promise as maintenance therapy in HR+/HER2+ metastatic disease. While ongoing research shows promising results, there are currently no FDAapproved CDK 4/6 inhibitors in HER2+ breast cancer. Hopefully we will see indications for CDK 4/6 inhibitors approved in HER2+ breast cancer in the future.

CDK 4/6 Inhibitors and Immunotherapy

Currently, there are ongoing preclinical and clinical trials investigating the combination of CDK 4/6 inhibitors with immunotherapy for breast cancer. Rugo et al studied the combination of abemaciclib and pembrolizumab (Keytruda; Merck) with/without anastrozole in patients with HR+/HER2– MBC with and without prior CDK 4/6 inhibitor exposure.¹⁸ Abemaciclib plus pembrolizumab demonstrated antitumor activity, but high rates of interstitial lung disease (ILD)/pneumonitis and severe transaminase elevations occurred with/without anastrozole compared with previous reporting.

Recently, the NEWFLAME trial (NCT02779751), a phase 2 study, assessed the effectiveness of combining nivolumab, abemaciclib, and ET (fulvestrant or letrozole) in patients with HR+/HER2‒ MBC.¹⁹ While the results indicated an antitumor response, they were accompanied by a high incidence of severe immune-related adverse effects (AEs), which does not warrant further investigation. Based on the results of these studies, the combination of CDK 4/6 inhibitor with immunotherapy does not significantly enhance responses and increases rates of toxicity. Table 3^20-25 provides an overview of ongoing clinical trials of CDK 4/6 inhibitors.

Role of the Oncology Clinical Pharmacist

Specialty pharmacists and clinical pharmacists play vital roles in ensuring patients have access to CDK 4/6 inhibitors and are managed appropriately while on therapy. Clinical pharmacists can help in CDK 4/6 inhibitor selection, taking into account literature, AE profile of each agent, specific monitoring requirements, patient-specific factors, and drug interactions.

Patients should be educated on the most common AEs of these agents, such as neutropenia, leukopenia, fatigue, nausea, infection, arthralgia, anemia, headache, and diarrhea.^26-28 They also need to be aware of specific monitoring requirements before starting these medications, such as checking labs every 2 weeks for the first 2 months and then monthly, or as clinically indicated, to check for bone marrow suppression and hepatotoxicity. Pharmacists can also help manage these patients by ensuring the correct dose is ordered based on indication, monitoring parameters are followed per package insert recommendations, and AEs/toxicities are managed appropriately.

When comparing the current agents, palbociclib is known to cause the highest rate of bone marrow suppression among the 3 CDK 4/6 inhibitors followed by ribociclib, and then abemaciclib.^26-28 This should be considered for patients who are either not able to maintain adequate blood counts while on treatment or for patients with bone marrow involvement of their disease. Furthermore, QT prolongation has been reported with ribociclib use and the package labeling requires a Fridericia-corrected QT interval (QTcF) at baseline, 14 days after treatment initiation, and as clinically indicated.²⁶ A QTcF of less than 450 msec is recommended before starting treatment. During therapy, if the QTcF is 480 msec or greater, patients must hold therapy and additional dose modification may be required. Pharmacists play a role in monitoring QTcF and reviewing concomitant medications that may prolong QT to ensure safe prescribing.

Abemaciclib has the highest incidence of diarrhea compared with the other agents and education on appropriate antidiarrheal use should occur before starting treatment.²⁷ Abemaciclib also causes increases in serum creatinine; however, this is due to inhibition of renal tubular secretion of creatinine and does not reflect a true change in the glomerular filtration rate (GFR), which measures kidney function.²⁹ If concerned about renal function, pharmacists can recommend ordering a cystatin C level to better assess GFR. Cystatin C levels can be costly and should only be used when there is thought to be discordance between serum creatinine and the GFR.

As a class, patients should be monitored for hepatotoxicity regularly, with ribociclib having the highest reported incidence.²⁶ Additionally, in September 2019, the FDA warned that rare but severe, life-threatening, or fatal ILD and pneumonitis can occur in patients treated with CDK 4/6 inhibitors.³⁰ This should be strongly considered for patients with preexisting pulmonary conditions and patients should be monitored for and instructed to report new or worsening pulmonary symptoms such as cough and shortness of breath.

Pharmacists must be highly embedded in management of CDK 4/6 inhibitor treatment for patients with breast cancer. Oncology pharmacists are responsible for reviewing appropriateness of the agent, dosing, and reviewing pertinent drug interactions alongside medical oncologists. Additionally, pharmacists need to ensure that patients get appropriate labs completed at the correct interval and follow up with the patient via telephone if not seen by the provider on that day. This frequently involves coordinating local lab work for patients who live long distances from the medical institution. Pharmacist virtual check-ins help to open up medical oncologist time by allowing them to see other patients during their clinic day, complete other administrative duties, and manage higher patient volumes.

The pharmacotherapy of CDK 4/6 inhibitors continues to evolve as therapeutic drug monitoring of CDK 4/6 inhibitors and therapy modification for geriatric patients is currently under investigation.^31,32 It is essential that clinical oncology pharmacists keep up with the constantly changing landscape and management of CDK 4/6 inhibitors for patients with breast cancer.

Role of the Specialty Pharmacist

Specialty pharmacists are integral in CDK 4/6 inhibitor patient access. Most, if not all, CDK 4/6 inhibitors require prior authorizations (PAs), co-pay assistance, and specialized monitoring. PAs can be an arduous and lengthy task if not done properly and by a designated team. Having the specialty pharmacist complete PAs ensures they are done quickly and accurately, leading to timely approval and therapy initiation. Insurance approval is often the limiting factor of getting these agents in the hands of patients and so having it done correctly is essential. Once a patient obtains insurance approval, they can still be left with an unaffordable co-pay; sometimes, several thousand dollars per month.

Specialty pharmacists are knowledgeable about and can swiftly apply for grants, co-pay cards, and other funding to lessen financial stress to patients. If a patient is uninsured, the specialty pharmacist can also assist the patient in applying for patient access programs to receive drugs at no cost from the manufacturer.

Finally, at the beginning of treatment, most patients will see a provider weekly, biweekly, or monthly. However, after the initial period, visits may be spaced out and the specialty pharmacist may be the only frequent contact a patient has with the care team for 2-to-3-month intervals. This provides the opportunity for continued monitoring such as adherence checks, assessments of any AEs, and ensuring patients have timely clinic follow-up and laboratory monitoring. This is an additional layer of care that specialty pharmacists can provide to ensure safe and effective treatment.

Lastly, specialty pharmacists must also be familiar with handling and storage of the CDK 4/6 inhibitors prior to and following dispense. As an example, in September 2024, the FDA updated storage requirements for ribociclib. Previously, ribociclib was stored at room temperature before and after dispensing to patients.³³ The new storage requirements have been modified to mandate that ribociclib is stored in the refrigerator until dispensed to patients. Specialty pharmacists are a crucial component in ensuring that CDK 4/6 inhibitors reach patients in a timely manner, are handled and administered correctly, and are affordable for all patients.

Conclusion

In summary, CDK 4/6 inhibitors have changed the treatment landscape for patients with breast cancer. Pharmacists across various settings are heavily involved in the management of patients on these agents. CDK 4/6 inhibitor use has moved from the metastatic setting to the adjuvant setting and will continue to expand in additional settings for the treatment of breast cancer. It is vital that pharmacists are familiar with this drug class including AE management, monitoring, drug interactions, and new literature to ensure safety and tolerability of this widely used drug class.

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