- Adjuvant abemaciclib is an option for patients with appropriate disease characteristics and a high risk of recurrence. Future trials will help answer remaining questions on the use of CDK4/6 inhibitors in early-stage hormone receptor–positive breast cancer.
- In metastatic hormone receptor–positive breast cancer, a CDK4/6 inhibitor should be considered as a first-line option in combination with endocrine therapy in the majority of patients. The treatment landscape post CDK4/6 inhibitors is evolving; many novel therapies are in development for this setting.
- Targeted therapies for hormone receptor–positive breast cancer are associated with various adverse events, including neutropenia, diarrhea, hyperglycemia, and pneumonitis. Monitoring and prevention strategies are recommended to minimize toxicity and promote adherence.
The treatment of hormone receptor–positive (HR+) breast cancer is continually evolving, with significant advances recently presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting. In this commentary from a live symposium, Komal Jhaveri, MD, FACP; Erica L. Mayer, MD, MPH; and Laura M. Spring, MD, highlight key updates in the management of HR+ breast cancer.
Erica L. Mayer, MD, MPH
Considerations With Targeted Therapy for Early-Stage HR+ Breast Cancer
- Based on the results of the monarchE trial, abemaciclib was approved by the FDA in the adjuvant setting for early-stage node-positive HR+/HER2- breast cancer with a high risk of recurrence and Ki-67 ≥20%.The addition of 2 years of abemaciclib is appropriate for high-risk, node-positive patients and is associated with a 30% reduction in the risk of disease recurrence.
- The best candidates for abemaciclib not only have the appropriate disease and risk characteristics, but also are motivated to take 2 years of an extra medication with potential adverse events (AEs), in addition to the need to take ongoing adjuvant endocrine therapy.
How necessary is Ki-67 testing?
Although Ki-67 testing is widely available and inexpensive, there is significant interobserver variability and a lack of well-established thresholds to determine what constitutes a high and low expression; reasons for the selection of a 20% threshold in monarchE are unclear.
- Benefit from the use of abemaciclib in monarchE was independent of Ki-67 score. The test was prognostic for outcome but not predictive of drug benefit. In addition, of the patients who may be considered anatomic highest risk—those with 4 involved lymph nodes—approximately one half were categorized as low Ki-67 but, in subset analysis, had a preserved hazard ratio favoring abemaciclib. If following the FDA approval, these patients who may derive the greatest absolute benefit from adjuvant abemaciclib would be excluded from the ability to receive it.
- Updated guidelines from ASCO and the National Comprehensive Cancer Network support the use of adjuvant abemaciclib without Ki-67 restriction.
- At my institution, we are not currently using Ki-67 to make treatment decisions regarding abemaciclib. Instead, we are using the eligibility criteria from monarchE—patients with a larger tumor, multiple involved nodes, and high-grade disease.
Why do we see a benefit with abemaciclib in monarchE but not with palbociclib in PALLAS and PENELOPE-B?
Three large, adjuvant CDK4/6 inhibitor trials (PALLAS, PENELOPE-B, and monarchE) have been presented with disparate results, causing much discussion in the breast cancer community. One possible explanation is that the PALLAS population was broader and not as high risk as that in monarchE, although approximately 60% of patients in PALLAS did have high anatomic risk disease, which is similar to the monarchE population. However, given that PENELOPE-B had the highest-risk patients and we did not see a benefit with adjuvant palbociclib, we cannot explain the differences based on risk.
- Both PALLAS and monarchE data were presented earlier after shorter follow-up, with PENELOPE-B having the most mature data; more time is necessary to determine whether follow-up is relevant.
- Higher rates of discontinuation were observed in PALLAS with 42% at 2 years vs 30% in monarchE. However, analyses of PALLAS data have demonstrated that there is no apparent benefit in patients who had either longer duration or higher dose intensity of palbociclib.
- Finally, we need to consider that abemaciclib and palbociclib are different drugs with different targets and dosing schedules, and this difference may have led to the differential trial results.
- The ongoing NATALEE study is evaluating ribociclib for 3 years at a reduced dose, and anticipated results will inform and increase our understanding of the role of adjuvant CDK4/6 inhibitors.
For early-stage, node-positive patients at a high risk for relapse who are eligible for adjuvant abemaciclib and have an identified gBRCA mutation, what are your thoughts on using both abemaciclib and olaparib in the adjuvant setting?
- In this era of new agents for early-stage disease, we do find ourselves having to determine which of these agents is higher or lower priority. For a patient with an identified gBRCA mutation and HR+/HER2- disease at high risk per the OlympiA trial eligibility, I may prioritize an upfront year of olaparib. However, monarchE allowed patients to enroll within 16 months of surgery, so theoretically one could get in the entire year of adjuvant olaparib and then initiate abemaciclib still within the overall structure of monarchE. Thus, it is possible to sequence the 2 agents with ongoing concomitant adjuvant endocrine therapy (ET).
Novel Therapies in the Early-Stage Setting
Oral Selective Estrogen Receptor Degraders (SERDs)
- Trials evaluating oral SERDs are initiating in the early-stage setting. Of note, AMEERA-6, lidERA, and EMBER-4 are looking at amcenestrant, giredestrant, and imlunestrant, respectively.
- AMEERA-6 is recruiting patients who were initiated on adjuvant aromatase inhibitor and had to discontinue due to toxicity; they will be randomized to receive up to 5 years of amcenestrant or tamoxifen. This study will be particularly interesting to determine if an oral SERD could become a routine part of our adjuvant practice for patients unable to tolerate aromatase inhibitors.
Komal Jhaveri, MD, FACP
CDK4/6 Inhibitor Updates for Advanced HR+ Breast Cancer
- The MONALEESA-3 trial in HR+/HER2- advanced breast cancer evaluated fulvestrant ± ribociclib in both treatment-naive patients and those who had progressed on prior ET.
- Recently, updated overall survival (OS) results were presented from the first-line cohort, where we continue to see an OS benefit with the addition of ribociclib: 67.6 months vs 51.8 months. These results are unprecedented.
- Recently presented were the OS results from PALOMA-2, which evaluated the addition of palbociclib to letrozole in the frontline setting for metastatic HR+ breast cancer.
- Here, there was no statistically significant improvement in OS with the addition of palbociclib to letrozole, with a median OS of 54 months vs 51 months and a hazard ratio of 0.96.
- There was a statistically significant delay in time to use of chemotherapy with palbociclib: 38.1 months vs 29.8 months.
- In an unplanned exploratory analysis, there was a progression-free survival (PFS) benefit (64 months vs 45 months) in patients with a disease-free interval >12 months in a combined analysis of PALOMA-1 and PALOMA-2.
Why do we see differences in OS outcomes with ribociclib plus ET vs palbociclib plus ET, and how does this affect practice?
- First, as a reminder, PFS—not OS—was the primary endpoint for these trials.
- The conflicting OS data are frustrating and present a dilemma; looking at the primary endpoint of PFS, we see identical curves and hazard ratios.
- Potential reasons for differences in OS could include missing data (21% in the control arm in PALOMA- 2), lack of crossover data, and potential differences in patient population. Finally, we need to consider that there might be differences between palbociclib and ribociclib/abemaciclib.
- We previously had an OS benefit with ribociclib in our premenopausal patients from MONALEESA-7, but how does this affect our postmenopausal patients? We lack head-to-head trials comparing these agents.
- However, we need to acknowledge the efficacy results we have, especially the consistent OS benefit seen across the MONALEESA trials, then consider comorbidities, concurrent medications, etc. Ultimately, the selection of CDK4/6 inhibitors comes down to shared decision-making between the patient and physician.
- For patients who have been maintained on, say, palbociclib and are doing well, there is nothing to suggest that they need to be changed to ribociclib given the recent data.
Is there a role for CDK4/6 inhibitors after progression on a CDK4/6 inhibitor?
The recently presented phase II MAINTAIN trial evaluated ribociclib plus ET (fulvestrant or exemestane) vs placebo plus ET after progression on any CDK4/6 inhibitor plus ET in 120 patients with HR+ disease; patients may have received up to 1 prior line of chemotherapy.
- The primary endpoint of PFS was significantly improved in the ribociclib arm compared with placebo; median PFS was 5.3 months vs 2.8 months.
- We need more definitive trials to validate if continuation of a CDK4/6 inhibitor after progression should become the standard of care. The ongoing PACE (NCT03147287), PALMIRA (NCT03809988), postMONARCH (NCT05169567), and EMBER-3 (NCT04975308) trials will help answer this question.
Novel Therapies in the Metastatic Setting
Oral SERDs are being evaluated in an attempt to improve on fulvestrant and to enhance options for patients with ESR1 mutations.
- Amcenestrant, camizestrant, elacestrant, giredestrant, imlunestrant, and rintodestrant are a few of the oral SERDs currently in clinical trials.
- The recently published EMERALD trial is the first to present phase III randomized data for an oral SERD—elacestrant—vs investigator’s choice ET.
- In patients who had previously received a CDK4/6 inhibitor plus ET, there was a statistically significant reduction in progression or death with elacestrant, and the 6-month and 12-month PFS rates favored elacestrant both in the intent-to-treat and ESR1-mutated patients.
- The phase III DESTINY-Breast04 trial evaluated trastuzumab deruxtecan vs treatment of physician’s choice for patients with HER2-low (IHC1+ or IHC2+/ISH-) breast cancer who had received up to 2 previous lines of chemotherapy in the metastatic setting.
- In the approximately 500 patients with HR+ disease, trastuzumab deruxtecan demonstrated a significant improvement in PFS and a dramatic OS benefit of approximately 6 months; the benefit was maintained in all patients, as well.
- We are hopeful for FDA approval for trastuzumab deruxtecan in patients with HER2-low breast cancer, which will significantly affect treatment for our patients.
- The phase III TROPiCS-02 trial evaluated sacituzumab govitecan vs treatment of physician’s choice in more than 500 patients with HR+/HER2- locally recurrent inoperable or metastatic breast cancer; patients had received 2-4 lines of chemotherapy in the metastatic setting.
- The median PFS was improved from 4 months to 5.5 months with sacituzumab govitecan vs treatment of physician’s choice in this heavily pretreated population; OS results are not yet mature.
Laura M. Spring, MD
Key Points with Targeted Therapy Toxicity Prevention and Management
- With the CDK4/6 inhibitors, diarrhea is most prominent with abemaciclib, whereas neutropenia is observed more with palbociclib and ribociclib. Hepatobiliary toxicity is more likely to be seen with abemaciclib and ribociclib. Ribociclib may cause QT prolongation and requires ECG monitoring.
- Recently published data from monarchE on the onset and severity of diarrhea with abemaciclib found that it was mostly low grade, occurred early, and was short lived.
- The most common AEs seen with the PI3K inhibitor alpelisib include hyperglycemia, diarrhea, rash, and stomatitis. Hyperglycemia and rash tend to occur earlier, whereas diarrhea can be seen later. An antihistamine can be administered prophylactically to reduce the risk of rash, and there are recommendations to support prophylactic administration of metformin in patients with risk factors for hyperglycemia. It is important to check A1C prior to initiating alpelisib and to monitor glucose closely.
- An online interactive tool is available with guidance on managing AEs with oral targeted therapies for HR+/HER2- breast cancer and can be found here.
AEs With Novel Therapies for HR+ Breast Cancer
- With the oral SERDs, nausea appears to be the most notable AE at present compared with standard ET.
- Pneumonitis/interstitial lung disease is a known risk with trastuzumab deruxtecan and was reported in 12.1% of patients in the DESTINY-Breast04 trial.
- With sacituzumab govitecan, the common AEs neutropenia, diarrhea, and nausea were reported in TROPiCS-02, which is consistent with previous studies of this antibody–drug conjugate.
What have been your successes and challenges with targeted therapies for patients with HR+ breast cancer? Have you used targeted therapy for your patients with early stage disease yet? Answer the polling question and join the conversation by posting a comment in the discussion section below.