Over the past few years, the treatment of advanced or metastatic hormone receptor–positive, HER-2–negative (HR+/HER2-) breast cancer has been transformed by the introduction of cyclin-dependent kinase-4 and -6 (CDK4/6) inhibitors. Three CDK4/6 inhibitors are now available around the world—palbociclib, ribociclib, and abemaciclib. Major guidelines recommend the use of these agents in both first-line and second-line treatment, and they have now become the standard of care.[1,2]
These therapies were approved based on the results of several large international, multicenter, randomized clinical trials. Since the initial publication of those trials, longer-term data have been reported and additional studies have shed further light on the effects of CDK4/6 inhibitors on key outcome measures.
CDK4/6 Inhibitors in First-Line Treatment
Current guidelines are unequivocal in recommending that women with advanced or metastatic HR+/HER2- breast cancer should receive first-line treatment with either an aromatase inhibitor or fulvestrant, together with a CDK4/6 inhibitor.[1,2] Although CDK4/6 inhibitors have not been systematically evaluated in men, guidelines indicate that it is reasonable to recommend these agents for men based on extrapolation of data from studies that primarily enrolled women and also on recent real-world studies.[1,2]
Palbociclib was the first CDK4/6 inhibitor to be approved for use in clinical practice. The benefits of palbociclib as initial treatment in advanced or metastatic HR+/HER2- breast cancer were demonstrated in the phase II PALOMA-1 trial. In 165 postmenopausal women with advanced disease, addition of palbociclib to letrozole significantly increased progression-free survival (PFS) compared with letrozole monotherapy (20.2 months versus 10.2 months; HR 0.488, 95% CI 0.319 to 0.748, P=0.0004).
These findings were confirmed in the larger, phase III PALOMA-2 study, in which 666 previously untreated postmenopausal women were randomized to receive either palbociclib plus letrozole or placebo plus letrozole until disease progression or unacceptable toxicity occurred. The median PFS was 24.8 months in women who received palbociclib plus letrozole compared with 14.5 months in those who received placebo plus letrozole (HR 0.58, 95% CI 0.46 to 0.72, P<0.001).
Despite the large number of women who participated in PALOMA-2, the diverse patient population was not conducive to statistical demonstration of OS benefit. Patients treated with palbociclib plus letrozole had a numerically longer OS (53.9 months) compared with those who received placebo and letrozole (51.2 months). This lack of overall survival benefit can be attributed to multiple factors. The trial was not powered to demonstrate an OS benefit. The study included a significant proportion of women (20%) who had relapsed within a year of completing adjuvant endocrine therapy. There was also a substantial proportion of patients with missing survival data, 13% versus 21% in the palbociclib and placebo arms respectively. At the time of the final analysis, 10% of women in the palbociclib group and 2% in the placebo group were still on study treatment.
A CDK4/6 inhibitor is generally given with letrozole in the first-line setting; the PARSIFAL trial was designed to determine whether fulvestrant would be a more effective option. A total of 486 women were randomized to receive either palbociclib and letrozole or palbociclib and fulvestrant. The study found no difference between the two regimens with respect to either PFS or OS.
The safety and efficacy of ribociclib as first-line treatment in postmenopausal women was demonstrated in the MONALEESA-2 trial. In this phase III study, 668 women with HR+/HER2- recurrent/metastatic breast cancer were randomized to receive either ribociclib and letrozole or placebo and letrozole. After a median follow-up duration of 26.4 months, the median PFS for the ribociclib group was 25.3 months versus 16.0 months for the placebo group (HR 0.568, 95% CI 0.457 to 0.704, P=9.63×10-8). This benefit was maintained regardless of PIK3CA or TP53 mutation status, but it was more pronounced in patients with wild-type tyrosine kinase genes compared with those who had alterations in these genes. After a median follow-up of 6.6 years, a significant improvement in OS was demonstrated for the addition of ribociclib (63.9 months versus 51.4 months; HR 0.76, 95% CI 0.63 to 0.93, P=0.008).
The phase III MONALEESA-7 trial was the first major study to evaluate a CDK4/6 inhibitor in premenopausal women. It included 672 women with advanced or metastatic HR+/HER2- advanced breast cancer who were randomized to receive ribociclib or placebo, together with goserelin and either an aromatase inhibitor or tamoxifen. Women treated with ribociclib had a significantly longer median PFS of 23.8 months compared with 13.0 months in women who received placebo (HR 0.55, 95% CI 0.44 to 0.69, P<0.0001). A subsequent analysis with median follow-up of 53.5 months, demonstrated a median OS of 58.7 months with ribociclib versus 48.0 months with placebo (HR 0.76, 95% CI 0.61 to 0.96).
The MONALEESA-3 trial found the combination of ribociclib and fulvestrant to be an appropriate alternative to a CDK inhibitor and letrozole in the first-line setting. The study enrolled both endocrine-naïve postmenopausal women and postmenopausal women who had received prior endocrine therapy. Among the total study population, 367 of the women (51%) had not received prior endocrine therapy or chemotherapy for advanced disease. In this subgroup, the combination of ribociclib and fulvestrant improved PFS compared to placebo and fulvestrant (HR 0.577, 95% CI 0.415 to 0.802).
Abemaciclib was evaluated as first-line therapy in the phase III MONARCH 3 trial, which involved 493 postmenopausal women with advanced HR+/HER2- breast cancer, who had no prior systemic therapy in the advanced setting. These patients were randomized to receive treatment with either abemaciclib or placebo, together with an aromatase inhibitor. After a median follow-up of 26.73 months, the median PFS in abemaciclib-treated patients was 28.18 months, compared with 14.76 months in placebo-treated patients (HR 0.540, 95% CI 0.418 to 0.698, P=0.000002). Recently presented data with a median follow-up of 70.2 months also showed a nonsignificant trend towards increased OS (67.1 months versus 54.5 months; HR 0.754, 95% CI 0.584 to 0.974, P=0.03).
Real-World Outcomes After First-Line CDK4/6 Inhibitor
Patients who are treated in the typical oncology practice are commonly quite different from those enrolled in controlled clinical trials, which generally have strict inclusion and exclusion criteria. Real-world evidence can provide valuable insights into the effects of therapies in the oncology clinic.
A recent systematic literature review examined 114 real-world studies evaluating CDK4/6 inhibitors in patients with HR+/HER2- advanced or metastatic breast cancer. More than two-thirds of those studies looked at the effects of palbociclib treatment; only a limited number of conference abstracts assessed real-world outcomes with ribociclib or abemaciclib. The review found that overall PFS was similar to the results seen in clinical trials. However, the majority of real-world studies included data from relatively small numbers of patients and many did not capture OS.
The P-REALITY X study analyzed real-world data from a large and diverse US patient population in the Flatiron Health Analytic Database. Patients with metastatic breast cancer in this database have been shown to be consistent with data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results program and the US Centers for Disease Control’s National Program of Cancer Registries. P-REALITY X looked at outcomes for 2888 postmenopausal women and men with HR+/HER2− metastatic breast cancer who had received first-line treatment with either palbociclib and an aromatase inhibitor (AI) or an AI alone.
Whereas the median age of patients in PALOMA-2 was 61 to 62 years, the patient population in P-REALITY X was somewhat older, with a median age of 70 years. Demonstrating PFS and OS improvement in these older patients would be expected to be more challenging. Nevertheless, the benefits of first-line treatment with palbociclib and endocrine therapy were confirmed in this real-world population—patients who received palbociclib had a significantly longer PFS (19.3 months versus 13.9 months; HR 0.70, 95% CI 0.62 to 0.78, P<0.0001) and a significantly longer OS (49.1 months versus 43.2 months; HR 0.76, 95% CI 0.65 to 0.87, P<0.0001). Improvement in PFS and OS was observed across almost all subgroups, regardless of age, gender, race, performance status, disease stage at diagnosis, time from diagnosis to metastatic disease, and number of metastases. More than 90% of patients in P-REALITY X were treated in community clinics, rather than academic medical centers, which suggests that the observations may be more generalizable to routine clinical practice than the results of PALOMA-2.
An analysis of the real-world benefits of first-line treatment with ribociclib and an aromatase inhibitor was recently conducted using data from 160 patients at 17 sites in Australia. Whereas the mean age of women in MONALEESA-2 was 62.0 years, the mean age of patients in the real-world analysis was just 54.3 years. After a median follow-up of 36.5 months the median PFS had not been reached, and no OS data were available.
CDK4/6 Inhibitors After Progression on Endocrine Therapy
Current guidelines recommend treatment with a CDK4/6 inhibitor and fulvestrant for second-line therapy in patients who experience disease progression during or after an aromatase inhibitor, and who have not previously received a CDK4/6 inhibitor.[1,2] Other targeted therapies that may be considered include fulvestrant and alpelisib in patients with PIK3CA-mutated tumors. Other choices include fulvestrant monotherapy, and everolimus plus endocrine therapy. These recommendations are supported by several large studies.
The PALOMA-3 study included 521 women who had already experienced disease progression during or after previous endocrine therapy. Therefore, palbociclib was combined with fulvestrant instead of letrozole in this study. Once again, there was a significant increase in PFS for patients treated with palbociclib and fulvestrant compared with those who received placebo and fulvestrant (9.5 months versus 4·6 months; HR 0.46, 95% CI 0.36 to 0.59, P<0·0001).
Across the total study population, treatment with palbociclib and fulvestrant was also associated with a 6.9-month increase in the median OS compared with placebo and fulvestrant (34.9 months versus 28.0 months; HR 0.81, 95% CI 0.64 to 1.03, P=0.09). The survival benefit of palbociclib addition was greatest in patients who had sensitivity to previous endocrine therapy—within that subgroup, women who were treated with palbociclib and fulvestrant had a 10-month increase in OS (39.7 months versus 29.7 months; HR 0.72, 95% CI 0.55 to 0.94). Four years after publication of the original OS data from PALOMA-3, an updated analysis was conducted with a median follow-up of 73.3 months. It showed a 6-year OS rate of 19.1% for patients treated with palbociclib compared with 12.9% for those given placebo. This benefit was observed in most subgroups and was not affected by ESR1, PIK3CA, or TP53 mutation status.
In the MONALEESA-3 trial discussed above, 345 of the women (48%) had experienced disease progression after receiving up to one line of prior endocrine therapy for advanced disease. The median PFS in women treated with ribociclib and fulvestrant as second-line treatment was 14.6 months compared with 9.1 months in women who received placebo and fulvestrant (HR for disease progression or death 0.57, 95% CI 0.44 to 0.74). At data cut-off, median OS for second-line treatment with ribociclib was 39.7 months compared with 33.7 months for the placebo group (HR 0.78, 95% CI 0.59 to 1.04).
The MONARCH 2 trial examined the effects of adding abemaciclib to fulvestrant in 669 premenopausal, perimenopausal, and postmenopausal women who had experienced disease progression on prior endocrine therapy. Treatment with abemaciclib and fulvestrant in this broad population resulted in a significantly longer PFS compared with placebo and fulvestrant (16.4 months versus 9.3 months; HR 0.553, 95% CI 0.449 to 0.681, P<0.001). An increase in the median OS was also observed in this study—46.7 months for abemaciclib-treated patients versus 37.3 months for the placebo group (HR 0.757, 95% CI 0.606 to 0.945, P=0.01). The benefits of abemaciclib treatment in this population were more pronounced in patients with visceral disease or with primary resistance to prior endocrine therapy, but they were unaffected by menopausal status.
Treatment Options After Progression on a CDK4/6 Inhibitor
The most effective therapeutic approach when patients with advanced or metastatic HR+/HER2- breast cancer experience disease progression on or after treatment that includes a CDK4/6 inhibitor has not yet been established. At this time, few studies have looked at whether continued inhibition of CDK4/6 is still beneficial in this situation.
This question was explored in the phase II MAINTAIN trial, which involved 120 patients whose cancer had progressed during treatment with a CDK4/6 inhibitor and endocrine therapy. They were randomized to receive fulvestrant or exemestane with or without ribociclib. Patients who continued CDK4/6 inhibition with ribociclib had a significantly increased median PFS compared with those who did not receive ribociclib (5.33 months versus 2.76 months; HR 0.56, 95% CI 0.37 to 0.83, P=0.004). These results suggest that continuation of CDK4/6 inhibition may be beneficial in a subset of patients.
Research suggests that development of resistance to endocrine therapy is likely to precede resistance to a CDK4/6 inhibitor. That principle is consistent with observational data indicating that continuing treatment with the same CDK4/6 inhibitor and switching to a different endocrine therapy may be beneficial. However, no large prospective trials have evaluated this approach. Since only 11% of patients on the MAINTAIN study received ribociclib, the study also does not provide insight into whether there is a need to change to a different CDK4/6 inhibitor or the same drug can be continued with just change of the endocrine therapy.
In the recently published phase II BioPER trial, 33 women who experienced disease progression after previously achieving clinical benefit on palbociclib and endocrine therapy were rechallenged with palbociclib together with an endocrine therapy selected by the treating physician. The clinical benefit rate (complete response, partial response, or stable disease lasting 24 weeks or longer) was 34.4% (95% CI 18.6 to 53.2, P<0.001) and only 13% of tumors (95% CI 5.2 to 27.5) showed loss of retinoblastoma protein expression, which is associated with CDK4/6-independent breast cancer progression. Although a number of patients did not respond to palbociclib rechallenge, the study showed that certain biomarkers may be helpful in identifying patients who are most likely to benefit from continuation of CDK4/6 inhibition. Almost all of the patients who did not experience clinical benefit in this study had at least one baseline biomarker associated with worsened outcome (low Rb score, high cyclin E1 score, or ESR1 mutation).
A real-world study using a US electronic health record–derived database identified 839 patients who had experienced disease progression on first-line treatment with a CDK4/6 inhibitor and subsequently received a second-line therapy. In 36.0% of those patients, the second-line regimen included a CDK4/6 inhibitor (in most cases, it was the same CDK4/6 inhibitor that had been given in the first-line regimen). In 29.7% of patients, chemotherapy was the second-line treatment. Patients who received a CDK4/6 inhibitor in both the first-line and second-line setting had a longer PFS (HR 0.48, 95% CI 0.43 to 0.53, P<0.0001) and increased OS (HR 0.30, 95% CI 0.26 to 0.35, P<0.0001) compared with those who switched to chemotherapy.
More insight into the benefits of continuing treatment with the same CDK4/6 inhibitor is expected to be provided by the ongoing phase II PALMIRA trial. This study is measuring PFS in women who progressed on or after treatment with endocrine therapy and palbociclib and were subsequently treated with a second-line endocrine therapy with or without palbociclib.
The results of large international, multicenter, randomized clinical trials have shown that the use of a CDK4/6 inhibitor in both first-line and second-line treatment of advanced or metastatic HR+/HER2- breast cancer can significantly improve PFS and OS. Additional real-world evidence—particularly the findings from the P-REALITY X trial evaluating palbociclib—confirm that these benefits appear to be generalizable to patients seen in the typical oncology clinic.
There remains a question about the optimal therapeutic approach when patients experience disease progression after treatment with endocrine therapy and a CDK4/6 inhibitor. Although more data are needed to answer that question, studies so far suggest that a subset of patients will benefit from continued treatment with the CDK4/6 inhibitor. Certain biomarkers, such Rb score, cyclin E1 score, and ESR1 mutation, may be helpful in identifying patients who are most likely to benefit from continuation of CDK4/6 inhibition.
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Cite this: Dr Senthil J Rajappa. Current Challenges in the Treatment of HR-Positive/HER2-Negative Metastatic Breast Cancer - Medscape - Mar 30, 2023.