Real-World Tumor Response of Palbociclib Plus Letrozole Versus Letrozole for Metastatic Breast Cancer in US Clinical Practice

In the USA, it was estimated that 276,480 women would be diagnosed with invasive breast cancer and 42,170 women would die from breast cancer in 2020 [1]. The majority of patients with breast cancer have hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2‒) disease [2], and approximately one-third of those diagnosed with early breast cancer eventually develop metastatic disease, for which there is no cure [3, 4]. A cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, such as palbociclib, in combination with endocrine therapy (ET) has been recommended as standard of care for patients with HR+/HER2‒ advanced or metastatic breast cancer (MBC) [5, 6].

In the PALOMA-2 clinical study, first-line palbociclib plus letrozole therapy significantly improved median progression-free survival (PFS) compared with placebo plus letrozole (27.6 vs. 14.5 months; P < 0.0001; data cutoff: 31 May 2017) in postmenopausal women with estrogen receptor-positive (ER+)/HER2‒ MBC [7]. The objective response rate (defined as confirmed complete response (CR) or partial response (PR) based on Response Evaluation Criteria in Solid Tumors (RECIST)) was 42.1% with palbociclib plus letrozole compared with 34.7% with placebo plus letrozole (odds ratio (OR), 1.40 (95% confidence interval (CI), 0.98‒2.01), P = 0.06) [8].

Using real-world evidence to complement data from randomized controlled clinical studies is important because the stringent inclusion and exclusion criteria of oncology clinical studies exclude a substantial proportion of the patient population with cancer [9, 10]. The evaluation of multiple clinical outcomes is also important to further understand the effectiveness of treatments in the real-world setting. The various real-world endpoints have unique strengths and limitations [11, 12]. Real-world time to treatment failure is defined as the time from the start of treatment to treatment discontinuation for any reason, including death, disease progression, or adverse events [13]. However, time to treatment failure is usually not recommended as an outcome for the regulatory approval evaluation of a new treatment because many factors may affect the time to treatment failure [13]. Real-world time to next treatment, which is defined as the time from the end of the initial treatment to the start of the next treatment, is another clinical outcome that may be evaluated, but is limited by variability in practice patterns and inaccuracy in capturing precise times of treatment initiation [12]. Real-world tumor response is evaluated based on radiologic evidence for change in disease burden throughout the course of treatment as assessed by the treating physician [14]. Real-world PFS (rwPFS) is defined as the time from the start of treatment to death or disease progression, with the treating clinician determining disease progression using radiology, pathology, laboratory findings, or clinical assessment [14]. Real-world tumor response may be assessed more reliably and objectively than rwPFS; however, there is a lack of uniformity in the timing or frequency and criteria of tumor assessment during treatment in clinical practice [12]. In addition, real-world tumor response alone may under-estimate treatment effectiveness as many patients derive benefit from prolonged stable disease [12]. Therefore, evaluation of the clinical effectiveness of a treatment utilizing multiple outcome measures is more robust and can provide a more complete understanding of treatment benefit than using any one real-world endpoint.

Findings from small and single-arm real-world studies evaluating rwPFS and OS outcomes have supported the benefit of palbociclib observed in clinical trials [15‐21]. A real-world comparative effectiveness analysis using the Flatiron Health Analytics database showed that first-line palbociclib plus letrozole was more effective than letrozole alone based on median real-world PFS (20.2 vs. 11.9 months; hazard ratio, 0.54 (95% CI 0.46‒0.65); P < 0.0001) and overall survival (OS) results (not reached vs. 43.1 months; hazard ratio 0.58 (95% CI 0.46‒0.73); P < 0.0001) after propensity-score matching (PSM) [22]. Additionally, a recent real-world study using the Flatiron Health database evaluated tumor response to abemaciclib in 118 patients with HR+/HER2‒ MBC who received abemaciclib across various lines of treatment [23].The analysis showed that 41.2% of patients had a real-world best response (defined as real-world CR or PR).

There is limited information, however, regarding tumor response to palbociclib plus an aromatase inhibitor (AI) compared with an AI alone in real-world clinical practice [24]. A multi-country retrospective medical chart review of patients with HR+/HER2‒ advanced breast cancer (ABC) or MBC, who received palbociclib in combination with either an AI or fulvestrant in real-world clinical practice, reported a real-world objective response rate (based on physicians’ assessments) of 79.5% in the USA and 66% in Argentina [19]. Additionally, a small real-world study of patients with HR+/HER2‒ ABC or MBC treated with palbociclib plus an AI or fulvestrant in Italy demonstrated a real-world objective response rate of 31% [21]. The variation in response rates observed could be attributed to differences in patient characteristics as well as the methods and criteria used to assess tumor response.

To add to the rwPFS and OS results previously reported from the Flatiron Health Analytics database [22], this retrospective analysis (using the same database) describes demographic and clinical characteristics and real-world best tumor response (rwBTR, defined as CR or PR based on the treating clinician’s assessment of radiologic evidence) among a large sample of HR+/HER2‒ MBC patients initiating palbociclib plus letrozole compared with letrozole alone as first-line therapy in routine US clinical practice. This analysis also evaluated rwBTR rates by subgroup, including by visceral disease and bone-only metastases.

To our knowledge, this is the first comparative analysis of real-world tumor response in patients with HR+/HER2‒ MBC treated with first-line palbociclib plus letrozole versus letrozole alone in the real-world clinical setting. Tumor response assessments are important in clinical practice when treating patients with cancer [29]. A previous study has shown that partial or complete tumor response is associated with cancer-related symptom improvement in patients with MBC [30]. Moreover, early identification of nonresponding tumors and ineffective therapies are important to minimize the risk of disease progression and to decrease the extent of visceral disease [29].

Findings from this comparative analysis showed that patients treated in the first-line setting with palbociclib plus letrozole had an associated increased likelihood of tumor response compared with those treated with letrozole alone (after PSM, 58.6% vs. 39.1%, respectively; OR 2.21 (95% CI 1.50‒3.25), P < 0.0001). Additionally, a generally consistent benefit of palbociclib plus letrozole versus letrozole alone was shown across subgroups, including by visceral disease and presence of bone-only metastases, with no significant interactions demonstrated in any of the subgroups evaluated. These findings complement data from randomized clinical studies showing the efficacy of palbociclib plus letrozole [7, 8, 31].

Patients included in the PALOMA-2 clinical study were postmenopausal with ER+/HER2‒ ABC who had not received prior systemic therapy for advanced disease [8]. Among all the randomized patients, the objective response rate was 42.1% (95% CI 37.5‒46.9) with palbociclib plus letrozole and 34.7% (95% CI 28.4‒41.3) with placebo plus letrozole [8]. Among patients who had measurable disease based on the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, the objective response rate was 55.3% (95% CI 49.9‒60.7) with palbociclib plus letrozole and 44.4% (95% CI 36.9‒52.2) with placebo plus letrozole [8]. Results from this comparative analysis also demonstrated that the real-world CR rates were similar between patients treated with palbociclib plus letrozole and those who received letrozole alone (approximately 10% in both groups before and after PSM/stabilized inverse probability of treatment weighting). These results complement the CR rates reported in postmenopausal women with ER+/HER2– ABC who received first-line palbociclib plus letrozole or letrozole alone (1% in both groups) in the PALOMA-1 randomized clinical study [32] and in those who received first-line palbociclib plus letrozole or placebo plus letrozole (2.0% and 2.3%, respectively) in the PALOMA-2 randomized clinical study (data on file; Pfizer Inc, Full Clinical Study Report A5481008; 2016). The differences in CR rates observed between this present analysis and findings from the randomized clinical studies can be attributed to the differences in tumor response assessment and criteria.

The present real-world data and previous results from palbociclib clinical studies were generally similar to findings shown in randomized clinical studies of other CDK4/6 inhibitors for the treatment of women with HR+/HER2‒ ABC who had not received prior systemic therapy for advanced disease [32, 33]. In the MONALEESA-2 study, the objective response rate among all patients was 47% (95% CI 38‒57) in the ribociclib plus letrozole group and 34% (95% CI 25‒42) in the placebo plus letrozole group [32]. In patients who had measurable disease, the objective response rate was 56% (95% CI 46‒66) with ribociclib plus letrozole and 45% (95% CI 34‒55) with placebo plus letrozole [32]. Similarly, findings from the MONARCH 3 study reported an objective response rate of 48.2% (95% CI 42.8‒53.6) with abemaciclib plus a nonsteroidal AI and 34.5% (95% CI 27.3‒41.8) with placebo plus a nonsteroidal AI [33]. In patients with measurable disease, the objective response rate was 59.2% (95% CI 53.3‒65.1) in the abemaciclib group and 43.8% (95% CI 35.3‒52.4) in the placebo group [33]. Together, these studies highlight the consistency of tumor response data across all CDK4/6 inhibitors, and consistent with National Comprehensive Cancer Network guidelines [5], support CDK4/6 inhibitors in combination with ET as first-line therapy for HR+/HER2‒ advanced/MBC.

This analysis also showed the benefit of palbociclib plus letrozole compared with letrozole alone in terms of median rwPFS and OS results. After PSM, median rwPFS was 27.4 months with palbociclib plus letrozole and 15.4 months with letrozole alone (hazard ratio, 0.60 (95% CI 0.46‒0.79), P = 0.0002); median OS was not reached in either the palbociclib plus letrozole or the letrozole alone group (hazard ratio, 0.58 (95% CI 0.39‒0.85), P = 0.0052). These findings are consistent with a previous Flatiron Health real-world comparative effectiveness analysis; palbociclib plus letrozole was associated with longer median rwPFS and OS compared with letrozole alone (20.2 vs. 11.9 months and not reached vs. 43.1 months, respectively, both P < 0.0001) [22]. These results also complement the results from the PALOMA-2 clinical study, which reported a median PFS of 27.6 months with palbociclib plus letrozole versus 14.5 months with placebo plus letrozole (P < 0.0001; data cutoff: 31 May 2017) [7]. OS data from PALOMA-2 have not been reported yet.

The present findings should be interpreted in the context of the following limitations. First, this is a retrospective analysis of data from an EHR database and causal relationships to treatment cannot be determined. Second, similar to other EHR databases, the Flatiron Health database may have missing or erroneous data, including data that may not be missing at random [34]. Tumor response assessments were missing in a higher proportion of patients treated with letrozole alone compared with those treated with palbociclib plus letrozole. Third, tumor assessments in routine practice were not scheduled and were not confirmed by additional imaging. These data were limited by the clinician’s interpretation and documentation of tumor response based on radiologic evidence for change in burden of disease, and tumor response assessment was not based on RECIST. Fourth, although PSM was used to balance patient characteristics and stabilized inverse probability of treatment weighting was used as a sensitivity analysis, other variables unavailable in the database, such as menopausal status, disease-free interval, and endocrine sensitivity could not be statistically controlled. Additionally, tolerability and adverse events data were not collected in the database and were not evaluated in this analysis. Moreover, these findings may not be generalizable to other patient populations.

Despite these limitations, the real-world tumor response findings and associated response benefit shown in patients treated with palbociclib plus letrozole are supported by the observed rwPFS and OS benefit. In addition, results from the stabilized inverse probability of treatment weighting sensitivity analysis were consistent with findings from the PSM analysis. Moreover, the real-world tumor response variable is less likely to be confounded by comorbid conditions, unobserved variables, or subsequent treatments that may affect PFS or OS. Although further real-world studies are needed, these findings add to the current body of evidence supporting the effectiveness of palbociclib combination therapy in the first-line setting, complementing the results from randomized clinical studies and other evidence of effectiveness endpoints. Real-world studies provide valuable insights into the benefits of palbociclib in a general oncology population of patients with HR+/HER2‒ ABC/MBC treated in routine clinical practice, including those with demographic and disease characteristics that may not be represented in randomized clinical trials.

Patients with HR+/HER2‒ MBC treated with first-line palbociclib plus letrozole were associated with a significantly higher likelihood of tumor response than those treated with letrozole alone in this large cohort of general oncology practice patients in the USA. In addition, treatment with first-line palbociclib plus letrozole was associated with significant rwPFS and OS improvement compared with letrozole alone. These data complement the clinical benefit observed with palbociclib plus endocrine therapy in randomized clinical trials and support palbociclib plus letrozole as a standard of care for patients with HR+/HER2‒ MBC.