Efficacy and safety of palbociclib in combination with letrozole as first-line treatment of ER-positive, HER2-negative, advanced breast cancer: expanded analyses of subgroups from the randomized pivotal trial PALOMA-1/TRIO-18

Cyclin-dependent kinases (CDKs) are a large family of serine-threonine kinases that play several critical roles in cell cycle regulation. They are an attractive therapeutic target given that alterations in cell cycle genes have been implicated in breast cancer as well as multiple other malignancies. Palbociclib (PD-0332991) is a first-in-class, orally active, selective, reversible inhibitor of CDK 4 and 6 [1]. Pre-clinical studies have demonstrated the activity of palbociclib in blocking growth of estrogen receptor (ER)-positive luminal cell lines alone and in combination with anti-estrogens [2]. Clinical data have recently established palbociclib as a novel therapeutic option for women with ER+, human epidermal growth factor receptor 2 (HER2)-negative, advanced breast cancer [3–5]. In the randomized, open-label, phase II PALOMA-1/TRIO-18 trial, the safety and efficacy of palbociclib in combination with the aromatase inhibitor letrozole was compared with letrozole alone as first-line treatment of women with ER-positive, HER2-negative (ER+/HER2–), advanced breast cancer [3]. A total of 165 postmenopausal women with ER+/HER2– advanced breast cancer who had not received any treatment for their advanced disease were randomized (1:1), 84 to palbociclib plus letrozole and 81 to letrozole alone. The study stratified patients by disease site and disease-free interval. The primary endpoint was investigator-assessed progression-free survival (PFS). At the time of the data cut-off for the final analysis (29 November 2013), median follow-up was 29.6 months (95 % confidence interval (CI) 27.9–36.0) for the palbociclib plus letrozole arm and 27.9 months (95 % CI 25.5–31.1) for the letrozole arm [3]. Median PFS in the intention-to-treat (ITT) population was 20.2 months (95 % CI 13.8–27.5) for the palbociclib plus letrozole arm and 10.2 months (95 % CI 5.7–12.6) for the letrozole arm (hazard ratio (HR) = 0.488, 95 % CI 0.319–0.748; one-sided p = 0.0004) [3]. The clinical benefit response (CBR) rate (complete response + partial response + stable disease ≥24 weeks) for the ITT population was 81 % in the palbociclib plus letrozole arm and 58 % in the letrozole arm [3]. Overall survival data were not mature at the time of the data cut-off. Grade 3 neutropenia was the most common adverse effect in the palbociclib plus letrozole arm (48 % versus 1 % in the letrozole alone arm) [3]. On the basis of these data, palbociclib (Ibrance®, Pfizer) was granted accelerated approval by the US Food and Drug Administration (FDA) in February 2015, in combination with letrozole as initial endocrine-based therapy for postmenopausal women with ER+/HER2– metastatic breast cancer [6].

Despite the high incidence of neutropenia in the palbociclib plus letrozole arm of the PALOMA-1/TRIO-18 trial, there were no reported cases of febrile neutropenia or neutropenia-related infections. This is in contrast to cytotoxic chemotherapy where neutropenia is not only a common dose-limiting toxicity but is also associated with serious infections and infection-related morbidity [7, 8]. Ensuing complications can result in hospitalization, high treatment costs, and increased mortality [9–11].

There are two objectives in the current study: 1) to perform an expanded analysis of the efficacy (PFS and CBR) and safety of palbociclib plus letrozole in clinically relevant subgroups from the PALOMA-1/TRIO-18 trial including age <65 years or ≥65 years, pathologic type (ductal versus lobular carcinoma), effect of prior neoadjuvant/adjuvant systemic treatment, and metastasis in bone only, visceral sites, or other sites (i.e., soft-tissue, nodes, and so forth); and 2) to further delineate clinical patterns of neutropenia associated with palbociclib in the PALOMA-1/TRIO-18 trial in order to aid clinicians in the management of palbociclib-induced neutropenia.

Hormone receptor-positive (HR+) breast cancer remains the most common sub-type of breast cancer. Historically, the most important therapeutic intervention in the management of patients with HR+ breast cancer has been the use of anti-estrogen therapy, including tamoxifen, aromatase inhibitors, and fulvestrant. Advanced breast cancer remains incurable, although with currently available therapies median survival is in the order of 3–4 years [12–14]. The PALOMA-1/TRIO-18 data and the regulatory approval of palbociclib represent the first novel non-endocrine therapy to improve PFS in the front-line setting of postmenopausal women with ER+/HER2– advanced breast cancer. While confirmation of this finding is pending the results of the PALOMA-2/TRIO-22 study which is a randomized, double-blind study of palbociclib and letrozole versus placebo and letrozole, results from the double-blind, placebo-controlled PALOMA-3 study, evaluating palbociclib and fulvestrant versus fulvestrant in a hormone-refractory population confirm the important role of CDK 4/6 inhibition in ER+/HER2– breast cancer. At this time, survival data from both studies are not mature, but the significant improvement in PFS of over 10 months in PALOMA-1/TRIO-18 is clinically meaningful. It is also interesting to note that the FIRST study, an open label, randomized, phase II study comparing fulvestrant versus anastrozole in a front-line, aromatase inhibitor-naive, ER+ population, demonstrated an improvement of 10 months in time to progression with fulvestrant (23.4 months for fulvestrant versus 13.1 months with anastrozole) [15] that ultimately resulted in an improvement in overall survival [12].

In the current study, we explored the clinical benefit and safety profile of palbociclib and letrozole in various sub-groups from the PALOMA-1/TRIO-18 trial, on the basis of both patient and tumor characteristics. When the subgroups were analyzed on the basis of age (<65 years and ≥65 years), there was a consistent benefit from the addition of palbociclib regardless of age. These observations are important given that age-related disparities have been reported for breast cancer outcomes [16]. Furthermore, the incidence of Grade 3/4 adverse events, the rate of dose reductions, and the rate of discontinuations were similar in the two age groups.

PALOMA-1/TRIO-18 was a front-line treatment study for advanced breast cancer, but about half of the patients had prior systemic therapy in the neoadjuvant/adjuvant setting. The prior systemic therapy received included both chemotherapy and anti-hormone approaches such as non-steroidal aromatase inhibitors, steroidal aromatase inhibitors, and tamoxifen. Consistent with our understanding of drug resistance, the largest benefit with palbociclib plus letrozole was seen in those patients that had never received any prior adjuvant therapy (HR = 0.341, 95 % CI 0.194–0.599; p = 0.00004). However, even in those patients that received prior systemic therapy, the benefit of treatment was clinically meaningful (HR = 0.539, 95 % CI 0.302–0.962; p = 0.0169). Importantly, in those patients that had had prior endocrine therapy, the HR was 0.46 (95 % CI 0.222–0.956; p = 0.0165), supporting our hypothesis that CDK 4/6 inhibition with palbociclib can overcome resistance to endocrine therapy [2].

In regard to tumor characteristics, we evaluated both histologic features and anatomic features. While the majority of invasive breast cancers are ductal in origin, approximately 10–15 % are lobular. As expected, the majority of patients in the PALOMA-1 trial had ductal carcinoma. In general, it is felt that lobular carcinomas have a better prognosis than ductal carcinomas, are more sensitive to endocrine therapy, and do not respond as well to systemic chemotherapy [17]. With these factors in mind, we explored whether there was a differential effect seen with the addition of palbociclib in these two histologies. When comparing the letrozole arms of the two subgroups, the ductal carcinoma subgroup had a better PFS than the lobular carcinoma subgroup (11.1 months versus 4.8 months). This observation clearly needs to be interpreted with caution given that there were only 19 patients in the letrozole arm of the lobular carcinoma subgroup and other clinical factors were not accounted for; for example, more patients with lobular carcinoma received adjuvant systemic therapy versus the ductal group. Nevertheless, both groups appear to have benefited from the addition of palbociclib, with a HR of 0.393 (95 % CI 0.239–0.647; p = 0.00007) in the ductal group and 0.626 (95 % CI 0.282–1.391; p = 0.123) in the lobular group. The p value of 0.123 in the lobular group likely reflects the small sample size. Whether or not this difference in degree of benefit is significant will need to be established in larger studies.

Another relevant baseline prognostic factor we evaluated was anatomic stage of the disease. While virtually all of the patients had Stage IV disease, there was a mixture of those that had visceral disease versus bone-only or other sites of disease, such as soft tissue or lymph node metastases. The HR values for these groups (visceral disease, bone-only, other sites) were 0.547 (95 % CI 0.317–0.944; p = 0.0137), 0.294 (95 % CI, 0.092–0.945; p = 0.0148), and 0.402 (95 % CI, 0.200–0.808; p = 0.0040), respectively. While the degree of benefit mimics the prognosis for these groups, even in the worst prognosis patient group (i.e., those with visceral disease) there was a 45 % decrease in the risk of progression with palbociclib. In addition, the clinical benefit rate in this group, while less than the other two groups, was still over 75 %, confirming that the combination is an appropriate option for women with visceral disease. This is particularly relevant given that this group of patients is often considered for front-line chemotherapy over endocrine therapy.

Finally, the therapeutic benefit of any new agent needs to be weighed against its side effects profile. As previously reported [3], the most common side effects with the combination therapy were neutropenia, leukopenia, and fatigue. Palbociclib is dosed using a 3-week on, 1-week off regimen to manage the neutropenia/leukopenia side effect. While the high incidence of Grade 3/4 events in the neutropenia/leukopenia categories is cause for concern, importantly these events were not associated with serious infections. This observation was also made in the larger, double-blind, placebo-controlled PALOMA-3 study [5]. The current US Prescribing Information for Palbociclib (Ibrance®) [18] recommends checking the absolute neutrophil count on day 1 and day 14 of the first two cycles of therapy. This monitoring schedule was chosen considering that the onset of neutropenia occurred early during treatment, with median time to any grade, Grade ≥3, and Grade 4 neutropenia being 20 days, 28 days, and 16 days, respectively. The study data demonstrate that there is no cumulative toxicity with regard to neutropenia; instead, its incidence decreases over time.

For a newly diagnosed patient with ER+/HER2– advanced breast cancer, the treating physician is faced with the decision of treating with endocrine therapy or chemotherapy. This decision is affected by factors such as menopausal status, ECOG performance status, sites of disease, and type and length of time from prior adjuvant therapy. Based on the data from PALOMA-1/TRIO-18, palbociclib received accelerated approval from the US FDA for use in these patients. The role of CDK 4/6 inhibition in ER+/HER2– breast cancer has now been further validated in the larger, PALOMA-3 study. The findings presented here confirm the consistent benefit of palbociclib and letrozole in several relevant clinical subgroups, including patients of older age, patients with both lobular and ductal carcinoma, and patients with various disease sites and prior adjuvant therapy. The PALOMA-1/TRIO-18 study was the first study to demonstrate a significant improvement in PFS with a novel agent in the first-line treatment of advanced ER+/HER2– breast cancer. These findings now await confirmation in the larger, phase III, double-blind, placebo-controlled PALOMA-2/TRIO-22 study which has completed enrollment and is awaiting analyses based on accruing events (NCT01740427).

We performed an expanded analysis of the efficacy (PFS and CBR) as well as the safety of palbociclib plus letrozole in clinically relevant subgroups from the PALOMA-1/TRIO-18 trial. The degree of benefit in both median PFS and the CBR rate observed as a result of the addition of palbociclib to letrozole was consistent in nearly all subgroups analyzed and was consistent with that seen in the overall study population. The safety profile of the combination treatment in all subgroups was comparable to that in the overall safety population of the study. The frequency of Grade 3–4 neutropenia in the overall safety population of the study decreased over time. Neutropenia was not associated with serious infections or infectious complications.