Palbociclib Plus Letrozole as First-Line Therapy in Postmenopausal Asian Women With Metastatic Breast Cancer: Results From the Phase III, Randomized PALOMA-2 Study.

PURPOSE: In PALOMA-2, palbociclib plus letrozole significantly improved progression-free survival (PFS) as initial treatment of estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer. We assessed the benefit of palbociclib plus letrozole in Asians. PATIENTS AND METHODS: Of 666 enrolled postmenopausal women with estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer (no prior treatment of advanced disease), 95 were Asian. Patients were randomly assigned 2:1 to receive palbociclib plus letrozole or placebo plus letrozole. The primary end point was investigator-assessed PFS. Secondary end points were overall survival, objective response, patient-reported outcomes, pharmacokinetics, and safety.
RESULTS: Median PFS was significantly longer in Asian patients who received palbociclib plus letrozole versus placebo plus letrozole (25.7 months [95% CI, 19.2 months to not estimable] v 13.9 months [95% CI, 7.4 to 22.0 months]; hazard ratio, 0.49; 95% CI, 0.27 to 0.87; P = .007). The most common toxicities with palbociclib were hematologic and more frequent among Asians versus non-Asians: neutropenia (any grade, 95.4% v 76.8%; grade 3/4, 89.2% v 62.5%), leukopenia (43.1% v 38.3%; 32.3% v 23.5%), and thrombocytopenia (27.7% v 13.5%; 4.6% v 1.1%). No Asians had febrile neutropenia. Discontinuation rates as a result of adverse events were similar among Asian and non-Asian patients who received palbociclib plus letrozole (10.8% and 9.5%). In Asians, quality of life (QOL) was maintained with no significant differences observed between treatments from baseline in breast cancer-specific QOL and general health status scores. Change from baseline in EuroQol five dimensions index scores was significantly higher with palbociclib plus letrozole (0.013 v -0.069; P = .0132). Geometric mean palbociclib trough concentration values were higher in Asians versus non-Asians (93.8 v 61.7 ng/mL).
CONCLUSION: Consistent with the overall study population, the addition of palbociclib to letrozole significantly improved PFS in Asians. Hematologic toxicities were more frequent in Asians versus non-Asians but manageable with early dose modifications while maintaining QOL.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Breast cancer accounts for 25% of all cancers and 15% of all cancer deaths among women worldwide, with incidence rates generally higher in North America than in Asia.[1] Although the incidence of breast cancer has been declining in some regions of the world,[2] it remains a leading cause of cancer death among Asian women.[3] The age-standardized incidence rates of advanced breast cancer in recent generations of Asian women have risen and, in some countries, surpassed the historically high rates in the United States. Globally, the majority of breast malignancies are hormone receptor positive/human epidermal growth factor receptor 2 (HER2) negative for which endocrine therapy has been a mainstay of treatment.[4,5] However, de novo and acquired resistance to endocrine therapy can develop, which often results in a therapeutic switch to chemotherapy that is associated with clinically significant toxicity.[5] Treatment options that improve outcomes with endocrine-based therapy and delay the use of chemotherapy are needed.

Palbociclib is a first-in-class oral small-molecule inhibitor of cyclin-dependent kinases 4 and 6 indicated for the treatment of hormone receptor‒positive/HER2-negative advanced or metastatic breast cancer in combination with fulvestrant in women with disease progression after endocrine therapy and in combination with an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women.[6] PALOMA-1 was an open-label, phase II study that evaluated palbociclib plus letrozole versus letrozole alone as frontline treatment in postmenopausal women with advanced estrogen receptor (ER)–positive/HER2-negative breast cancer.[4] This study was based on preclinical data that demonstrated that palbociclib preferentially inhibited the growth of ER-positive breast cancer cell lines and was synergistic with anti-estrogens.[7] In PALOMA-1, the addition of palbociclib significantly improved progression-free survival (PFS), which supported the accelerated approval of the combination in the United States.[4] Although relatively few Asians were enrolled in PALOMA-1, the phase III PALOMA-3 study included 102 pre- and postmenopausal Asian patients with hormone receptor‒positive/HER2-negative advanced breast cancer and prior endocrine resistance whose median PFS was significantly improved with palbociclib plus fulvestrant versus fulvestrant monotherapy.[8] The combination also was well tolerated, and global quality of life (QOL) was maintained.[8] To date, there are limited data on Asian patients in the first-line setting in which the duration of treatment generally is prolonged.

PALOMA-2 was designed to confirm the results of PALOMA-1 and further evaluate the safety and efficacy of the combination in a larger patient population. Published results from this study have reported significant improvement in median PFS with palbociclib plus letrozole versus placebo plus letrozole (24.8 v 14.5 months; hazard ratio [HR], 0.58; 95% CI, 0.46 to 0.72; P < .001).[9] Because ethnic differences may play a role in the efficacy and safety of anticancer drugs,[10-12] it is also important to analyze results from clinical studies that test new drugs in subgroups with different ethnicities. Because more Asian patients were enrolled in the PALOMA-2 study than in PALOMA-1, we examined the efficacy and safety results in Asian and non-Asian patients enrolled in PALOMA-2.

PATIENTS AND METHODS

Study Design and Patients

In the double-blind, international, phase III PALOMA-2 study, women with advanced ER-positive/HER2-negative breast cancer were randomly assigned 2:1 to receive palbociclib (125 mg/d orally for 3 weeks followed by 1 week off of a 4-week cycle) or matching placebo. Both treatment arms received letrozole 2.5 mg/d orally continuously. Palbociclib or placebo dose reductions as a result of adverse events (AEs) were allowed, but dose reduction of letrozole was not permitted (Appendix Table A1). Women were required to be postmenopausal with no prior systemic therapy for advanced disease, adequate organ function, and an Eastern Cooperative Oncology Group performance status of 0 to 2. They also were required to have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1[13] or bone-only disease. Additional eligibility criteria and study design details were described previously.[9]

TABLE A1

Guidelines for Dose Modification as a Result of Adverse Events

The PALOMA-2 study was approved by an institutional review board/independent ethics committee and was conducted in accordance with Good Clinical Practice principles and the Declaration of Helsinki. All patients provided informed consent before the study.

End Points and Assessments

The primary study end point was investigator-assessed PFS. Subgroup analyses by baseline characteristics, including race, were preplanned in the study analysis plan; the current analysis examines results in patients of Asian ethnicity, regardless of their geographic region. Additional information on end points, assessments, procedures, and statistical analyses are described in the Appendix.

RESULTS

Patients

Between February 2013 and July 2014, 95 patients of Asian ethnicity were enrolled in the study, with 65 in the palbociclib plus letrozole group and 30 in the placebo plus letrozole group (Appendix Fig A1). Demographic and baseline disease characteristics were generally similar between the Asian and non-Asian populations except for weight (mean, 57.0 v 73.0 kg, respectively), the proportion of patients with bone-only disease (15.8% v 23.8%), the proportion who were newly diagnosed (20.0% v 33.5%), and baseline mean absolute neutrophil count (ANC; 3.42 v 4.17 × 109/L; Table 1). The median age of Asian patients was 60 years. Most (58.9%) had visceral disease at baseline, and 66.3% had received prior adjuvant hormonal therapy; more than one half (52.6%) had received prior chemotherapy in the early breast cancer setting. Among Asian patients, demographic and baseline disease characteristics were generally balanced between the treatment arms.

FIG A1

Patient disposition. (*) Patients who discontinued palbociclib (PAL) or placebo (PCB) could continue to receive letrozole (LET) alone. AE, adverse event; GDHS, global deterioration of health status; PD, progressive disease.

TABLE 1

Patient Demographics and Clinical Characteristics in the Asian and Non-Asian Populations

Efficacy

In both Asian and non-Asian patients, the addition of palbociclib resulted in improved PFS (Figs 1A and 1B). Data assessed at the February 26, 2016, cutoff date demonstrated that median PFS in Asians was significantly longer in the palbociclib arm than in the placebo arm (25.7 months [95% CI, 19.2 months to not estimable (NE)] v 13.9 months [95% CI, 7.4 to 22.0 months]; HR, 0.49; 95% CI, 0.27 to 0.87; one-sided P = .007; Fig 1A). Among non-Asians, the median PFS was 24.8 months (95% CI, 21.5 months to NE) in the palbociclib arm versus 15.9 months (95% CI, 11.8 to 18.5 months) in the placebo arm (HR, 0.58; 95% CI, 0.46 to 0.73; one-sided P < .001). Data assessed at the cutoff date of May 31, 2017, showed that PFS in Asians remained significantly longer with palbociclib than with placebo (25.7 months [95% CI, 19.2 months to NE] v 13.9 months [95% CI, 7.4 to 22.0 months]; HR, 0.55; 95% CI, 0.32 to 0.95]; one-sided P = .0155; Fig 1B). Among non-Asians, the median PFS was 27.6 months (95% CI, 22.1 to 30.4 months) in the palbociclib arm versus 15.9 months (95% CI, 11.3 to 18.5 months) in the placebo arm (HR, 0.57; 95% CI, 0.46 to 0.70; one-sided P < .001). In addition, dose reductions did not have a negative impact on the PFS benefit observed with palbociclib in both groups (Fig 2).

FIG 1

Investigator-assessed progression-free survival in Asian and non-Asian patients (intention-to-treat population) at the data cutoff dates of (A) February 26, 2016, and (B) May 31, 2017. HR, hazard ratio; LET, letrozole; NE, not estimable; PAL, palbociclib; PCB, placebo.

FIG 2

Investigator-assessed progression-free survival in Asian and non-Asian patients with palbociclib dose reductions (intention-to-treat population). Gray line indicates the median progression-free-survival.

The objective response rate among Asians in the intention-to-treat (ITT) population and in those with measurable disease was 49.2% (95% CI, 36.6% to 61.9%) and 61.5% (47.0% to 74.7%), respectively, in the palbociclib arm versus 50.0% (95% CI, 31.3% to 68.7%) and 55.6% (35.3% to 74.5%) in the placebo arm (Table 2). The rate of clinical benefit response was numerically higher with palbociclib versus placebo in the ITT population (84.6% [95% CI, 73.5% to 92.4%] v 73.3% [95% CI, 54.1% to 87.7%]) and in patients with measurable disease (84.6% [95% CI, 71.9% to 93.1%] v 74.1% [95% CI, 53.7% to 88.9%]). The amount of improvement in clinical benefit response with palbociclib was similar in Asians and non-Asians and in the ITT population (Table 2).[9] At the time of this analysis, survival data were not yet mature. Double blinding has been maintained to allow for ongoing follow-up for overall survival.

TABLE 2

Best Overall Response in Asian and Non-Asian Patients (investigator-assessed, intention-to-treat population)

Study Treatment Exposure

Consistent with the overall study population, median treatment duration was longer in the palbociclib versus placebo arm for both Asians (88.6 weeks [range, 3.0 to 131.4 weeks] v 59.0 weeks [range, 3.0 to 109.4 weeks]) and non-Asians (86.1 weeks [range, 0.1 to 148.1 weeks] v 58.6 weeks [range, 1.4 to 153.0 weeks]; Appendix Table A2). Palbociclib dose reductions (all causality) were more common among Asians versus non-Asians (56.9% v 32.5%), and median time to first palbociclib dose reduction was shorter in Asians versus non-Asians (56 days [range, 28 to 785 days] v 92 days [range, 28 to 716 days]). Dose reductions and dose interruptions/delays as a result of AEs in the palbociclib arm were also more common among Asians versus non-Asians (56.9% and 93.8%, respectively, v 32.5% and 72.3%), with neutropenia (38.5%) and neutrophil count decrease (16.9%) being the main reasons for palbociclib dose reductions in Asian patients. Median relative palbociclib dose intensity was lower in Asians versus non-Asians (78.5% v 94.5%).

TABLE A2

Treatment Exposure and Duration in Asian and Non-Asian Patients

As of the data cutoff (February 26, 2016), 57 Asian patients (60.0%) had permanently discontinued study treatment, including 33 in the palbociclib arm (50.8%) and 24 in the placebo arm (80.0%). Of the 571 non-Asians, 349 (61.1%) discontinued study treatment, including 212 in the palbociclib arm (55.9%) and 137 in the placebo arm (71.4%). Disease progression was the most common reason for permanent discontinuation overall; however, fewer patients in the palbociclib arm (Asians, 23, 35.4%; non-Asians, 148, 39.1%) versus the placebo arm (Asians, 19, 63.3%; non-Asians, 107, 55.7%) discontinued for this reason. Discontinuation as a result of AEs occurred in a similar proportion of Asian (nine, 9.5%) and non-Asian patients (47, 8.2%), among whom seven (10.8%) and 36 (9.5%), respectively, were in the palbociclib arm.

Safety

The most common AEs among both Asian and non-Asian patients in the palbociclib arm were hematologic (Table 3). Hematologic AEs were generally more frequent with palbociclib versus placebo. In the palbociclib arm, incidence of any-grade neutropenia and thrombocytopenia was higher among Asians versus non-Asians (95.4% v 76.8% and 27.7% v 13.5%, respectively). With the exception of neutropenia and leukopenia, AEs were typically of grade 1 or 2 severity. The most common grade 3/4 hematologic AEs among Asians and non-Asians were neutropenia (89.2% v 62.5%), leukopenia (32.3% v 23.5%), anemia (6.2% v 5.3%), and thrombocytopenia (4.6% v 1.1%); neutropenia was the only grade 4 AE experienced by Asian patients in the palbociclib plus letrozole arm (21.5%). Although the incidence of neutropenia was high, only three Asians (4.6%) and four non-Asians (1.1%) permanently discontinued palbociclib treatment because of this AE (Appendix Table A3). Febrile neutropenia occurred in eight patients (1.8%) in the palbociclib arm in the overall population, none of whom were of Asian ethnicity. Nonhematologic AEs are described in the Appendix.

TABLE 3

Treatment-Emergent AEs That Occurred in 10% or More Patients in Either Arm (as-treated population)

TABLE A3

AEs Associated With Permanent Discontinuation and Grade 5 AEs in Asian and Non-Asian Patients

In the palbociclib versus placebo arms, respectively, serious AEs (SAEs) of any cause occurred in nine (13.8%) versus five (16.7%) Asian patients and 78 (20.6%) versus 23 (12.0%) non-Asian patients (Appendix Table A4). Febrile neutropenia was reported as serious in seven patients (1.1%) overall, all of whom were non-Asians in the palbociclib arm. No other individual SAE occurred at an incidence rate of 2% or more in either Asians or non-Asians in the palbociclib arm. Infections (any preferred term under the System Organ Class Infections and Infestations) were the most common SAEs among both Asians and non-Asians; however, no individual SAE classified as an infection occurred in more than one Asian patient. Ten on-study deaths (2.3%) occurred in the palbociclib arm and four (1.8%) occurred in the placebo arm (Appendix Table A3). One on-study death occurred among Asian patients (as a result of disease progression in a patient who received placebo plus letrozole). One death was considered treatment related (as a result of pulmonary embolism and lower respiratory tract infection in a non-Asian patient who received placebo plus letrozole).

TABLE A4

Treatment-Emergent SAEs That Occurred in More than One Patient in Either Arm (as-treated population)

Pharmacokinetics

Within-patient mean steady-state trough concentration (Ctrough) of palbociclib was examined in 38 Asian and 142 non-Asian patients. Geometric mean palbociclib Ctrough values were higher in Asians relative to non-Asians (93.8 v 61.7 ng/mL), which indicated greater palbociclib exposure in Asians (Appendix Table A5). However, variability (percent coefficient of variance) was substantially higher in non-Asians (59.1%) than in Asians (32.3%), and the distribution of Ctrough values in Asian patients was generally within range of those observed in non-Asian patients (Appendix Fig A2). There was no apparent relationship between Ctrough and body dimensions in Asian and non-Asian populations (data not shown).

TABLE A5

Summary Statistics of Within-Patient Mean Steady-State Palbociclib Ctrough in Asian and Non-Asian Patients

FIG A2

Individual and geometric mean steady-state palbociclib trough concentration (Ctrough) in Asian and non-Asian patients. Analysis included all patients with reported steady-state Ctrough data from day 14 of cycles 1 and 2 and under fed conditions at the time of pharmacokinetic sampling, regardless of antacid use. The diamonds represent the geometric mean of within-patient mean values of steady-state Ctrough, the circles represent individual of within-patient mean values of steady-state Ctrough, and the dashed line represents the arithmetic mean of data from all patients. Box plots provide median and 25%/75% quartiles with whiskers to the last point within 1.5 times the interquartile range.

Patient-Reported Outcomes

Across all cycles, 90% to 100% of all Asian patients in each treatment arm completed at least one question. No statistically significant between-arm differences were observed in overall change from baseline scores among Asian patients for the Functional Assessment of Cancer Therapy-Breast (FACT-B) or FACT-General total scores, the Breast Cancer Subscale, or the Trial Outcome Index score as well as for the FACT-B scales that describe physical, social/family, emotional, and functional well-being (Fig 3). Among Asians, overall change from baseline in EuroQol five dimensions (EQ-5D) index scores was significantly higher in the palbociclib versus placebo arm (0.013 v –0.069; P = .0132). No significant differences were observed between treatment arms in general health status scores assessed by EQ-5D.

FIG 3

Between-treatment comparison of changes from baseline scores among Asian patients (patient-reported outcome analysis set). FACT-B, Functional Assessment of Cancer Therapy-Breast; FACT-G, Functional Assessment of Cancer Therapy-General; LET, letrozole; PAL, palbociclib; PCB, placebo; TOI, Trial Outcome Index.

DISCUSSION

There have been considerable efforts to identify therapies that improve outcomes in patients with advanced breast cancer. Results from PALOMA-2 confirmed those observed in PALOMA-1, with both studies demonstrating that the addition of palbociclib to a standard endocrine therapy (letrozole) as first-line treatment of ER-positive/HER2-negative breast cancer significantly improves outcomes, including investigator-assessed PFS, irrespective of age, performance status, disease site, prior chemotherapy, prior endocrine therapy, disease-free interval after adjuvant treatment, or histologic subtype.[4,9] However, outcomes by ethnicity have not previously been reported from this study.

Palbociclib has been approved in the United States since February 2015,[14] and substantial clinical data are now available; however, most data are in white patients.[4,15] Although few Asian patients were enrolled in PALOMA-1,[4] 95 (14.3%) in PALOMA-2 were Asian, which allowed for the assessment of palbociclib efficacy, safety, pharmacokinetics, and patient-reported outcomes (PROs) in patients of this ethnicity. In addition, to our knowledge, this report is the first to provide prospective data with regard to clinical outcomes with letrozole treatment in Asian patients with breast cancer, despite its wide use. Because disparities in the safety and efficacy of anticancer therapies in patients of different ethnicities exist,[10-12] it is important to explore whether distinct safety profiles and/or anticancer activity of therapies are observed in different patient populations.

In this study, stomatitis was more common among Asians versus non-Asians in the palbociclib plus letrozole arm. However, all but four patients (all non-Asian) experienced grade 1 or 2 AEs and the incidence of grade 2 stomatitis was similar among Asians and non-Asians. The incidence of any-grade neutropenia (95.4% v 76.8%) and thrombocytopenia (27.7% v 13.5%) was also higher among Asians. These results could be due to higher exposure in Asian patients relative to non-Asian patients, as assessed by within-patient mean steady-state Ctrough values. However, recent results have shown that patients with a lower baseline ANC are significantly more likely to experience grade 3/4 neutropenia while receiving palbociclib plus letrozole.[16] Of note, in the PALOMA-3 study population, Asian patients had a baseline ANC that was 20% lower on average compared with non-Asians.[8] In the current analysis, Asian patients had a mean baseline ANC value approximately 18% lower than non-Asians. Although the incidence of hematologic toxicities was high, the toxicities were effectively managed with dose adjustments, and few patients permanently discontinued palbociclib because of these AEs. The US prescribing information for palbociclib currently recommends that all patients have a CBC before and during palbociclib therapy.[6] Dosing interruption (including cycle delay) or dose reduction is recommended for patients who develop grade 3 or 4 neutropenia.[6]

Despite the higher incidence of hematologic toxicity and a lower proportion of patients with either bone-only or de novo stage IV disease in the Asian group, median treatment duration in both arms was similar among Asians and non-Asians and in the full study population and consistently longer in the palbociclib treatment arm. A difference in palbociclib dose intensity was observed between Asians and non-Asians in the palbociclib arm, with Asian patients having a lower mean relative dose intensity than non-Asian patients. This is reflected by a greater percentage of Asian patients who experienced dose reductions and dose interruptions compared with non-Asian patients. Dose reductions occurred early during treatment, yet even with a higher frequency of dose reductions and dose interruptions, the palbociclib treatment effect was comparable in Asian and non-Asian patients, with a similar median PFS. Furthermore, palbociclib exposure was higher in Asian patients versus non-Asian patients, although, within-patient mean steady-state palbociclib Ctrough values in Asians were generally within the range of those observed for non-Asians.

The efficacy and safety findings presented herein are comparable to preliminary results of other cyclin-dependent kinase 4/6 inhibitors in Asians with breast cancer. In subgroup analyses of MONALESSA-2 and MONARCH-2, the addition of ribociclib or abemaciclib to endocrine therapy significantly prolonged median PFS in Asians, with safety profiles consistent with each study’s respective overall population.[17,18] In the phase Ib study of ribociclib in Asian, non-Japanese patients with hormone receptor–positive, HER2-negative advanced breast cancer (MONALESSASIA), neutropenia was the most common AE.[19] Similar to the results presented with palbociclib, the incidence of grade 3/4 neutropenia with ribociclib plus letrozole in MONALEESA-2 was higher in Asians than in non-Asians (71% and 58%, respectively).[17] In subgroup analyses of PALOMA-3, all-grade neutropenia in the palbociclib arm was higher in Asians versus non-Asians (92% v 78%, respectively) and was also increased in Japanese patients versus the overall PALOMA-3 population (93% v 79%, respectively).[8,20] Moreover, in a Japanese phase II study with palbociclib plus letrozole, neutropenia was the most common AE (100%).[21]

In addition to efficacy and safety, assessment of PROs is crucial to fully understand risk-benefit profiles and to optimize treatment outcomes. Analyses of PROs among Asian patients in the study revealed significantly higher EQ-5D index scores in the palbociclib arm versus placebo arm. Scores for all scales indicated maintenance of quality of life even with the addition of palbociclib to letrozole. Together, these results suggest that the addition of palbociclib to endocrine therapy is well tolerated, which allows Asian patients to maintain quality of life while benefiting from the same degree of significant disease control as non-Asians.

As observed in the full PALOMA-2 study population, the addition of palbociclib to letrozole resulted in significantly improved PFS compared with letrozole alone in Asian patients with advanced ER-positive/HER2-negative breast cancer. The safety profile of palbociclib plus letrozole was consistent with those previously reported and was similar in Asians and non-Asians with the exception of hematologic AEs, which were more frequent among Asian patients. Although relatively common, hematologic toxicities were manageable with early dose modifications, with no deterioration in quality of life and few permanent discontinuations as a result of these events. Furthermore, febrile neutropenia was not observed in any Asian patients in this study. Overall, these findings confirm the efficacy and safety results observed in the full study population and indicate that palbociclib plus letrozole is a reasonable treatment option in Asian patients with ER-positive/HER2-negative advanced breast cancer.