Online-Only Supplementary Materials

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1 Online-Only Supplementary Materials Online-Only Supplementary Methods: Eligibility Criteria and Study Endpoints and Assessments Supplementary Table 1. Demographic and Baseline Characteristics in Patients Receiving Endocrine Therapy With or Without Placebo by Age Group Supplementary Table 2. Summary of Palbociclib Clearance Estimates by Age Group Supplementary Table 3. Drug Exposure and Dose Intensity for Palbociclib Supplementary Table 4. Serious Treatment-Emergent Adverse Events occurring in 1% of Older Patients in Either Treatment Group Supplementary Fig. 1. PALOMA Study Designs Supplementary Fig. 2. Overall Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT-B) Scores for Patients Aged years (A) and 75 years (B) in the PALOMA-2 Study Supplementary Fig. 3. Time to Deterioration in Pain for Patients Aged years (A) and 75 years (B) in the PALOMA-3 Study

2 Online-Only Supplementary Methods Eligibility Criteria Patients were excluded if they received prior treatment for advanced breast cancer, treatment with a cyclindependent kinase (CDK) inhibitor, or prior neoadjuvant/adjuvant treatment with letrozole within 12 months before study entry (PALOMA-1); prior neoadjuvant/adjuvant nonsteroidal aromatase inhibitor treatment with disease recurrence during or within 12 months of completing therapy (PALOMA-2); or if they received prior treatment with a CDK inhibitor, fulvestrant, everolimus, or any inhibitors of phosphoinositide 3-kinase or the rapamycin pathway (PALOMA-3). Study Endpoints and Assessments Treatment-emergent AEs for the clustered terms anemia, infections, leukopenia, neutropenia, pulmonary embolism; thrombocytopenia, stomatitis, and rash are reported and defined as follows: anemia includes the preferred terms anemia, hematocrit decreased, and hemoglobin decreased; infections includes any reported preferred terms of the system organ class infections and infestations; leukopenia includes the preferred terms leukopenia and white blood cell count decreased; neutropenia includes the preferred terms neutropenia and neutrophil count decreased; thrombocytopenia includes the preferred terms platelet count decreased and thrombocytopenia; stomatitis includes the preferred terms aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral pain, oropharyngeal discomfort, oropharyngeal pain, and stomatitis; rash includes the preferred terms dermatitis or dermatitis acneiform or rash or rash erythematous or rash maculo-papular or rash papular or rash pruritic or toxic skin eruption; pulmonary embolism includes the preferred terms pulmonary artery thrombosis or pulmonary embolism or pulmonary thrombosis.

3 Supplementary Table 1. Demographic and Baseline Characteristics in Patients Receiving Endocrine Therapy With or Without Placebo by Age Group a PALOMA-1 PALOMA-2 PALOMA-3 Age, y: Characteristic (n=42) (n=32) (n=7) (n=141) (n=62) (n=19) (n=131) (n=37) (n=6) Race White 35 (83.3) 31 (96.9) 6 (85.7) 107 (75.9) 50 (80.6) 15 (78.9) 100 (76.3) 29 (78.4) 4 (66.7) Nonwhite b 7 (16.7) 1 (3.1) 1 (14.3) 34 (24.1) 12 (19.4) 4 (21.1) 31 (23.7) 8 (21.6) 2 (33.3) ECOG performance status 0 23 (54.8) 19 (59.4) 3 (42.9) 70 (49.6) 26 (41.9) 6 (31.6) 93 (71.0) 19 (51.4) 4 (66.7) 1 19 (45.2) 13 (40.6) 4 (57.1) 70 (49.6) 34 (54.8) 13 (68.4) 38 (29.0) 18 (48.6) 2 (33.3) ( 1.0) 2 (3.2) Disease site c,d Visceral 22 (52.4) 15 (46.9) 6 (85.7) 73 (51.8) 29 (46.8) 8 (42.1) 73 (55.7) 25 (67.6) 6 (100.0) Bone only e 3 (7.1) 9 (28.1) 0 68 (48.2) 33 (53.2) 11 (57.9) 32 (24.4) 6 (16.2) 0 Others 17 (40.5) 8 (25.0) 1 (14.3) (19.8) 6 (16.2) 0 Disease-free interval f De novo metastatic 23 (54.8) 12 (37.5) 2 (28.6) 44 (31.2) 30 (48.4) 7 (36.8) mo, n (%) 7 (16.7) 5 (15.6) 2 (28.6) 39 (27.7) 4 (6.5) 5 (26.3) 3 (3.2) 0 0 >12 mo, n (%) 12 (28.6) 15 (46.9) 3 (42.9) 58 (41.1) 28 (45.2) 7 (36.8) 91 (96.8) 25 (100) 4 (100) Previous endocrine therapy Tamoxifen only 9 (21.4) 7 (21.9) 0 57 (40.4) 12 (19.4) 4 (21.1) 3 (2.3) 1 (2.7) 0 AI only 2 (4.8) 1 (3.1) 1 (14.3) 16 (11.3) 7 (11.3) 5 (26.3) 12 (9.2) 3 (8.1) 1 (16.7) Both AI and tamoxifen 2 (4.8) 5 (15.6) 1 (14.3) 14 (9.9) 8 (12.9) 3 (15.8) 61 (46.6) 17 (45.9) 3 (50.0) Comorbidities Metabolism and nutrition disorders 9 (21.4) 13 (40.6) 2 (28.6) 33 (23.4) 30 (48.4) 10 (52.6) 32 (24.4) 16 (43.2) 4 (66.7) Diabetes mellitus 4 (9.5) 1 (3.1) 0 8 (5.7) 8 (12.9) 1 (5.3) 5 (3.8) 4 (10.8) 0 Renal and urinary disease 3 (7.1) 5 (15.6) 0 13 (9.2) 10 (16.1) 4 (21.1) 11 (8.4) 4 (10.8) 0 Vascular disorders 18 (42.9) 26 (81.3) 5 (71.4) 67 (47.5) 40 (64.5) 15 (78.9) 54 (41.2) 25 (67.6) 2 (33.3) Hypertension 10 (23.8) 19 (59.4) 5 (71.4) 41 (29.1) 38 (61.3) 13 (68.4) 31 (23.7) 18 (48.6) 2 (33.3) AI, aromatase inhibitor; Gr, grade; ECOG, Eastern Cooperative Oncology Group. Data are n (%). a Intent-to-treat analysis. b Nonwhite includes Asian, Black, Other, and Unspecified race categories. c Based on case report form data. d In PALOMA-1, Visceral was defined as lung and/or liver ± any other site; Bone only was defined as no visceral, no other; and Other was defined as bone with other nonvisceral disease site or other disease site alone. In PALOMA-2, Visceral was defined as any lung (including pleura) and/or liver involvement. In PALOMA-3, Visceral was defined as lung, liver, brain, pleural, or peritoneal involvement. e In PALOMA-2, data are Nonvisceral, not Bone only. f Disease-free interval is the time between the end of adjuvant treatment and onset of metastatic disease or disease recurrence.

4 Supplementary Table 2. Summary of Palbociclib Clearance Estimates by Age Group a Age <65 y (n=536) Age y (n=207) Age y (n=71) Age 85 y (n=9) Arithmetic mean CL/F, L/h Median CL/F, L/h Geometric mean CL/F, L/h CL/F=apparent oral clearance. a Includes PALOMA-1 (NCT ), PALOMA-2 (NCT ), and PALOMA-3 (NCT ) studies.

5 Supplementary Table 3. Drug Exposure and Dose Intensity for Palbociclib 65 y (n=46) Duration of treatment, 418 median (range), d b ( ) Relative dose, median (range), % c 97.1 ( ) PALOMA-1 a PALOMA-2 a PALOMA-3 a 65 y (n=37) 442 ( ) 99.4 ( ) 65 y (n=263) ( ) 98.2 ( ) 65 y (n=181) ( ) 97.0 ( ) 65 y (n=259) (1 680) 95.6 (22 107) 65 y (n=86) (6 662) 97.3 (25 105) a Drug exposure and dose intensity for palbociclib for all cycles combined in patients receiving palbociclib plus letrozole (PALOMA-1 and PALOMA-2) or palbociclib plus fulvestrant (PALOMA-3). One patient in PALOMA-1 and 2 patients in PALOMA-3 were randomized to palbociclib plus endocrine therapy but not treated. b The duration is defined as the total number of days = Last Dose Date First Dose Date + 1. c Relative dose = [(Actual Dose)/(Intended Dose)] 100%.

6 Supplementary Table 4. Serious Treatment-Emergent Adverse Events Occurring in 1% of Older Patients in Either Treatment Group Age 65 y (n=568) Palbociclib + Endocrine Therapy a Age y (n=221) Age 75 y (n=83) Age 65 y (n=310) Comparator b Age y (n=129) Age 75 y (n=32) All Gr Gr 3 All Gr Gr 3 All Gr Gr 3 All Gr Gr 3 All Gr Gr 3 All Gr Gr 3 Any AE c (30.1) 28 (9.0) 4 (12.5) (15.1) (11.6) (24.9) (20.4) (24.1) (11.9) (18.6) (14.0) (9.4) Infections d (12.5) (3.7) (2.3) (6.3) (5.9) (3.6) (4.8) (2.9) (1.9) (2.3) (2.3) (6.3) Disease progression (0.5) (0.53) (1.4) (1.4) Urinary tract infection (0.2) (1.4) (0.90) (0.3) Diverticulitis (6.3) (6.3) Pleural effusion (0.32) (0.4) (0.18) (1.4) (0.45) (1.2) (0.6) (1.6) 1 (0.78) 0 0 Pulmonary embolism d 5 (6.0) 1 (0.32) (0.5) (0.53) (1.4) (1.4) (6.0) (0.6) (0.8) 1 (0.78) 0 0 AE, adverse event; Gr, grade. a Includes patients in PALOMA-1 and PALOMA-2 who received palbociclib plus letrozole and patients in PALOMA-3 who had endocrine-resistant metastatic breast cancer and received palbociclib plus fulvestrant. b Includes patients in PALOMA-1 who received letrozole alone, patients in PALOMA-2 who received letrozole plus placebo, and patients in PALOMA-3 who received fulvestrant plus placebo. c All-causality treatment-emergent AEs occurring in 1% of patients 65 years old in the as-treated population in either treatment group. AEs were graded in accordance with the maximum grade per Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 (PALOMA-1) or 4.0 (PALOMA-2 and -3), and classified according to the Medical Dictionary for Regulatory Activities, version d Clustered preferred terms defined as follows: infections includes any reported preferred terms of the system organ class infections and infestations; pulmonary embolism is any event having a preferred term that is equal to pulmonary artery thrombosis or pulmonary embolism or pulmonary thrombosis.

7 Supplementary Fig. 1. PALOMA Study Designs ABC, advanced breast cancer; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; IM, intramuscular; MBC, metastatic breast cancer; NSAI, nonsteroidal aromatase inhibitor; PFS, progression-free survival; PRO, patient-reported outcome; QD, once daily; Q4W, every 4 weeks. a Actual enrollment rather than planned enrollment; b All received goserelin; c Includes overall response (complete or partial response) and clinical benefit (complete response, partial response, or stable disease for 24 weeks) according to Response Evaluation Criteria in Solid Tumors, 1.0 (PALMA-1) or 1.1 (PALOMA-2 and PALOMA-3). Tumor assessments were performed at screening and every 8 (PALOMA-1 and PALOMA-3) or 12 (PALOMA-2) weeks; after 1 year, assessments in PALOMA-3 were performed every 12 weeks.

8 Supplementary Fig. 2. Overall Change From Baseline in Functional Assessment of Cancer Therapy-Breast (FACT- B) Scores for Patients Aged Years (A) and 75 Years (B) in the PALOMA-2 Study A. 5 Overall Change From Baseline Palbociclib + Letrozole Placebo + Letrozole FACT-B FACT-G PWB SFWB EWB FWB BCS TOI -4-5 B. Overall Change From Baseline Palbociclib + Letrozole Placebo + Letrozole -5 FACT-B FACT-G PWB SFWB EWB FWB BCS TOI BCS, breast cancer subscale; EWB, emotional well-being; FWB, functional well-being; FACT-G, Functional Assessment of Cancer Therapy - General; PWB, physical well-being; SFWB, social/family well-being; TOI, trial outcome index.

9 Supplementary Fig. 3. Time to Deterioration in Pain for Patients Aged Years (A) and 75 Years (B) in the PALOMA-3 Study A.

10 B.