Trial Outcomes & Findings for A Phase II Randomized Study Evaluating the Biological and Clinical Effects of the Combination of Palbociclib With Letrozole as Neoadjuvant Therapy in Post-Menopausal Women With Estrogen-Receptor Positive Primary Breast Cancer (NCT NCT02296801)

NCT ID: NCT02296801

Last Updated: 2022-01-13

Results Overview

The change in Ki67 from baseline to 14 weeks.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

307 participants

Primary outcome timeframe

Baseline and at 14 weeks

Results posted on

2022-01-13

Participant Flow

Participant milestones

Participant milestones
Measure	A: Letrozole letrozole 2.5 mg tablet orally daily for 14 weeks Letrozole	B: Letrozole Then Letrozole + Palbociclib letrozole 2.5 mg orally daily plus beginning 2 weeks after starting letrozole, palbociclib 125 mg capsule orally daily for 1 week then 1 week off, then a 3 weeks on and 1 week off cycle for a total of 14 weeks from start of letrozole therapy Letrozole palbociclib	C: Palbociclib Then Letrozole + Palbociclib palbociclib 125 mg capsule orally daily (for a 3 weeks on and 1 week off cycle for a total of 14 weeks from start of palbociclib) plus beginning 2 weeks after starting palbociclib, letrozole 2.5 mg tablet orally daily for a total of 12 weeks from start of letrozole therapy Letrozole palbociclib	D: Letrozole + Palbociclib letrozole 2.5 mg tablet orally daily for a total of 14 weeks plus palbociclib 125 mg capsule orally daily for a 3 weeks on and 1 week off cycle, for a total of 14 weeks from start of therapy Letrozole palbociclib
Overall Study STARTED	103	68	69	67
Overall Study COMPLETED	83	53	50	58
Overall Study NOT COMPLETED	20	15	19	9

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

A Phase II Randomized Study Evaluating the Biological and Clinical Effects of the Combination of Palbociclib With Letrozole as Neoadjuvant Therapy in Post-Menopausal Women With Estrogen-Receptor Positive Primary Breast Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	A: Letrozole n=103 Participants letrozole 2.5 mg tablet orally daily for 14 weeks Letrozole	B: Letrozole Then Letrozole + Palbociclib n=68 Participants letrozole 2.5 mg orally daily plus beginning 2 weeks after starting letrozole, palbociclib 125 mg capsule orally daily for 1 week then 1 week off, then a 3 weeks on and 1 week off cycle for a total of 14 weeks from start of letrozole therapy Letrozole palbociclib	C: Palbociclib Then Letrozole + Palbociclib n=69 Participants palbociclib 125 mg capsule orally daily (for a 3 weeks on and 1 week off cycle for a total of 14 weeks from start of palbociclib) plus beginning 2 weeks after starting palbociclib, letrozole 2.5 mg tablet orally daily for a total of 12 weeks from start of letrozole therapy Letrozole palbociclib	D: Letrozole + Palbociclib n=67 Participants letrozole 2.5 mg tablet orally daily for a total of 14 weeks plus palbociclib 125 mg capsule orally daily for a 3 weeks on and 1 week off cycle, for a total of 14 weeks from start of therapy Letrozole palbociclib	Total n=307 Participants Total of all reporting groups
Age, Customized Age 40-49	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants
Age, Customized Age 50-59	32 Participants n=5 Participants	15 Participants n=7 Participants	19 Participants n=5 Participants	22 Participants n=4 Participants	88 Participants n=21 Participants
Age, Customized Age 60-69	34 Participants n=5 Participants	31 Participants n=7 Participants	29 Participants n=5 Participants	30 Participants n=4 Participants	124 Participants n=21 Participants
Age, Customized Age 70-79	30 Participants n=5 Participants	14 Participants n=7 Participants	17 Participants n=5 Participants	12 Participants n=4 Participants	73 Participants n=21 Participants
Age, Customized Greater than or equal to 80	7 Participants n=5 Participants	8 Participants n=7 Participants	3 Participants n=5 Participants	3 Participants n=4 Participants	21 Participants n=21 Participants
Sex: Female, Male Female	103 Participants n=5 Participants	68 Participants n=7 Participants	69 Participants n=5 Participants	67 Participants n=4 Participants	307 Participants n=21 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Race/Ethnicity, Customized White-British-UK patients	48 Participants n=5 Participants	32 Participants n=7 Participants	28 Participants n=5 Participants	30 Participants n=4 Participants	138 Participants n=21 Participants
Race/Ethnicity, Customized White-Other-UK patients	5 Participants n=5 Participants	1 Participants n=7 Participants	7 Participants n=5 Participants	2 Participants n=4 Participants	15 Participants n=21 Participants
Race/Ethnicity, Customized Indian-UK patients	0 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants	1 Participants n=4 Participants	3 Participants n=21 Participants
Race/Ethnicity, Customized Other Asian background-UK patients	0 Participants n=5 Participants	2 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	3 Participants n=21 Participants
Race/Ethnicity, Customized Caribbean-UK patients	1 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	3 Participants n=21 Participants
Race/Ethnicity, Customized Other Black backgroud-UK patients	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants
Race/Ethnicity, Customized Other-UK-patients	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants
Race/Ethnicity, Customized Data not received-UK patients	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	2 Participants n=21 Participants
Race/Ethnicity, Customized White-Not hispanic/latino-NA patient	38 Participants n=5 Participants	25 Participants n=7 Participants	26 Participants n=5 Participants	27 Participants n=4 Participants	116 Participants n=21 Participants
Race/Ethnicity, Customized White-Hispanic/latino-NA patient	4 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants	7 Participants n=21 Participants
Race/Ethnicity, Customized White-Not known-NA patient	1 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants	1 Participants n=4 Participants	4 Participants n=21 Participants
Race/Ethnicity, Customized Black or African American-NA patient	1 Participants n=5 Participants	2 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	4 Participants n=21 Participants
Race/Ethnicity, Customized Asian-patient-NA patient	1 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants	4 Participants n=21 Participants
Race/Ethnicity, Customized Other-patient-NA patient	1 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	3 Participants n=21 Participants
Race/Ethnicity, Customized Data not received-NA patient	1 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	3 Participants n=21 Participants
Region of Enrollment North America	47 Participants n=5 Participants	31 Participants n=7 Participants	32 Participants n=5 Participants	31 Participants n=4 Participants	141 Participants n=21 Participants
Region of Enrollment United Kingdom	56 Participants n=5 Participants	37 Participants n=7 Participants	37 Participants n=5 Participants	36 Participants n=4 Participants	166 Participants n=21 Participants

PRIMARY outcome

Timeframe: Baseline and at 14 weeks

Population: Paired Ki67 data from baseline and end of treatment were available for 190 patients. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.

The change in Ki67 from baseline to 14 weeks.

Outcome measures

Outcome measures
Measure	A: Letrozole n=65 Participants letrozole 2.5 mg tablet orally daily for 14 weeks Letrozole	B, C + D Palbociclib + Letrozole Regimen n=125 Participants Comparison between Group A and Group (B,C+D).	C: Palbociclib Then Letrozole + Palbociclib palbociclib 125 mg capsule orally daily (for a 3 weeks on and 1 week off cycle for a total of 14 weeks from start of palbociclib) plus beginning 2 weeks after starting palbociclib, letrozole 2.5 mg tablet orally daily for a total of 12 weeks from start of letrozole therapy Letrozole palbociclib	D: Letrozole + Palbociclib letrozole 2.5 mg tablet orally daily for a total of 14 weeks plus palbociclib 125 mg capsule orally daily for a 3 weeks on and 1 week off cycle, for a total of 14 weeks from start of therapy Letrozole palbociclib	B, C + D Palbociclib + Letrozole Regimen Comparison between Group A and Group (B,C+D).
Measurement of the Proliferation Marker Ki67 (% Positive Tumor Cells)	-2.2 log fold change in Ki67 Interval -3.4 to -1.0	-4.1 log fold change in Ki67 Interval -5.0 to -2.8	—	—	—

PRIMARY outcome

Timeframe: Baseline and at 14 weeks

Population: Clinical response data were available for 279 patients.

Clinical Response is assessed by ultrasound at the end of the treatment (week 14) according to ECOG response criteria defined in Appendix A1 of the protocol. Number of participants with clinical complete response.

Outcome measures

Outcome measures
Measure	A: Letrozole n=93 Participants letrozole 2.5 mg tablet orally daily for 14 weeks Letrozole	B, C + D Palbociclib + Letrozole Regimen n=63 Participants Comparison between Group A and Group (B,C+D).	C: Palbociclib Then Letrozole + Palbociclib n=61 Participants palbociclib 125 mg capsule orally daily (for a 3 weeks on and 1 week off cycle for a total of 14 weeks from start of palbociclib) plus beginning 2 weeks after starting palbociclib, letrozole 2.5 mg tablet orally daily for a total of 12 weeks from start of letrozole therapy Letrozole palbociclib	D: Letrozole + Palbociclib n=62 Participants letrozole 2.5 mg tablet orally daily for a total of 14 weeks plus palbociclib 125 mg capsule orally daily for a 3 weeks on and 1 week off cycle, for a total of 14 weeks from start of therapy Letrozole palbociclib	B, C + D Palbociclib + Letrozole Regimen n=186 Participants Comparison between Group A and Group (B,C+D).
Clinical Response : Number of Patients Who Have Resolution of Measurable Lesions or no New Lesions or Other Signs of Disease Progression Compared to Baseline.	46 Participants	31 Participants	35 Participants	35 Participants	101 Participants

SECONDARY outcome

Timeframe: 14 weeks

Population: There is response data for 279 patients. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.

Pathologic complete response in the breast (pCR breast) is defined as no histologic evidence of invasive tumour cells in the surgical breast specimen. Pathologic complete response in breast and axillary lymph nodes as well as non-axillary SN (pCR breast \& nodes) is defined as no histologic evidence of invasive tumour cells in the surgical breast specimen, axillary nodes, or SNs identified after neoadjuvant treatment. Data shows the pCR rates by randomised group.

Outcome measures

Outcome measures
Measure	A: Letrozole n=91 Participants letrozole 2.5 mg tablet orally daily for 14 weeks Letrozole	B, C + D Palbociclib + Letrozole Regimen n=187 Participants Comparison between Group A and Group (B,C+D).	C: Palbociclib Then Letrozole + Palbociclib palbociclib 125 mg capsule orally daily (for a 3 weeks on and 1 week off cycle for a total of 14 weeks from start of palbociclib) plus beginning 2 weeks after starting palbociclib, letrozole 2.5 mg tablet orally daily for a total of 12 weeks from start of letrozole therapy Letrozole palbociclib	D: Letrozole + Palbociclib letrozole 2.5 mg tablet orally daily for a total of 14 weeks plus palbociclib 125 mg capsule orally daily for a 3 weeks on and 1 week off cycle, for a total of 14 weeks from start of therapy Letrozole palbociclib	B, C + D Palbociclib + Letrozole Regimen Comparison between Group A and Group (B,C+D).
Pathological Complete Response (pCR): Number of Patients With no Lesions in Breast and Nodes at Time of Surgery	0.0 percentage of participants Interval 0.0 to 4.0	1.1 percentage of participants Interval 0.0 to 3.8	—	—	—

SECONDARY outcome

Timeframe: 14 weeks

Population: 194 patients have ER, Ki67, tumour size and nodal status available. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.

The PEPI score estimates the risk of cancer recurrence after treatment. Analysis of the PEPI score were pre-specified in the protocol and statistical analysis plan. However, pathological/biomarker characteristics which comprise this score such as the Allred score for ER status were not collected during the trial so cannot be calculated at this stage. PEPI Scale range is 0-16 for RFS. Higher score represents worse outcome. No combination of subscales.

Outcome measures

Outcome measures
Measure	A: Letrozole n=65 Participants letrozole 2.5 mg tablet orally daily for 14 weeks Letrozole	B, C + D Palbociclib + Letrozole Regimen n=129 Participants Comparison between Group A and Group (B,C+D).	C: Palbociclib Then Letrozole + Palbociclib palbociclib 125 mg capsule orally daily (for a 3 weeks on and 1 week off cycle for a total of 14 weeks from start of palbociclib) plus beginning 2 weeks after starting palbociclib, letrozole 2.5 mg tablet orally daily for a total of 12 weeks from start of letrozole therapy Letrozole palbociclib	D: Letrozole + Palbociclib letrozole 2.5 mg tablet orally daily for a total of 14 weeks plus palbociclib 125 mg capsule orally daily for a 3 weeks on and 1 week off cycle, for a total of 14 weeks from start of therapy Letrozole palbociclib	B, C + D Palbociclib + Letrozole Regimen Comparison between Group A and Group (B,C+D).
Preoperative Endocrine Prognostic Index (PEPI) Score:	3.7 score on a scale Standard Deviation 2.3	3.6 score on a scale Standard Deviation 2.3	—	—	—

SECONDARY outcome

Timeframe: Baseline and weekly through 12 months after randomization

Population: Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.

To evaluate the overall safety and tolerability for the combination of letrozole and palbociclib. The number of patients experiencing at least one adverse event. Refer to Adverse Events section for more details.

Outcome measures

Outcome measures
Measure	A: Letrozole n=100 Participants letrozole 2.5 mg tablet orally daily for 14 weeks Letrozole	B, C + D Palbociclib + Letrozole Regimen n=201 Participants Comparison between Group A and Group (B,C+D).	C: Palbociclib Then Letrozole + Palbociclib palbociclib 125 mg capsule orally daily (for a 3 weeks on and 1 week off cycle for a total of 14 weeks from start of palbociclib) plus beginning 2 weeks after starting palbociclib, letrozole 2.5 mg tablet orally daily for a total of 12 weeks from start of letrozole therapy Letrozole palbociclib	D: Letrozole + Palbociclib letrozole 2.5 mg tablet orally daily for a total of 14 weeks plus palbociclib 125 mg capsule orally daily for a 3 weeks on and 1 week off cycle, for a total of 14 weeks from start of therapy Letrozole palbociclib	B, C + D Palbociclib + Letrozole Regimen Comparison between Group A and Group (B,C+D).
Number and Severity of Adverse Events	91 Participants	199 Participants	—	—	—

SECONDARY outcome

Timeframe: Week 2 and week 14

Population: Data included for 176 patients that had a 2 week sample.

To compare Ki67 results after 2 weeks and 14 weeks of study therapy. Log fold change in Ki67 from week 2-week 14.

Outcome measures

Outcome measures
Measure	A: Letrozole n=61 Participants letrozole 2.5 mg tablet orally daily for 14 weeks Letrozole	B, C + D Palbociclib + Letrozole Regimen n=39 Participants Comparison between Group A and Group (B,C+D).	C: Palbociclib Then Letrozole + Palbociclib n=44 Participants palbociclib 125 mg capsule orally daily (for a 3 weeks on and 1 week off cycle for a total of 14 weeks from start of palbociclib) plus beginning 2 weeks after starting palbociclib, letrozole 2.5 mg tablet orally daily for a total of 12 weeks from start of letrozole therapy Letrozole palbociclib	D: Letrozole + Palbociclib n=32 Participants letrozole 2.5 mg tablet orally daily for a total of 14 weeks plus palbociclib 125 mg capsule orally daily for a 3 weeks on and 1 week off cycle, for a total of 14 weeks from start of therapy Letrozole palbociclib	B, C + D Palbociclib + Letrozole Regimen n=115 Participants Comparison between Group A and Group (B,C+D).
Measurement of Ki67 Marker	-0.1 log fold change in Ki67 Interval -1.1 to 0.4	-2.1 log fold change in Ki67 Interval -3.5 to -1.3	-0.4 log fold change in Ki67 Interval -2.1 to 0.0	0.0 log fold change in Ki67 Interval -0.1 to 0.9	-1.0 log fold change in Ki67 Interval -2.2 to 0.0

SECONDARY outcome

Timeframe: Time frame between baseline and surgery date. (Note-surgical intent happened before randomization).

Population: Data included for 268 patients where surgical type and intent was available. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.

To compare changes between surgical intent at baseline; surgical intent after 14 weeks; and actual surgery received after treatment with letrozole with or without palbociclib. Percentage of patients change to receiving breast conservation and receiving breast conservation.

Outcome measures

Outcome measures
Measure	A: Letrozole n=90 Participants letrozole 2.5 mg tablet orally daily for 14 weeks Letrozole	B, C + D Palbociclib + Letrozole Regimen n=178 Participants Comparison between Group A and Group (B,C+D).	C: Palbociclib Then Letrozole + Palbociclib palbociclib 125 mg capsule orally daily (for a 3 weeks on and 1 week off cycle for a total of 14 weeks from start of palbociclib) plus beginning 2 weeks after starting palbociclib, letrozole 2.5 mg tablet orally daily for a total of 12 weeks from start of letrozole therapy Letrozole palbociclib	D: Letrozole + Palbociclib letrozole 2.5 mg tablet orally daily for a total of 14 weeks plus palbociclib 125 mg capsule orally daily for a 3 weeks on and 1 week off cycle, for a total of 14 weeks from start of therapy Letrozole palbociclib	B, C + D Palbociclib + Letrozole Regimen Comparison between Group A and Group (B,C+D).
Comparison of Surgical Intent (Mastectomy; Breast Conservation) Change to breast conservation (actual surgery received) from mastectomy (intended at baseline)	16 Participants	25 Participants	—	—	—
Comparison of Surgical Intent (Mastectomy; Breast Conservation) Breast conservation received (actual surgery) unchanged from what was intended at baseline	63 Participants	123 Participants	—	—	—
Comparison of Surgical Intent (Mastectomy; Breast Conservation) Change to planned breast conservation (intended at the end of tx) from planned mastectomy	14 Participants	25 Participants	—	—	—
Comparison of Surgical Intent (Mastectomy; Breast Conservation) Breast conservation planned (at the end of tx) unchanged from what was intended at baseline	62 Participants	118 Participants	—	—	—

Adverse Events

A: Letrozole

Serious events: 3 serious events

Other events: 91 other events

Deaths: 1 deaths

B+D+C Palbociclib + Letrozole Regimen

Serious events: 17 serious events

Other events: 199 other events

Deaths: 3 deaths

Serious adverse events

Other adverse events

Additional Information

Director, Department of Site and Study Management

NSABP Foundation Inc

Phone: 1-800-270-3165

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Measure	A: Letrozole n=100 participants at risk letrozole 2.5 mg tablet orally daily for 14 weeks Letrozole	B+D+C Palbociclib + Letrozole Regimen n=201 participants at risk Comparison between Group A and Group (B,C+D).
Cardiac disorders Cardiac failure	0.00% 0/100 • Baseline and weekly through 12 months after randomization To evaluate the overall safety and tolerability for the combination of letrozole and palbociclib. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.	0.50% 1/201 • Baseline and weekly through 12 months after randomization To evaluate the overall safety and tolerability for the combination of letrozole and palbociclib. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.
Gastrointestinal disorders Diarrhoea	0.00% 0/100 • Baseline and weekly through 12 months after randomization To evaluate the overall safety and tolerability for the combination of letrozole and palbociclib. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.	0.50% 1/201 • Baseline and weekly through 12 months after randomization To evaluate the overall safety and tolerability for the combination of letrozole and palbociclib. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.
Gastrointestinal disorders Enterocolitis	0.00% 0/100 • Baseline and weekly through 12 months after randomization To evaluate the overall safety and tolerability for the combination of letrozole and palbociclib. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.	0.50% 1/201 • Baseline and weekly through 12 months after randomization To evaluate the overall safety and tolerability for the combination of letrozole and palbociclib. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.
Infections and infestations Neutropenic sepsis	0.00% 0/100 • Baseline and weekly through 12 months after randomization To evaluate the overall safety and tolerability for the combination of letrozole and palbociclib. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.	0.50% 1/201 • Baseline and weekly through 12 months after randomization To evaluate the overall safety and tolerability for the combination of letrozole and palbociclib. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.
Infections and infestations Periorbital cellulitis	0.00% 0/100 • Baseline and weekly through 12 months after randomization To evaluate the overall safety and tolerability for the combination of letrozole and palbociclib. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.	0.50% 1/201 • Baseline and weekly through 12 months after randomization To evaluate the overall safety and tolerability for the combination of letrozole and palbociclib. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.
Infections and infestations Pneumonia	0.00% 0/100 • Baseline and weekly through 12 months after randomization To evaluate the overall safety and tolerability for the combination of letrozole and palbociclib. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.	0.50% 1/201 • Baseline and weekly through 12 months after randomization To evaluate the overall safety and tolerability for the combination of letrozole and palbociclib. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.
Infections and infestations Skin infection	1.0% 1/100 • Baseline and weekly through 12 months after randomization To evaluate the overall safety and tolerability for the combination of letrozole and palbociclib. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.	0.00% 0/201 • Baseline and weekly through 12 months after randomization To evaluate the overall safety and tolerability for the combination of letrozole and palbociclib. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.
Infections and infestations Urinary tract infection	0.00% 0/100 • Baseline and weekly through 12 months after randomization To evaluate the overall safety and tolerability for the combination of letrozole and palbociclib. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.	0.50% 1/201 • Baseline and weekly through 12 months after randomization To evaluate the overall safety and tolerability for the combination of letrozole and palbociclib. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.
Injury, poisoning and procedural complications Head injury	0.00% 0/100 • Baseline and weekly through 12 months after randomization To evaluate the overall safety and tolerability for the combination of letrozole and palbociclib. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.	0.50% 1/201 • Baseline and weekly through 12 months after randomization To evaluate the overall safety and tolerability for the combination of letrozole and palbociclib. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.
Injury, poisoning and procedural complications Hip fracture	0.00% 0/100 • Baseline and weekly through 12 months after randomization To evaluate the overall safety and tolerability for the combination of letrozole and palbociclib. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.	0.50% 1/201 • Baseline and weekly through 12 months after randomization To evaluate the overall safety and tolerability for the combination of letrozole and palbociclib. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.
Investigations Alanine aminotransferase increased	0.00% 0/100 • Baseline and weekly through 12 months after randomization To evaluate the overall safety and tolerability for the combination of letrozole and palbociclib. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.	0.50% 1/201 • Baseline and weekly through 12 months after randomization To evaluate the overall safety and tolerability for the combination of letrozole and palbociclib. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.
Investigations Aspartate aminotransferase increased	0.00% 0/100 • Baseline and weekly through 12 months after randomization To evaluate the overall safety and tolerability for the combination of letrozole and palbociclib. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.	0.50% 1/201 • Baseline and weekly through 12 months after randomization To evaluate the overall safety and tolerability for the combination of letrozole and palbociclib. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.
Investigations Blood alkaline phosphatase increased	0.00% 0/100 • Baseline and weekly through 12 months after randomization To evaluate the overall safety and tolerability for the combination of letrozole and palbociclib. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.	0.50% 1/201 • Baseline and weekly through 12 months after randomization To evaluate the overall safety and tolerability for the combination of letrozole and palbociclib. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.
Investigations Gamma-glutamyltransferase increased	0.00% 0/100 • Baseline and weekly through 12 months after randomization To evaluate the overall safety and tolerability for the combination of letrozole and palbociclib. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.	0.50% 1/201 • Baseline and weekly through 12 months after randomization To evaluate the overall safety and tolerability for the combination of letrozole and palbociclib. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.
Metabolism and nutrition disorders Dehydration	0.00% 0/100 • Baseline and weekly through 12 months after randomization To evaluate the overall safety and tolerability for the combination of letrozole and palbociclib. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.	0.50% 1/201 • Baseline and weekly through 12 months after randomization To evaluate the overall safety and tolerability for the combination of letrozole and palbociclib. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.
Metabolism and nutrition disorders Hyperglycaemia	1.0% 1/100 • Baseline and weekly through 12 months after randomization To evaluate the overall safety and tolerability for the combination of letrozole and palbociclib. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.	0.00% 0/201 • Baseline and weekly through 12 months after randomization To evaluate the overall safety and tolerability for the combination of letrozole and palbociclib. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.
Metabolism and nutrition disorders Hyponatraemia	0.00% 0/100 • Baseline and weekly through 12 months after randomization To evaluate the overall safety and tolerability for the combination of letrozole and palbociclib. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.	0.50% 1/201 • Baseline and weekly through 12 months after randomization To evaluate the overall safety and tolerability for the combination of letrozole and palbociclib. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.
Musculoskeletal and connective tissue disorders Pain in extremity	1.0% 1/100 • Baseline and weekly through 12 months after randomization To evaluate the overall safety and tolerability for the combination of letrozole and palbociclib. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.	0.00% 0/201 • Baseline and weekly through 12 months after randomization To evaluate the overall safety and tolerability for the combination of letrozole and palbociclib. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.
Respiratory, thoracic and mediastinal disorders Acute respiratory distress syndrome	0.00% 0/100 • Baseline and weekly through 12 months after randomization To evaluate the overall safety and tolerability for the combination of letrozole and palbociclib. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.	0.50% 1/201 • Baseline and weekly through 12 months after randomization To evaluate the overall safety and tolerability for the combination of letrozole and palbociclib. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.
Vascular disorders Hypotension	0.00% 0/100 • Baseline and weekly through 12 months after randomization To evaluate the overall safety and tolerability for the combination of letrozole and palbociclib. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.	0.50% 1/201 • Baseline and weekly through 12 months after randomization To evaluate the overall safety and tolerability for the combination of letrozole and palbociclib. Patients treated with letrozole with palbociclib, i.e. groups B+C+D, were pooled and compared to those treated with letrozole alone (group A). The pooling of groups B-D was pre-planned and defined in the Statistical Analysis Plan.