Study of Letrozole With or Without BYL719 or Buparlisib, for the Neoadjuvant Treatment of Postmenopausal Women

Objective Response Rate (ORR) defined as the proportion of patients with a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) based on local investigator's assessment according to Response Evaluation Criteria In Solid Tumors Criteria (RECIST) 1.1. BOR was assessed per MRI or Ultrasound and defined as per RECIST 1.1 as CR for a disappearance of all non-nodal target lesions (TL)/non-target lesions (NTL) and a reduction in short axis to \< 10 mm of any pathological lymph nodes assigned as TL/NTL and no new lesion; as PR if not qualifying for CR but with a decrease from baseline ≥ 30% in the sum of diameter of all TL, no progression of NTL and no new lesion.

Time frame: After 24 weeks of treatment

Population: The Full Analysis Set (FAS) for the PIK3CA wild-type cohort comprised all randomized participants who were assigned to the PIK3CA wild-type cohort based on tumor tissue for the randomization.

Objective Response Rate (ORR) defined as the proportion of patients with a Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) based on local investigator's assessment according to Response Evaluation Criteria In Solid Tumors Criteria (RECIST) 1.1. BOR was assessed per MRI or Ultrasound and defined as per RECIST 1.1 as CR for a disappearance of all non-nodal target lesions (TL)/non-target lesions (NTL) and a reduction in short axis to \< 10 mm of any pathological lymph nodes assigned as TL/NTL and no new lesion; as PR if not qualifying for CR but with a decrease from baseline ≥ 30% in the sum of diameter of all TL, no progression of NTL and no new lesion.

Time frame: After 24 weeks of treatment

Population: The Full Analysis Set (FAS) for the PIK3CA mutant cohort comprised all randomized participants who were assigned to the PIK3CA mutant cohort based on tumor tissue for the randomization.

Pathologic complete response (pCR) defined as absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes following completion of 24 weeks of treatment by local assessment (ypT0/Tis ypN0). Patients who experienced progression of disease while undergoing neoadjuvant therapy, or who did not receive surgery for any reason, or received antineoplastic treatment other than study drug(s) before surgery were considered as non-responders for the calculation of pCR rate.

Time frame: After 24 weeks of treatment

Population: The Full Analysis Set (FAS) for the PIK3CA mutant cohort comprised all randomized participants who were assigned to the PIK3CA mutant cohort based on tumor tissue for the randomization.

Pathologic complete response (pCR) defined as absence of any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes following completion of 24 weeks of treatment by local assessment (ypT0/Tis ypN0). Patients who experienced progression of disease while undergoing neoadjuvant therapy, or who did not receive surgery for any reason, or received antineoplastic treatment other than study drug(s) before surgery were considered as non-responders for the calculation of pCR rate.

Time frame: After 24 weeks of treatment

Population: The Full Analysis Set (FAS) for the PIK3CA wild-type cohort comprised all randomized participants who were assigned to the PIK3CA wild-type cohort based on tumor tissue for the randomization.

Summary of primary PK parameters for alpelisib plasma concentration

Time frame: Cycle 1 Day 1 (each cycle is 28 days)

Population: Alpelisib Pharmacokinetic Analysis Set (BYL PAS): The BYL PAS included all participants who received at least one dose of alpelisib and had at least one evaluable post-treatment alpelisib concentration measurement.

Summary of primary PK parameters for alpelisib plasma concentration

Time frame: Cycle 1 Day 1 (each cycle is 28 days)

Population: The BYL FPAS included participants who received at least 1 dose of alpelisib, had at least 1 evaluable post-treatment alpelisib concentration, received adequate doses of alpelisib and letrozole prior to full PK assessment, did not vomit within 4 hours of alpelisib or letrozole dosing on the day of full PK and had an evaluable full PK profile.

Summary of primary PK parameters for alpelisib plasma concentration

Time frame: Cycle 4 Day 1 (each cycle is 28 days)

Population: Alpelisib Pharmacokinetic Analysis Set (BYL PAS): The BYL PAS included all participants who received at least one dose of alpelisib and had at least one evaluable post-treatment alpelisib concentration measurement.

Summary of primary PK parameters for alpelisib plasma concentration

Time frame: 0, 0.5, 1, 3, 6, 9 and 24 hours post-dose at Cycle 1 Day 1 (each cycle is 28 days)

Population: The BYL FPAS included participants who received at least 1 dose of alpelisib, had at least 1 evaluable post-treatment alpelisib concentration, received adequate doses of alpelisib and letrozole prior to full PK assessment, did not vomit within 4 hours of alpelisib or letrozole dosing on the day of full PK and had an evaluable full PK profile.

Summary of primary PK parameters for alpelisib plasma concentration

Time frame: 0, 0.5, 1, 3, 6, 9 and 24 hours post-dose at Cycle 4 Day 1 (each cycle is 28 days)

Population: The BYL FPAS included participants who received at least 1 dose of alpelisib, had at least 1 evaluable post-treatment alpelisib concentration, received adequate doses of alpelisib and letrozole prior to full PK assessment, did not vomit within 4 hours of alpelisib or letrozole dosing on the day of full PK and had an evaluable full PK profile.

Summary of primary PK parameters for alpelisib plasma concentration

Time frame: Cycle 4 Day 1 (each cycle is 28 days)

Population: Alpelisib Pharmacokinetic Analysis Set (BYL PAS): The BYL PAS included all participants who received at least one dose of alpelisib and had at least one evaluable post-treatment alpelisib concentration measurement.

Association Between pCR and Changes in Ki67 From Baseline for Alpelisib vs. Placebo - PIK3CA Mutant Cohort: Non-responders as Per pCR.

Time frame: Baseline, Cycle 1 Day 15 (each cycle is 28 days ) and surgery (End of Treatment (EOT) expected after 24 weeks of treatment)

Population: The Full Analysis Set (FAS) for the PIK3CA mutant cohort comprised all randomized participants who were assigned to the PIK3CA mutant cohort based on tumor tissue for the randomization. Only non-responders as per pCR are considered for this analysis.

Association Between pCR and Changes in Ki67 From Baseline for Alpelisib vs. Placebo - PIK3CA Mutant Cohort: Responders as Per pCR

Time frame: Baseline, Cycle 1 Day 15 (each cycle is 28 days) and surgery (End of Treatment (EOT) expected after 24 weeks of treatment)

Population: The FAS for the PIK3CA mutant cohort comprised all randomized participants who were assigned to the PIK3CA mutant cohort based on tumor tissue for the randomization. Only responders as per pCR were considered for this analysis. No patient had data reported at end of trial (EOT), hence the percent change from baseline at EOT could not be reported.

Association between pCR and changes in Ki67 from baseline for alpelisib vs. placebo - PIK3CA wild-type cohort: non-responders as per pCR

Time frame: Baseline, Cycle 1 Day 15 (each cycle is 28 days) and surgery (End of Treatment (EOT) expected after 24 weeks of treatment)

Population: The Full Analysis Set (FAS) for the PIK3CA wild-type cohort comprised all randomized participants who were assigned to the PIK3CA wild-type cohort based on tumor tissue for the randomization. Only non-responders as per pCR are considered for this analysis.

Association between pCR and changes in Ki67 from baseline for alpelisib vs. placebo - PIK3CA wild-type cohort: responders as per pCR

Time frame: Baseline, Cycle 1 Day 15 (each cycle is 28 days) and surgery (End of Treatment (EOT) expected after 24 weeks of treatment)

Population: FAS for PIK3CA wild-type cohort comprised all rand. Parts. assigned to PIK3CA wild-type cohort based on tumor tissue for rand. Only responders as per pCR were considered for this analysis. No patient had data reported at C1D15 \& EOT for Placebo, hence percent change from baseline could not be reported.

Summary of primary PK parameters for buparlisib plasma concentration

Time frame: Cycle 4 Day 1 (each cycle is 28 days)

Population: Buparlisib Pharmacokinetic Analysis Set (BKM PAS): The BKM PAS included all participants who received at least one dose of buparlisib and had at least one evaluable post-treatment buparlisib concentration measurement.

Summary of primary PK parameters for Buparlisib plasma concentration

Time frame: 0, 0.5, 1, 3, 6, 9 and 24 hours post-dose at Cycle 4 Day 1 (each cycle is 28 days)

Population: BKM FPAS: The BKM FPAS included participants who received at least 1 dose of buparlisib, had at least 1 evaluable post-treatment concentration, received adequate doses of buparlisib and letrozole prior to full PK assessment, did not vomit within 4 hours of buparlisib or letrozole dosing on the day of full PK and had an evaluable full PK profile.

Summary of primary PK parameters for buparlisib plasma concentration

Time frame: Cycle 1 Day 1 (each cycle is 28 days)

Population: The BKM FPAS included participants who received at least 1 dose of buparlisib, had at least 1 evaluable post-treatment concentration, received adequate doses of buparlisib and letrozole prior to full PK assessment, did not vomit within 4 hours of buparlisib or letrozole dosing on the day of full PK and had an evaluable full PK profile.

Summary of primary PK parameters for Buparlisib plasma concentration

Time frame: 0, 0.5, 1, 3, 6, 9 and 24 hours post-dose at Cycle 1 Day 1 (each cycle is 28 days)

Population: The BKM FPAS included participants who received at least 1 dose of buparlisib, had at least 1 evaluable post-treatment concentration, received adequate doses of buparlisib and letrozole prior to full PK assessment, did not vomit within 4 hours of buparlisib or letrozole dosing on the day of full PK and had an evaluable full PK profile.

Summary of primary PK parameters for buparlisib plasma concentration

Time frame: Cycle 1 Day 1 (each cycle is 28 days)

Population: Buparlisib Pharmacokinetic Analysis Set (BKM PAS): The BKM PAS included all participants who received at least one dose of buparlisib and had at least one evaluable post-treatment buparlisib concentration measurement.

Summary of primary PK parameters for buparlisib plasma concentration

Time frame: Cycle 4 Day 1 (each cycle is 28 days)

Population: Buparlisib Pharmacokinetic Analysis Set (BKM PAS): The BKM PAS included all participants who received at least one dose of buparlisib and had at least one evaluable post-treatment buparlisib concentration measurement.

Summary of primary PK parameters for Letrozole plasma concentration

Time frame: 0, 0.5, 1, 3, 6, 9 and 24 hours post-dose at Cycle 1 Day 1 (each cycle is 28 days)

Population: The LZ FPAS included participants who received at least 1 dose of letrozole, had at least 1 evaluable post-treatment letrozole concentration, received adequate doses of letrozole prior to full PK assessment, did not vomit within 4 hours of letrozole dosing on the day of full PK and had an evaluable full PK profile.

Summary of primary PK parameters for letrozole plasma concentration

Time frame: Cycle 1 Day 1 (each cycle is 28 days)

Population: The LZ FPAS included participants who received at least 1 dose of letrozole, had at least 1 evaluable post-treatment letrozole concentration, received adequate doses of letrozole prior to full PK assessment, did not vomit within 4 hours of letrozole dosing on the day of full PK and had an evaluable full PK profile.

Summary of primary PK parameters for letrozole plasma concentration

Time frame: Cycle 4 Day 1 (each cycle is 28 days)

Population: The LZ FPAS included participants who received at least 1 dose of letrozole, had at least 1 evaluable post-treatment letrozole concentration, received adequate doses of letrozole prior to full PK assessment, did not vomit within 4 hours of letrozole dosing on the day of full PK and had an evaluable full PK profile.

Summary of primary PK parameters for Letrozole plasma concentration

Time frame: 0, 0.5, 1, 3, 6, 9 and 24 hours post-dose at Cycle 4 Day 1 (each cycle is 28 days)

Population: Letrozole Pharmacokinetic Analysis Set (LZ PAS): The LZ PAS included all participants who received at least one dose of letrozole and had at least one evaluable post-treatment letrozole concentration measurement.

Summary of primary PK parameters for letrozole plasma concentration

Time frame: Cycle 1 Day 1 (each cycle is 28 days)

Population: The LZ FPAS included participants who received at least 1 dose of letrozole, had at least 1 evaluable post-treatment letrozole concentration, received adequate doses of letrozole prior to full PK assessment, did not vomit within 4 hours of letrozole dosing on the day of full PK and had an evaluable full PK profile.

Summary of primary PK parameters for letrozole plasma concentration

Time frame: Cycle 4 Day 1 (each cycle is 28 days)

Population: The LZ FPAS included participants who received at least 1 dose of letrozole, had at least 1 evaluable post-treatment letrozole concentration, received adequate doses of letrozole prior to full PK assessment, did not vomit within 4 hours of letrozole dosing on the day of full PK and had an evaluable full PK profile.

pCR and Objective response rate according to RECIST 1.1 per investigator assessment after 24 weeks of treatment

Time frame: After 24 weeks of treatment

Population: The FAS comprised all randomized participants. This analysis was to be done in patients with PIK3CA mutation based on Circulating tumor DNA (ctDNA). Data could not be reported as the ctDNA analysis was not done after the primary endpoint was negative.

pCR and Objective response rate according to RECIST 1.1 per investigator assessment after 24 weeks of treatment

Time frame: After 24 weeks of treatment

Population: The Full Analysis Set (FAS) comprised all randomized participants in the study. This analysis was to be done in PIK3CA wild-type patients based on Circulating tumor DNA (ctDNA). Data could not be reported in this table as the ctDNA analysis was not done after the primary endpoint was negative.

Preoperative endocrine prognostic index (PEPI) response as per central assessment for alpelisib vs. placebo - PIK3CA mutant cohort. The total PEPI score assigned to each patient is the sum of the risk points derived from the pT stage, pN stage, Ki67 level, and ER status of the surgical specimen (Ellis et al, Contemp Clin Trials 2008). The PEPI score ranges from 0 to to 12, and a higher score means a worse outcome. PEPI response is defined as a PEPI score of 0.

Time frame: At the time of surgery (expected after 24 weeks of treatment)

Population: The Full Analysis Set (FAS) for the PIK3CA mutant cohort comprised all randomized participants who were assigned to the PIK3CA mutant cohort based on tumor tissue for the randomization.

Preoperative endocrine prognostic index (PEPI) response as per central assessment for alpelisib vs. placebo - PIK3CA wild-type cohort. The total PEPI score assigned to each patient is the sum of the risk points derived from the pT stage, pN stage, Ki67 level, and ER status of the surgical specimen (Ellis et al, Contemp Clin Trials 2008). The PEPI score ranges from 0 to to 12, and a higher score means a worse outcome. PEPI response is defined as a PEPI score of 0.

Time frame: At the time of surgery (expected after 24 weeks of treatment)

Population: The Full Analysis Set (FAS) for the PIK3CA wild-type cohort comprised all randomized participants who were assigned to the PIK3CA wild-type cohort based on tumor tissue for the randomization.

Breast conserving surgery is defined for participants who underwent surgery and did not have a mastectomy. The row no surgery provides the number of patients who did not undergo surgery at all for various reasons.

Time frame: After 24 weeks of treatment

Population: The Full Analysis Set (FAS) for the PIK3CA mutant cohort comprised all randomized participants who were assigned to the PIK3CA mutant cohort based on tumor tissue for the randomization. PIK3CA mutation is based on tumor tissue.

Breast conserving surgery is defined as the percentage of participants with no mastectomy following completion of 24 weeks of treatment. Breast conserving surgery is defined for participants who underwent surgery and did not have a mastectomy. The row no surgery provides the number of patients who did not undergo surgery at all for various reasons.

Time frame: After 24 weeks of treatment

Population: The Full Analysis Set (FAS) for the PIK3CA wild-type cohort comprised all randomized participants who were assigned to the PIK3CA wild-type cohort based on tumor tissue for the randomization. PIK3CA mutation is based on tumor tissue.