PFS: Time (months) from start of the study treatment to first documented progression or death due to any cause, whichever came first. Kaplan-Meier estimates. Persistent Wild Type: Wild Type (or single nucleotide polymorphisms [SNPs] only) at screening without hotspot mutations at any later assessment. Confirmed cleared: Mutated, with 100% decrease in target mutation variant allele frequency (VAF) at C1D15 or at C2D1 also observed at FI. Unconfirmed cleared: Mutated that cleared or at C1D15 or at C2D1 that were not cleared at FI. Late cleared: Mutated without 100% decrease in target mutation VAF at C1D15 and at C2D1 with 100% decrease in target mutation VAF at FI. New mutated: Wild Type ( [SNPs] only) at screening with hotspot mutations at C1D15 or C2D1. Late mutated: Wild Type patients (or SNPs only) at screening without hotspot mutations at C1D15 and C2D1 with hotspot mutations at FI. Confirmed mutated: Mutated without 100% decrease in target mutation VAF at any later assessment.

The biomarker analysis set (BAS) included participants who received at least one dose of either ribociclib or letrozole and who had an evaluable biomarker profile (i.e., both valid liquid biopsy and TK1 serum samples collected at screening) and who did not have violations of the main inclusion-exclusion criteria. Data are reported only for participants who had a valid sample at screening, Cycle 1 Day 15, Cycle 2 Day 1, and at the first imaging evaluation. Each cycle was 28 days.

Kaplan-Meier estimates. Persistent Wild Type: Wild Type (or single nucleotide polymorphisms [SNPs] only) at screening without hotspot mutations at any later assessment. Confirmed cleared: Mutated, with 100% decrease in target mutation variant allele frequency (VAF) at C1D15 or at C2D1 also observed at FI. Unconfirmed cleared: Mutated that cleared or at C1D15 or at C2D1 that were not cleared at FI. Late cleared: Mutated without 100% decrease in target mutation VAF at C1D15 and at C2D1 with 100% decrease in target mutation VAF at FI. New mutated: Wild Type ( [SNPs] only) at screening with hotspot mutations at C1D15 or C2D1. Late mutated: Wild Type patients (or SNPs only) at screening without hotspot mutations at C1D15 and C2D1 with hotspot mutations at FI. Confirmed mutated: Mutated without 100% decrease in target mutation VAF at any later assessment.

The biomarker analysis set (BAS) included participants who received at least one dose of either ribociclib or letrozole and who had an evaluable biomarker profile (i.e., both valid liquid biopsy and TK1 serum samples collected at screening) and who did not have violations of the main inclusion-exclusion criteria. Data are reported only for participants who had a valid sample at screening, Cycle 1 Day 15, Cycle 2 Day 1, and at the first imaging evaluation. Each cycle was 28 days.

Hotspot mutational analysis on liquid biopsy was performed on the 39 genes belonging to the BioItaLEE custom panel. The data row labels below refer to the number of hotspot-mutated genes at each timepoint. Each cycle was 28 days. PD = progressive disease.

The biomarker analysis set (BAS) included participants who received at least one dose of either ribociclib or letrozole and who had an evaluable biomarker profile (i.e., both valid liquid biopsy and TK1 serum samples collected at screening) and who did not have violations of the main inclusion-exclusion criteria.

The target mutation was defined as the hotspot mutation with the highest molecular frequency observed at screening excluding single nucleotide polymorphisms (SNPs, i.e., hotspot mutations observed at all timepoints with a minimum molecular frequency value of 30% and a variation coefficient greater than 0.15). The molecular frequency of target mutation at performed assessments during which the target mutation was not detected was assumed to be equal to 0%.

The biomarker analysis set (BAS) included participants who received at least one dose of either ribociclib or letrozole and who had an evaluable biomarker profile (i.e., both valid liquid biopsy and TK1 serum samples collected at screening) and who did not have violations of the main inclusion-exclusion criteria. Data are reported only for participants with target mutation.

PR was assessed per Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1, criteria and was defined as at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the screening sum of diameters.

The biomarker analysis set - extension phase (BAS-EXT) included participants entering the extension phase who received at least one dose of study medication defined as either alpelisib or fulvestrant who had an evaluable biomarker profile (at least baseline samples) and who did not have violations of the main inclusion-exclusion criteria.

The biomarker analysis set (BAS) included participants who received at least one dose of either ribociclib or letrozole and who had an evaluable biomarker profile (i.e., both valid liquid biopsy and TK1 serum samples collected at screening) and who did not have violations of the main inclusion-exclusion criteria.

Hotspot mutational analysis on liquid biopsy was performed on the 39 genes belonging to the BioItaLEE custom panel. Data row labels refer to the number of hotspot-mutated genes at each timepoint. Each cycle was 28 days. PD = progressive disease.

The biomarker analysis set (BAS) included participants who received at least one dose of either ribociclib or letrozole and who had an evaluable biomarker profile (i.e., both valid liquid biopsy and TK1 serum samples collected at screening) and who did not have violations of the main inclusion-exclusion criteria.

Hotspot mutational analysis on liquid biopsy was performed on the 39 genes belonging to the BioItaLEE custom panel. Data row labels refer to the number of hotspot-mutated genes at each timepoint. Each cycle was 28 days. PD = progressive disease.

The biomarker analysis set (BAS) included participants who received at least one dose of either ribociclib or letrozole and who had an evaluable biomarker profile (i.e., both valid liquid biopsy and TK1 serum samples collected at screening) and who did not have violations of the main inclusion-exclusion criteria.

The target mutation was defined as the hotspot mutation with the highest molecular frequency observed at screening excluding single nucleotide polymorphisms (SNPs, i.e., hotspot mutations observed at all timepoints with a minimum molecular frequency value of 30% and a variation coefficient greater than 0.15). The molecular frequency of target mutation at performed assessments during which the target mutation was not detected was assumed to be equal to 0%.

The biomarker analysis set (BAS) included participants who received at least one dose of either ribociclib or letrozole and who had an evaluable biomarker profile (i.e., both valid liquid biopsy and TK1 serum samples collected at screening) and who did not have violations of the main inclusion-exclusion criteria. Data are reported only for participants with target mutation.

The target mutation was defined as the hotspot mutation with the highest molecular frequency observed at screening excluding single nucleotide polymorphisms (SNPs, i.e., hotspot mutations observed at all timepoints with a minimum molecular frequency value of 30% and a variation coefficient greater than 0.15). The molecular frequency of target mutation at performed assessments during which the target mutation was not detected was assumed to be equal to 0%.

The biomarker analysis set (BAS) included participants who received at least one dose of either ribociclib or letrozole and who had an evaluable biomarker profile (i.e., both valid liquid biopsy and TK1 serum samples collected at screening) and who did not have violations of the main inclusion-exclusion criteria. Data are reported only for participants with the target mutation.

Hotspot mutational analysis on liquid biopsy was performed on the 39 genes belonging to the BioItaLEE custom panel. Data row labels refer to the number of hotspot-mutated genes at each timepoint. Each cycle was 28 days. PD = progressive disease.

The biomarker analysis set (BAS) included participants who received at least one dose of either ribociclib or letrozole and who had an evaluable biomarker profile (i.e., both valid liquid biopsy and TK1 serum samples collected at screening) and who did not have violations of the main inclusion-exclusion criteria.

Hotspot mutational analysis on liquid biopsy was performed on the 39 genes belonging to the BioItaLEE custom panel. Data row labels refer to the number of hotspot-mutated genes at each timepoint. Each cycle was 28 days. PD = progressive disease.

The biomarker analysis set (BAS) included participants who received at least one dose of either ribociclib or letrozole and who had an evaluable biomarker profile (i.e., both valid liquid biopsy and TK1 serum samples collected at screening) and who did not have violations of the main inclusion-exclusion criteria.

Results data refer to the total number of evaluations (i.e. the number of participants in the biomarker analysis set with both valid baseline liquid biopsy and tissue sample multiplied by 39 considered genes).

The biomarker analysis set (BAS) included participants who received at least one dose of either ribociclib or letrozole and who had an evaluable biomarker profile (i.e., both valid liquid biopsy and TK1 serum samples collected at screening) and who did not have violations of the main inclusion-exclusion criteria. Data are reported for participants with both valid baseline liquid biopsy and tissue samples.

Results data refer to the total number of evaluations (i.e. the number of participants in the biomarker analysis set with both valid baseline liquid biopsy and tissue sample multiplied by 39 considered genes).

The biomarker analysis set (BAS) included participants who received at least one dose of either ribociclib or letrozole and who had an evaluable biomarker profile (i.e., both valid liquid biopsy and TK1 serum samples collected at screening) and who did not have violations of the main inclusion-exclusion criteria. Data are reported for participants with both valid baseline liquid biopsy and tissue samples.

Time to progression (TTP) was defined as time from date of start of treatment to the date of event defined as the first documented progression or death due to underlying cancer.

BAS (core phase) and BAS-EXT (extension phase)

ORR was defined as the percentage of participants with a best overall response defined as complete response (CR) or partial response (PR): (CR+PR) per Response Evaluation Criteria in Solid Tumors (RECIST), v. 1.1. CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm; PR= At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.

BAS (core phase) and BAS-EXT (extension phase)

Clinical benefit rate (CBR) was defined as the percentage of participants with a best overall response of complete response (CR), or partial response (PR) or an overall lesion response of stable disease (SD), lasting as per local review, for a duration of at least 24 weeks. Per RECIST v. 1.1, CR was defined as disappearance of all target lesions. PR was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum longest diameter since the treatment started.

BAS (core phase) and BAS-EXT (extension phase)

An insufficient number of tissue samples were collected at the end-of-treatment timepoint to enable scientifically meaningful analyses. Tissue collection at this timepoint was subject to feasibility and patient consent. Given the limited number of samples obtained, the study team concluded that the scientific objective could not be achieved. Consequently, it was concluded and documented in the statistical analysis plan that this analysis would not be performed.

An insufficient number of tissue samples were collected at the end-of-treatment timepoint to enable scientifically meaningful analyses. Tissue collection at this timepoint was subject to feasibility and patient consent. Given the limited number of samples obtained, the study team concluded that the scientific objective could not be achieved. Consequently, it was concluded and documented in the statistical analysis plan that this analysis would not be performed.