A Phase 1/2 Trial of ARV-471 Alone and in Combination With Palbociclib (IBRANCE®) in Participants With ER+/HER2- Locally Advanced or Metastatic Breast Cancer

AUCtau was defined as area under the concentration-time curve during a dosing interval calculated by linear up/log down trapezoidal summation. Based on predefined reporting convention in the SAP, summary statistics describing variability (standard deviation/geometric coefficient of variation) were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.

AUClast was defined as area under the concentration-time curve from time 0 through the last quantifiable concentration (AUClast). Based on predefined reporting convention in the SAP, summary statistics describing variability (standard deviation/geometric coefficient of variation) were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.

Cmax was defined as the maximum observed plasma concentration obtained directly from the observed concentration versus time data. Based on predefined reporting convention in the SAP, summary statistics describing variability (standard deviation/geometric coefficient of variation) were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.

Cmin was defined as the minimum observed plasma concentration. Based on predefined reporting convention in the SAP, summary statistics describing variability (standard deviation/geometric coefficient of variation) were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.

CL/F was defined as the apparent oral plasma clearance of vepdegestrant. Based on predefined reporting convention in the SAP, summary statistics describing variability (standard deviation/geometric coefficient of variation) were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.

Tmax was defined as the time of maximum observed plasma concentration. Based on predefined reporting convention in the SAP, summary statistics describing variability (median) was not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.

Rac was calculated as the ratio of Day 15/Day 1 based on AUCtau. AUCtau was defined as area under the concentration-time curve during a dosing interval calculated by linear up/log down trapezoidal summation. Based on predefined reporting convention in the SAP, summary statistics describing variability (standard deviation/geometric coefficient of variation) were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.

Rac was calculated as the ratio of Day 15/Day 1 based on Cmax. Cmax was defined as the maximum observed plasma concentration obtained directly from the observed concentration versus time data. Based on predefined reporting convention in the SAP, summary statistics describing variability (standard deviation/geometric coefficient of variation) were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.

Effective half-life based on accumulation ratio of RAUC(0-tau). Accumulation ratio was calculated as the ratio of Day 15/Day 1 based on AUCtau. AUCtau was defined as area under the concentration-time curve during a dosing interval calculated by linear up/log down trapezoidal summation. Based on predefined reporting convention in the SAP, summary statistics describing variability (standard deviation/geometric coefficient of variation) were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.

The epimer ARV-473 to parent ratio based on Cmax was reported. Cmax was defined as the maximum observed plasma concentration obtained directly from the observed concentration versus time data. Based on predefined reporting convention in the SAP, summary statistics describing variability (standard deviation/geometric coefficient of variation) were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.

The epimer ARV-473 to parent ratio based on AUCtau was reported. AUCtau was defined as area under the concentration-time curve during a dosing interval calculated by linear up/log down trapezoidal summation. Based on predefined reporting convention in the SAP, summary statistics describing variability (standard deviation/geometric coefficient of variation) were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.

ORR was defined as the percentage of participants with best overall response (BOR) of CR and PR as per Response Evaluation Criteria in Solid Tumours (RECIST version [v] 1.1). BOR: best response was recorded from start of study treatment until disease progression or death due to any cause. CR was defined as disappearance of all TLs and non-TLs and normalization of tumor marker levels initially above upper limits of normal. PR was defined as >30% decrease in the sum of the LD of TLs, taking as reference the baseline sum LD. PD: >20% increase in the sum of the LD of TLs, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non-TLs. Only participants with measurable disease at baseline were included in the analysis of ORR.

CBR: percentage of participants with summation of CR, PR or SD of 24 weeks duration or longer. CR: disappearance of all TLs and non-TLs and normalization of tumor marker levels initially above upper limits of normal. PR: >30% decrease in the sum of the LD of TLs, taking as reference the baseline sum LD. SD of TLs was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. SD of non-TLs Persistence of one or more non-TLs or/and maintenance of tumor marker level above the normal limits. PD: >20% increase in the sum of the LD of TLs, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non-TLs.

DCR: percentage of participants with CR, PR or SD. CR: disappearance of all TLs and non-TLs and normalization of tumor marker levels initially above upper limits of normal. PR: >30% decrease in the sum of the LD of TLs, taking as reference the baseline sum LD. SD of TLs was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. SD of non-TLs Persistence of one or more non-TLs or/and maintenance of tumor marker level above the normal limits. PD: >20% increase in the sum of the LD of TLs, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non-TLs. DCR was based on confirmed responses. Confirmed responses were at least 4 weeks after the criteria for response were first met.

PFS: time from first dose of the study drug until date of documented radiological PD based on RECIST V1.1, or until death due to any cause, whichever occurred first. PD: >20% increase in the sum of the LD of TLs, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non-TLs. Kaplan-Meier (KM) estimate was used for analysis.

DOR was defined as the time interval from the date of first documented confirmed CR/PR to the date of PD or death, whichever occurred first per RECIST version v 1.1. CR: disappearance of all TLs and non-TLs and normalization of tumor marker levels initially above upper limits of normal. PR: >30% decrease in the sum of the LD of TLs, taking as reference the baseline sum LD. PD: >20% increase in the sum of the LD of TLs, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non-TLs. KM estimate was used for analysis.

ORR was defined as the percentage of participants with BOR of CR and PR as per RECIST version [v] 1.1. BOR: best response was recorded from start of study treatment until disease progression or death due to any cause. CR was defined as disappearance of all TLs and non-TLs and normalization of tumor marker levels initially above upper limits of normal. PR was defined as >30% decrease in the sum of the LD of TLs, taking as reference the baseline sum LD. PD: >20% increase in the sum of the LD of TLs, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non-TLs. Only participants with measurable disease at baseline were included in the analysis of ORR.

PFS: time from first dose of the study drug until date of documented radiological PD based on RECIST V1.1, or until death due to any cause, whichever occurred first. PD: >20% increase in the sum of the LD of TLs, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non-TLs. KM estimate was used for analysis.

DOR was defined as the time interval from the date of first documented confirmed CR/PR to the date of PD or death, whichever occurred first per RECIST version v 1.1. CR: disappearance of all TLs and non-TLs and normalization of tumor marker levels initially above upper limits of normal. PR: >30% decrease in the sum of the LD of TLs, taking as reference the baseline sum LD. PD: >20% increase in the sum of the LD of TLs, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non-TLs. KM estimate was used for analysis.

OS was defined as the time from first dose of the study drug until the documented date of death from any cause. KM estimate was used for analysis.

An AE is any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. Treatment-related AE was any untoward medical occurrence attributed to study treatment in a participant who received study treatment. Relatedness was judged by investigator. SAE was an AE resulted in any of the following outcomes: death, inpatient hospitalization or prolongation of existing hospitalization; was life-threatening experience (immediate risk of dying); resulted in persistent or significant disability/incapacity; congenital anomaly/birth defect or was otherwise considered medically important. A TEAE was an AE occurring on/after the date of first dose of study medication and within 30 days of the last dose of study medication. TEAEs included both Serious TEAEs and non-serious TEAEs.

Pre-dose Plasma concentrations of vepdegestrant and ARV-473 was reported. Based on predefined reporting convention in the SAP, summary statistics describing variability (standard deviation/geometric coefficient of variation) were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.

AUCtau was calculated by linear up/log down trapezoidal summation. As planned for Part C, PK data of vepdegestrant \& ARV-473 and palbociclib for arms administered with 125 mg palbociclib was reported for C1D1 and C1D15. PK data of vepdegestrant \& ARV-473 data for arm administered with 100 mg palbociclib was reported for combined C1D21 and C2D15, and palbociclib PK data for C1D8 and combined C1D21 and C2D15. As per protocol, in the arm administered with 100 mg palbociclib, if the intensive PK sample collection was not done on C1D21, it was postponed to C2D15. Only combined data on C1D21 and C2D15 represented all the data at the steady state of the combination of vepdegestrant 200 mg QD with palbociclib and were used for drug-drug interaction (DDI) evaluation. Based on predefined reporting convention in the SAP, summary statistics were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.

As planned for Part C, PK data of vepdegestrant and ARV-473 and palbociclib for arms administered with 125 mg palbociclib was reported for C1D1 and C1D15. PK data of vepdegestrant and ARV-473 data for arm administered with 100 mg palbociclib was reported for combined C1D21 and C2D15, and palbociclib PK data for C1D8 and combined C1D21 and C2D15. As per protocol, in the arm administered with 100 mg palbociclib, if the intensive PK sample collection was not done on C1D21, it was postponed to C2D15. Only combined data on C1D21 and C2D15 represented all the data at the steady state of the combination of vepdegestrant 200 mg QD with palbociclib and were used for DDI evaluation. Based on predefined reporting convention in the SAP, summary statistics were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.

As planned for Part C, PK data of vepdegestrant and ARV-473 and palbociclib for arms administered with 125 mg palbociclib was reported for C1D1 and C1D15. PK data of vepdegestrant and ARV-473 data for arm administered with 100 mg palbociclib was reported for combined C1D21 and C2D15, and palbociclib PK data for C1D8 and combined C1D21 and C2D15. As per protocol, in the arm administered with 100 mg palbociclib, if the intensive PK sample collection was not done on C1D21, it was postponed to C2D15. Only combined data on C1D21 and C2D15 represented all the data at the steady state of the combination of vepdegestrant 200 mg QD with palbociclib and were used for DDI evaluation. Based on predefined reporting convention in the SAP, summary statistics were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.

Cmin was defined as the minimum observed plasma concentration. As planned for Part C, PK data of vepdegestrant and ARV-473 and palbociclib for arms administered with 125 mg palbociclib was reported for C1D15. PK data of vepdegestrant and ARV-473 data for arm administered with 100 mg palbociclib was reported for combined C1D21 and C2D15, and palbociclib PK data for C1D8 and combined C1D21 and C2D15. As per protocol, in the arm administered with 100 mg palbociclib, if the intensive PK sample collection was not done on C1D21, it was postponed to C2D15. Only combined data on C1D21 and C2D15 represented all the data at the steady state of the combination of vepdegestrant 200 mg QD with palbociclib and were used for DDI evaluation. Based on predefined reporting convention in the SAP, summary statistics were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.

As planned for Part C, PK data of vepdegestrant and palbociclib for arms administered with 125 mg palbociclib was reported for C1D15. PK data of vepdegestrant data for arm administered with 100 mg palbociclib was reported for combined C1D21 and C2D15, and palbociclib PK data for C1D8 and combined C1D21 and C2D15. As per protocol, in the arm administered with 100 mg palbociclib, if the intensive PK sample collection was not done on C1D21, it was postponed to C2D15. Only combined data on C1D21 and C2D15 represented all the data at the steady state of the combination of vepdegestrant 200 mg QD with palbociclib and were used for DDI evaluation. Based on predefined reporting convention in the SAP, summary statistics were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.

Tmax was defined as the time of maximum observed plasma concentration. As planned for Part C, PK data of vepdegestrant and ARV-473 and palbociclib for arms administered with 125 mg palbociclib was reported for C1D1 and C1D15. PK data of vepdegestrant and ARV-473 data for arm administered with 100 mg palbociclib was reported for combined C1D21 and C2D15, and palbociclib PK data for C1D8 and combined C1D21 and C2D15. As per protocol, in the arm administered with 100 mg palbociclib, if the intensive PK sample collection was not done on C1D21, it was postponed to C2D15. Only combined data on C1D21 and C2D15 represented all the data at the steady state of the combination of vepdegestrant 200 mg QD with palbociclib and were used for DDI evaluation. Based on predefined reporting convention in the SAP, summary statistics were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.

Rac was calculated as the ratio of Day 15/Day 1 based on AUCtau. AUCtau was defined as area under the concentration-time curve during a dosing interval calculated by linear up/log down trapezoidal summation. As planned for Part C, PK data of vepdegestrant and ARV-473 and palbociclib for arms administered with 125 mg palbociclib was reported for C1D1 and C1D15. As prespecified, participants in the Part C - Phase 1b: Vepdegestrant 200 mg + Palbociclib 100 mg Arm were not assessed. Based on the predefined reporting convention in the SAP, summary statistics describing variability (standard deviation/geometric coefficient of variation) were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.

Rac was calculated as the ratio of Day 15/Day 1 based on Cmax. Cmax was defined as the maximum observed plasma concentration obtained directly from the observed concentration versus time data. As planned for Part C, PK data of vepdegestrant and ARV-473 and palbociclib for arms administered with 125 mg palbociclib was reported for C1D1 and C1D15. As prespecified, participants in the Part C - Phase 1b: Vepdegestrant 200 mg + Palbociclib 100 mg Arm were not assessed. Based on the predefined reporting convention in the SAP, summary statistics describing variability (standard deviation/geometric coefficient of variation) were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.

Effective half-life based on accumulation ratio of RAUC(0-tau). Accumulation ratio was calculated as the ratio of Day 15/Day 1 based on AUCtau. AUCtau was defined as area under the concentration-time curve during a dosing interval calculated by linear up/log down trapezoidal summation. As planned for Part C, PK data of vepdegestrant and ARV-473 and palbociclib for arms administered with 125 mg palbociclib was reported for C1D1 and C1D15. Based on the predefined reporting convention in the SAP, summary statistics describing variability (standard deviation/geometric coefficient of variation) were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.

Epimer ARV-473 to parent ratio based on Cmax was reported. Cmax was defined as the maximum observed plasma concentration obtained from the observed concentration versus time data. As planned for Part C, PK data of vepdegestrant, ARV-473 and palbociclib for arms administered with 125 mg palbociclib was reported for C1D1/C1D15. PK data of vepdegestrant and ARV-473 data for arm administered with 100 mg palbociclib was reported for combined C1D21/C2D15. As per protocol, in 100 mg palbociclib administered arm, intensive PK sample collection not done on C1D21 was postponed to C2D15. Only combined data on C1D21 and C2D15 represented all the data at the steady state of the combination of vepdegestrant 200 mg QD with palbociclib and were used for DDI evaluation. Based on predefined reporting convention in the SAP, summary statistics were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.

Epimer ARV-473 to parent ratio based on AUCtau was reported. AUCtau was calculated by linear up/log down trapezoidal summation. As planned for Part C, PK data of vepdegestrant and ARV-473 and palbociclib for arms administered with 125 mg palbociclib was reported for C1D1 and C1D15. PK data of vepdegestrant and ARV-473 data for arm administered with 100 mg palbociclib was reported for combined C1D21 and C2D15. As per protocol, in the arm administered with 100 mg palbociclib, if the intensive PK sample collection was not done on C1D21, it was postponed to C2D15. Only combined data on C1D21 and C2D15 represented all the data at the steady state of the combination of vepdegestrant 200 mg QD with palbociclib and were used for DDI evaluation. Based on predefined reporting convention in the SAP, summary statistics were not calculated or presented for analysis groups or timepoints if fewer than 3 participants had reportable parameter values.

ORR was defined as the percentage of participants with BOR of CR and PR as per RECIST version [v] 1.1. BOR: best response was recorded from start of study treatment until disease progression or death due to any cause. CR was defined as disappearance of all TLs and non-TLs and normalization of tumor marker levels initially above upper limits of normal. PR was defined as >30% decrease in the sum of the LD of TLs, taking as reference the baseline sum LD. PD: >20% increase in the sum of the LD of TLs, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non-TLs. Only participants with measurable disease at baseline were included in the analysis of ORR.

CBR: percentage of participants with summation of CR, PR or SD of 24 weeks duration or longer. CR: disappearance of all TLs and non-TLs and normalization of tumor marker levels initially above upper limits of normal. PR: >30% decrease in the sum of the LD of TLs, taking as reference the baseline sum LD. SD of TLs was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. SD of non-TLs Persistence of one or more non-TLs or/and maintenance of tumor marker level above the normal limits. PD: >20% increase in the sum of the LD of TLs, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non-TLs.

PFS: time from first dose of the study drug until date of documented radiological PD based on RECIST V1.1, or until death due to any cause, whichever occurred first. PD: >20% increase in the sum of the LD of TLs, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non-TLs. KM estimate was used for analysis.

OS was defined as the time from first dose of the study drug until the documented date of death from any cause. KM estimate was used for analysis.

DOR was defined as the time interval from the date of first documented confirmed CR/PR to the date of PD or death, whichever occurred first per RECIST version v 1.1. CR: disappearance of all TLs and non-TLs and normalization of tumor marker levels initially above upper limits of normal. PR: >30% decrease in the sum of the LD of TLs, taking as reference the baseline sum LD. PD: >20% increase in the sum of the LD of TLs, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non-TLs. KM estimate was used for analysis.