Clinical efficacy across lines of therapy

PALOMA-3

Study design
PALOMA-3 was a randomised double-blind, placebo-controlled, Phase III study that assessed the efficacy of IBRANCE® in combination with fulvestrant vs placebo + fulvestrant in patients with HR+/HER2- ABC who had progressed on or after prior ET in the adjuvant or metastatic setting. Trial included 21% of patients who were treated in first line and/or pre-/peri-menopausal.2 One previous line of chemotherapy (CT) in advanced disease was allowed.2
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Adapted from Cristofanilli M, et al. 2016.2

*Defined as progression during or within 1 month after the end of prior ET in the context of metastatic disease or progression during or within 12 months after discontinuation of adjuvant ET. 21% of patients had not received prior treatment for their metastatic disease (1st line). Pre-/peri-menopausal patients received the LHRH agonist goserelin for at least 4 weeks prior to and for the duration of the trial.2 †Sensitivity to prior hormonal therapy was defined as documented clinical benefit (CR, PR, or SD ≥24 weeks) to ≥1 prior hormonal therapy regimen in the metastatic setting or ≥24 months of adjuvant hormonal therapy before recurrence.2 ‡Evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1.#ORR was defined as confirmed complete response (CR) or partial response (PR).2 §CBR was defined as CR or PR or stable disease for ≥24 weeks.2

PALOMA-3 Baseline Characteristics

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Adapted from Cristofanilli M, et al. 2016.2
Data cut-off date: March 16, 2015.
Data are number (%), unless otherwise specified. Because of rounding, some percentages do not total 100% when summed.
*Per protocol, visceral refers to lung, liver, brain, pleural, and peritoneal involvement, and was a study stratification factor.2 Data were unavailable for one patient in the ITT fulvestrant + placebo group.2 Disease-free interval was defined as time from diagnosis of primary breast cancer to first relapse in patients who received adjuvant therapy. Data for disease-free interval were available only for patients who were initially diagnosed with early breast cancer and then experienced disease relapse; percentages are calculated on the basis of available data.2 §Patients did not receive chemotherapy in the context of metastatic disease. #Previous sensitivity to endocrine therapy was based on randomisation.2  ¶For classification of receptor status (≥median of distribution, <median of distribution) the H-score was used. The median was calculated on the basis of the number of patients who were tested by the central laboratory (250 patients in the fulvestrant plus IBRANCE® group and 130 patients in the fulvestrant plus placebo group).2

PALOMA-3 Inclusion and Exclusion Criteria

 

Adapted from Cristofanilli M, et al. 2016.2
*Pre-/peri-menopausal patients received the LHRH agonist goserelin for at least 4 weeks prior to and for the duration of the trial.2

ABC = advanced breast cancer; AI = aromatase inhibitor; CDK = cyclin-dependent kinase; CNS = central nervous system; CT = chemotherapy;
ECOG = Eastern Cooperative Oncology Group; ET = endocrine therapy; FUL = fulvestrant;
HR+/HER2- = hormone receptor-positive, human epidermal growth factor receptor 2-negative; IQR = interquartile range; ITT = intention to treat; LHRH = luteinising hormone-releasing hormone;
mTOR = mechanistic target of rapamycin; = number of patients; PFS = progression-free survival; PI3K = phosphoinositide 3-kinase;
PLA = placebo; SD = standard deviation; RECIST = Response Evaluation Criteria In Solid Tumors.
 
 
Primary endpoint: mPFS
IBRANCE® in combination with fulvestrant in 1st line or later doubled mPFS vs placebo + fulvestrant in patients with progression on/after ET in the PALOMA-3 trial*1,2
In a 2:1 randomised, double-blind, Phase III trial of women with HR+/HER2- mBC whose disease progressed following ET (N=521)2
clinical-efficacy-across-lines-therapy
 

Adapted from Cristofanilli M, et al. 20162 and IBRANCE® SmPC.1
*Evaluated according to RECIST Version 1.1.2 Data cut-off date: March 16, 2015. Updated non-prespecified analysis. Data cut-off date: October 23, 2015.

CI = confidence interval; ET = endocrine therapy; FUL = fulvestrant; HR+/HER2- = hormone receptor-positive/human epidermal growth factor receptor 2-negative; HR = hazard ratio; mBC = metastatic breast cancer; mPFS = median progression-free survival; N/n = number of patients; PFS = progression-free survival;  PLA = placebo; RECIST = Response Evaluation Criteria in Solid Tumors; SmPC = Summary of Product Characteristics.

ibrance-hcp-portal_rwe-update

Secondary endpoint: tumour control 
Improved tumour response with IBRANCE® + fulvestrant vs placebo + fulvestrant in 1st line or later (secondary endpoint)1clinical-efficacy-across-lines-therapy
Adapted from IBRANCE® SmPC.1

Data cut-off date: October 23, 2015.
*Defined as confirmed complete response or partial response.2 †Defined as confirmed complete response or partial response or stable disease for ≥24 weeks.2

CBR = clinical benefit rate; FUL = fulvestrant; ITT = intention to treat; = number of patients; ORR = objective response rate; PLA = placebo; SmPC = Summary of Product Characteristics.

Secondary endpoint: OS
The PALOMA-3 OS final analysis of IBRANCE® + fulvestrant in 1st line or later demonstrated a numerical difference favouring IBRANCE® + fulvestrant vs placebo + fulvestrant that did not reach statistical significance4

Adapted from Turner NC, et al. 2018.2
Data cut-off date: April 13, 2018.

The difference in median OS with IBRANCE® + fulvestrant in 1st or later line (not statistically significant) was similar to the improvement in mPFS previously seen with the addition of IBRANCE® to fulvestrant in
PALOMA-34

clinical-efficacy-across-lines-therapy

Adapted from Turner NC, et al. 2018.4
*Data cut-off date: October 23, 2015. Data cut-off date: April 13, 2018.

CI = confidence interval; FUL = fulvestrant; HR = hazard ratio; mPFS = median progression-free survival; = number of patients; OS = overall survival; PFS = progression-free survival; PLA = placebo; SmPC = Summary of Product Characteristics.

ibrance-hcp-portal_rwe-update

 
Exploratory post-hoc analysis: time to subsequent therapy
In an exploratory post-hoc analysis of PALOMA-3, IBRANCE® + fulvestrant in 1st or later line delayed median time to chemotherapy by 8.8 months vs placebo + fulvestrant2
Time to first subsequent CT from randomisation3
 

clinical-efficacy-across-lines-therapy

Adapted from Turner et al. 2018.3
Data cut-off date: April 13, 2018.

Delaying CT can help delay the impact of CT-associated AEs on the patient5

 

In this exploratory post-hoc analysis, using IBRANCE® + fulvestrant in 1st or later line did not compromise the treatment benefit of subsequent therapies:2,3
  • Patients were able to receive ET and CT as further treatment options following progression on IBRANCE® + fulvestrant2
  • Median time from randomisation to end of immediate subsequent line of therapy delayed by 4.7 months with IBRANCE® + fulvestrant vs placebo + fulvestrant3 
AE = adverse event; CI = confidence interval;  CT = chemotherapy; ET = endocrine therapy; FUL = fulvestrant; HR = hazard ratio; = number of patients; PLA = placebo; TCT = time to chemotherapy.
 
 
References

1. IBRANCE® Summary of Product Characteristics.
2. Cristofanilli M, et al. Lancet Oncol. 2016;17(4):425-439.
3. Turner NC, et al. Ann Oncol. 2018;29(3):669-680.
4. Turner NC, et al. N Engl J Med. 2018;379(20):1926.
5. Brufsky A. Clinical Medicine Insights: Oncology. 2015;9:137:147.

 

mPFS = median progression-free survival; OS = overall survival.

 

 

PP-IBR-IRL-0373 Date of Preparation January 2020