CARE Initiative: Real-world Emulation of the PALOMA-2 Trial

CARE Initiative Study: Real-world Emulation of the PALOMA-2 Comparative Effectiveness Trial of Palbociclib and Letrozole vs. Placebo and Letrozole for the First-line Treatment of ER+/HER2- Advanced Breast Cancer

The goal of this non-interventional study is to emulate the PALOMA-2 randomized controlled trial of palbociclib as first-line therapy in patients with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer using real-world, electronic health record data. The main questions this study aims to answer are:

1. Do patients with metastatic ER+/HER2- breast cancer treated with palbociclib and letrozole have improved real-world progression-free survival (rwPFS) compared with patients treated with letrozole alone?
2. How do the results of this non-interventional study compare to those of the PALOMA-2 randomized controlled trial?

Study Overview

• Status: Completed
• Conditions: Metastatic Breast Cancer
• Intervention / Treatment: Drug: Palbociclib; Drug: Letrozole

Detailed Description

The Coalition to Advance Real-World Evidence through Randomized Controlled Trial Emulation (CARE) Initiative is a program designed to build an empirical evidence base for the use of real-world data (RWD) in clinical and regulatory decision-making. Using randomized controlled trials (RCT) as a benchmark for causal effect estimates, a series of RCT emulations will be conducted across varying trials, real world data sources, and study design elements to better understand under what conditions non-interventional studies, using data generated during routine clinical care, can provide reliable conclusions about drug effectiveness.

In this study, real-world electronic health record (EHR) data will be used to emulate the Palbociclib: Ongoing Trials in the Management of Breast Cancer (PALOMA-2) efficacy trial of palbociclib as first-line therapy in patients with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer.2 Similarly to the PALOMA-2 trial, this study will compare real-world progression-free survival (rwPFS) between patients who initiate palbociclib and letrozole and those initiating letrozole alone.

• Study Type: Observational
• Enrollment (Actual): 724

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients identified in the electronic health record data source with metastatic ER+/HER2- breast cancer initiating treatment with the study drugs (palbociclib, letrozole)

Description

Inclusion Criteria:

• Breast cancer diagnosis
• Histology not indicative of non-adenocarcinoma histologies
• Metastatic disease
• Estrogen-receptor positive (ER+)
• No prior systemic treatment for metastatic breast cancer
• Post-menopausal
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2 or missing or Karnofsky performance status >=50 or missing
• No lab results indicating inadequate organ function, as defined in the PALOMA-2 RCT protocol

Exclusion Criteria:

• Human epidermal growth factor receptor 2 (HER2) positive tumor
• Diagnosis of brain, central nervous system, and/or spinal cord metastases
• Neoadjuvant or adjuvant treatment with anastrozole or letrozole ≤12 months before metastatic diagnosis
• Prior treatment with treatment with ribociclib, abemaciclib, or palbociclib
• Treatment with a CYP3A4 inhibitor or inducer or drugs known to prolong the QT interval, as specified in the PALOMA-2 trial protocol, in the 7 days prior to study treatment initiation
• Anti-cancer therapy or major cancer-related surgery within 2 weeks before study treatment initiation
• Diagnosis of a second primary malignancy within 3 years prior to study treatment initiation
• Diagnosis of long or short QT syndrome, Brugada syndrome, QTc prolongation, or Torsade de Pointes
• Diagnosis of hypocalcemia, hypokalemia, or hypomagnesemia
• Diagnosis of myocardial infarction, angina, ongoing cardiac dysrhythmias, atrial fibrillation, congestive heart failure, cerebral infarction, transient ischemic attack, or pulmonary embolism in the 6 months prior to study treatment initiation
• Diagnosis of inflammatory bowel disease chronic diarrhea, or short bowel syndrome
• Diagnosis of human immunodeficiency virus infection

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Exposed; Patients initiating treatment with palbociclib and letrozole as first-line treatment for metastatic ER+/HER2- breast cancer	Drug: Palbociclib; Treatment information in the electronic health record indicates initiation of palbociclib after metastatic diagnosis; Drug: Letrozole; Treatment information in the electronic health record indicates initiation of letrozole after metastatic diagnosis
Comparator; Patients initiating treatment with letrozole as first-line treatment for metastatic ER+/HER2- breast cancer	Drug: Letrozole; Treatment information in the electronic health record indicates initiation of letrozole after metastatic diagnosis

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Real-world progression-free survival (rwPFS)	Time from study treatment initiation to disease progression or death	From study treatment initiation until the date of disease progression, death from any cause or censoring, whichever came first, assessed up to 33 months.

Collaborators and Investigators

• Sponsor: Aetion, Inc.
• Collaborators: Bayer; Pfizer; AbbVie; Gilead Sciences; AstraZeneca; Amgen; Janssen, LP

Publications and helpful links

General Publications

• Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K, Harbeck N, Lipatov ON, Walshe JM, Moulder S, Gauthier E, Lu DR, Randolph S, Dieras V, Slamon DJ. Palbociclib and Letrozole in Advanced Breast Cancer. N Engl J Med. 2016 Nov 17;375(20):1925-1936. doi: 10.1056/NEJMoa1607303.

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2010
• Primary Completion (Actual): July 20, 2023
• Study Completion (Actual): July 20, 2023

Study Registration Dates

• First Submitted: September 19, 2024
• First Submitted That Met QC Criteria: September 19, 2024
• First Posted (Actual): September 23, 2024

Study Record Updates

• Last Update Posted (Actual): September 23, 2024
• Last Update Submitted That Met QC Criteria: September 19, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Keywords: oncology; comparative effectiveness research; pharmacoepidemiology; real-world data; real-world evidence; trial emulation
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Protein Kinase Inhibitors; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Letrozole; Palbociclib
• Other Study ID Numbers: DS3-PALOMA2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes