Palbociclib for Male Patients with Metastatic Breast Cancer

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Author Manuscript Published OnlineFirst on October 24, 2019; DOI: 10.1158/1078-0432.CCR-19-2580 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.

CCR-19-2580

Title: FDA Approval Summary: Palbociclib for Male Patients with Metastatic Breast

Cancer

Authors: Suparna Wedam1*, Lola Fashoyin-Aje1*, Erik Bloomquist1, Shenghui Tang1,

Rajeshwari Sridhara1, Kirsten B. Goldberg2, Marc R. Theoret1, Laleh Amiri-Kordestani1,

Richard Pazdur1,2, Julia A. Beaver1

Authors’ Affiliation: 1Center for Drug Evaluation and Research, U.S. Food and Drug

Administration; 2Oncology Center of Excellence, U.S. Food and Drug Administration

Running Title: FDA Approval of Palbociclib for Male Breast Cancer

Corresponding Author: Suparna Wedam, Office of Hematology and Oncology Products,

CDER, U.S. Food and Drug Administration, WO22 Room 2112, 10903 New Hampshire

Avenue, Silver Spring, MD 20993. Phone: 301-796-1776 Fax: 301-796-9909. Email:

[email protected]

*: SW and LF-A contributed equally to this publication.

Note: This is a U.S. Government work. There are no restrictions on its use.

Disclosure of Potential Conflicts of Interest: The authors report no financial interests or

relationships with the commercial sponsors of any products discussed in this report.

Word count: Abstract, 187. Text: 2836. Tables: 1. Figures: 1. References: 17

Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 24, 2019; DOI: 10.1158/1078-0432.CCR-19-2580 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.

Abstract

On April 4, 2019, the Food and Drug Administration (FDA) approved a supplemental new drug application for palbociclib (IBRANCE®), to expand the approved indications in women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer (MBC) in combination with an aromatase inhibitor or fulvestrant, to include men. Palbociclib was first approved in 2015 for use in combination with letrozole for the treatment of estrogen receptor (ER)-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy in postmenopausal women and subsequently in 2016 in combination with fulvestrant in women with HR-positive, HER2-negative advanced breast cancer with disease progression following endocrine therapy. The current approval was primarily based on the results of the PALOMA-2 and PALOMA-3 trials and, supported by real-world data

(RWD) from electronic health records and insurance claims. To support the safety evaluation in male patients, data from two phase 1 studies with palbociclib and safety information from the global safety database, were also reviewed. This article summarizes FDA decision-making and data supporting the approval of palbociclib for the treatment of male patients with HR-positive,

HER2-negative advanced or metastatic breast cancer.

Introduction

There will be an estimated 2,670 new cases of breast cancer in men in 2019 which represents less than 1 percent of all newly diagnosed breast cancer cases (1-4). Most breast cancers in men express estrogen and/or progesterone receptor., but very rarely overexpress HER2 or are triple negative (5). While data on molecular subtyping and genomic profiling of breast cancer tumors in men are scarce, the available data suggests some potential biologic differences between breast

cancer in men and women. Luminal B and HER2 phenotypes are much less common in men than

women (5-7). One study has shown that there may be a lower frequency of certain somatic

mutations (PIK3CA and TP53) that are commonly seen in ER-positive/Her2-negative female

breast cancers (8). Stage for stage, prognosis for men is comparable to that of women, but men

are more likely to be diagnosed at an older age and with more advanced disease (2, 9, 10). Men

have historically been excluded from breast cancer clinical trials. In the absence of safety and

efficacy data from adequate and well-controlled studies in male patients with breast cancer,

current clinical practice standards support treatment of men according to a similar treatment

paradigm as women.

Palbociclib is an inhibitor of the cyclin-dependent kinases (CDK) 4 and 6. Palbociclib initially

received accelerated approval on February 3, 2015, for use in combination with letrozole for the

treatment of ER-positive, HER2-negative metastatic breast cancer (MBC) as initial endocrine-

based therapy in postmenopausal women (11). On February 19, 2016, the U.S. Food and Drug

Administration (FDA) granted regular approval for palbociclib in combination with fulvestrant,

for the treatment of women with HR-positive, HER2-negative MBC with disease progression

following endocrine therapy based on PALOMA-3, a multicenter trial in which men were not eligible (12). On March 31, 2017, FDA granted regular approval for palbociclib as initial

endocrine-based therapy for postmenopausal women in combination with any aromatase

inhibitor based on PALOMA-2, a multicenter trial in which men were not eligible (13). In this

article, we present the FDA rationale for the approval of palbociclib for the use in the treatment

of men with breast cancer.

Methods: Data Sources

The following data were reviewed to support the expansion of the palbociclib indications to

include men: the results of the PALOMA-2 and PALOMA-3 trials, real-world data (RWD) from

electronic health records (EHRs) of male patients with breast cancer treated with palbociclib,

insurance claims data for male patients with breast cancer treated with palbociclib, information

from the global safety database for palbociclib and from two studies of palbociclib in male

patients with other solid tumors, postmarketing reports for palbociclib from the FDA Adverse

Event Reporting System (FAERS), and a literature search.

PALOMA-2

This is a randomized, double-blind trial in 666 postmenopausal women with ER-positive, HER2-

negative MBC naïve to systemic treatment for advanced disease. Patients received palbociclib or placebo, in combination with letrozole. The primary endpoint was investigator-assessed progression free survival (PFS) with key secondary endpoints including overall survival (OS) and objective response rate (ORR).

PALOMA-3

PALOMA-3 is a multicenter, double-blind trial which randomized (2:1) 521 women with HR-

positive, HER2-negative MBC and disease that progressed on or after prior endocrine therapy to

receive palbociclib or placebo, in combination with fulvestrant. The primary endpoint was

investigator-assessed PFS with key secondary endpoints including OS and ORR.

Flatiron Health Analytic Database

A retrospective outcomes analysis based upon data from EHRs in the Flatiron Health Analytic

Database (FHAD) was submitted. The FHAD contains clinical data and outcomes collected

through EHRs used by participating providers of cancer care across the U. S. who primarily

provide such care in community oncology clinics. The EHR data processing methods used in the

FHAD have been described (14, 15). This analysis identified male patients from the Flatiron database with an International Classification of Diseases (ICD) coding for MBC.

Patient-level data were collected between January 1, 2011, and July 31, 2017. The data described

the clinical characteristics and outcomes in a cohort of male patients with HR-positive, HER2-

negative MBC who had either received a palbociclib-based regimen in any line of therapy

(palbociclib cohort), or who had received an endocrine therapy-based regimen in any line of

therapy but were never treated with a palbociclib-containing regimen (endocrine cohort). No

formal hypothesis testing was performed.

Patients were selected for the analysis and were included in one of the two cohorts based upon

whether they had a structured medication order for palbociclib, or a structured medication order

for endocrine therapy such as tamoxifen or fulvestrant, and without an order for palbociclib.

Additional inclusion rules and data processing steps were applied to identify a subgroup of

patients who would be included in the current indication for palbociclib (see Figure 1 for the data

processing steps).

Random sampling was used in the endocrine cohort to reduce the unstructured processing. An

activity gap was employed to eliminate individuals who had an initial consult but who received

therapy elsewhere. FDA excluded patients treated with tamoxifen since it is not approved for use

in combination with palbociclib.

Real-world tumor response was based on clinician assessed reports of radiologic findings as

documented in the EHR as part of routine clinical care; this information was supplemented by

reports of the physical exam, symptom improvement, and the pathology reports. The treating

clinician’s assessment was mapped to one of the following tumor response categories: complete

response, partial response, stable disease, or progressive disease (15, 16).

A pre-specified abstraction of adverse event (AE) data from the EHR was conducted for the

palbociclib cohort only; this was limited to AEs attributed to palbociclib. The selection of which

AEs were of interest was based on the known safety profile of palbociclib; these AEs included fatigue, febrile neutropenia, neutropenia, pulmonary embolism, and stomatitis.

IQVIA Analysis

This was a descriptive and retrospective claims data analysis, utilizing secondary de-identified data sources to describe patterns of palbociclib usage among male patients with MBC in the U.S.

The two-part analysis was based upon data from the Specialty Pharmacy Datamart and Pharmacy and Medical claims databases. In Part 1, patients who were identified in the Specialty Pharmacy

Datamart were matched to QuintilesIMS Pharmacy and Medical claims databases using a unique

identifier to provide information on the use and duration of prescription orders. Data were

collected from January 1, 2010, to April 30, 2017, to allow for an exploratory analysis of

treatment patterns pre- and post-palbociclib approval. In Part 2, an IQVIA longitudinal de-

identified pharmacy claims dataset that tracks the claim adjudication between the retail/specialty pharmacy, payer, and patient at the point of sale was used. As a baseline comparator, pharmacy adjudication patterns for female patients prescribed palbociclib during the same time were assessed to identify potential differences.

Phase 1 Studies

Study 1001 was an open-label, dose-finding study conducted in patients with advanced cancer who received palbociclib in accordance with either dosing Schedule 3/1 or Schedule 2/1 (i.e., dosing schedule of 3 or 2 weeks on treatment/1 week off treatment) until disease progression or unacceptable toxicity occurred.

Study 1002 was conducted to evaluate and compare biomarkers of CDK4/6 inhibition in tumor biopsies with changes in positron emission tomography, to assess antitumor activity and safety of palbociclib in patients with mantle cell lymphoma who were previously treated with at least one prior therapy.

Global safety database

The palbociclib global safety database was queried through January 31, 2018, to identify male patients with breast cancer who received palbociclib.

Postmarketing analysis

FDA conducted a review of postmarketing reports for palbociclib from FAERS, and the

Sponsor’s latest Periodic Adverse Drug Experience Report (PADER) for the reporting period

between November 3, 2017, and February 2, 2018.

Results

The results of an unplanned analysis of PALOMA-2 reflecting an additional 15 months of

follow-up were similar to the previously reviewed initial analysis which showed a statistically

significant improvement in PFS (HR 0.58; 95% CI: 0.46, 0.72; p<0.0001) at 23 months of

median follow up. PALOMA-3 also showed a statistically significant improvement in median

PFS from 4.6 months to 9.5 months (HR 0.46; 95% CI: 0.36, 0.59; p<0.0001) with the addition

of palbociclib to fulvestrant.

The Flatiron analysis initially identified 2,675 male patients; after additional data processing

steps were applied (Figure 1) only 28 patients remained available for analysis. Baseline

characteristics were not well balanced across the two cohorts (Table 1). Compared to the patients

in the Endocrine Cohort, patients in the Palbociclib Cohort tended to be younger and to be more

refractory (i.e., fewer first line patients).

Three out of 12 patients in the Palbociclib Cohort experienced a real-world partial or complete

response. One additional patient in Palbociclib Cohort experienced a response after progressive

disease and was not considered a responder. In the Endocrine Cohort, 2 out of 16 experienced a

response. Duration of response data was limited due to the small number of responders and the lack of standard scheduled follow-ups.

In the IQVIA analysis, for patients identified as first-line patients with MBC (n=37 for palbociclib + endocrine, n=214 for endocrine), the palbociclib + endocrine treated patients had an estimated median prescription order duration of 8.5 months (95% CI: 4.4, 13.0) and the endocrine-only treated patients had an estimated median prescription order duration of 4.3 months (95% CI: 3.0, 5.7). In the second-line male patients with MBC, (n=10 for palbociclib + fulvestrant, n=24 for fulvestrant), the estimated median prescription order duration was 2.7 months in the palbociclib and fulvestrant treated patients and 1.0 month in the fulvestrant treated patients. Demographic information for these patients was limited.

Overall, 5 of the 12 (42%) patients in the Palbociclib Cohort from the Flatiron Database experienced at least 1 of the 5 prespecified AEs of interest: neutropenia (n=4) , fatigue (n=2) , and stomatitis (n=1) . One patient each experienced both neutropenia and fatigue and neutropenia and stomatitis. There were no reports of febrile neutropenia or pulmonary embolism.

In Study 1001, a total of 36 male patients received palbociclib, of whom 15 received palbociclib at a starting dose of 75 mg QD (n=3), 100 mg QD (n=1), or 125 mg QD (n=11) on Schedule 3/1, the currently approved dosing regimens in the palbociclib U.S. Prescribing Information (USPI).

Colon cancer, malignant melanoma, pancreatic carcinoma, and sarcoma (2 patients each) comprised the most common cancers in these 15 patients. There were no Grade 4 or 5 AEs reported for the 15 patients. The most frequently reported treatment-related AEs (>25% of

patients) of any grade were fatigue (53.3%), neutropenia (33.3%), nausea (33.3%), and diarrhea

(26.7%). In Study 1002, 14 male patients received palbociclib at a starting dose of 125 mg QD

on Schedule 3/1. There were 2 patients with Grade 4 AEs (leukopenia, thrombocytopenia, and neutropenia in one patient and leukopenia and thrombocytopenia in one patient) and one patient

with a Grade 5 AE (cardiac arrest). The Grade 5 AE was not considered to be treatment-related.

The most frequently reported treatment-related AEs (>25% of patients) of any grade were fatigue

(42.9%) and neutropenia (35.7%).

In the palbociclib global safety database, a total of 362 cases of male breast cancer with 752

reported AEs were identified. Adverse reactions were reported in greater than 5% of patients

include: fatigue (28%), neutropenia (17%), white blood cell count decreased (15%), nausea

(12%), diarrhea (10%), decreased appetite (9%), vomiting (7%), asthenia (7%), anemia (7%), neutrophil count decreased (6%), neuropathy peripheral (6%), dyspnea (6%).

The FAERS search yielded 23,251 reports, including 569 reports of palbociclib use in men. The

top 20 reported MedDRA preferred terms (PTs) were generally similar for male and female

patients receiving palbociclib, and consistent with the palbociclib USPI. Additionally, a review

of the most recent PADER included 62 male patients; overall, the drug sponsor did not identify new safety issues that would alter palbociclib’s known safety profile. A literature search

retrieved four clinical studies evaluating palbociclib for treatment of multiple myeloma,

retinoblastoma protein (Rb)-positive germ cell tumors, liposarcoma, and Rb-positive advanced

solid tumors, that enrolled both female and male patients. The trials did not reveal any

differences in toxicities observed among male patients compared to female patients receiving

palbociclib.

Regulatory Insights

The results of the real-world analyses submitted to support the application for FDA approval of

palbociclib for male patients had many limitations. For the Flatiron analysis, a mere 1% of the initial sample of 2,500 patients were ultimately available for the analysis after data processing

steps were applied, limiting the interpretation of the findings. Additionally, because of the small

sample size, matching methods could not be employed to balance baseline prognostic factors.

For example, substantially more refractory patients were included on the palbociclib cohort

compared to the endocrine cohort, and thus no direct comparison between cohorts was made and the palbociclib cohort was considered as a single-arm analysis. In this case, while RWD provided

some evidence that palbociclib in combination with endocrine therapy has anti-tumor activity (as

measured by the real-world response rate) in men with MBC, the data did not isolate the effect of

palbociclib. Ultimately, FDA relied on the isolation of effect of palbociclib demonstrated in the

large randomized studies in women.

The IQVIA data were similarly limited. While the analysis provided information on prescription

duration, the relationship between prescription order and commonly used measures of drug

efficacy is unclear. And while the duration of a prescription order may serve as a proxy for

duration of treatment in a cancer population, the application did not include information to

support such a relationship nor provide justification to infer that durable prescription order may

translate to an improvement in more clinically relevant endpoints such as OS or PFS. The IQVIA

database also did not provide prior patient treatment or tumor characteristics therefore precluding

the ability to put the 8.5-month prescription order duration into context. Ultimately, the RWD

provided in this application did not allow for substantial conclusions regarding the efficacy of

palbociclib in men and were considered supportive to the totality of data from PALOMA-2 and

PALOMA-3.

FDA relied primarily on the established safety profile of palbociclib to characterize safety risk in

male patients. Review of the safety data package did not reveal new safety signals in male breast

cancer patients and, in general, the AE profile for male patients appeared to be consistent with

the known AE profile of palbociclib.

The rarity of breast cancer in males precludes the conduct of large randomized trials in men and

has historically led to the exclusion of men from trials of breast cancer drugs. The clinical

management of male breast cancer is generally based on extrapolation from results of studies

conducted in women (17). However, trials supporting recent FDA approvals for atezolizumab,

alpelisib, and talazoparib have included men and women with breast cancer, and the indications reflect this inclusion. FDA has also extrapolated results from women for some breast cancer

drug approvals where there is scientific rationale to expect no difference between effectiveness

in men and women; this approach is usually supported by data from additional clinical

development, drug mechanism of action, and/or literature. Examples of recent FDA approvals

employing this approach include abemaciclib as monotherapy, trastuzumab and hyaluronidase-

oysk, and neratinib. Given the use of palbociclib with endocrine therapy, and the differences in

hormonal axis between men and women, additional supportive data was requested to describe

anti-tumor effects and safety in male patients.

Real world data (RWD) to generate RWE may be derived from a variety of sources, such as

EHRs, medical claims, product and disease registries, laboratory test results and mobile devices.

Retrospective examination of RWD may provide the opportunity to gain insight into treatment patterns in oncology particularly for demographic subgroups that are underrepresented or

excluded from participating in clinical trials. Such analysis as palbociclib demonstrates, may

provide supportive and/or complementary information to the known safety and efficacy of

approved therapies, to aid regulatory decision-making. In addition, FDA continues to discuss the potential for the use of RWE as primary evidence to support regulatory decision making

including adding or modifying an indication, such as adding a new population or adding

comparative effectiveness or safety information.

Conclusions

To expand the palbociclib indications to include men, FDA relied primarily on the previous

findings of a favorable benefit:risk assessment of palbociclib in women based on several large

randomized clinical trials and supportive RWD which provided descriptive information about

outcomes in a cohort of palbociclib treated male patients with MBC. The limitations of the RWD

in this setting underscore the importance of including male patients in prospective trials

evaluating breast cancer therapies. Low expected accrual of men in trials should not preclude

eligibility in breast cancer trials, as their inclusion, even in small numbers, could potentially

support a broadened indication.

References

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Table 1: Flatiron Analysis Baseline Characteristics

Palbociclib cohort Endocrine cohort Total

Demographic Parameters N=12 N=16 N=28

N (%) N (%) N (%)

Age at diagnosis of metastatic disease

Median (years) 62.0 71.0 68.0

Age Group

35-49 0 (0) 2 (12.5) 2 (7.1)

50-64 7 (58.3) 4 (25.0) 11 (39.3)

64+ 5 (41.7) 10 (62.5) 15 (53.6)

Race

White 7 (58.3) 11 (68.8) 18 (64.3)

Black or African American 2 (16.7) 2 (12.5) 4 (14.3)

Asian 2 (16.7) 1 (6.2) 3 (10.7)

Other/unknown 1 (8.3) 2 (12.5) 3 (10.7)

Region within United States

West 1 (8.3) 1 (6.2) 2 (7.1)

Midwest 3 (25.0) 6 (37.5) 9 (32.1)

South 6 (50.0) 5 (31.2) 11 (39.3)

Northeast 2 (16.7) 3 (18.8) 5 (17.9)

Other/unknown 0 (0) 1 (6.2) 1 (3.6)

Practice Type

Academic 0 (0.0) 1 (6.2) 1 (3.6)

Community 12 (100.0) 15 (93.8) 27 (96.4)

Stage and Initial Diagnosis

I-III 10 (83.3) 13 (81.2) 23 (82.1)

IV 1 (8.3) 3 (18.8) 4 (14.2)

Progesterone Receptor

Status

Positive 8 (66.7) 13 (81.2) 21 (75.0)

Negative 2 (16.7) 3 (18.8) 5 (17.9)

Line of Therapy

First-line 6 (50.0) 13 (81.2) 19 (67.9)

Second-line 2 (16.7) 2 (12.5) 4 (14.3)

Third or later line 4 (33.3) 1 (6.2) 5 (17.9)

Figure 1: Flatiron Database Analysis Consort Diagram. Numbers in parentheses represent the number of patients available after each step is applied.

Male patient with mBC ICD diagnosis (2,675)

Two recorded visits after 2011 (2,416) Palbociclib cohort Endocrine cohort

Structured prescription order for palbociclib (77) Structured order for endocrine therapy, no order for palbociclib (1,295)

Random sampling for unstructured processing (664)

Metastatic breast cancer and pathology consistent Metastatic breast cancer and pathology consistent (67) (102)

HR positive and HER2 negative and less than 30 HR positive and HER2 negative and less than 30 day activity gap and recent disease after 2011 (30) day activity gap and recent disease after 2011 (47)

Confirmed male and confirmed palbociclib regimen Confirmed male and confirmed endocrine regimen (25) and confirmed no palbociclib regimen (34)

Endocrine therapy other than tamoxifen (21)

On study radiological reports (12) On study radiological reports (16)

FDA Approval Summary: Palbociclib for Male Patients with Metastatic Breast Cancer

Suparna Wedam, Lola Fashoyin-Aje, Erik Bloomquist, et al.

Clin Cancer Res Published OnlineFirst October 24, 2019.

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