collaborative management of patients with advanced ... · resume at same dose when gr ≤ 2 day 15...

Collaborative Management of Patients With Advanced

Estrogen Receptor–Positive Breast Cancer

Lee Schwartzberg, MD, FACPHeather Greene, FNP, AOCNP®

West Cancer CenterMemphis, Tennessee

Learning Objectives• Describe the mechanism of action of CDK inhibitors and how

they differ from that of other forms of breast cancer treatments• Explain why combining a CDK inhibitor with endocrine therapy

may be beneficial in certain breast cancer subgroups• Review the side-effect profile of CDK inhibitors, especially

neutropenia, and how to manage toxicities while preserving dose delivery

• Determine when to adjust dosing of palbociclib for hematologic toxicities

Financial Disclosure• Dr. Schwartzberg has served on the speakers bureau for

Novartis and acted as a consultant for Pfizer.• Ms. Greene has served on the speakers bureau for Pfizer.

Case Study• 65-year-old female, diagnosed in 2003 with a 7.5-cm ductal ca,

3/17 nodes +, ER/PR+, HER2-• s/p left mastectomy (pT3, pN2, M0) • Adjuvant EC x 4à docetaxel x 4, XRT to chest wall• Adjuvant tamoxifen 2004–2006• Adjuvant anastrozole x 1 yr à exemestane through 2011, then

observation

Case Study• November 2015 developed lower pelvic pain• Ortho à plain film and MRI: mets• Biopsy R posterior iliac sclerotic lesion c/w metastatic

adenocarcinoma breast primary• ER/PR+ (100%), HER2-• PET/CT: mediastinal adenopathy, one non-calcified RLL nodule,

SQ gluteal and back nodules, and blastic mets at T11, T6, R & L iliac crests, L femur

Case Study

• January 2016: 79 years old• DM type 2, vertigo, hypertension, CHF, hypothyroidism,

GERD, depression• Metastatic ER/PR+, HER2- breast cancer with bone, nodal

and cutaneous mets• Started fulvestrant, palbociclib, and denosumab (2/16)

PET/CT Scan 1/16

Images courtesy of West Clinic.

Goals of Endocrine Therapy in Metastatic Breast Cancer

• Reduce cancer-related symptoms

• Increase progression-free survival

• Increase time to chemotherapy

• Improve quality of life

• Increase overall survival

Incidence of Metastatic Breast Cancer• 3%–6% of patients have MBC at the initial diagnosis of breast

cancer in US• 20% of patients with stage I to III at diagnosis will develop MBC

American Cancer Society. Breast Cancer Facts & Figures 2005-2006.

Today’s Biology in the Clinic

Incidence Therapy

ER+/- PR + 75%Endocrine

chemotherapy

HER2+ 15–30% Anti-HER2

Triple negative 10–20% Chemotherapy

American Cancer Society. Breast Cancer Facts & Figures 2005-2006.

Clinical Predictors of Outcome for ER+ Breast Cancer• Disease-free interval• Prior endocrine therapy

• Clinical history radically different now than 20+ years ago with widespread use of adjuvant therapy

• Quantitative ER expression• Bone-only vs. visceral metastases• HER2 expression• PR negativity

Oh DS, et al. J Clin Oncol 2006;24(11):1656-64; Rakha EA, et al. J Clin Oncol 2007;25(30):4772-8; Sainsbury JR, et al. Lancet 1987;1(8547):1398-402; Loi S, et al. BMC Genomics 2008;9:239; Ross JS, et al. Oncologist 2008;13(5):477-93; Weigel MT, et al. Endocr Relat Cancer 2010;17(4):R245-62; Taneja P, et al. Clin Med Insights Oncol 2010;4:15-34; Niikura N, et al. Oncologist 2011;16(2):155-64; Kurebayashi J, et al. Oncology 2000;59(suppl 1)31-7.

NCCN Clinical Practice Guidelines in Oncology. Breast cancer, v1.2012; Osborne CK, et al. Ann Rev Med. 2011;62:233-47.

NCCN Guidelines Recommend Serial Endocrine Tx for HR+, HER2- Advanced Breast Cancer Not in Visceral Crisis

Presented by Nicholas Turner at 2015 ASCO Annual Meeting

Finn RJ, et al. Breast Cancer Res 2009:11(5):R77.

PALOMA-1 Phase II Design

N = 66

1:1

Part 1

RANDOMIZATION

PD 0332991 125 mg QDa +

Letrozole 2.5 mg QD

Letrozole 2.5 mg QD

Part 2

N = 99

1:1

ER+, HER2–BC with

CCND1 amp and/or loss

of p16

RANDOMIZATION

PD 0332991 125 mg QDa +

Letrozole 2.5 mg QD

Letrozole 2.5 mg QD

Primary Endpoint PFSStratification Factors• Disease Site (Visceral vs Bone only vs Other)• Disease-Free Interval (>12 vs ≤12 mo from end of

adjuvant to recurrence or de novo advanced disease)

ER+, HER2–BC

a Schedule 3/1.

Finn RS, et al. Lancet Oncol 2015;16(1):25-35.

Finn RS, et al. Lancet Oncol 2015;16(1):25-35.

Based on These Phase II Data…• Palbociclib received the first designation as breakthrough

therapy by the FDA• Prior to the phase III study results being presented, palbociclib

was granted accelerated FDA approval in February 2015 for patients with metastatic ER+ breast cancer

PALOMA3June 2015

Turner NC, et al. N Engl J Med 2015;373(3):209-19.

Double-blind, phase III

Primary endpoint: PFS

https://clinicaltrials.gov/ct2/show/NCT01942135

Demographics and Baseline Tumor Characteristics


Tumor Characteristics and Prior Treatment


Progression-free Survival


Summary of Key Secondary Efficacy Endpoints


Adverse Events—All Cause


PALOMA3: Summary of Adverse Events• In patients receiving palbociclib + fulvestrant vs placebo +

fulvestrant:• Overall incidence of SAEs was similar (9.6% vs. 14.0%)• Incidence of febrile neutropenia was the same (0.6% vs. 0.6%)• Infections (any grade) were more common (34.2% vs. 24.4%)

• The vast majority were of grade 1 or 2 (32.5% vs. 22.7%)

• There were no deaths due to AEs/toxicity

AE = adverse event; SAE = serious adverse event.Turner NC, et al. N Engl J Med 2015;373(3):209-19.

PALOMA3: Conclusions• Palbociclib combined with fulvestrant improved PFS compared to

placebo and fulvestrant in women with HR+/HER2- advanced breast cancer whose disease had progressed on prior endocrine therapy

• HR = 0.422 (95% CI, 0.318 to 0.560; P < .000001)

• Benefit from palbociclib was also demonstrated across prespecifiedsubgroups

• Palbociclib was well tolerated

• Palbociclib in combination with fulvestrant is an effective treatment option for women whose cancer progressed on prior endocrine therapy


Presented by Richard Finn at 2016 ASCO Annual Meeting

PFS: Investigator-Assessed - (ITT Population)


Key Secondary Efficacy Endpoints


Consistency of 1o and 2o Efficacy Endpoints Across PALOMA-1 and PALOMA-2 Studies


TEAEs Occurring in ≥15% of Patients─All Causality <br />


Palbociclib• CDK4/6 inhibitor• Postmenopausal, HR+ Her2- advanced or MBC

• In combination with letrozole as initial endocrine-based therapy • Or with fulvestrant in disease progression following endocrine therapy

Ibrance [package insert]. New York, NY: Pfizer, 2016

Dosing Starting dose 125 mg/day1st reduction 100 mg/day

2nd reduction 75 mg/day

• Starting dose 125 mg daily x 21 days q28days

• Take with food • Some side effects may

require dose interruptions, delays, or modifications


Side EffectsSide effect

Paloma 1All Gr (Gr 3+4) %

Paloma 3All Gr (Gr 3+4) %

Neutropenia 75 (54) 83 (66)

Anemia 35 (6) 30 (3)Thrombocytopenia 17 (2) 23 (3)Infections 31 (1) 47 (4)Decreased appetite 16 (1) 16 (1)Alopecia 22 (N/A) 18 (N/A)Fatigue 41 (4) 41 (2)Stomatitis 25 (0) 28 (1)Nausea/Vomiting 25 (2)/15 (0) 34 (0)/19 (1)Diarrhea 21 (4) 24 (0)Epistaxis 11 (0) 7 (0)Ibrance [package insert].

New York, NY: Pfizer, 2016

Side Effects Unique to PALOMA3

Side effect All Gr (Gr 3+4)Eye disorders 16 (0)Headache 26 (1) Constipation 20 (0)Rash 17 (1)Pyrexia 13 (<1)


Hematologic ToxicitiesCTCAE grade Dose modificationsGr 1 -2 No change

Gr 4 Hold until Gr <2 Resume at next LOWER dose


Hematologic ToxicitiesCTCAE grade Dose modifications

Gr 3 Day 1 of any cycle:Hold doseRepeat CBC in 1 weekResume at SAME dose when Gr ≤ 2

Day 15 of cycles 1 and 2:Continue current doseRepeat CBC day 21*consider dose reduction if > 1 week recovery time or recurrent Gr 3 neutropenia in subsequent cycles

Gr 3 neutropenia (ANC <1000–500/mm3)WITH FEVER ≥ 38.5∘C (101.3∘F) and/or infection

Hold until recovery Gr ≤ 2Resume at next LOWER dose


CTCAE Neutropenia Grading• Gr 1: ANC < LLN - 1500/mm3

• Gr 2: ANC 1000 - <1500/mm3

• Gr 3: ANC 500 - <1000/mm3

• Gr 4 <500 mm3

National Cancer Institute, USDHHS, Common Terminology Criteria for Adverse Events (CTACAE) v. 4.0.

Non-Hematologic ToxicitiesCTCAE grade Dose modifications

Gr 1-2 No changes

Gr ≥ 3 (despite medical treatment) Hold until:Gr ≤ 1Gr ≤ 2 (if no safety risks)Resume at next LOWER dose


Drug InteractionsCYP3A Inhibitors• ↑ palbo levels

• Clarithromycin• Grapefruit • Ketoconazole

• Consider ↓ dose to 75 mg/day

CYP3A Inducers

CYP3A substrates • May need dose reduction

as palbo ↑ exposure • Cyclosporine • Everolimus • Fentanyl• Tacrolimus/sirolimus

PPI • ↓ palbo levels when

fasting• NO EFFECT when taken

WITH food


• ↓ palbo levels up to 85%– Carbamazepine– Phenytoin– St John’s wort

Case Study• C1D1

• WBC 4800• ANC 2150• Hgb 12, plts 197k

• Medication review• PPI à Take palbociclib with

food

• C1D15• WBC 1200 ANC 750• Hgb 10.5, plts 130k• Severe URI symptoms• Requires antibiotics• No fever• Palbociclib held

Case Study• C2D1

• WBC 4400, ANC 2100• Hgb 11.4, plts 344k

• Dose resumed with one dose reduction• Palbociclib 100 mg/day

Case Study• No further dose reductions • Gr 1-2 nausea, fatigue and anorexia• No other Gr 3 toxicities

• Except ongoing intermittent neutropenia, but no infections or fever• Pain improved• PET/CT 5/2016 improvement in hypermetabolic areas

Jan 2015 May 2015

Images courtesy of West Clinic

Other CDK4/6 InhibitorsRibociclib

Abemaciclib

0.0

0.1

1.0

HCC2218

MDA

-MB-175

MDA

-MB-134

UACC-893

EFM-19

CAMA-1

ZR-75-1

MDA

-MB-415

HCC202

HCC1419

BT-474

HCC1500

MDA

-MB-453

EFM-192A

T-47D

UACC-732

MDA

-MB-231

MCF-7

SUM-190

MDA

-MB-361

HCC1395

HCC38

ZR-75-30

HCC1143

HCC1569

184A

1184B5

BT-20

BT-549

CAL-51

COLO

-824

DU4475

HCC1187

HCC1806

HCC1937

HCC1954

HCC70

Hs578T

KPL-1

MCF-10A

MDA

-MB-157

MDA

-MB-435

MDA

-MB-436

MDA

-MB-468

SK-BR-3

SUM-225

UACC-812

IC50μM

ER+ ER-

CDK4/6inhibitor,LEE011ismostactiveinER+breastcancercelllinesNeilO’Brien,DennisSlamon.AACRAnnualMeeting2014.

Ribociclib: NVP-LEE011: CDK4/6 Inhibitor

MONALEESA-2: A Phase III, Double-Blind, Placebo-Controlled Study of Ribociclib + Letrozole

• Tumor assessments were performed every 8 weeks for 18 months, then every 12 weeks thereafter• Final analysis planned after 302 PFS events

• 93.5% power to detect a 33% risk reduction (hazard ratio 0.67) with one-sided α=2.5%• Interim analysis planned after ~70% PFS events

• Two-look Haybittle–Peto stopping criteria: hazard ratio ≤0.56 and p < .0000129

PFS = progression-free survival.MONALEESA-2 is registered at ClinicalTrials.gov (NCT01958021); Hortobagyi GN, et al. ESMO 2016.

Randomization (1:1)

Stratified by the presence/absence of liver and/or lung

metastases

Ribociclib (600 mg/day)3-weeks-on/1-week-off

+Letrozole (2.5 mg/day)

n=334

Placebo+

Letrozole (2.5 mg/day)n=334

Primary endpoint• PFS (locally assessed per

RECIST v1.1)Secondary endpoints• Overall survival (key)• Overall response rate• Clinical benefit rate• Safety

• Postmenopausal women with HR+/HER2– advanced breast cancer

• No prior therapy for advanced disease

• N=668

Primary Endpoint WAS MET EARLY

• Let, le troz o le; NR, not reac hed.

No. of patients at riskRibociclib + Let 334 294 277 257 240 226 164 119 68 20 6 1 0

Placebo + Let 334 279 264 237 217 192 143 88 44 23 5 0 0

Prob

abilit

y of

Prog

ressio

n-free

Surv

ival (%

)

0

20

40

60

80

100

0 4 8 12 16 20 24 Time (months)

PFS (Investigator Assessment)

Ribociclib + Let

n=334Placebo + Let

n=334

Number of events, n (%) 93 (28) 150 (45)

Median PFS, months (95% CI)

NR(19.3–NR)

14.7 (13.0–16.5)

Hazard ratio (95% CI) 0.556 (0.429–0.720)One-sided p value 0.00000329

Hortobagyi GN, et al. ESMO 2016.

Abemaciclib Is a Selective Inhibitor of CDK4 & 6

Presented by Maura N. Dickler, 2016 ASCO Annual Meeting.

MONARCH 1: Response Summary

Presented by Maura N. Dickler, 2016 ASCO Annual Meeting.

Summary• CDK 4/6 inhibitors are an important new class of drugs for ER+

breast cancer• MOA suggests inhibition of cell cycle pathway reduces

resistance to endocrine blockade• Palbociclib is approved with aromatase inhibition in the first-line

advanced breast cancer setting and with fulvestrant following prior endocrine therapy (including adjuvant)

• Toxicity is predominantly hematologic, but not clinically serious• Substantial clinical benefit is seen with CDK 4/6 inhibitors

added to endocrine therapy in ER+ ABC

collaborative management of patients with advanced ... · resume at same dose when gr ≤ 2 day 15...

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