Collaborative Management of Patients With Advanced Estrogen Receptor Positive Breast Cancer

Transcription

1 Collaborative Management of Patients With Advanced Estrogen Receptor Positive Breast Cancer Lee Schwartzberg, MD, FACP Heather Greene, FNP, AOCNP West Cancer Center Memphis, Tennessee

2 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

3 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.

4 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 Adjuvant anastrozole x 1 yr à exemestane through 2011, then observation

5 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

6 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)

7 PET/CT Scan 1/16 Images courtesy of West Clinic.

8 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

9 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

10 Today s Biology in the Clinic Incidence ER+/- PR + 75% Therapy Endocrine chemotherapy HER % Anti-HER2 Triple negative 10 20% Chemotherapy American Cancer Society. Breast Cancer Facts & Figures

11 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): ; Rakha EA, et al. J Clin Oncol 2007;25(30):4772-8; Sainsbury JR, et al. Lancet 1987;1(8547): ; 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.

12 NCCN Guidelines Recommend Serial Endocrine Tx for HR+, HER2- Advanced Breast Cancer Not in Visceral Crisis NCCN Clinical Practice Guidelines in Oncology. Breast cancer, v1.2012; Osborne CK, et al. Ann Rev Med. 2011;62:

13 Slide 2 Presented by Nicholas Turner at 2015 ASCO Annual Meeting

14 Slide 6 Finn RJ, et al. Breast Cancer Res 2009:11(5):R77.

15 PALOMA-1 Phase II Design Part 1 Part 2 ER+, HER2 BC R A N D O M I Z A T I O N 1:1 PD mg QD a + Letrozole 2.5 mg QD Letrozole 2.5 mg QD ER+, HER2 BC with CCND1 amp and/or loss of p16 R A N D O M I Z A T I O N 1:1 PD mg QD a + Letrozole 2.5 mg QD Letrozole 2.5 mg QD a Schedule 3/1. Finn RS, et al. Lancet Oncol 2015;16(1): N = 66 Primary Endpoint PFS Stratification 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) N = 99

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

17 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

18 PALOMA3 June 2015 Slide 21 Turner NC, et al. N Engl J Med 2015;373(3):

19 Double-blind, phase III Primary endpoint: PFS

20 Turner NC, et al. N Engl J Med 2015;373(3): Demographics and Baseline Tumor Characteristics

21 Tumor Characteristics and Prior Treatment Turner NC, et al. N Engl J Med 2015;373(3):

22 Turner NC, et al. N Engl J Med 2015;373(3): Progression-free Survival

23 Slide 16 Turner NC, et al. N Engl J Med 2015;373(3):

24 Slide 17 Turner NC, et al. N Engl J Med 2015;373(3):

25 Summary of Key Secondary Efficacy Endpoints Turner NC, et al. N Engl J Med 2015;373(3):

26 Adverse Events All Cause Turner NC, et al. N Engl J Med 2015;373(3):

27 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):

28 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 = (95% CI, to 0.560; P < ) Benefit from palbociclib was also demonstrated across prespecified subgroups Palbociclib was well tolerated Palbociclib in combination with fulvestrant is an effective treatment option for women whose cancer progressed on prior endocrine therapy Turner NC, et al. N Engl J Med 2015;373(3):

29 Slide 8 Presented by Richard Finn at 2016 ASCO Annual Meeting

30 PFS: Investigator-Assessed - (ITT Population) Presented by Richard Finn at 2016 ASCO Annual Meeting

31 Slide 12 Presented by Richard Finn at 2016 ASCO Annual Meeting

32 Key Secondary Efficacy Endpoints Presented by Richard Finn at 2016 ASCO Annual Meeting

33 Presented by Richard Finn at 2016 ASCO Annual Meeting Consistency of 1o and 2o Efficacy Endpoints Across PALOMA-1 and PALOMA-2 Studies

34 TEAEs Occurring in 15% of Patients All Causality <br /> Presented by Richard Finn at 2016 ASCO Annual Meeting

35 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

36 Dosing Starting dose 125 mg daily x 21 days q28days Take with food Some side effects may require dose interruptions, delays, or modifications Starting dose 1st reduction 2nd reduction 125 mg/day 100 mg/day 75 mg/day Ibrance [package insert]. New York, NY: Pfizer, 2016

37 Side Effects Ibrance [package insert]. New York, NY: Pfizer, 2016 Side effect Paloma 1 All 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) Paloma 3 All Gr (Gr 3+4) % Nausea/Vomiting 25 (2)/15 (0) 34 (0)/19 (1) Diarrhea 21 (4) 24 (0) Epistaxis 11 (0) 7 (0)

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

39 Hematologic Toxicities CTCAE grade Gr 1-2 Dose modifications No change Gr 4 Hold until Gr <2 Resume at next LOWER dose Ibrance [package insert]. New York, NY: Pfizer, 2016

40 Hematologic Toxicities CTCAE grade Gr 3 Gr 3 neutropenia (ANC < /mm 3 ) WITH FEVER 38.5 C (101.3 F) and/or infection Dose modifications Day 1 of any cycle: Hold dose Repeat CBC in 1 week Resume at SAME dose when Gr 2 Day 15 of cycles 1 and 2: Continue current dose Repeat CBC day 21 *consider dose reduction if > 1 week recovery time or recurrent Gr 3 neutropenia in subsequent cycles Hold until recovery Gr 2 Resume at next LOWER dose Ibrance [package insert]. New York, NY: Pfizer, 2016

41 CTCAE Neutropenia Grading Gr 1: ANC < LLN /mm 3 Gr 2: ANC <1500/mm 3 Gr 3: ANC <1000/mm 3 Gr 4 <500 mm 3 National Cancer Institute, USDHHS, Common Terminology Criteria for Adverse Events (CTACAE) v. 4.0.

42 Non-Hematologic Toxicities CTCAE grade Gr 1-2 Gr 3 (despite medical treatment) Dose modifications No changes Hold until: Gr 1 Gr 2 (if no safety risks) Resume at next LOWER dose Ibrance [package insert]. New York, NY: Pfizer, 2016

43 Drug Interactions CYP3A Inhibitors palbo levels Clarithromycin Grapefruit Ketoconazole Consider dose to 75 mg/day CYP3A Inducers palbo levels up to 85% Carbamazepine Phenytoin St John s wort 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 Ibrance [package insert]. New York, NY: Pfizer, 2016

44 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

45 Case Study C2D1 WBC 4400, ANC 2100 Hgb 11.4, plts 344k Dose resumed with one dose reduction Palbociclib 100 mg/day

46 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

47 Images courtesy of West Clinic Jan 2015 May 2015

48 Other CDK4/6 Inhibitors Ribociclib Abemaciclib

49 Ribociclib: NVP-LEE011: CDK4/6 Inhibitor ER+ ER- 1.0 IC 50 μm 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 HCC1143 HCC A1 184B5 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 Neil O Brien, Dennis Slamon. AACR Annual Meeting CDK4/6 inhibitor, LEE011 is most active in ER+ breast cancer cell lines

50 MONALEESA-2: A Phase III, Double-Blind, Placebo-Controlled Study of Ribociclib + Letrozole Postmenopausal women with HR+/HER2 advanced breast cancer No prior therapy for advanced disease N=668 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 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 < PFS = progression-free survival. MONALEESA-2 is registered at ClinicalTrials.gov (NCT ); Hortobagyi GN, et al. ESMO 2016.

51 Primary Endpoint WAS MET EARLY Probability of Progression-free Survival (%) PFS (Investigator Assessment) Ribociclib + Let n=334 Placebo + Let n=334 Number of events, n (%) 93 (28) 150 (45) Median PFS, months (95% CI) NR (19.3 NR) 14.7 ( ) Hazard ratio (95% CI) ( ) One-sided p value Hortobagyi GN, et al. ESMO Time (months) No. of patients at risk Ribociclib + Let Placebo + Let Let, letrozole; NR, not reached.

52 Abemaciclib Is a Selective Inhibitor of CDK4 & 6 Presented by Maura N. Dickler, 2016 ASCO Annual Meeting.

53 MONARCH 1: Response Summary Presented by Maura N. Dickler, 2016 ASCO Annual Meeting.

54 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