Case #2: Hormonal Therapy for Advanced Premenopausal Breast Cancer

Case #2: Hormonal Therapy for Advanced Premenopausal Breast Cancer Fellow Presenter: Katherine Clifton, MD Faculty Discussant: Debu Tripathy, MD 7 th Annual June 1, 2018

Topics to Be Discussed: Staging and biomarker determination Selection and sequencing of therapy in the metastatic setting for HR+/HER- MBC CDK 4/6 inhibitors in premenopausal patients Management of refractory disease HR, hormone receptor; HER, human epidermal growth factor receptor; MBC, metastatic breast cancer; CDK, cyclin-dependent kinases

The Case 42-year-old female presents after self-palpating a left breast mass Past medical history: Seasonal allergies Past surgical history: Exploratory laparotomy with removal of ovarian cysts (benign) Social history: Works as a chemist, no tobacco or illicit drug use, drinks 5 glasses of wine per week Gynecologic history: G2 P2, premenopausal Family history: Denies any family history of breast or ovarian cancer

MD Anderson Exam Physical exam: 2.5-cm x 3-cm left breast mass with no skin or nipple changes Palpable left axillary node No right breast masses or right axillary lymphadenopathy

Imaging Bilateral mammogram: Left breast spiculated mass measuring 5 cm with left axillary dense nodes Ultrasound: Left breast mass at 3:30 measuring 3.0 cm x 2.4 cm x 1.6 cm, and an abnormal left axillary node measuring 1.8 cm and suspicious left second space internal mammary lymph node

Pathology Core biopsy of breast mass: Invasive ductal carcinoma, Nottingham combined histologic grade 2, ER positive (90%, 3+), PR positive (90%, 2+), HER2/neu nonamplified by FISH FNA of left axillary lymph node: Positive for metastatic disease FNA of left internal mammary lymph node: Positive for metastatic disease ER, estrogen receptor; PR, progesterone receptor; FNA, fine-needle aspiration; FISH, fluorescence in situ hybridization

Staging: Stage IIIB (ct2n3bm0) ER/PR+ HER2 CT chest, abdomen/pelvis: No evidence of distant metastatic disease Bone scan: No evidence of osseous involvement Genetic testing (indication: Breast cancer diagnosed <age 50 years): negative for BRCA1/2 mutations CT, computed tomography Amin MB, et al (ed). AJCC Cancer Staging Manual. 8 th edition. Switzerland: Springer, 2017.

Treatment Neoadjuvant: Paclitaxel 80 mg/m 2 IV weekly x 12 weeks, followed by FAC: 5-fluorouracil 500 mg/m 2 IV, doxorubicin 50 mg/m 2 IV, and cyclophosphamide 500 mg/m 2 IV every 3 weeks x 4 cycles Surgery: Segmental mastectomy with left axillary node dissection Pathology: Invasive ductal carcinoma, grade 2 measuring 3.2 cm, 7/15 lymph nodes positive. ypt2n2a IV, intravenous

1x: Lymph node with metastatic IDC

1x ER

10x H&E Stained Slide

10X ER

MD Anderson Treatment Radiation to chest wall and supraclavicular fields Adjuvant hormonal therapy: Tamoxifen started as patient premenopausal prior to chemotherapy Side effects: Hot flashes, abnormal vaginal bleeding (biopsy benign) 5 months after completing chemotherapy, patient s regular menstrual cycles resumed 1.5 years later, patient presented with shortness of breath

PE, pulmonary embolism Vascular Medicine. www.angiologist.com. Accessed May 24, 2018. Found to have new PE

Workup CBC WBC 11.3 Hemoglobin 12.2 Platelets 152 Other INR 1.0 CBC, complete blood count; WBC, white blood cell; INR, international normalized ratio Chemistries Na 140 K 4 Cl 102 HCO3 24 BUN 11 Cr 0.62 Glucose 135 ALT 91 AST 172 AP 205 Tbili 0.8 Albumin 3.8

Bone scan: Multiple foci of abnormal increased radiotracer activity, compatible with bone metastases involving the spine, multiple ribs bilaterally, and pelvis

Workup Liver Biopsy: Moderately to poorly differentiated adenocarcinoma, consistent with metastasis from patient s known breast primary. ER positive (100%), PR positive (95%), and HER2 negative (0 by IHC) IHC, immunohistochemistry

21 Question 1 Part A Which therapy would you choose for the patient as front-line in the metastatic setting 1.5 years post initiation of adjuvant hormonal therapy? 1. Combination chemotherapy 2. Single-agent chemotherapy 3. Aromatase inhibitor with ovarian suppression +/- CDK inhibitor 4. Fulvestrant with ovarian suppression+/- CDK inhibitor

Question 1 Part B If you decided to use endocrine therapy in this patient, would you also use a CDK inhibitor? 1. Yes 2. No

MD Anderson Treatment Patient received 4 cycles of docetaxel 75 mg/m 2 IV every 3 weeks Side effects: Grade 1 neuropathy, nausea, fatigue Repeat labs show improvement in LFTs Restaging scans: LFT, liver function test

Initial Follow Up

MD Anderson Treatment Patient received an additional 5 cycles of docetaxel with continued improvement of liver metastasis on most recent restaging LFTs have normalized Although irregular, she continues to have menstrual cycles Patient has now developed worsening neuropathy and fatigue secondary to chemotherapy

Question 2 Part A What treatment regimen would you consider next? 1. Continue docetaxel 2. Eribulin 3. Ovarian suppression with endocrine therapy +/- CDK inhibitor

Question 2 Part B If choosing ovarian suppression with CDK inhibitor + endocrine therapy in a premenopausal patient, which CDK inhibitor would you select (assuming all are available in your practice)? 1. Palbociclib 2. Ribociclib 3. Abemaciclib

Question 2 Part C What endocrine partner would you choose? 1. Aromatase inhibitor 2. Fulvestrant 3. Tamoxifen

Treatment Patient is started on leuprolide acetate followed by palbociclib 125 mg PO days 1-21 and letrozole CBC prior to C1: CBC prior to C2: CBC WBC 11.9 ANC 10.95 Hemoglobin 12.2 Platelets 160 CBC WBC 2.3 ANC 1.33 Hemoglobin 11.5 Platelets 105 PO, by mouth

Monitoring on Palbociclib Monitor CBC prior to start of palbociclib and at beginning of each cycle, as well as day 15 of first 2 cycles ANC Grading: Grade 1: LLN 1500 Grade 2: 1000 - <1500 Grade 3: 500- <1000 Grade 4: <500 Palbociclib [prescribing information]. New York, New York; Pfizer, Inc; 2017.

Treatment Palbociclib is continued at same dose with continued grade 2 neutropenia but no further side effects Patient undergoes restaging scans after 3 cycles:

Prior Scan Current Scan

MD Anderson Restaging CT chest, abdomen/pelvis: Continued decrease in size of hepatic metastases with an example 4.1 cm x 3.1 cm segment-8 metastasis decreased from 4.2 cm x 3.7 cm and a 3.7 cm x 3.1 cm segment-6 metastasis decreased from 4.2 cm x 3.7 cm Increasing sclerosis of multifocal osseous metastases, which may be related to posttreatment effects

Treatment Patient continues on palbociclib 125 mg PO days 1-21 and letrozole for an additional 2 cycles CBC prior to C6: CBC WBC 2.9 ANC 2.03 Hemoglobin 12.5 Platelets 83

Monitoring on Palbociclib Table applies to all hematologic adverse events except lymphopenia (unless lymphopenia is associated with clinical event such as opportunistic infection) Thrombocytopenia Grading: Grade 1: LLN 75 Grade 2: 50-75 Grade 3: 10-50 Grade 4: <10 Palbociclib [prescribing information]. New York, New York; Pfizer, Inc; 2017.

Treatment Patient continues on palbociclib 125 mg PO days 1-21 and letrozole for a total of 6 cycles

Question 3 If patient developed worsening aromatase-related side effects, such as joint pain, could you consider changing to tamoxifen? 1. Yes 2. No

Question 4 What treatment would you offer the patient upon progression? 1. CDK inhibitor + fulvestrant 2. Fulvestrant alone 3. Capecitabine 4. Everolimus + exemestane

Case #2: Faculty Discussant: Debu Tripathy, MD 7 th Annual June 1, 2018

Gene Expression Profiles Reveal Distinct Breast Cancer Subsets HER2 Enriched 1. 15% to 20% of cases 2. Prognostic/predictive 2. Proliferation 3. Two types (ER /+) Basal 1. 10% to 15% of cases 2. ER/PR/HER2 3. Proliferative 4. EGFR, c-kit, myc, p53 mutations 5. Includes BRCA1 mutations Luminal A and B 1. ER+, PR+/ 2. Prognostic/predictive 3. ER-GATA3, CCND1 amplif, PI3K, RUNX1 mutations Ki67, STK6, survivin, cyclin B1, MYBL2 Sorlie T, et al. Proc Natl Acad Sci USA. 2003;100(14):8418-8423. 40

Genomic Landscape Varies Among Receptor Subtypes of Breast Cancer The Cancer Genome Atlas Network. Nature. 2012;490(7418):61-70. 41

Question 1 Which therapy would you choose for the patient as front-line in the metastatic setting 1.5 years post initiation of adjuvant hormonal therapy? 1. Combination chemotherapy 2. Single-agent chemotherapy 3. Aromatase inhibitor with ovarian suppression +/- CDK inhibitor 4. Fulvestrant with ovarian suppression+/- CDK inhibitor Would you use a CDK inhibitor with endocrine therapy? 1. Yes 2. No

Diagnosis and Treatment of Hormone Receptor Positive Metastatic Breast Cancer *OS if premenopausal, and if so, can use AI after tamoxifen/toremifene Adapted from Rugo HS, et al. J Clin Oncol. 2016;34(25):3069-3103. OS, overall survival

Question 2 Part A What treatment regimen would you consider next? 1. Continue docetaxel 2. Eribulin 3. Ovarian suppression with endocrine therapy +/- CDK inhibitor

CDK4/6 Controls Cell-Cycle Progression From G1 to S Phase by Regulating the Activity of Rb Synthesis of D-type cyclins (cyclin D1, D2, and D3) and association with CDK4/6 is initiated in response to mitogenic signaling pathways 1 Active cyclin D CDK4/6 phosphorylates Rb, decoupling Rb from E2F and allowing transcription of genes required for cell cycle progression 1 Rb inhibits E2F-mediated transcription by binding to and sequestering E2F 2 E2F activates transcription of genes necessary for S-phase entry and cell cycle progression 2 1. Lange CA, et al. Endocr Relat Cancer. 2011;18(4):C19-24 2. Rader J, et al. Clin Cancer Res. 2013;19(22):6173-6182. Lange CA, et al. Endocr Relat Cancer. 2011;18(4):C19-24.

CDK4/6 Inhibitors in Clinical Use/Testing FDA Approved (February 4, 2015) Palbociclib PD 0332991 FDA Approved (March 13, 2017) Ribociclib LEE011 FDA Approved (September 27, 2017) Abemaciclib LY2835219 FDA, US Food and Drug Administration

Properties of Approved CDK4/6 Inhibitors IC 50 (nm) on target CDKs CDK4 cyclin D1 CDK6 cyclin D1/2/3 IC 50 (nm) on other CDKs CDK1 cyclin B CDK2 cyclin A/E CDK5 p25 CDK9 cyclin T Ribociclib Palbociclib Abemaciclib 10 39 113,000 76,000 43,900 NR 11 16 >10,000 >10,000 >10,000 NR 2 10 1627 504 355 57 Kinase partition index 0.99 0.96 0.88 Lipophilicity (clogp) 2.3 2.7 5.5 IC 50 against bone marrow mononuclear cells (nm) 1700 ± 231 240 ± 43 230 ± 27 Half-life 33 hr to 42 hr 26 hr to 27 hr 17 hr to 38 hr T max 1 hr to 5 hr 6 hr to 12 hr 4 hr to 6 hr Tripathy D, et al. Clin Cancer Res. 2017;23(13):3251-3262.

PALOMA-2: Phase 3 Study Palbociclib + Letrozole as First-Line Therapy in HR+, HER2 Advanced BC PALOMA-2 (N = 666) Postmenopausal women 18 years of age ER+, HER2 ABC No prior systemic treatment for advanced disease Palbociclib + Letrozole vs Placebo + Letrozole Median PFS 24.8 months vs 14.5 months HR = 0.58 (95% CI: 0.46-0.72) P<.001 Palbociclib + letrozole n = 444 Placebo + letrozole n = 222 BC, breast cancer; ABC, advance breast cancer; PFS, progression-free survival; CI, confidence interval Finn RS, et al. N Engl J Med. 2016;375(20):1925-1936.

Finn RS, et al. N Engl J Med. 2016;375(20):1925-1936. Subgroup Analysis: PALOMA-2

Finn RS, et al. N Engl J Med. 2016;375(20):1925-1936. Adverse Events: PALOMA-2

PALOMA-3: Progression-Free Survival Relapsed on or within 12 months after completion of adjuvant ET or within 1 month after therapy for advanced disease Probability of Progression-Free Survival, % ET, endocrine therapy Turner NC, et al. N Engl J Med. 2015;373(3):209-219.

MONALEESA-2: Phase III Double-Blind, Placebo- Controlled Study of Ribociclib + Letrozole N = 668 Postmenopausal women with HR+, HER2 advanced breast cancer No prior therapy for advanced disease Randomization (1:1) Stratified by the presence/absence of liver and/or lung metastases Ribociclib + Letrozole* n = 334 Placebo + Letrozole* n = 334 Primary endpoint PFS (locally assessed per RECIST v1.1) Secondary endpoints OS (key) ORR CBR 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 (HR = 0.67) with one-sided α = 2.5% *Ribociclib 600 mg per day, 3 weeks on/1 week off; letrozole 2.5 mg/day. With supportive independent central review; MONALEESA-2 is registered at ClinicalTrials.gov (NCT01958021). CBR, clinical benefit rate; ORR, overall response rate; RECIST, Response Evaluation Criteria In Solid Tumors Hortobagyi GN, et al. N Engl J Med. 2016;375(18):1738-1748.

MONALEESA-2: Primary Endpoint at First Analysis Probability of progression-free survival, % 100 80 60 40 20 Ribociclib + Letrozole Placebo + Letrozole Ribo + Let ORR* 52.7% 37.1% Placebo + LET *In measurable disease, P<.001 Ribo + LET n = 334 PBO + LET n = 334 Number of events, n (%) 93 (27.8) 150 (44.9) 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.00000329 0 0 4 8 12 16 20 24 No. Patients at Risk Months Ribo + LET 334 294 277 257 240 226 164 119 68 20 6 1 0 PBO + LET 334 279 264 237 217 192 143 88 44 23 5 0 0 Hortobagyi GN, et al. N Engl J Med. 2016;375(18):1738-1748

MONALEESA-2: Secondary Endpoints Rate, % 100 80 60 40 20 All Patients P =.000155 41 28 Patients With Measurable Disease Rate, % 100 80 60 40 20 53 P =.00028 37 Ribociclib + Letrozole Placebo + Letrozole 0 Objective Response Rate ORR 0 Objective Response Rate ORR Clinical benefit rate in patients with measurable disease*: 80% ribociclib arm vs 72% placebo arm (P =.02) Overall survival data were immature at the cutoff date for interim analysis Hortobagyi GN, et al. N Engl J Med. 2016;375(18):1738-1748.

MONALEESA-7 Pre/Perimenopausal With Ovarian Suppression + AI or Tamoxifen With Placebo vs Ribociclib ELIGIBILITY PFS (investigator assessment) Ribociclib + tamoxifen/nsai n = 335 Placebo + tamoxifen/nsai n = 337 Number of events, n (%) 131 (39.1) 187 (55.5) Median PFS, months (95% CI) 23.8 (19.2 NR) 13.0 (11.0 16.4) Hazard ratio (95% CI) 0.553 (0.441 0.694) One-sided P value.0000000983 Pre/perimenopausal women (per NCCN guidelines) 1 measurable lesion (RECIST 1.1) or 1 predominantly lytic bone lesion ECOG performance status of 1 1 line of chemotherapy for ABC Prior (neo)adjuvant therapy was allowed: If no prior endocrine therapy OR if 12 months since the last dose, patient was eligible for tamoxifen or an NSAI, per investigator/patient choice If last dose of tamoxifen was <12 months prior to randomization, patient was eligible for an NSAI If last dose of AI/NSAI was <12 months prior to randomization, patient was eligible for tamoxifen Probability of PFS,% NSAI, non-steroidal aromatase inhibitors; NCCN, National Comprehensive Cancer Network; ECOG, Eastern Cooperative Oncology Group Tripathy D, et al. Lancet Oncol. May 24, 2018 [epub ahead of print]. 100 90 80 70 60 50 40 30 20 10 0 CI, confidence interval; NR, not reached. Goserelin included in all combinations. 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 No. at risk Time (months) Ribociclib + tamoxifen/nsai 335 301 284 264 245 235 219 178 136 90 54 40 20 3 1 0 Placebo + tamoxifen/nsai 337 273 248 230 207 183 165 124 94 62 31 24 13 3 1 0

MONALEESA-7 Pre/Perimenopausal With Ovarian Suppression + AI or Tamoxifen With Placebo vs Ribociclib PFS (Investigator Assessment) Ribociclib Arm n = 87 Tamoxifen Placebo Arm n = 90 Ribociclib Arm n = 248 NSAI Placebo Arm n = 247 Number of events, n 39 55 92 132 Median PFS, months (95% CI) 22.1 (16.6 24.7) 11.0 (9.1 16.4) 27.5 (19.1 NR) 13.8 (12.6 17.4) Hazard ratio (95% CI) 0.585 (0.387 0.884) 0.569 (0.436 0.743) Tripathy D, et al. Lancet Oncol. May 24, 2018 [epub ahead of print].

Differences in PFS based on age in population receiving palbociclib as standard of care Clifton et al., ASCO 2018

MONARCH 1: Monotherapy in Patients Progressing on Prior Endocrine and 2 Prior Chemotherapies Investigator-Assessed Response Confirmed objective response rate (ORR = CR + PR) (95% CI) CR PR Abemaciclib 200 mg (N = 132) 19.7% (13.3 27.5) 0% 19.7% Stable disease 6 months 22.7% Clinical benefit rate (CBR = ORR +SD 6 mo) 42.4 % Dickler MN, et al. Clin Cancer Res. 2017;23(17):5218-5224. CR, complete response; SD, stable disease

Study Summary of CDK 4/6 Inhibitor Results in HR+ MBC First-Line Metastatic Breast Cancer PALOMA-1 Letrozole Letrozole + palbociclib PALOMA-2 Letrozole + placebo Letrozole + palbociclib MONALEESA-2 Letrozole + placebo Letrozole + ribociclib MONALEESA-7 (pre-menopausal) Letrozole + goserelin + placebo Letrozole + goserelin + ribociclib MONARCH 3 Letrozole + placebo Letrozole + abemaciclib Second-Line Metastatic Breast Cancer BOLERO-2 Exemestane + placebo Exemestane + everolimus PALOMA-3 Fulvestrant + palbociclib Fulvestrant + placebo MONARCH 2 Fulvestrant + abemaciclib Fulvestrant + placebo Refractory Metastatic Breast Cancer 81 84 222 444 334 334 337 335 165 328 239 485 347 174 446 223 N ORR,* % (Mz) 33 (39) 43 (56) 35 (44) 42 (55) 28 (37) 41 (53) 30 (36) 41 (51) 35 (44) 48 (59) 9.4 0.4 10.4 6.3 35 (48) 16 (21) 58 81 71 84 72 80 67 80 69 79 26.4 51.3 34.0 19.0 73 52 CBR,* % mpfs, mo (95% CI) 10.2 (5.7-12.6) 20.2 (13.8-27.5) 14.5 (12.9-17.1) 24.8 (22.1-NR) 14.7 (13.0-16.5) NR (19.3-NR) 13.0 (11.0-16.4) 23.8 (19.2-NR) 14.7 NR 2.8 6.9 9.2 (7.5-NR) 3.8 (3.5-5.5) 16.4 9.3 mpfs HR 0.488 (0.319 0.748) 0.58 (0.46 0.72) 0.556 (0.429 0.720) 0.553 (0.441 0.694) 0.543 (0.409 0.723) 0.43 (0.35 0.54) 0.422 (0.318 0.560) 0.553 (0.45 0.68) MONARCH 1 (Phase II) Abemaciclib 132 (20) 42 6.0 N/A N/A.0004 <.0001 P-value.00000329.0000000983.000021 <.001 <.000001 <.0000001 mpfs, median progression-free survival in months; NA, not applicable; *% (Mz), in patients with measurable disease; for CBR, Mz values provided

Question 3 If patient developed worsening aromatase-related side effects, such as joint pain, could you consider changing to tamoxifen? 1. Yes 2. No

Question 4 What treatment would you offer the patient upon progression? 1. CDK inhibitor + fulvestrant 2. Fulvestrant alone 3. Capecitabine 4. Everolimus + exemestane

Revote

65 Question 1 Part A Which therapy would you choose for the patient as front-line in the metastatic setting 1.5 years post initiation of adjuvant hormonal therapy? 1. Combination chemotherapy 2. Single-agent chemotherapy 3. Aromatase inhibitor with ovarian suppression +/- CDK inhibitor 4. Fulvestrant with ovarian suppression+/- CDK inhibitor

Question 1 Part B If you decided to use endocrine therapy in this patient, would you also use a CDK inhibitor? 1. Yes 2. No