METASTATIC BREAST CANCER HER2+

METASTATIC BREAST CANCER HER2+

Silvia P. Neciosup

ORAL PRESENTATIONS

NEOADJUVANT TREATMENT

A phase II randomized trial evaluating neoadjuvant therapy with weekly paclitaxel (P) plus neratinib (N) or trastuzumab (T) or neratinib and trastuzumab (N+T) followed by doxorubicin and cyclophosphamide

(AC) with postoperative T in women with locally advanced HER2-positive breast cancer

Jacobs SA, Robidoux A, Garcia JMP, Abraham J, La Verde N, Orcu; JM, Cazzaniga ME, Calvo L, Aguirre E, Buyse M, Pogue-‐Geile KL, Srinivasan A, Song N, Balousek AD, Wolmark N. NSABP

FoundaLon, Inc.; The University of Pi;sburgh Cancer InsLtute; Centre Hospitalier de l'université de Montréal; Hospital Universitario Vall d´Hebrón; MedSIR, Barcelona; West Virginia University;

Azienda Ospedaliera Fatebenefratelli e OYalmico; Roper St. Francis Healthcare; Azienda Ospedaliera San Gerardo, Monza; Hospital Universitario; InternaLonal Drug Development

InsLtute (IDDI); Allegheny Cancer Center, Allegheny General Hospital.

NSABP FB-7: Background

• Combined HER2 inhibi/on has demonstrated early efficacy in HER2+ breast cancer • Phase II NeoSphere trial: pertuzumab plus trastuzumab plus docetaxel improved pCR vs trastuzumab plus docetaxel[1]

• Phase III NeoALTTO trial: lapa/nib plus trastuzumab increased pCR vs trastuzumab alone[2]

• Phase II I-‐SPY 2 trial demonstrated efficacy of nera/nib plus paclitaxel followed by doxorubicin and cyclophosphamide in HER2+ breast cancer[3]

• Current study evaluated paclitaxel plus nera/nib or trastuzumab, or both, each followed by doxorubicin and cyclophosphamide in HER2+ locally advanced breast cancer[4]

1. Gianni L, et al. Lancet Oncol. 2012;13:25-32. 2. de Azambuja E, et al. Lancet Oncol. 2014;15:1137-1146. 3. Park JW, et al. AACR 2014. Abstract CT227. 4. Jacobs SA, et al. SABCS 2015. Abstract PD5-04.

• Primary endpoint: pCR in breast and axilla aQer neoadjuvant therapy

• Secondary endpoints: safety, molecular/gene/c response

NSABP FB-7: Study Design

Women with HER2+ locally

advanced operable breast

cancer (N = 126)

Paclitaxel* + Trastuzumab† AC (n = 42)

Paclitaxel* + Trastuzumab†

+ Neratinib§ AC (n = 42)

Paclitaxel* + Neratinib‡ AC (n = 42)

Jacobs SA, et al. SABCS 2015. Abstract PD5-04.

Surgery followed by trastuzumab

for 1 yr

*Paclitaxel 80 mg/m2 IV on Days 1, 8, 15 for 4 cycles. †Trastuzumab 4 mg/kg loading dose, then 2 mg/kg IV weekly for 4 cycles. ‡

Nera/nib 240 mg PO daily for 4 cycles. §Nera/nib 200 mg PO daily for 4 cycles. AC: 60/600 mg/m2 IV doxorubicin/cyclophosphamide.

Pts receiving nera/nib given loperamide an/diarrheal prophylaxis q6h for first 2 wks followed by taper (US/Canadian pts), or for 4 wks (European pts).

NSABP FB-7: Baseline Characteristics Characteristic P + T

(n = 42) P + N (n = 42)

P + T + N (n = 42)

Median age, yrs (range) 50 (33-71) 56 (29-71) 50 (31-77)

ECOG PS 0, % 100 100 97.6

Tumor stage, % IIB III Inflammatory Missing

42.8 50.0 9.5 7.1

45.2 47.6 16.7 7.1

47.6 52.3 9.5 0

Premenopausal, % 60 38 55

HR+ HR-

67 33

69 31

55 45

Median tumor size, cm (range) 3.7 (0-18.0) 5.5 (0-10.0) 5.0 (0-9.0)

HER2, % IHC ISH IHC and ISH

57.1 35.7 7.1

57.1 28.6 14.3

59.5 26.2 14.3


NSABP FB-7: Drug Intensity

Drug Intensity P + T (n = 42)

P + N (n = 42)

P + T + N (n = 42)

Paclitaxel, % of target dose 94 90 84 Neratinib, % of target dose -- 88 84 Trastuzumab, % of target dose 105 -- 95 Pts with ≥ 1 dose reduction, % Paclitaxel Neratinib

10 --

12 38

12 52

Discontinued prior to completion of 4 cycles, % 10 17 24


NSABP FB-7: pCR in Breast and Nodes • ORR higher with dual vs single HER2 inhibi/on • Response rates higher in women with HR-‐ disease across treatment arms


pCR Breast and Nodes, % P + T (n = 42)

P + N (n = 42)

P + T + N (n = 42)

All pts 38.1 33.3 50.0 Pts with HR+ disease 29.6 27.6 30.4 Pts with HR- disease 57.1 46.2 73.7

NSABP FB-7: Predictors of pCR • HR-‐ status and FCGR3A genotype predic/ve for pCR • Biomarkers: PIK3CA, PTEN, FCGR2A, TILs, PgR were not predic/ve for pCR

• Analysis of addi/onal biomarkers ongoing


Predictors of pCR (Preliminary Analysis; All Arms), % No pCR pCR Observed P Value

FCGR3A (N = 58) F/F (n = 27) V/V or F/V (n = 31)

74.1 38.7

25.9 61.3 .009

ER status (N = 65) ER+ (n = 36) ER- (n = 29)

72.2 34.5

27.8 65.5 .003

NSABP FB-7: Safety • No grade 4 treatment-‐related AEs observed

• Use of 4-‐wk loperamide prophylaxis at European sites associated with reduced rate of grade 3 diarrhea in nera/nib recipients: 17% with P + N vs 24% for P + T + N across all cycles Jacobs SA, et al. SABCS 2015. Abstract PD5-04.

Treatment-Related AEs During Neoadjuvant Tx, %

P + T (n = 42)

P + N (n = 42)

P + T + N (n = 42)

Grade 1/2

Grade 3 Grade 1/2

Grade 3 Grade 1/2

Grade 3

Nausea 29 0 42 0 43 2

Diarrhea 38 0 69 31 66 31

Rash 17 0 22 0 15 0

Transaminase elevation 33 2 66 7 69 7

Fatigue 43 0 48 2 40 2

Neuropathy 40 0 40 0 26 2

NSABP FB-7: Conclusions • Use of paclitaxel plus nera/nib/trastuzumab resulted in higher pCR vs paclitaxel plus either HER2-‐targeted agent alone in women with HER2+ locally advanced breast cancer

• Response rates higher in women with HR-‐ disease across treatment arms

• HR-‐ status and FCGR3A genotype predicted increased likelihood of pCR

• No grade 4 treatment-‐related AEs observed • Use of 4-‐wk loperamide prophylaxis reduced rate of grade 3 diarrhea in nera/nib recipients


METASTATIC DISEASE

Abemaciclib Combinations in MBC: Background

Abemaciclib: inves/ga/onal oral small molecule inhibitor of CDK 4/6[1] • Induces cell cycle arrest in Rb-‐proficient cancers

• Exhibits clinical ac/vity as single agent[2] and acceptable safety profiles in combina/on with either fulvestrant[3] or aromatase inhibitors[4] in previously treated HR+ MBC

• Current study evaluated safety and an/tumor ac/vity of abemaciclib when given with endocrine or HER2-‐targeted therapies for the treatment of MBC[5]

1. Gelbert LM, et al. Invest New Drugs. 2014;32:825-837. 2. Tolaney SM, et al. SABCS 2014. Abstract P5-19-13. 3. Patnaik A, et al. ASCO 2014. Abstract 534. 4. Tolaney SM, et al. ASCO 2015. Abstract 522. 5. Goetz MP, et al. SABCS 2015. Abstract P4-13-25.

Abemaciclib Combinations in MBC: Study Design

• Phase Ib study

• Primary objec/ve: safety

• Secondary objec/ve: an/tumor ac/vity, PK Goetz MP, et al. SABCS 2015. Abstract P4-13-25. ClinicalTrials.gov. NCT02057133.

Abemaciclib 200 mg Q12H + Cohort A: Letrozole 2.5 mg QD (n= 20)

Cohort B: Anastrozole 1 mg QD (n = 16) Cohort C: Tamoxifen 20 mg QD (n = 15)

Cohort D: Exemestane 25 mg QD (n = 15) Cohort E*: Abemaciclib 150/200 mg Q12H +

Exemestane 25 mg QD + Everolimus 5 mg QD (n = 17)

Cohort F:* Abemaciclib 150/200 mg Q12H + + Trastuzumab 6-8 mg/kg IV on Day 1 of 21-day cycle (n = 10)

Pts with HR+, HER2- MBC; premenopausal + ovarian

suppression or postmenopausal; ECOG PS 0 or 1;

no prior CT for MBC (N = 83)

Pts with HER2+ MBC; pre- or postmenopausal;

ECOG PS 0 or 1; ≥ 1 prior CT for MBC

(N = 10) *Abemaciclib 3 + 3 dose escala/on with fixed doses of the combina/on drug(s). Sequen/al enrollment. Sequen/al dose adjustments of 50 mg allowed for toxicity. Abemaciclib given un/l progression, unacceptable toxicity, or pt elected to stop.

Abemaciclib Combinations in MBC: Baseline Characteristics

Characteristic Abe + Let

(n = 20)

Abe + Ana

(n = 16)

Abe + Tam

(n = 16)

Abe + Exe

(n = 15)

Abe + Exe/Eve Abe + Tras

150 mg (n = 13)

200 mg (n = 4)

150 mg (n = 4)

200 mg (n = 6)

Age, median yrs (range)

59.0 (33-73)

55.5 (26-72)

59.5 (46-77)

52.0 (40-73)

57.0 (41-73)

64.5 (50-68)

53.5 (45-64)

59.5 (48-76)

White race, % 100 88 100 93 92 100 75 100

ECOG PS, % 0 1 2

80 15 5

81 19 0

75 25 0

80 20 0

31 61 8

75 25 0

25 75 0

67 33 0

Prior systemic therapies, median n (range)

2 (1-4)

3 (1-8)

3 (1-6)

4 (1-6)

3 (1-6)

2.5 (2-5)

10.5 (1-15)

6.5 (4-8)

Measurable disease, % 45 56 50 67 62 50 100 83

HR/HER status, % HR+/HER- HR+/HER+ HR-/HER2+

100 0 0

100 0 0

100 0 0

100 0 0

100 0 0

100 0 0

0 25 75

0 83 17

Goetz MP, et al. SABCS 2015. Abstract P4-13-25.

Abemaciclib Combinations in MBC: Treatment-Emergent AEs, Cohorts

A-D


TEAEs in > 33% of Pts in Any Cohort, %

Abe + Let (n = 20) Abe + Ana (n = 16) Abe + Tam (n = 16) Abe + Exe (n = 15)

Grade 1/2 Grade 3

Grade 1/2 Grade 3

Grade 1/2 Grade 3

Grade 1/2 Grade 3

Diarrhea 55 45 60 31 63 31 67 27

Fatigue 65 20 63 19 44 31 53 13

Nausea 60 15 75 0 63 6 67 0

Vomiting 30 10 31 6 31 0 40 0

Anemia 25 0 31 0 44 0 27 0

Decreased appetite 45 5 50 0 25 0 20 0

Abdominal pain 30 5 50 0 50 0 40 20

Dehydration 15 0 31 6 13 13 13 7

Rash 15 0 31 0 6 0 7 0

WBC decreased 70 5 63 31 56 13 67 0

Neutrophils decreased 50 20 56 25 50 6 53 20

Lymphocytes decreased 50 5 56 13 31 6 27 13

Platelet count decreased 30 0 50 0 50 0 20 0

Creatinine increased 100 0 100 0 88 6 88 0

Hypercalcemia 10 0 31 0 6 0 40 0

Abemaciclib Combinations in MBC: Treatment-Emergent AEs, Cohorts E and F


TEAEs in > 33% of Pts in Any Cohort, %

Abe + Exe/Eve Abe + Tras

150 mg (n = 13) 200 mg (n = 4) 150 mg (n = 4) 200 mg (n = 6)

Grade 1/2 Grade 3 Grade 1/2 Grade 3 Grade 1/2 Grade 3 Grade 1/2 Grade 3

Diarrhea 62 15 75 25 50 0 17 83

Fatigue 54 8 100 0 25 0 33 17

Nausea 31 0 50 0 25 0 33 0

Vomiting 31 0 0 0 0 0 17 0

Anemia 23 8 25 0 25 0 17 33

Decreased appetite 38 8 50 0 0 0 33 0

Abdominal pain 46 0 25 0 0 0 0 0

Dehydration 8 0 0 0 0 0 17 0

Rash 23 8 75 0 25 0 0 0

WBC decreased 54 23 50 25 50 0 33 17

Neutrophils decreased 54 23 25 75 50 0 50 17

Lymphocytes decreased 23 31 75 0 0 0 33 17

Platelet count decreased 31 0 50 0 50 0 17 0

Creatinine increased 92 0 75 25 75 0 50 17

Abemaciclib Combinations in MBC: PFS and Tumor Response, Cohorts

A-E Response, % Abe + Let

(n = 20) Abe + Ana (n = 16)

Abe + Tam (n = 16)

Abe + Exe (n = 15)

Abe + Exe/Eve

150 mg (n = 13)

200 mg (n = 4)

Best overall response CR PR SD PD Unknown

0 10 50 10 30

0 19 69 6 6

0 19 56 19 6

7 27 40 20 7

0 15 39 0

46

0 0

75 0

25

ORR (CR + PR) All pts Pts with measurable

disease

10 22

19 33

19 38

33 50

15 25

0 0

Disease control rate (CR + PR + SD) 60 88 75 73 54 75

Clinical benefit rate (CR + PR + SD > 24 wks) 40 81 75 60 Not mature Not mature

6-mo PFS, % (95% CI) 76.2 (42.7-91.7)

66.7 (56.4-96.5)

73.3 (43.6-89.1)

75.2 (40.7-91.4) Not mature Not mature

12-mo PFS, % (95% CI) 76.2 (42.7-91.7)

79.4 (48.8-92.9)

64.2 (33.3-83.6) Not mature Not mature Not mature


Abemaciclib Combinations in MBC: Conclusions

• Abemaciclib + endocrine and HER2-‐targeted therapies achieved tumor responses in pts with MBC

• No observed drug–drug interac/ons between abemaciclib and tamoxifen, exemestane, or trastuzumab

• Most frequent grade 3 toxici/es included diarrhea, neutropenia, and leukopenia

• Ongoing randomized phase III trials are evalua/ng abemaciclib + AIs and the an/estrogen fulvestrant in MBC

• Recommended abemaciclib dose 150 mg Q12H in combina/on with AI, tamoxifen, or exemestane

Goetz MP, et al. SABCS 2015. Abstract P4-13-25.ClincalTrials.gov. NCT0224662. ClincalTrials.gov. NCT02107703.

POSTER PRESENTATION

GRACIAS

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METASTATIC BREAST CANCER HER2+