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Novel insights into therapy for HER2-positive breast cancer

Debates and Didactics in Hematology and Oncology, August 8th, Sea Island, GA

Ruth M. O’Regan, MD Professor and Vice-Chair for Educational Affairs, Department of Hematology and Medical Oncology, Emory University, Chief of Hematology and Medical Oncology, Georgia Cancer Center for Excellence, Grady Memorial Hospital

Disclosures

• Consulting fees from: Novartis
• Contracted research from:

– Genentech, and Novartis

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Adjuvant management of HER2- positive breast cancer

• The addition of trastuzumab to

chemotherapy has clearly improved

• utcome for patients with early stage

HER2-positive breast cancer but ….

– Can we do better by adding other targeted agents? – Are we over-treating small HER2-positive cancers? – Do all HER2-positive cancers need trastuzumab, chemotherapy, both…?

NeoALTTO Primary Outcome Measure: pCR*

*Pathologic complete response (pCR) rate defined as the absence of invasive cancer in the breast at the time of surgery.

25% 30% 51% 0% 20% 40% 60% 80% 100% pCR

Lapatinib n = 154 Trastuzumab n = 149

Lapatinib + Trastuzumab n = 152

Lapatinib n = 154 Trastuzumab n = 149 Lapatinib + Trastuzumab n = 152 P Value pCR HR+ Subset 16% 23% 42% 0.03 pCR HR- Subset 34% 37% 61% 0.005

Baselga J, et al. Lancet. 2012;379(9816):633-640.

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NeoALTTO : Does pCR Translate Into Improved EFS and OS?

• Found correlation between

pCR and EFS and OS

• 3-year EFS was 86% for

those who achieved pCR, 72% for those who did not (P = 0.0003)

• OS was 94% for those who

achieved pCR, 87% for those who did not (P = 0.005)

• Most notable in HR-negative

disease

• Not powered to detect

difference in survival between study arms

Piccart-Gebhart M, et al. Presented at the 2013 San Antonio Breast Cancer Symposium. Abstract S1-01

Phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO)

Surgery

____________

At least 4 cycles

• f (neo) adjuvant

chemotherapy Trastuzumab (n=2097) Lapatinib

Trastuzumab

Break

Lapatinib (n=2091) Lapatinib + Trastuzumab (n= 2093)

12 weeks 6 weeks 34 weeks

Design 1 no concurrent taxane ____________ Design 2 concurrent taxane (12 weeks) R A N D O M I Z A T I O N

Available at: http://www.cancer.gov/search/clinical_trials/.gov..

Hormone receptor-positive: ≈57% Node-negative: 40%

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DISEASE-FREE SURVIVAL (DFS) ANALYSIS

Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting

DFS BY Hormone Receptor Status

Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting

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OVERALL SURVIVAL (OS) ANALYSIS

Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting

MAIN DIFFERENCES IN AEs BY TREATMENT ARM

Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting

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Addition of bevazicumab to trastuzumab- based chemotherapy (BETH): IDFS

1.0 0.8 0.6 0.4 0.2

• No. at risk:

CTxHB-HB 1752 1692 1672 1648 1601 1510 1108 641 287 62 3 CTxH-H 1757 1717 1690 1657 1607 1518 1106 642 282 57 1

Time (months)

Estimated probability

CTx +H (N=1757) CTx + H+ BEV (N=1752) 145 (8) 147 (8) 1.00 (0.79–1.26) 0.9789 1.02 (0.81–1.28) 0.8791

92% 92 %

Median Follow-up: 38 months

Slamon D, et al, SABCS 2013, S1-03

Addition of bevazicumab to trastuzumab- based chemotherapy (BETH): OS

• No. at risk:

CTHB-HB 1752 1696 1680 1664 1637 1548 1135 660 297 65 3 CTH-H 1757 1722 1702 1690 1660 1565 1153 665 294 58 1 CTx + H (N=1757) CTx + H + BEV (N=1752) Events, n (%) 62 (4) 54 (3) Stratified HR (95% CI) Log‐rank p‐ value 0.87 (0.60–1.25) 0.4387

6 12 18 24 30 36 42 48 54 60 Time (months) 1.0 0.8 0.6 0.4 0.2

Estimated probability

97 % 96%

Median Follow-up: 38 months

Slamon D, et al, SABCS 2013, S1-03

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Phase III Trial of Pertuzumab + Chemotherapy + Trastuzumab as Adjuvant Therapy (APHINITY)

Non- metastatic node- positive HER2+ BC S U R G E R Y R A N D O M I Z A T I O N

Placebo + Trastuzumab 6-8 cycles of AC-

• r non-AC-based

chemo Pertuzumab + Trastuzumab 6-8 cycles of AC-

• r non AC-based

chemo

52 weeks

Primary endpoint : Invasive disease free survival (IDFS)

http://clinicaltrials.gov/NCT01358877

HER2-Positive Tumors ≤ 2cm

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Small HER2-positive Tumor Meta-analysis

O’Sullivan CC, et al. SABCS 2013 S6‐03 O’Sullivan SABCS 2013

Small HER2-positive Tumor Meta-analysis

O’Sullivan CC, et al. SABCS 2013 S6‐03 O’Sullivan SABCS 2013

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Cumulative Incidence of Recurrence or Death: <br />HR-Positive Disease with Tumors ≤ 2cm Cumulative Incidence of Recurrence or Death: <br />HR-Positive Disease with Tumors ≤ 2cm and N 0/1

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Cumulative Incidence of Recurrence or Death: <br />HR-Negative Disease with Tumors ≤ 2cm

Genomic analysis of immune function genes and clinical outcome in N9831

• Whole gene profiling of 1282 specimens from

N9831 trial performed to develop a multi-gene predictive signature of trastuzumab benefit

• Identified 6 biological pathways associated

with increased RFS in trastuzumab-treated patients

– 4 of these pathways linked to immunological functions

• Percent immune-response enriched tumors in

N9831 DASL cohort

– Arm A (no trastuzumab) = 52% – Arm B/C (trastuzumab) = 52%

Perez et al Proc ASCO 2014

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Slide 12 Slide 13

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Adjuvant Paclitaxel and Trastuzumab

Tolaney S, et al. SABCS 2013, S1-04

T1A/B = 50% T!C/2 = 50%

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Heterogeneity of HER2-positive cancers

HER2 LUM A LUM B Basal Claudin-low Normal

31% 30% 30% 6% 1% 2%

Carey et al Proc ASCO 2014

N = 265

Intrinsic subtyping of HER2-positive breast cancers

HER2 LUM A LUM B Basal Claudin-low Normal

17% 34% 48% 1% 51% 24% 12% 5% 3% 5%

HR-positive HR-negative

Carey et al Proc ASCO 2014 N =109 N = 156

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Prognostic ability of 70-gene signature in HER2+, ER+ cancers: untreated patients (n = 89)

Knauer et al BJC 2010

21-gene signature not useful as HER2+ cancers have intermediate or high recurrence scores

Bi-directional cross-talk between ER and HER2

• Signaling through EGFR family including HER2

down-regulates ER

• Conversely, inhibition of HER2 with trastuzumab
• r lapatinib increases signaling through ER
• ER signaling is increased in HER2-positive cell

lines that are resistant to HER2-directed agents

• HER2 expression and activity is increased in

hormone-resistant cancers, compared to hormone-sensitive cancers

Pinzone Mol Cell Biol 2004, Stoia J Endocrinol 2000, Sabnis Cancer Res 2009, Xia PNAS 2006, Valabrega Oncogene 2005

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ER ER

ERE FOXO3a PI3-K AKT HER2 HER1/2/3

FOXO3a

ER-regulated gene transcription

x

Ras MEK Erk1/2

Nucleus Cytoplasm Membrane ER ER

ERE FOXO3a PI3-K AKT HER2 HER1/2/3 ER-regulated gene transcription Ras MEK Erk1/2

Nucleus Cytoplasm Membrane

TKI

x x

TRAST

HER2 signaling decreases ER activation and inhibition of HER2 increases ER-regulated gene transcription

Xia PNAS 2006, Valabrega Oncogene 2005

Clinical relevance of this cross-talk

• Inhibition of HER2 without inhibition of

ER may increase ER signaling allowing ER to act as an escape mechanism

– This could contribute to the lower PCR seen in ER+ HER2+ breast cancers and have potential implications in the metastatic setting – There may be a subset of ER+ HER2+ breast cancers where ER inhibition is critical (more important than chemotherapy)

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Response to pre-operative trastuzumab and lapatinib ± letrozole (12 weeks)

10 20 30 40 50 60 pCR (%) 70 All ER+ ER - 40% 21% 28 % 53 % 56 % 48 % All ER+ ER-

pCR pCR + npCR

Rimawi CCR 2013

npCR = < 1cm residual cancer in the breast

*

* NeoSphere: PCR 6% with dual HER2 inhibition without ER inhibition

TEL trial: Pre-operative Trastuzumab, everolimus and letrozole in HR-positive, HER2- positive breast cancer (PI O’Regan)

EVEROLIMUS T T T T LET

HR+ HER2+ Resectable

Sx*

T BX

*Further treatment (including chemotherapy at physician’s discretion) Biopsy (Bx) to assess ER and HER2 signaling

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Summary

• Excellent outcomes noted for patients

with early stage HER2-positive breast cancer treated with trastuzumab-based chemotherapy

• Addition of other growth factor receptor

inhibitors has not improved outcome in the adjuvant setting

• A “less is more” approach may be

appropriate for a subset of HR-positive, HER2-positive cancers but these are not as yet clearly defined