HER2 Support Group Forums - dual her2 blockade w herceptin + Lapatinib shrinks tumors in 11 days(better report)

European Cancer Organisation

EBCC-10 NEWS: Combination of lapatinib and trastuzumab shrinks HER2 positive breast cancer significantly in 11 days after diagnosis
Amsterdam, The Netherlands: Approximately a quarter of women with HER2 positive breast cancer, who were treated with a combination of the targeted drugs lapatinib and trastuzumab before surgery and chemotherapy, saw their tumours shrink significantly or even disappear, according to results from a clinical trial.

Professor Nigel Bundred told the 10th European Breast Cancer Conference (EBCC-10) today (Thursday): “This has ground-breaking potential because it allows us to identify a group of patients who, within 11 days, have had their tumours disappear with anti-HER2 therapy alone and who potentially may not require subsequent chemotherapy. This offers the opportunity to tailor treatment for each individual woman.”

Prof Bundred, who is Professor of Surgical Oncology at The University of Manchester and the University Hospital of South Manchester NHS Foundation Trust (UK), was presenting results from the UK EPHOS-B multi-centre, clinical trial, in which 257 women with newly-diagnosed, operable, HER2 positive disease were recruited between November 2010 and September 2015.

The trial had two parts; in part one, 130 women were randomised to receive no pre-operative treatment (the control group), or trastuzumab (Herceptin ®) only, or lapatinib (Tyverb ®) only, for 11 days after diagnosis and before surgery. However, as evidence emerged from other trials of the efficacy of the combination of lapatinib and trastuzumab to treat HER2 positive breast cancer in other settings, the second part of the trial was amended so that, from August 2013, the next 127 women were randomised to the control group, or to receive trastuzumab only, or the combination treatment. For both parts of the trial, the women continued to receive standard of care treatment after surgery.

Samples of tumour tissue were taken from the first biopsy, which had been used to confirm the cancer diagnosis, and then again during surgery. The samples were analysed to see if there had been a drop in levels of the Ki67 protein, an indicator of cell proliferation, or a rise in apoptosis (programmed cell death) of 30% or more from the time of the first biopsy. In addition, investigators reviewed the pathology reports on the tissue taken during surgery, and the women were then categorised as either having pathological complete response (pCR) if no active cancer cells had been found, minimal residual disease (MRD) if the tumour was less than 5mm in diameter, or other.

Results from the second part of the trial, analysed in February 2016, showed that, in addition to observing a drop in Ki67, for women who received the combination treatment 11% had pCR and 17% had MRD. For those women randomised to receive only trastuzumab, 0% had pCR and 3% had MRD and no patients had either pCR or MRD in the control group.

The group of women who responded to the combination treatment included women who had presented with Stage 2 breast cancer (where it had spread to their lymph nodes).

Speaking at the EBCC-10 press conference, Professor Judith Bliss, lead researcher from The Institute of Cancer Research, London, which co-led the trial, said: “These results show that we can get an early indication of pathological response within 11 days, in the absence of chemotherapy, in these patients on combination treatment. Most previous trials have only looked at the pathological response after several months of treatment.

“Clearly these results need further confirmation, but I suspect the excitement from seeing the speed of disappearance of the tumours will mean that several trials will attempt to confirm these results.”

So far, EPHOS-B is the only trial that has investigated giving combination treatment alone, without chemotherapy, in the two weeks between diagnosis and routine surgery. “Other trials have looked at anti-HER2 therapy, with and without chemotherapy, including an assessment of the combination of trastuzumab and lapatinib, and have reported impressive response rates but these trials have only reported results after several months of therapy. Potentially, giving treatment while waiting for surgery can identify a group of patients whose disease is particularly sensitive to anti-HER2 therapy, which would allow individualisation of therapy in women with HER2 positive cancers,” said Prof Bundred.

Chair of EBCC-10, Professor Fatima Cardoso, who is Director of the Breast Unit at the Champalimaud Clinical Centre, Lisbon, Portugal, said: “The results of this important trial confirm previous initial suggestions that most probably there are patients who can be treated with dualblockade (two anti-HER2 agents simultaneously) alone, without chemotherapy. This study proposes a simple way to identify those patients very early on, which could help spare them unnecessary chemotherapy. What is now indispensable is to confirm if these early responses translate into better or equal long-term survival.”

HER2 positive breast cancer is breast cancer that has a high number of receptors for the human epidermal growth factor (HER2) on the surfaces of the cancer cells. These receptors stimulate the cancer cells to divide and grow. HER2 positive breast cancers tend to grow more quickly than HER2 negative cancers but can be treated with targeted therapies such as trastuzumab and lapatinib.

Abstract no: 6 LBA. “Effects of perioperative lapatinib and trastuzumab, alone and in combination, in early HER2+ breast cancer – the UK EPHOS-B trial (CRUK/08/002)”, Thursday, Clinical science symposium: HER2 positive breast cancer, 16.00-17.30 hrs, Elicium. When obtaining outside comment, journalists are requested to ensure that their contacts are aware of the embargo on this release.

Note: The study was funded by Cancer Research UK and GlaxoSmithKline and co-sponsored by The Institute of Cancer Research and The University of Manchester / University Hospital of South Manchester NHS Foundation Trust. Lapatinib is now owned by Novartis. Page last modified: 4 March 2016

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Abstract Search - EBCC10

Session title: HER 2 Positive Breast Cancer
Session type: Clinical Science Symposium
Track:
Abstract number: 6LBA
Abstract title:
LATE BREAKING ABSTRACT: Effects of perioperative lapatinib and trastuzumab, alone and in combination, in early HER2+ breast cancer - the UK EPHOS-B trial (CRUK/08/002)

N. Bundred (1), D. Cameron (2), A Armstrong(3), A Brunt(4), A Cramer(5), D Dodwell(6), A Evans(7), A Hanby(6), S Hartup(6), A Hong(8), K Horgan(6), I Khattak(9), J Morden(10), J Naik(11), S Narayan(12), J Ooi(13), A Shaaban(14), R Smith(12), M Webster-Smith(10), J Bliss(10)

(1)University Hospital of South Manchester NHS Foundation Trust, Academic department of surgery, Manchester, United Kingdom
(2)University of Edinburgh and NHS Lothian, Edinburgh Cancer Centre, Edinburgh, United Kingdom
(3)The Chrtistie NHS Foundation, Manchester, United Kingdom
(4) University Hospitals of North Midlands NHS Trust and Keele University
Stoke-on-Trent, United Kingdom
(5) The Christie Pathology Partnership, Manchester, United Kingdom
(6) Leeds Teaching Hospital, Leeds, United Kingdom
(7) Poole Hospital NHS Foundation Trust, poole, United Kingdom
(8) Royal devon & Exeter NHS Foundation Trust, Exeter, United Kingdom
(9) Betsi Cadwaladr University Health Board, Bangor, United Kingdom
(10) The Institute of Cancer Research, ICR -CTSU, Clinical Studies, London, United Kingdom
(11) Mid Yorkshire Hospitals NHST, Wakefield, United Kingdom
(12) University Hospitals of North Midlands NHS Trust, Cancer Clincial Trials, Stoke-on-Trent , United Kingdom
(13) Bolton NHS FT, Bolton, United Kingdom
(14) University Hospitals Birmingham NHS Foundation Trust, department of Cellular Pathology, Birmingham, United Kingdom
Background: Optimal management of HER2+ cancers remains unclear. The window between diagnosis and definitive surgery provides an opportunity to assess biological drug effects in a treatment naïve primary breast cancer (BC) population. EPHOS-B was designed to measure the effect of 10–12 days' pre-operative anti-HER2 therapy on proliferation and apoptosis in HER2+ BC patients.

Patients and Methods: EPHOS-B is a multicentre, 2-part randomised trial in patients with operable newly diagnosed HER2+ primary BC. In Part 1 patients were randomised (1:2:2) to no perioperative treatment (control), trastuzumab only (6 mg/kg on days 1 & 8 pre-surgery) or lapatinib only (1500 mg/day). Emerging evidence on the efficacy of combination anti-HER2 therapy led to amendment to Part 2 where patients were allocated to control, trastuzumab only (as above) or combination of lapatinib (1000 mg/day) and trastuzumab (1:1:2). Analyses of Part 1 and Part 2 are presented.

Primary endpoint is change in Ki67 and/or apoptosis. Response is defined as a drop in Ki67 of ≥30% or a rise in apoptosis of ≥30% from baseline.

Tissue samples were taken at diagnostic core biopsy and surgery and analysed centrally for Ki67, apoptosis (activated caspase 3) and PgR, by immunohistochemistry (IHC). As an exploratory analysis, patients with insufficient tumour at surgery were categorised using pathological reports obtained from centres, blinded to randomised treatment allocation as having either pathological complete response in the breast (pCR), minimal residual disease (MRD, defined as <5 mm invasive tumour), or other. Full central pathology review with analysis of samples for Ki67/apoptosis is due for completion end of February 2016.

Control (N = 51) Lapatinib (N = 51) Trastuzumab (N = 89) Combination (N = 66)
Part 1 N = 22 N = 51 N = 57 −
Tumour size (cm) at entry, median (IQR) 2.0 (1.3–2.5) 2.5 (1.3–3.0) 2 (1.5–3.3) −
Breast pCR 0 (0%) 0 (0%) 1 (1.8%) −
MRD 0 (0%) 0 (0%) 1 (1.8%) −
Part 2 N = 29 − N = 32 N = 66
Tumour size (cm) at entry, median (IQR) 1.8 (1.5–2.3) − 1.6 (1.3–2.7) 1.7 (1.2–2.7)
Breast pCR 0 (0%) − 0 (0%) 7 (10.6%)
MRD 0 (0%) − 1 (3.1%) 11 (16.7%)
(Please note: complete table to follow).

Results: 257 patients were recruited (130 in Part 1 and 127 in Part 2); all were HER2+ (91% IHC 3+ and 9% amplified by FISH, locally assessed). Median age was 52 years (IQR 48–62); 48% had tumours >2 cm and 51% were grade 3 on biopsy at entry. According to local assessment, 67% were ER+ and 40% PgR+.

Response by treatment group is shown in the table.

Conclusion: The early reduction or absence of invasive disease in approximately quarter of patients after only 11 days' preoperative combination HER2 therapy identifies cancers addicted to the HER2 pathway. Using preoperative antiHER2 therapy offers potential to personalise therapy for these patients. Further trials are required to determine which patients may need only antiHER2 combination therapy continued thus avoiding chemotherapy.

Conflict of interest: Other Substantive Relationships: J. Bliss, Educational grant received by ICR in relation to EPHOS-B Trial from GSK. Advisory boards: J. Naik for Astra Zeneca and Novartis and I provided some paid training for Roche employees.

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