I’m very pleased to introduce, talk about, this trial data. Actually this is a trial of the collaboration study between the Korean Breast Cancer Study Group and the Japanese Breast Cancer Research Group, the name is CREATE-X. This is a very brief background of this trial. The standard regimens of neoadjuvant chemotherapy contain anthracycline and taxane; I think it has not changed very much. The patients with pathological disease after neoadjuvant chemotherapy have higher risk for relapse in general and particularly for oestrogen receptor negative cases. It is unclear whether the possibility of resistant chemotherapy following that is able to prolong the survival or not. This trial was designed as a multi-centre open label randomised phase III trial evaluating the efficacy of adjuvant capecitabine used for patients having which means a non-pathological complete response or node negative or node positive after.

This is a very brief sketch of the trial design CREATE-X. We had some negative primary breast cancer patients starting with neoadjuvant chemotherapy and surgery and if pathologically the diagnosis said non pCR or node positive which is able to be enrolled in this trial and randomised to control, that means standard treatment. If hormone receptor positive hormonal treatment should be considered and in comparison the standard treatment plus capecitabine which is the trial arm, capecitabine arm, the rest of the hormone receptor negative no further systemic treatment. The stratification factors were oestrogen receptor positive, unlimited age, more than 50 or less than 50. The neoadjuvant chemotherapy anthracycline and taxane or anthracycline containing. The nodal status, the node negative and 1-3 nodes and over four nodes, and the 5FU containing or not in the regimens of neoadjuvant chemotherapy and institution, those were the stratification factors.

Radiotherapy was used, was given, if they needed. That’s the capecitabine treatment, the arm, 2,500mg/day about the two weeks on, one week off, repeated every three weeks for eight cycles. Because of safety concerns, we started with the second cycle of capecitabine treatment then we planned to have a safety interim analysis of the first fifty patients treated with six cycles of capecitabine. According to this, the safety interim analysis, actually it was feasible the IDMC recommended the extension of capecitabine treatment to eight cycles.

Endpoints: the primary endpoint, the disease free survival. The secondary endpoints were overall survival the first day of the preoperative chemotherapy to recurrence or death, safety and cost effectiveness. Consult the diagram and the trial progress; actually from 2007, February, to 2012 in July 304 Korean patients and 660 Japanese patients were randomised into the capecitabine arm and the control arm actually equally. And not meeting inclusion criteria, patients withdrew, no follow-up data, those patients were excluded from the full analysis. The capecitabine arm actually 440, control arm 445. The other cut-off was actually the at the end of September 2015.

In 2015 March, the end of March, the first pre-planned interim analysis was carried out at a point of two years’ follow-up from the last patient enrolling. After the IDMC recommended that this study should be discontinued according to the protocol. That’s the main result, primary endpoint, disease free survival. After five years disease free survival was 74% for the capecitabine arm, 67.7% for the control arm. The hazard ratio was 0.70 and the p-value was 0.00524 which was smaller than the 0.0067. Because of that the IDMC recommended to discontinue the trial.

So the conclusion. After standard neoadjuvant chemotherapy containing anthracycline and/or taxanes the possibility of adjuvant use of capecitabine improves disease free survival significantly in HER2 negative primary breast cancer patients with pathologically proven or else was significantly improved by capecitabine adjuvant therapy for non pCR or node positive patients after neoadjuvant chemotherapy as well. The balance of the benefit and the toxicity would favour the use of capecitabine in the post neoadjuvant chemotherapy situation but the prediction for the therapeutic benefit needs to be further investigated. The cost-effectiveness analysis should be carried out soon. I think that’s all.

Thank you Dr Toi. So, just to summarise this phase III clinical trial, you have patients who had received neoadjuvant chemotherapy, had not had eradication of their breast cancer and adjuvantly they were able to receive 24 weeks of capecitabine. What Dr Toi’s study showed was that the capecitabine improved both disease free survival, which was the primary endpoint of the study, and overall survival in this study population. So, Dr Toi, tell me, Monday morning we’re in clinic seeing patients and I have a patient who has residual disease after neoadjuvant chemotherapy. What do I tell her?

I think we need to take care of the reimbursement issue. However, personally I’d like to consider this treatment. Also we need to prepare for the reimbursement issue, that’s the very important thing I guess.

As we move on to the questions please either wait for a microphone or if you’re on the phone press star one to ask a question. Thanks.

So, what Dr Toi said was that’s one major issue of reimbursement. These are patients that will be receiving chemotherapy for an extra 24 weeks and when it’s an oral chemotherapy that right now is not approved by the FDA in this country, and I’m sure in Japan as well, would have a problem covering, having insurance coverage.

Hi, with Medscape. Dr Toi, could you please explain the therapeutic rationale for capecitabine? Why capecitabine and not another agent?

I think multiple issues, the most important one it’s a non-cross resistance agent. Anthracycline, taxane and capecitabine, capecitabine is not cross-resistant to these two major compounds, agents. This is the biggest and the second issue is it’s possible to use after neoadjuvant chemotherapy. It’s a kind of chronic treatment for six months’ time. That’s another advantage presumably for the capecitabine treatment. That’s the major two things.

OK, thank you.

Thank you.

Alice Goodman with the ASCO Post. Why did the IDMC recommend stopping the trial? Was it because it was so effective they stopped it or because it was toxic? I don’t understand why the trial was stopped at the interim analysis.

The original protocol said it should be five years, five years’ follow-up study. That’s predetermined by the protocol. Also efficacy. Obviously we can monitor there for a long time while I think it is possible to follow-up further the prognostic outcomes.

We’re just asking if it stopped because the capecitabine arm was so good? Is that why it stopped early or was it going to be stopped anyway at five years?

That’s the time to open the data for public and obviously we can continue the monitoring.

OK, you said overall survival was improved but we don’t have the numbers for the overall survival. Can you give us those?

Yes, that’s right. At the time of preparation of abstract it was just marginal but with the data after September we didn’t recently analyse it then the new data showed us it is significant.

But we don’t have numbers so how can we report overall survival being better if we don’t tell what the numbers are?

Do you remember the median overall survival in each group?

I don’t remember exactly. I will tell you later.

We can get you those numbers we have those.

Charles Today. What can you tell us about the surgery these patients had and did you do pathologic analysis afterward? And did the surgery have no impact on the residual disease? Because initially as I read this it wasn’t clear that they had surgery but I do see now that they did so what can you tell us about the surgery and the status of the patients after surgery before you started the capecitabine?

Actually the surgical procedure should be determined. The best line staging and also response to the treatment, neoadjuvant chemotherapy, after that for each individual the surgical treatment, the procedure, should be chosen. The impact, in terms of the impact to the capecitabine treated arm, according to the subgroup analysis we haven’t got any trend so almost for all types of surgery, so the surgery wouldn’t be the important factor to select the patients if you have the different benefits.

So the surgery was standard of care regardless of the arm that the patient was going to be on. If a patient was eligible for a lumpectomy and sentinel node biopsy that’s what was done. The axilla was evaluated at the time of surgery?

Yes, yes.

But whether a patient had a lumpectomy or a mastectomy it didn’t make any difference. Again, the margins would have been clear at surgery. What was the important thing was residual disease at surgery.

Thank you.

Chris Wilson. Did you include triple negative patients in this study and if so did you break out any data on that subgroup?

Yes, we included triple negative patients. OK, I showed you the subgroup analysis in the presentation in the main conference but for triple negative and for luminal disease there was no difference so they’re almost equally effective for these two major subtypes. But obviously this is a subgroup analysis.