2011 SABCS, San Antonio Breast Cancer Symposium, 6-10 December, San Antonio, USA

CLEOPATRA trial to evaluate the efficacy and safety of pertuzumab + trastuzumab + docetaxel

Professor José Baselga – Massachusetts General Hospital Cancer Center, Boston, MA

Good morning everybody and thank you for being here so early today. I’m going to be presenting the results of CLEOPATRA on behalf of the study investigators. Before I start, just some principles. This is the way pertuzumab works: it binds to HER2, to the HER2 receptor in a similar concept as Herceptin does, this would be Herceptin that binds to this area of the HER2 extra cellular domain. Pertuzumab, however, binds to the receptor but it binds to it in a different site and this is the site that is important for the dimerisation between HER3 and HER2. So pertuzumab is a dimerisation blocker and therefore it prevents quite efficiently ligand dependent receptor activator. The two antibodies given together are extremely complimentary in pre-clinical models and they are synergistic and we have shown in the past in patients with more advanced disease that the two antibodies together were quite active.

This was a randomised registration placebo-controlled phase III study and the design is shown here – 800 patients, 1-1 randomisation, placebo plus trastuzumab plus docetaxel in the control arm, pertuzumab plus trastuzumab plus docetaxel in the experimental arm. Therapy with docetaxel was given every three weeks and it was recommended that, at minimum, six cycles of docetaxel are to be administered. After that it was left at the criteria of the investigations and the patients to continue or not. On the other hand, either placebo trastuzumab or pertuzumab and trastuzumab were given every three weeks until disease progression or side effects. What you have here is the dosing schedule, as you can see pertuzumab is given on a fixed dose.

Patients were randomised based on the geographic region, this is a true global study, and also on the prior therapy that the patients had received, in particular if the patients had received prior neoadjuvant or adjuvant chemotherapy. In terms of the eligibility criteria, these are all patients with centrally confirmed HER2 positive disease, either by IHC or FISH; patients had first line metastatic disease, no prior therapy with the only exception of one line of hormone therapy. Patients had measurable or non-measurable disease to be eligible and patients had to have a good cardiac function. If they had received, in the adjuvant setting, either taxanes or trastuzumab, more than one year had to have elapsed before entering into the protocol.

The baseline characteristics of the patients are well-balanced, as you can see the median age is 54 years which is classical in this patient population - these HER2 positive patients tend to be a little younger than other patients with high disease; well-balanced by performance status, well-balanced by attrition. What you have here is the HER2 status, all patients but one were positive either by HER2 immunohistochemistry or FISH. About 50% of patients were ER positive and also what you have here, in the bottom of the slide, is the distribution on the percentage of patients that had visceral disease, again classically of HER2 positive disease the majority of patients, north of 75%, had visceral disease.

And here’s the prior chemotherapy in the adjuvant or neoadjuvant setting. About 45-47% of patients had received prior adjuvant and you have here, in the bottom of the slide, the types of chemotherapy that these patients had received in the adjuvant setting.

Now to the primary efficacy endpoint that was independently reviewed progression free survival. These are the findings: the control arm had a median time to disease progression of 12.4 months, the experimental arm with pertuzumab 18.5. That’s a six months delta difference, hazard ratio of 0.5, the p-value is shown here as well.

When it comes to the pre-specified subgroups in the study, you see this first plot here and you can see that the benefits of pertuzumab were seen across these variables. People question sometimes when they see this data, what happens with patients with non-visceral disease in which, I don’t know if you see it, but there seems to be less of a benefit. I think this relates more to the difficulty, and that’s a hypothesis, of measuring bone disease alone which is what these patients are. It is hard sometimes in bone disease to really know when these patients are progressing but if we take this away all the other parameters are clearly favouring pertuzumab.

When it comes to survival, the study had a pre-defined interim analysis at the time of progression free survival. These results show a strong trend in favour of survival, hazard ratio of 0.64 and here you have the p-value. Now this is not significant because this is an interim analysis and in order to be significant it would have to cross a pre-specified O’Brien-Fleming stopping boundary that is quite stringent and that was not met. So we need to wait longer to have meaningful survival data.

In the response, and I’ll go very quickly, as you would expect a higher response rate with the pertuzumab arm from 69% to 80% and then in terms of side effects, what I have in this slide here are just the side effects that were grade 3 or greater. What you see is in the case of pertuzumab there is an excess febrile neutropenia, pertuzumab is on the right on this, and then also an excess diarrhoea, diarrhoea being a well-known side effect of pertuzumab. Of note, the majority of these events occurred during the first six cycles when docetaxel was being given. There was not a signal of any increased cardiac dysfunction at all in the pertuzumab arm.

So, in conclusion, CLEOPATRA met its primary endpoint and demonstrated a significantly statistically and clinically meaningful in progression free survival, the hazard ratio is 0.62 in patients with HER2 positive metastatic breast cancer. The progression free survival increased by 6.1 months and it was consistent across subgroups. It is supported by a strong trend in survival and by improvement in response rate. The combination of pertuzumab and trastuzumab and docetaxel did increase diarrhoea, rash and mucosal inflammation as well as febrile neutropenia. This regimen may be practice changing in HER2 positive patients in the first line setting. And with this I’ll finish and I’d like to thank you all for your attention.