So, I'm talking about the AMEERA-6, which is a trial which is currently ongoing. So, we don't yet have any data. That's a report on the relative activity of the 2 arms, but let me describe the trial to you because this is a trial for patients, men and with potentially curable hormone receptor, positive breast cancer who are currently being treated or have recently had to stop treatment with an aromatase inhibitor because they really are struggling with the side effects.
All of you who treat breast cancer patients will know that we have a significant minority of women and occasionally men who struggle with the side effects for aromatase inhibitors (AI). And often either don't take the drug and don't tell us or stop taking it and tell us that. And therefore, they lose the efficacy of aromatase inhibitors (AIs) inhibitors.
We know from several studies on either side of the Atlantic that if women come off an aromatase inhibitor (AI), they do not get the benefit that they would get if they were able to carry it on. And, in the AMEERA-6 trial, such women and occasionally men will be randomized between switching to Tam. Which is a well-established and effective drug in breast cancer, or one of the new oral SERDs amcenestrant (SAR439859), which is a drug being developed by Sanofi, who are the sponsor of the study.
And the study is being run in partnership with the breast international group based in Europe with member groups around the world and the Alliance foundation for trials in the us. So, it's a joint academic pharma company trial addressing this question. Can you use an oral se rather than Tamoxifen to get greater efficacy for those patients who are struggling with and may already have stopped taking an aromatase inhibitor due to this toxicity, which is a well-recognized problem for some patients with this class of drugs?
Why are you using Tamoxifen and an oral SERDs selection receptor down regulator as the test medicines in the trial?
I think gets forgotten is if you look, if one looks at the big 198 trial, which was the trial that put adjuvant letters all on the map, because it showed that 5 years of Letrozole was superior to five years of Tamoxifen.
There were 2 other arms in that study. And one of those arms was a couple of years of Letrozole followed by 3 years of Tamoxifen and in the big 198 trial. It was really very little difference in efficacy for those women who had five years of Letrozole compared to those who only had 2 followed by 3 years of Tamoxifen.
And in the clinic, we forget, therefore though, those patients who are struggling with an aromatase inhibitor, you try one, and you try another that actually on the basis of big 198 trial, switching them back to take Tamoxifen. We have evidence that this is an effective. And therefore, in the trial we picked Tamoxifen cause it's usually better tolerated than aromatase inhibitors as our control arm.
So, at least the women are getting something that we know works and there's an evidence base for that sequence of an AI followed by Tamoxifen. And then the randomization is against one of these new oral SERDs, amcenestrant (SAR439859), both because we have reasons to believe that they are likely to be more effective than Tamoxifen.
Do minority of patients in the adjuvant setting who do have an emerging ESR1 mutation profile?
Because there are some data that the oral surgeons may be more effective, particularly in those cancers with an emerging ESR one mutation. Now we're not testing for that prospectively in this study, but we will be collecting blood samples.
Blood samples, whether in fact they particularly get benefit from the use of the oral amcenestrant (SAR439859). There are some other minor questions we are mandating for free menopausal women and for men that they should take NHRH agonists because they would've needed that in combination with an AI, which ones can be used.
But the key one is really that question around why did we pick Tamoxifen as a control arm? And it's because we have evidence. The sequence of an AI followed by Tamoxifen is probably almost as good as 5 years of an AI. And these are women who can't tolerate 5 years of an AR that's the patient group we're targeting.
There's probably one other question people ask in our trial unusually for most of the adjuvant endocrine therapy studies, we are allowing women in irrespective of the, HER2 status. Most endocrine studies pick luminal cancers. That's hormone receptor positive HER2 negative, but we treat hormone receptor positive HER2 positive breast cancers with hormonal therapies.
So, why isn't the same question allowed to be asked in them? The answer is because it's a practical question in the clinic. These women do suffer from side effects. What is the best therapy for them? So, we're also including HER2 positive breast cancers provided. They meet the other criteria, including being hormone, receptor positive.
So, I think that they, the trial may itself already influence clinical practice on the basis that we are reminding people that there is evidence for the sequence of an aroma inhibitor followed by Tamoxifen as an. Effective treatment. And therefore, that should be increasingly used as an option for women who don't tolerate AI.
Clearly, our trial is designed to show that there is an even better solution, which is to sequence from the aromatase inhibitor to the oral SERDs amcenestrant (SAR439859) it's a hypothesis we won't know for a few years, whether that is true or not. So, in the future, we may well influence practice drug. Better and gets registered for the sequence of an AI followed by an oral third.
But before then, I'm hoping that people will be reminded that there is an option for patients who cannot go into our trial but are clearly struggling with aromatase inhibitor (AI). And that is to switch them to Tamoxifen it works.
The next step is to ramp up. Opening the study across the world, in the us in many European sites and sites outside, both Europe and north America enroll the patients because the patients are certainly there in a clinics, struggling with aromatase inhibitors (AIs). So, if we can enroll the trial, get it running, we can then deliver the answer in a few years’ time as to whether the amcenestrant (SAR439859) is gonna be better than.
I think the important thing is to remember that our patients sometimes struggle more on aromatase inhibitors than they admit to us. And up until now, perhaps as doctors, we've not always dealt with those concerns as much as we should do, because we felt that there aren't many other options. I think it's important when you see your patients to really find out just how much are they struggling, actually, just how much are they taking their aromatase inhibitors (AIs) pills?
And that there is an option. There is the option outside the trial of sequencing them to Tamoxifen. But also importantly, there is an option of the finding a site open with this trial and enrolling in a trial so that we can see whether there's an even better option and the patient could contribute to clinical research.
Whilst coming off the aromatase inhibitor or that minority who find that too disruptive in terms of their quality of life.
David Cameron, MD, Professor of Oncology at Edinburgh University, and works in NHS Lothian’s cancer centre treating breast cancer patients, and is the joint lead for the Edinburgh Experimental Cancer Medicine Centre. He is currently also the part/time deputy director role within the Scottish Government funded Innovative Health Care Delivery Programme (IHDP) which seeks to improve on access to, and enhance the use of, routine data on cancer patients within NHS Scotland. He also chairs the Scottish Cancer SACT data group, off label cancer medicines’ group and is Scottish Government R&D (CSO) clinical cancer research champion. In this video, he speaks about the ASCO 2022 - Abstract TPS607: Adjuvant study of amcenestrant (SAR439859) versus tamoxifen for patients with hormone receptor-positive (HR+) early breast cancer (EBC), who have discontinued adjuvant aromatase inhibitor therapy due to treatment-related toxicity (AMEERA-6).
Patients with HR+ EBC who have stopped adjuvant treatment with aromatase inhibitors (AIs) due to medication-related toxicity currently have few therapeutic alternatives. Amcenestrant is a powerful dual action oral selective estrogen receptor degrader (SERD) that antagonizes and degrades the ER, hence inhibiting the ER signaling pathway. Preliminary data from the phase 1/2 AMEERA-1 trial show that amcenestrant has meaningful antitumor activity and a favorable safety profile in the treatment of HR+ advanced breast cancer (Linden HM, Campone M, Bardia A, et al: Abstract PD8-08: A phase 1/2 study of SAR439859, an oral selective estrogen receptor (ER) degrader (SERD), as monotherapy and in combination with other anti-cancer therapies in post
AMEERA-6 is a phase 3 trial that is prospective, randomized, multinational, double-blind, and double-dummy. 3738 patients will be randomly assigned to either amcenestrant 200 mg or tamoxifen 20 mg daily. Patients with HR+ EBC (stage IIB-III) who have had at least 6 months of adjuvant AIs (at least 3 months in the adjuvant context if they have previously received neoadjuvant AI therapy) and quit them within 30 months of initiation due to treatment-related toxicity are eligible. Participants' ER+ and/or PgR+ (ten percent positive stained cells) status will be determined centrally using an immunohistochemical test. The use of adjuvant CDK4/6 inhibitors is permitted. Patients are eligible regardless of HER2 status; patients with HER2-positive illness must finish adjuvant anti-HER2 treatment and chemotherapy before to randomization. Duration of AI therapy, HER2 status, prior chemotherapy, prior CDK4/6 inhibitors, geographic location, and menopausal status are all stratification criteria. The treatment will last 5 years. Patients will be tracked for ten years after randomization. Invasive breast cancer-free survival is the primary outcome (IBCFS). A key secondary aim is invasive disease-free survival, with other secondary endpoints include distant relapse-free survival (RFS), locoregional RFS, overall survival, breast-cancer specific survival, safety, patient reported outcomes, and pharmacokinetics. Treatment adherence is an exploratory endpoint. AMEERA-6 began accepting applications in January 2022. NCT05128773 is the clinical trial number.