After having proven its effectiveness in metastatic forms1trastuzumab deruxtecan (Enhertu) now demonstrates major benefits for certain so-called HER2+ early breast cancers.
HER2+ cancers and the antibody-drug conjugate revolution
So-called breast cancers HER2 positive represent approximately one in five breast cancers. This subtype is characterized by overexpression of the HER2 gene, responsible for rapid tumor growth and a high risk of recurrence. Over the past twenty years, targeted therapies such as trastuzumab (Herceptin) have profoundly improved survival. But despite this progress, some patients still see the disease persist after standard treatments.
It is for these cases that a new class of drugs is changing the game: antibody-drug conjugates (ADCs). These “smart” treatments combine an antibody directed against HER2 with a powerful chemotherapeutic agent, delivered directly to the cancer cells. Until now reserved for the metastatic stages, these “targeted missiles” now enter the curative phase – before or after the surgery – with impressive results.
As an ESMO editorial summarizes, “New antibody-drug conjugates show unprecedented promise in early forms of cancer“.
After surgery: fewer recurrences and a possible new standard
The DESTINY-Breast05 trial included more than 1,600 patients with HER2+ breast cancer who still had residual disease after neoadjuvant treatment (Editor’s note: given before surgery) and surgery.3. This situation, with a high risk of recurrence, is today treated with the first antibody-drug conjugate T-DM1 (trastuzumab emtansine)2. The new antibody-drug conjugate Enhertu (trastuzumab deruxtecan) was compared to this standard.
The results are clear: the risk of invasive recurrence or death has been reduced by 53% with Enhertu compared to the T-DM1. Three years after treatment, 92.4% of patients treated with Enhertu were alive without signs of relapse, versus 83.7% in the T-DM1 group. The study also shows a notable reduction in brain metastases.
Professor Charles Geyer, professor of medicine at UPMC Hillman Cancer Center and principal investigator of the trial, said4 : “These results, combined with safety data, have the potential to transform clinical practice in this context for high-risk patients, with the potential for Enhertu to establish a new standard of care.”.
Side effects were generally considered manageable, although interstitial lung disease (lung inflammation) was observed in 10% of patients under Enhertu, versus 2% under T-DM1. Two deaths have been linked to it. Regular radiological monitoring is therefore now recommended.
Dr Thomas Bachelot from the Léon Bérard Center (Lyon), also an investigator in the study, welcomes this progress with enthusiasm. 5 :
“This is a truly remarkable advance, and I hope that this molecule can quickly be available to our patients. The benefit/risk ratio is quite favorable. The risk of pneumonia is perfectly manageable, when we know the molecule well and monitor patients closely.“.
Before surgery: more complete responses, less toxicity
The study DESTINY-Breast116for its part, evaluates the drug Enhertu even earlier, before surgery. She compares a protocol Enhertu followed by a mixture of chemotherapy and targeted therapies called THP (paclitaxel, trastuzumab, pertuzumab) to the classic regimen of multiple chemotherapies followed by THP called ddAC-THPwhich includes anthracyclines known for their cardiac toxicity.
Result: the rate of pathological complete response (pCR) – that is to say the total absence of invasive cancer cells at the time of the operation – achieved 67.3% with Enhertu-THP, against 56.3% with standard treatment. In detail, in patients whose tumor also presents hormone-dependent receptors, the pCR is 61.4%and 83.1% in those whose tumor does not depend on hormones.
Professor Nadia Harbeck, from University of Munich and principal investigator of the trial7summary :
“Treatment with trastuzumab deruxtecan followed by THP showed the highest pathological complete response rate ever reported in patients with HER2+ breast cancer“.
Dr Thomas Bachelot specifies: “We gained 10% of patients in complete remission, and in fact, This means that many more patients have no treatment at all after surgery, because the risk of relapse is considered very low.“.
He also highlights another advantage of this support: “Removing anthracycline and replacing it with T-DXd makes it less toxic to the heart.”.
In other words, used before surgery, Enhertu not only makes it possible to better eradicate the tumor, but also to reduce the serious side effects linked to old chemotherapies.
A new therapeutic era underway
The DESTINY-Breast05 and 11 trials, one after surgery and the other before, together outline the same horizon: that of a treatment capable of reduce recurrences andincrease the chances of recovery in early forms of HER2+ breast cancer. Everything suggests that this is a real paradigm shift in the treatment of this type of breast cancer, with more cures among high-risk patients.
These advances open up exciting prospects but still raise questions: “For example, toxicity profiles must be carefully defined and significant efforts are required to prevent permanent or fatal toxicities. Dosage, duration, and sequencing of ADCs should also be optimized to achieve maximum effectiveness with minimal side effects. The identification of predictive biomarkers allowing better personalization of ADC treatment and a reduction in overtreatment is equally crucial.says Dr. Paolo Tarantino of Dana-Farber Cancer Institute and Harvard Medical School Tarantino8.
So many challenges that research will have to meet to transform this scientific promise into lasting victory over the disease. But enthusiasm is in order: “This is a therapeutic strategy with considerable potential, which we are only beginning to exploit, promising to reduce recurrence rates and improve survival in many cancers in the years to come.”concludes Dr. Tarantino.