Gunter von Minckwitz, MD, PhD
Early intervention has increasingly become the new standard of care for many patients with breast cancer, with an ever-growing collection of phase III trials currently exploring several novel or improved approaches, according to leading researchers who spoke at the 33rd Annual Miami Breast Cancer Conference
The paradigm shift was kick-started by the FDA’s approval of neoadjuvant pertuzumab (Perjeta) in September 2013. This approval was based on pathological complete response (pCR) rates from the phase II NeoSphere trial. In a 5-year follow-up analysis of the trial,1
patients who were treated with pertuzumab, trastuzumab (Herceptin), and docetaxel had better long-term outcomes than those who received trastuzumab plus chemotherapy, and those outcomes correlated with pCR rates.
Pertuzumab was the first drug ever approved based on pCR as a surrogate endpoint, opening the floodgates to other novel agents, explained Gunter von Minckwitz, MD, during a presentation at MBCC, which Physicians’ Education Research (PER®) hosted in Miami Beach in March. Von Minckwitz is managing director of the German Breast Group and an associate professor and senior physician at University Women’s Hospital in Frankfurt. Now, there are a number of clinical trials evaluating novel regimens in the neoadjuvant setting as well as studies testing new strategies for the immediate aftermath of neoadjuvant therapy and in more traditional adjuvant scenarios. (Table)
Table. Key Open Phase III Studies for Early-Stage Breast Cancer
AC indicates doxorubicin and cyclophosphamide; EC, epirubicin and cyclophosphamide; EFS, event-free survival; FEC, fluorouracil, epirubicin, and cyclophosphamide; gBRCA, germline BRCA; HR, hormone receptor; HER2, human epidermal growth factor receptor-2; iDFS, invasive disease-free survival; pCR, pathological complete response; TNBC, triple-negative breast cancer.
Importance of Pathological Complete Response
The use of pCR as a clinical trial endpoint helped lay the groundwork for earlier intervention. “With the first example of pertuzumab, we can speculate that patients with early breast cancer got access to this innovative compound probably 3 to 4 years earlier compared with the usual pathway,” von Minckwitz said.
Although it can be used to expedite approvals, pCR is not meant to support a full FDA indication. Instead, pCR represents an intermediate endpoint, which is a surrogate marker of treatment efficacy assessed earlier than the true outcome of interest, such as survival, von Minckwitz noted.
There are benefits associated with the use of pCR as an endpoint for drug approvals, specifically earlier access to promising compounds with new mechanisms of action, said von Minckwitz. However, there are risks associated with its use, such as a lack of information on long-term efficacy and toxicity.
In the case of pertuzumab, the accelerated approval was not based solely on data from the neoadjuvant setting, von Minckwitz noted. “We had extraordinary efficacy in the metastatic setting, it has a very favorable toxicity profile, and it has no detrimental impact on the relative dose intensity of the backbone treatment,” he said.
In the metastatic setting, the phase III CLEOPATRA study showed an unprecedented 15.7-month improvement in overall survival (OS) with the combination of pertuzumab, trastuzumab, and docetaxel compared with trastuzumab and docetaxel alone.2
In the pertuzumab arm, the median OS was 56.5 months versus 40.8 months in the control arm (HR, 0.68; 95% CI, 0.56-0.84; P
With neoadjuvant approvals, the FDA has mandated that findings should be validated in a second study, preferably conducted in the adjuvant setting.
To confirm the pertuzumab approval, the phase III APHINITY trial is currently exploring pertuzumab, trastuzumab, and chemotherapy as an adjuvant therapy for women with HER2-positive breast cancer.
This trial has fully accrued 4805 patients for a year of treatment with the triplet compared with the trastuzumab and chemotherapy alone. The estimated study completion date is December 2023.3