The first data from IMpassion031, presented at the ESMO Virtual Congress 2020, provide significant new hope for patients with early triple-negative breast cancer (TNBC) (Abstract LBA11). In the study, neoadjuvant treatment with the PD-L1 inhibitor, atezolizumab, was associated with a significantly greater pathological complete response (pCR) rate of 57.6%, compared with 41.1% with placebo, in previously untreated patients with early TNBC (a difference of 16.5%; p=0.0044).
IMpassion031 is an ongoing, randomised, phase III trial in 333 patients with stage II–III TNBC and a tumour size >2 cm. Patients received neoadjuvant atezolizumab or placebo plus nab-paclitaxel followed by standard dose-dense chemotherapy with doxorubicin/cyclophosphamide, prior to surgery. Atezolizumab or placebo was continued after surgery to complete one year of therapy.
Providing effective therapies at early stages of tumour development is particularly important for patients with TNBC, as this tumour type is typically associated with earlier recurrence and metastasis compared with other forms of breast cancer. Advanced TNBC tumours are extremely difficult to treat and have markedly poor outcomes. While standard therapy for early TNBC tends to be based on a taxane plus anthracycline, it is hoped that immunotherapy, particularly checkpoint inhibitors, may provide a promising addition to early-stage regimens.
“The IMpassion031 data are tremendously important, as previous data with neoadjuvant PD-L1 inhibitors in early TNBC have been conflicting,” says Prof. Hope Rugo from the University of California San Francisco, CA, USA. Indeed, while the large KEYNOTE-522 trial showed a significant increase in pCR rate of 13.6% over placebo with neoadjuvant pembrolizumab–chemotherapy versus placebo–chemotherapy, two smaller studies, NeoTRIPaPDL1 and GeparNuevo, failed to show significant pCR improvements with the addition of PD-L1 inhibitors — atezolizumab and durvalumab, respectively — to chemotherapy in patients with early TNBC. “IMpassion031 provides crucial additional information on the benefits of immunotherapy in this setting, not only in terms of efficacy but in the added reassurance of only modest increases in toxicity in line with what is expected when adding a checkpoint inhibitor,” continues Rugo. Treatment-related serious adverse events in IMpassion031 were reported in 22.6% of patients receiving atezolizumab–chemotherapy compared with 15.6% of those receiving placebo–chemotherapy.
According to the breast cancer expert, it is key to understand the possible reasons for the disparity in pCR rates between these trials. "There are two potential explanations”, says Rugo. “Firstly, KEYNOTE-522 showed better pCR rates in patients with node-positive or stage III disease, and thus higher tumour burden, whereas the smaller GeparNuevo trial was not powered to look at this subgroup of patients. Secondly, NeoTRIPaPDL1 did not include an anthracycline in the neoadjuvant regimen, unlike KEYNOTE-522 and IMpassion031.” Anthracyclines may have immunostimulatory effects including increasing levels of tumour infiltrating lymphocytes (TILs), which may make them more appropriate for combination with immunotherapy. Rugo is keen to stress that further studies are needed to confirm which patients with early TNBC are likely to benefit the most from neoadjuvant immunotherapy and the relevance of including an anthracycline in the regimen.
Another important finding from IMpassion031 was that the improvement in pCR rate with atezolizumab was seen regardless of PD-L1 status. This is in alignment with KEYNOTE-522, which showed improvement in pCR with pembrolizumab in both PD-L1-positive and PD-L1-negative patients. “This is strikingly different to what we see in the metastatic setting, where clinically meaningful improvements appear to be restricted to patients with PD-L1-positive disease,” comments Rugo. “What makes the PD-L1 status data in early TNBC particularly compelling is that this finding is seen regardless of how PD-L1 status is assessed, as IMpassion031 and KEYNOTE-522 used different PD-L1 assays.”
The identification of prognostic and predictive biomarkers will greatly enhance the use of immunotherapy in clinical practice. High levels of TILs in early TNBC have been associated with improved prognosis. Further insights into the dynamics of immune modulation and predictive value of TILs following addition of atezolizumab to neoadjuvant therapy in early TNBC were provided from an analysis of the NeoTRIPaPDL1 data, presented at ESMO Virtual Congress 2020, which showed that atezolizumab increased pCR by ≥10% in tumours with PD-L1-positive immune cells (Abstract LBA13). Atezolizumab treatment also appeared to increase expression of PD-L1, although the patient numbers were very small. Interestingly, pCR was increased in tumours with intermediate/high levels of stromal TILs, compared to those with lower levels regardless of whether or not atezolizumab was administered. In addition, a retrospective study of 481 young women under 40 years of age with TNBC who did not receive adjuvant chemotherapy showed that moderate (≥30–<75%) and high (≥75%) levels of TILs were associated with 15-year OS rates of 76% and 93%, respectively (Abstract 159O). “These data from a young population—who may be considered likely to have a relatively intact immune system compared with much older patients— imply two interesting things,” says Rugo. “Firstly, these data support previous studies suggesting that higher levels of TILs are associated with better outcomes; secondly, there may be a subgroup of patients with TNBC and high TILs who do not require aggressive treatment, perhaps not even adjuvant chemotherapy. Further studies on this would be very interesting.”
Abstracts and sessions details:
- Harbeck N et al. IMpassion031: results from a Ph 3 study of neoadjuvant (neoadj) atezolizumab + chemotherapy in early triple-negative breast cancer (TNBC). ESMO Virtual Congress 2020, Abstract LBA11
Proffered Paper - Breast cancer, early stage, 20.09.2020, h. 12:30 – 14:10, Channel 3 - Bianchini G et al. Tumor infiltrating lymphocytes (TILs), PD-L1 expression and their dynamics in the NeoTRIPaPDL1 trial. ESMO Virtual Congress 2020 Abstract LBA 13
Mini Oral - Breast cancer, early stage, 18.09.2020 - De Jong VM et al. Prognostic value of tumour infiltrating lymphocytes in young triple negative breast cancer patients who did not receive adjuvant systemic treatment; by the PARADIGM study group. ESMO Virtual Congress 2020, Abstract 159O
Proffered Paper - Breast cancer, early stage, 20.09.2020, h. 12:30 – 14:10, Channel 3
ESMO 2020 Highlights on neoadjuvant ICI in early TNBC: The IMpassion031 study
