Neoadjuvant Durvalumab Regimen Improves Responses in Triple-Negative Breast Cancer

May 21, 2020

In an interview with Targeted Oncology, Lajos Pusztai, MD, DPhil, discussed the findings from the phase I/II clinical trial of durvalumab in combination with concurrent nab-paclitaxel and doxorubicin plus cyclophosphamide in the neoadjuvant setting for patients with triple-negative breast cancer.

A phase I/II study demonstrated that the addition of durvalumab in the neoadjuvant setting to nab-paclitaxel (Abraxane), doxorubicin, and cyclophosphamide-induced an improvement in pathologic complete response (pCR) rates compared with historical chemotherapy controls for patients with triple-negative breast cancer (TNBC).

The pCR rate observed in the 55 patients treated with the durvalumab regimen was 44% (95% CI, 30%-57%). Among patients with TNBC who had positive PD-L1 expression in their tumors, the pCR rate was 59% (95% CI, 0.39-0.76), while the pCR rate was 32% (95% CI, 0.12-0.56) in those with PD-L1–negative tumors, although this difference was not statistically significant (P =.26).

Overall, the durvalumab regimen appears to be a promising treatment option for patients with TNBC. The regimen was also well-tolerated, demonstrating no unexpected adverse events (AEs).

The most common grade 1/2 AEs with this regimen included fatigue (n = 55), nausea (n = 45), hypothyroidism (n = 32), maculopapular rash (n = 27), diarrhea (n = 23), and peripheral sensory neuropathy (n = 20). Grade 3 AEs were also observed, including hypothyroidism (n = 3), decreased neutrophil count (n = 3), decreased lymphocyte count (n = 3), white blood cell decrease (n = 2), hyperglycemia (n = 2), fatigue (n = 1), maculopapular rash (n = 1), oral mucositis (n = 1), and hypokalemia (n = 1). Grade 4 AEs included decreased white blood cells (n = 2), decreased neutrophil count (n = 1), and hyperglycemia (n = 1).

Investigators also noted that the most common immune-related AE was grade 1/2 hypothyroidism, and grade ≥3 immune-related AEs included hypothyroidism (n = 3), hyperglycemia (n = 3), colitis (n = 1), and Guillain-Barre syndrome (N = 1).

In an interview with Targeted Oncology, Lajos Pusztai, MD, DPhil, director of Breast Cancer Translational Research, Yale University, discussed the findings from the phase I/II clinical trial of durvalumab in combination with concurrent nab-paclitaxel and doxorubicin plus cyclophosphamide in the neoadjuvant setting for patients with TNBC.

Targeted Oncology: Could you provide an overview of your study?

Pusztai: This was a single-arm phase II trial to test if durvalumab could improve the pathological CR rates that chemotherapy alone could accomplish. The background of the trial is we wanted to see durvalumab could make an immune-poor cancer behave like an immune-rich cancer and improve the CR rate in those patients who otherwise would not have achieved a pCR with chemotherapy alone.

Targeted Oncology: What were the findings?

Pusztai: The pCR rate was 44%, which is better than the same regimen had done in the previous study, historically. However, this was not a comparative trial. It was 1 arm, so the inference that it is the pCR is higher is still an indirect comparison with our previous study. However, we think these results are promising, and this is in line with what other clinical trials in this space that have also demonstrated the same patient population that immune checkpoint inhibitors improve the pCR rate. This improvement is a little less than what we hoped for, so it is not a doubling of the pCR rate, but it is a 15% to 20% improvement, or 30% improvement at most. How this translates to an improvement in survival is still uncertain, but the largest study, the KEYNOTE-522 study, suggests that this will translate into an improvement in event-free survival.

Targeted Oncology: What kind of impact will these data have on the breast cancer paradigm?

Pusztai: I think this study adds an additional piece of evidence to this building wall that suggests that immunotherapy will make a major impact in the treatment of TNBC. There are 3 randomized trials that have shown an improvement in the pCR. Some studies were statistically significant and some were just barely missing the significance levels but were still supporting. This is an additional study that also suggests that the pCR rates are impressive, and I believe this will translate into an improvement in survival.

This does not mean much to physicians in practice today because we do not have an approved drug in this space, but hopefully in the not too distant future based on the KEYNOTE-522 trial which tests different drugs, we might have an approval in that space. If that happens, I think this will be part of the routine standard of care regimen for TNBC.

Targeted Oncology: What are the next steps for this trial?

Pusztai: We have a similar trial with a slightly similar regimen that includes the addition of a PARP inhibitor. The next step is to report out the results from that trial, which we hope could be done at American Association for Cancer Research or American Society of Clinical Oncology meetings.

What happens next with this particular combination depends on how the sponsoring company decides to follow up on these results.

Targeted Oncology: What is your key takeaway from this research?

Pusztai: The key takeaway from the emerging body of evidence, from which my trial is just a small part, is that immunotherapy does increase the pCR rate of the disease. This is accomplished with the mechanism we had hoped for, that immune-poor cancers start to behave like immune-rich. The next step is how we can make the pCR rates better. It is important, but it is no where close to 100%, so we would like to push this further. We want to answer the question of how this translates into improvement for recurrence-free and overall survival.

Targeted Oncology: Immunotherapy does appear to be emerging in breast cancer, so how is this affecting the sequencing of other regimens?

Pusztai: Immunotherapy has arrived in breast cancer, so the FDA approved the combination of atezolizumab and dexamethasone for first-line patients with PD-L1-positive TNBC. This is probably the new standard of care for frontline therapy. Single-agent chemotherapy will come into play in the second- and third-line settings. In the neoadjuvant space, they don’t currently have an impact on what we can do, but I think if an approval comes, this will change the paradigm in the early-stage setting by adding this new modality to the chemotherapy.

Targeted Oncology: Are there any research looking at immunotherapy and chemotherapy in combination?

Pusztai: Most of the research related to immunotherapy-chemotherapy combinations. My trial used standard of care chemotherapy regimen with the addition of durvalumab. In the metastatic trial that led to the registration also used chemotherapy as a backbone, so everybody got chemotherapy but half of the patients or so had atezolizumab. The [immunotherapy arm] did better in that study. Many studies are already exploring this synergy.

Targeted Oncology: Is there anything else you would like to highlight?

Pusztai: There is 1 last point to make, and that is the role of biomarkers. Currently, the most widely used FDA-approved standard to select patients for immunotherapy is PD-L1 immunohistochemistry. There are 3 or 4 different assays that are commonly used, but they are not completely interchangeable.

Another aspect of the research that is becoming clearer is that the rule of selection marker depends on the disease context in breast cancer. They may not be the same in other disease types in breast cancer, but there is consistent evidence now, much of which has been presented at the SABCS meeting. Data shows that those with early-stage disease benefit from an immune checkpoint inhibitor regardless of the absence of PD-L1 on a diagnostic assay.

For metastatic disease, the efficacy of the drugs is really dependent on PD-L1 expression. I think this reflects the immune microenvironment being different in these different disease settings. In metastatic disease, you need a lot of immune cells, and there needs to be really high PD-L1 expression to have an impact. In early-stage disease, we do not need a massive immune concentration, maybe because the immune microenvironment is more competent, so there is more immune activity and therefore an extra boost makes the effect. The metastatic disease setting is a little more immune-compromised and requires a big push.

Targeted Oncology: How would you recommend patients test for these biomarkers in breast cancer?

Pusztai: My institution and colleagues currently think doing PD-L1 immunohistochemistry at the time of recurrence of TNBC. The antibody that is the most precise is the SB142 antibody. It defines the population very clearly as far as who benefits, but we find this is a relatively small population of less than half the patients. Other antibodies have been shown to capture a larger population and designated as positive, but many patients who are positive for the SB142 antibody have a different result; they do not seem to benefit. SB142 seems to define benefit more clearly.

Targeted Oncology: Are there any other biomarkers besides PD-L1 that are coming down the pipeline now?

Pusztai: Tumor mutational burden is in the pipeline, as well as various gene signatures that integrate the information in a number of genes besides PD-L1. How they complement or replace the PD-L1 immunohistochemistry is now clear, but it is the focus of research.


Pusztai L, Reisenbichler E, Bai Y, et al. Durvalumab (MEDI4736) concurrent with nab-paclitaxel and dose dense doxorubicin cyclophosphamide (ddAC) as neoadjuvant therapy for triple negative breast cancer (TNBC). Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14; San Antonio, TX. Abstract PD1-01.

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