Immunotherapy Breaks Through in Breast Cancer

Peter Schmid, MD, PhD, associate professor of oncology and urology at Johns Hopkins Medicine

Peter Schmid, MD, PhD

In light of the results of the IMpassion130 trial, the combination of atezolizumab (Tecentriq) and nab-paclitaxel (Abraxane) is poised to become the new frontline standard of care for patients with metastatic triple-negative breast cancer (TNBC) with PD-L1—positive tumors. Lead author Peter Schmid, MD, PhD, said that these results have created an opportunity to improve outcomes for patients with TNBC.

IMpassion130 evaluated the added benefit of the checkpoint inhibitor atezolizumab to standard nab-paclitaxel chemotherapy in patients with metastatic TNBC with the endpoints of progression-free survival (PFS) and overall survival (OS).

Findings presented at the 2018 ESMO Congress showed that in patients who tested positive for PD-L1 expression, the median PFS was 7.5 months (95% CI, 6.7-9.2) with atezolizumab plus nab-paclitaxel versus 5.0 months (95% CI, 3.8-5.6) with chemotherapy (HR, 0.62; 95% CI, 0.49-0.78; P <.0001). This was the most compelling result, said Schmid. Additionally, the 1-year PFS rates were of note, with a PFS of 29% (95% CI, 22%-36%) for atezolizumab plus nab-paclitaxel and 16% (95% CI, 11%-22%) for nab-paclitaxel alone.

OncLive: Can you please discuss the findings of the IMpassion130 trial?

In an interview with OncLive^® during the 2018 ESMO Congress, Schmid, lead at the Centre for Experimental Cancer Medicine, Barts Cancer Institute, London, United Kingdom, shared the results of IMpassion130 and discussed his thoughts on the future of immunotherapy in breast cancer.Schmid: The IMpassion130 trial was a randomized phase III trial designed to test whether the addition of immune checkpoint inhibitor atezolizumab to standard chemotherapy could improve outcomes for patients with metastatic TNBC. The trial randomized patients to treatment with nab-paclitaxel and placebo or nab-paclitaxel and atezolizumab.

A total of 902 patients were enrolled in the study. Patients were not allowed to have received prior treatment for advanced disease but could have received prior chemotherapy in the neoadjuvant and adjuvant settings, as long as there was a treatment-free interval of at least 1 year. The trial had 4 coprimary endpoints—2 for progression-free survival [and 2 for OS]&mdash;both in the intent-to-treat (ITT) population, as well as in patients with PD-L1—positive tumors. PD-L1 positivity was defined as at least 1% of immune cells from PD-L1. Approximately 41% of patients were classified as PD-L1 positive.

At the 2018 ESMO Congress, we presented the final results for PFS and preliminary results for OS based on approximately 60% of the required events. The trial met its c-primary endpoints for PFS, demonstrating the benefit in the ITT population with an HR of 0.80. More importantly, we saw an HR of 0.62 in patients with PD-L1—positive tumors, establishing a clear benefit for the addition of atezolizumab to nab-paclitaxel chemotherapy. At this point in time, the OS analysis was not statistically significant. However, looking at patients with PD-L1–positive tumors, there was a substantial improvement in OS from 15.5 months to 25.0 months, with an HR of 0.62. The treatment was well tolerated, and we did not experience adverse effects that we did not know from atezolizumab or nab-paclitaxel.

Can you expand on the role of PD-L1 expression in breast cancer?

In my opinion, this trial is a practice-changing study that demonstrated clearly that the addition of atezolizumab to nab-paclitaxel chemotherapy improves outcomes in terms of PFS—but more important, OS&mdash;in this subgroup of patients with PD-L1—positive tumors. This is the first randomized trial to demonstrate the benefit of immunotherapy in breast cancer, but it is also the first randomized trial with a targeted therapy to demonstrate an OS benefit in metastatic TNBC. The trial gives me a lot of hope that we can introduce immunotherapy successfully to other subgroups of breast cancer. It is clearly establishing a new standard of care for patients with PD-L1–positive tumors in TNBC.PD-L1 expression turned out to be a really important biomarker in the IMpassion130 trial. All the benefit that we saw was in the PD-L1—positive subgroup; however, at this time, we cannot establish a clear benefit of adding immunotherapy in patients with PD-L1–negative tumors.

How will the introduction of immunotherapy affect the treatment paradigm of breast cancer?

In contrast to other cancer types, PD-L1 expression in TNBC is predominantly found on immune cells, hence the testing focused on PD-L1 staining on the immune cells around the actual cancer cells. There is very little PD-L1 expression on the cancer cells in breast cancer.IMpassion130 is the first positive trial of immunotherapy in breast cancer and is the first trial to show a survival benefit in metastatic TNBC. Therefore, I would consider this a practice-changing study.

There are a substantial number of phase III and earlier trials ongoing that will further establish the role of immunotherapy in breast cancer. Several phase III trials are looking at chemotherapy backbones in TNBC, such as paclitaxel and platinum-based chemotherapy. Also, other checkpoint inhibitors are being looked into, such as pembrolizumab (Keytruda). These results are expected within the next 1 to 2 years. There are other studies looking at different combinations. For example, small molecule inhibitors or other biological agents may further improve the activity of immunotherapy. Trials are moving into other subtypes of breast cancer, as well, such as estrogen receptor—positive and HER2-positive cancers.

What should the oncology community take away from the presentation of these results?

In my opinion, the most important thing is the impending findings from the phase III trials looking into the role of immunotherapy in early TNBC. Should these trials be positive, it will clearly have a substantial impact on how we treat patients with TNBC and, I hope, how we increase the cure rates for these patients. The IMpassion130 trial clearly established that immunotherapy can play a role in breast cancer, and it can play a substantial role in patients with metastatic TNBC with PD-L1—positive tumors. This is, in my opinion, the beginning of an era. We will need to do a lot of work to further establish the role of immunotherapy in other subgroups of breast cancer. I truly hope that immunotherapy will improve outcomes for patients with breast cancer.

Schmid P. IMpassion130: Results from a global, randomised, double-blind, phase 3 study of atezolizumab (atezo) + nab-paclitaxel (nab-P) vs placebo + nab-P in treatment-naive, locally advanced or metastatic triple-negative breast cancer (mTNBC). In: Proceedings from the 2018 European Society for Medical Oncology Congress; October 19-23, 2018; Munich, Germany. Abstract LBA1_PR.