Rugo Relays the State of Immunotherapy in TNBC

The addition of immunotherapy to the triple-negative breast cancer (TNBC) armamentarium has led to a paradigm shift and sparked an abundance of research with immuno-oncology (IO) drugs in new combinations and settings, explained Hope S. Rugo, MD.

"It is a really exciting time in breast cancer," said Rugo. "We've seen so many advances in the IO [arena] in a disease where we haven't had good treatment options."

For example, in March 2019, the FDA granted an accelerated approval to the combination of atezolizumab (Tecentriq) and nab-paclitaxel (Abraxane) for the frontline treatment of patients with unresectable locally advanced or metastatic PD-L1–positive TNBC.

The approval is based on findings from the phase 3 IMpassion130 trial, in which the combination led to a 40% reduction in the risk of disease progression or death compared with nab-paclitaxel alone in this patient population.

Results of the initial progression-free survival (PFS) analysis in the PD-L1–positive population showed a clinically meaningful median PFS of 7.4 months versus 4.8 months with atezolizumab/nab-paclitaxel versus nab-paclitaxel alone, respectively (HR, 0.60; 95% CI, 0.48-0.77; P <.0001).

Additionally, an interim analysis of the PD-L1–positive population indicated a clinically meaningful improvement in overall survival (OS) with the combination at 25.0 months versus nab-paclitaxel alone at 15.5 months, respectively (HR, 0.62; 95% CI, 0.45-0.86). At 2 years, the OS rates in the intent-to-treat population were 42% and 39%, respectively.

Notably, the 2-year OS rates were higher in the PD-L1–expressing population at 51% in the atezolizumab arm versus 37% in the chemotherapy-alone arm.

Since the approval, AKT inhibitors and PARP inhibitors have entered the pipeline as potential combination partners with immunotherapy in the metastatic setting. Moreover, immunotherapy is being evaluated in the neoadjuvant setting as a potential way to accelerate a more robust immune response, explained Rugo.

In an interview with OncLive, Rugo, professor in the Department of Medicine and director of Breast Oncology and Clinical Trials Education at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, discussed the research that was born from the results of the IMpassion130 trial and the future of immunotherapy in TNBC.

OncLive: How did the results of the IMpassion130 trial impact the paradigm?

Rugo: The combination of atezolizumab plus nab-paclitaxel was approved as first-line therapy for patients with metastatic PD-L1–positive TNBC who are at least 1 year out from their adjuvant or neoadjuvant taxane. The approval was [based on the IMpassion130 trial results]. Many patients [in that trial] had de novo metastatic disease.

IMpassion130 showed a significant, though modest, improvement in PFS, but a marked difference in OS. For the 41% of patients who have PD-L1–positive disease, this is very exciting.

What are some remaining questions regarding the use of immunotherapy in TNBC?

We learned from IMpassion130 that checkpoint inhibitors, like what we have seen with trastuzumab (Herceptin) and pertuzumab (Perjeta), can have a greater impact on OS than on PFS, which suggests that we are changing the immune milieu microenvironment. It is a fascinating area of study and something that we have not seen before, except for with these antibodies.

From IMpassion130, we learned that there are clearly some criteria that need to be met in order for a patient with metastatic disease to respond to a checkpoint inhibitor. The issue of what chemotherapy partner to use is also an issue.

We also learned to be more alert in managing immune-based toxicities. Breast cancer was relatively late to the field [of immunotherapy. [Since the approval, we’ve learned that it’s important to] understand symptoms beyond mouth sores and diarrhea, such as adrenal insufficiency.

We are interested in whether or not checkpoint inhibitors combined with different chemotherapy partners will work for patients who relapse in a 6- to 12-month time period. A number of trials are looking at atezolizumab with paclitaxel partners, so you would not have to give nab-paclitaxel. There are also trials looking at atezolizumab and pembrolizumab (Keytruda) in patients who relapse earlier.

We saw a press release regarding the phase 3 MK-3475-355/KEYNOTE-355 trial, which evaluated pembrolizumab with gemcitabine and carboplatin, or paclitaxel and nab-paclitaxel. Many of those patients relapsed between 6 and 12 months. It was noted in the press release that investigators met their primary PFS endpoint, but in a subpopulation of patients who had a combined positive score of at least 10. That PD-L1 test is generally positive in about 80% of tumors. We are awaiting OS data from that trial.

What does the future of immunotherapy look like in breast cancer?

The field is going to be directed by the results of the phase 3 MK-3475-522/KEYNOTE-522 trial, which was recently published in the New England Journal of Medicine. In that study, pembrolizumab was given in the neoadjuvant setting, along with a chemotherapy backbone, that included paclitaxel and carboplatin followed by doxorubicin or epirubicin and cyclophosphamide. Patients randomized to pembrolizumab or placebo continued the chosen agent for 6 months after surgery.

The investigators enrolled almost 1200 patients in that trial, which was powered to detect event-free survival (EFS) as an end point. They reported pathologic complete response (pCR) rates in more than 13% of the first 602 patients who enrolled in the trial.

At the 2019 San Antonio Breast Cancer Symposium, the investigators showed that there was more than a 20% improvement in the pCR rate in patients who had node-positive disease. Also, patients benefitted even if they could not complete the [full course] of treatment. These are striking data.

We are waiting for EFS data. We hope to get that later this year, but it is hard to know as it is all event driven. The median follow-up was only 15.5 months at the first presentation at the 2019 ESMO Congress. They may need 2 to 3 years to get enough events.

Could you shed light on ongoing research with immunotherapy?

We are interested in trying to make "cold" tumors "hot". Essentially, that means getting tumors to be more immuno-reactive, so the body can react to them. You need several factors [to do this]. The tumor needs to look foreign. It cannot have many other features that it overcomes any attempt of the immune system [to activate itself]. Tumors should not be heavily pretreated because they would likely have multiple mechanisms of resistance. Then, you want to have an effective immune system. The host can't be so immunocompromised that they cannot respond. Of course, the cancer also needs to be responsive to chemotherapy.

There are trials currently looking at combining treatment with an AKT inhibitor that have shown interesting data. One single-arm study will randomize patients to ipatasertib and a taxane with or without atezolizumab.

There are other trials looking at the AKT inhibitors, ipatasertib and capivasertib, [in combination] with checkpoint inhibitors in patients with TNBC who have alterations in the PI3K pathway.

Combinations with PARP inhibitors are also of great interest. The phase 2/3 MK-7339-009/KEYLYNK-009 trial will [randomize patients to] gemcitabine/carboplatin and pembrolizumab induction, followed by continued chemotherapy and pembrolizumab or pembrolizumab and olaparib (Lynparza) maintenance. [The trial will enroll] patients with TNBC regardless of homologous recombination defects or BRCA mutation status. We will see if we can stimulate the immune system in the maintenance phase to prolong disease control.

We also have vaccine trials and radiation trials looking at different ways to improve immune response. The space is evolving. We have a space for immunotherapy, but it is a small number of patients. We are looking to move these agents earlier in the course of therapy to cure more patients with this disease.

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