Atezolizumab Approval Sets Stage for Future Drug Development in TNBC

Mariana Chavez Mac Gregor, MD, MSc

The impact of the March 2019 FDA approval of atezolizumab (Tecentriq) plus nab-paclitaxel (Abraxane) in patients with locally advanced or metastatic PD-L1—positive triple-negative breast cancer (TNBC) is unmistakable, but according to Mariana Chavez Mac Gregor, MD, MSc, other agents of considerable merit include PARP inhibitors and antibody-drugs conjugates (ADCs).

The decision to approve the PD-L1 inhibitor atezolizumab was based on data from the phase III IMpassion130 trial, which demonstrated a 7.4-month median progression-free survival (PFS) with the combination versus 4.8 months with nab-paclitaxel alone in treatment-naïve patients with ≥1% PD-L1 expression on tumor-infiltrating immune cells (HR, 0.60; 95% CI, 0.48-0.77; P <.0001).

Moreover, the 2-year overall survival (OS) rates were 54% and 37% among the PD-L1—positive populations in the immunotherapy arm and chemotherapy-alone arm, respectively. Although the study was not formally designed to assess OS in a statistical design in the PD-L1–positive subgroup, the trend toward improved survival is evident in the overall population.

“TNBC is a very aggressive cancer. For many years, the only treatment we had was standard chemotherapy,” said Chavez Mac Gregor. “We're starting to see other agents that we can now use day-to-day in our clinic.”

Some of these agents include the PARP inhibitors olaparib (Lynparza) and talazoparib (Talzenna), which received FDA approval for the treatment of patients with germline BRCA-mutated disease who have received prior chemotherapy.

Moreover, the ADCs sacituzumab govitecan and ladiratuzumab vedotin (SGN-LIV1A) have shown encouraging objective response rates at approximately 36%. Although sacituzumab govitecan is the furthest along in clinical development, supplementary documents regarding chemistry, manufacturing, and control matters are pending, in accordance with a complete response letter issued by the FDA regarding an initial biologics license application for the agent.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Breast Cancer, Chavez Mac Gregor, associate professor, Department of Health Services Research, Division of OVP, Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, discussed recent shifts in the treatment of patients with metastatic TNBC.

OncLive: What recent trials have had the biggest implications on clinical practice in TNBC?

Chavez Mac Gregor: What really has come to change practice is immunotherapy—specifically, the use of atezolizumab in the first-line setting in combination with nab-paclitaxel in patients with PD-L1 positivity in their immune cells. [In the IMpassion130] trial, these patients experienced an improvement in PFS. Although the OS data are exploratory, there seems to be an advantage there as well. These data finally bring the use of immunotherapy to the clinic in breast cancer.

However, there are still many unknowns. We still need to determine the best way to identify PD-L1 positivity and what the best combination with chemotherapy is. Different trials have used different assays and different cutoffs. We're starting to get our feet wet in the world of immunotherapy. There are several clinical trials evaluating immunotherapy in combination with other agents that are really exciting. While we're exploring that across breast cancer subtypes, there's a lot of interest [with this approach], specifically in TNBC.

Other drugs that have also become available recently, which are changing the way we think about these tumors, are PARP inhibitors. These agents are not specific to TNBC, but many patients with breast cancer who have BRCA1/2 mutations have TNBC. Now we have 2 FDA-approved PARP inhibitors, both of which were approved last year. Olaparib and talazoparib were approved based on the results of the OlympiAD and EMBRACA trials, respectively. Patients were randomized to receive the PARP inhibitor versus physician’s choice of chemotherapy, and in both cases, patients treated with the PARP inhibitor had better outcomes with less toxicities. It's bringing a new target. Now, there are trials combining PARP inhibitors with immunotherapy. It's a very exciting time. Just in the last year, we now have 3 new drugs to treat patients with.

For patients who express PD-L1 and have a BRCA mutation, what is the recommended frontline treatment?

That's a very interesting question. The reality is that we don't know. As of today, we don’t know which patients from the IMpassion130 trial were BRCA-positive and whether their response was different. We want to give patients options. The data from IMpassion130 are in the first-line setting. If we're going to use [atezolizumab] based on the clinical trial, patients need to receive it in the first-line setting.

In the OlympiAD and EMBRACA trials, patients could have been previously treated with chemotherapy. If patients have PD-L1—positive disease, it's appropriate for them to go on chemotherapy plus immunotherapy in the first-line setting and then have treatment with a PARP inhibitor. Another possibility is for them to enroll on clinical trials with immunotherapy and PARP inhibition. I don't think we know what the optimal sequence of these drugs are. Since the only immunotherapy approval we have in breast cancer is in the first-line setting, that's the setting that I will use it in practice.

Could you speak to the promise of ADCs in TNBC?

The other class of drugs that we're very excited about are ADCs. We are expecting a positive result from the FDA for sacituzumab govitecan. Some of these drugs have a very interesting delivery method. Ado-trastuzumab emtansine (T-DM1; Kadcyla) is FDA-approved in the HER2-positive world, and in TNBC we've seen great results with sacituzumab govitecan. That agent has a topoisomerase inhibitor and has shown activity in patients with TNBC with a good toxicity profile. We are optimistic that the FDA is going to review the data favorably. Hopefully, we'll have yet another option for our patients.

Is it too early to comment on ladiratuzumab vedotin?

Yes, but as a class these drugs are very interesting. This idea of using an antibody, having a stabilized linker and a cytotoxic molecule, and then being able to deliver it in a very efficient way is fascinating. In doing so, we can deliver highly potent cytotoxic drugs to very specific cells. That is going to change the way we give treatment.

What do you identify as being the biggest challenge in the field and what are the steps being taken to address it?

The biggest challenge is that metastatic breast cancer is still incurable. We have to improve patient survival. We have to be able to identify which tumors benefit from which treatment strategy as a way to provide a more intelligent sequence of therapies and avoid treatments that are not going to be effective. There is a lot of work that we can still do to identify patients who are going to experience more toxicity.

We’re learning how heterogenous breast cancer is. It's a challenge, but it also offers an opportunity to take advantage of this heterogeneity and develop a more diverse pipeline of drugs. Of course, we have to be smarter, more creative, and more collaborative in our clinical trial designs. If we start cutting the pie into very thin slices, we're not going to be able to have clinical trials with thousands of patients at a single institution. That will bring us, as investigators, together to work towards a common goal.

At The University of Texas MD Anderson Cancer Center, we have worked with PARP inhibitors a lot. We’re now seeing their use in clinical trials in early-stage breast cancer. We're conducting a clinical trial under the leadership of Jennifer Keating Litton, MD, [which is looking at] talazoparib in the neoadjuvant setting. The initial pilot study was very positive. It may be that in patients who are very selected, we may get good initial responses without chemotherapy. This shows you how the field is moving and how all the advances in the metastatic setting are being explored in the early-stage setting. Hopefully, all the things that we're learning in the metastatic setting can be explored in early stages to cure more patients.

Schmid P, Adams S, Rugo HS, et al. IMpassion130: results from a global, randomised, double-blind, phase III study of atezolizumab (atezo) + nab-paclitaxel (nab-P) vs placebo + nab-P in treatment-naive, locally advanced or metastatic triple-negative breast cancer (mTNBC). Ann Oncol. 2018;29(suppl 8; abstr LBA1_PR). doi: 10.1093/annonc/mdy424.008.