TNBC Pipeline Bursting With Effective Agents

Meghna Trivedi, MD, associate professor of oncology and urology at Johns Hopkins Medicine

Meghna Trivedi, MD

Three classes of drugs have demonstrated promising outcomes in patients with metastatic triple-negative breast cancer (TNBC), and phase III data and longer follow-up are anticipated to determine how these agents can be best utilized in this space, explained Meghna Trivedi, MD.

First, 2 PARP inhibitors have been added to the TNBC armamentarium for patients with BRCA-mutant tumors. Olaparib (Lynparza) was approved by the FDA in January 2018 for the treatment of patients with germline BRCA-positive, HER2-negative metastatic breast cancer who have previously received chemotherapy. In October 2018, the agency approved talazoparib (Talzenna) for patients with deleterious or suspected deleterious germline BRCA-mutated, HER2-negative locally advanced or metastatic breast cancer.

Immunotherapy has also shown clinical activity in patients with PD-L1—positive TNBC. Results of the phase III IMpassion130 trial showed that the addition of atezolizumab (Tecentriq) to nab-paclitaxel (Abraxane) reduced the risk of disease progression or death by 38% versus nab-paclitaxel alone in patients with unresectable locally advanced or metastatic PD-L1–positive TNBC.¹ Based on these data, the FDA granted a priority review designation to a supplemental biologics license application for the frontline atezolizumab regimen in this patient population. Under the Prescription Drug User Fee Act, the FDA is scheduled to make its decision on the approval by March 12, 2019.

Moreover, antibody-drug conjugates have been investigated in this space. Sacituzumab govitecan was initially granted priority review designation status by the FDA, based on phase II data showing that the agent elicited a 34% objective response rate in patients with heavily pretreated mTNBC.² However, in January 2019, the FDA issued a complete response letter to Immunomedics, the developer of the antibody-drug conjugate, regarding its biologics license application as a treatment for patients with metastatic TNBC who have received ≥2 prior therapies, citing chemistry, manufacturing, and control matters.

Phase I data for ladiratuzumab vedotin, a second antibody-drug conjugate, demonstrated 49%, 24%, and 10% estimated 3-, 6-, and 9-month progression-free survival (PFS) rates, respectively, in patients with heavily pretreated metastatic TNBC.³

OncLive: How would you characterize a TNBC prognosis?

There have been recent intriguing data in TNBC. Could you highlight some of these promising findings?

In an interview during the 2018 OncLive^® State of the Science Summit on Advanced Breast Cancer, Trivedi, an associate professor of medicine at Columbia University Medical Center, highlighted these 3 classes of agents that are showing promise in patients with metastatic TNBC.Trivedi: Metastatic TNBC is a very aggressive cancer and generally [is associated with] poor outcomes. The standard of care is cytotoxic chemotherapy and the goal is to try and develop novel therapies that will lead to better outcomes, as well as less toxicity.In my talk [at this State of the Science Summit™] I highlighted 3 categories: the use of PARP inhibitors in BRCA1/2 germline mutation carriers with locally advanced or metastatic breast cancer, immunotherapy in TNBC, and antibody-drug conjugates—mainly focusing on 2 specific ones. The evidence for PARP inhibitors in BRCA-mutation carriers has come out through 2 trials: the OlympiAD trial, which looked at olaparib, and the EMBRACA trial, which looked at talazoparib. Both of these trials have shown improvements in PFS with PARP inhibitors compared with standard cytotoxic chemotherapy. This is a really promising and exciting new therapy for BRCA-mutation carriers.

Then, immunotherapy has shown lots of successes in many other different tumor types, such as melanoma and urologic cancers. Therefore, we have been waiting in breast cancer for there to be some exciting data. Most recently, the results of the IMpassion130 trial were presented and looked at atezolizumab plus nab-paclitaxel in metastatic TNBC. Therefore, these are very exciting data that showed that there is an improvement in PFS with this combination of nab-paclitaxel and atezolizumab compared with nab-paclitaxel by itself.

The data were particularly exciting in patients who have PD-L1—positive tumors, so this will be an exciting new therapy to offer our patients with metastatic TNBC who are PD-L1 positive.

Finally, with respect to antibody-drug conjugates, there are 2 drugs I talked about.

One is sacituzumab govitecan, which is an antibody-drug conjugate with SN-38 linked to an antibody for TROP-2. This drug has been shown to be effective in phase II studies in TNBC and is currently [being tested in] a larger phase III randomized trial.

Regarding the IMpassion130 trial, what hope are the data bringing to this difficult-to-treat subtype?

Reflecting on these recent successes, what unmet needs still need to be addressed?

Ladiratuzumab vedotin is an antibody-drug conjugate, with an antibody directed towards LIV-1 and the drug conjugate is MMAE; these are connected by a linker. This [agent] is in earlier-phase investigations; phase I trials showed promising results in TNBC. Additional trials are underway, looking at it in various settings [as a single agent], as well as in combination.The hope with immunotherapy in TNBC is that we can again improve the outcomes, improve PFS, OS, as well as minimize some of the toxicity that comes with the treatments that we give. The data from the IMpassion130 trial [have shown that], although it is still too early for OS benefit, there was an impressive numerical increase in OS of almost 10 months in the PD-L1—positive population during the interim analysis. While it is too early to say for sure, these are very intriguing and exciting data for the TNBC population.Again, because of the aggressive nature and the poor prognosis associated with TNBC, we still have a lot of work ahead of us, and I’m excited. Hopefully, for some of these novel therapies, the results of some of these larger phase III studies and final results for OS and PFS will help us figure out how we can best utilize these therapies in this patient population. If these drugs can demonstrate benefit in the metastatic setting, how can we use them earlier on in the treatment course for these patients with very aggressive tumors?

References

1. Schmid P, Adams S, Rugo HS, et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379(22):2108-2121. doi: 10.1056/NEJMoa1809615.
2. Bardia A, Vahdat LT, Diamond J, et al. Sacituzumab govitecan (IMMU-132), an anti-Trop-2-SN-38 antibody-drug conjugate, as ≥3rd-line therapeutic option for patients with relapsed/refractory metastatic triple-negative breast cancer (mTNBC): efficacy results. In: Proceedings from the 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX, December 5-9, 2017. Presentation GS1-07.
3. Modi S, Pusztai L, Forero A, et al. Phase 1 study of the antibody-drug conjugate ladiratuzumab vedotin (SGN-LIV1A) in patients with heavily pretreated triple-negative metastatic breast cancer. In: Proceedings from the 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract PD3-14.