New Research May Help Fill Unmet Treatment Need in TNBC

Hope Rugo, MD

Hope Rugo, MD

The revolution that has transformed the treatment of many breast cancers has largely bypassed patients with triple-negative tumors. The standard of care—combination chemotherapy with sequential anthracycline/ cyclophosphamide and a taxane—has stood for many years.

Efforts to find effective new treatments have a long history of disappointment, but new research, along with a significant number of clinical trials, may change that, Hope S. Rugo, MD, professor of medicine and director of the Breast Oncology Clinical Trials Program at the UCSF Helen Diller Family Comprehensive Cancer Center, said in her presentation at the 2017 Miami Breast Cancer Conference.

“There’s a huge amount of focus on triple-negative disease now, both because of the unmet need and because of the perceived progress,” Rugo said. “Immunotherapies and targeted antibody-drug conjugates have both produced promising results in early-stage trials. If larger trials succeed, effective new treatments could be available in the next few years. Looking a little further ahead, the rapid growth in our understanding of tumor biology may allow us to choose treatments based upon each patient’s subtype of triple-negative cancer.”

Several groups have been working to categorize different triple-negative breast cancers (TNBC) into clinically meaningful subtypes. An ongoing project at Vanderbilt University, for example, already allows users to upload normalized genetic data from tested tumors. Vanderbilt’s software then analyzes the data and puts the tumor into one of 6 groups: basal-like 1, basal-like 2, immunomodulatory, mesenchymal, mesenchymal stem—like, or luminal androgen receptor (AR).

Efforts to subtype triple-negative tumors have yet to validate different treatment strategies for the subtypes. A patient with an immunomodulatory tumor gets the same chemotherapy combination as a patient with a mesenchymal tumor.

Rugo outlined several ongoing research efforts that may eventually change treatment approaches. Standard chemotherapy for triple-negative tumors is toxic but highly effective; the goal for ongoing and future research is to understand who needs less and who needs more treatment to achieve optimal outcomes. One area of interest is triple-negative tumors that express the AR. Rugo discussed targeting AR in a separate presentation during the conference, as well as efforts to characterize the phenotype of this subtype of triple-negative disease.

Drugs targeting the AR, such as enzalutamide (Xtandi), have shown promise in early-phase testing. Some 42% of women with AR-positive, triple-negative tumors experienced clinical benefit after 16 weeks of treatment, so investigators have launched a phase III trial in combination with chemotherapy for advanced AR-expressed triple-negative disease.

Another experimental treatment strategy that could be beneficial is the use of PARP inhibitors in the treatment of the more than three-quarters of triple-negative tumors withBRCAmutations.

Normally functioningBRCArepairs double-strand DNA breaks, while PARP repairs single-strand breaks. The idea of inhibiting PARP in tumors withBRCAmutations is to allow single breaks to become double breaks, which cannot be repaired because of theBRCAmutation, which leads to the death of tumor cells. PARP inhibitors are not yet approved in the treatment of any breast cancers, but there are currently at least 9 trials that are using such medications (as part of a wide range of combinations) against triple-negative tumors. Results to date have been mixed, as Rugo illustrated, but the positive results released thus far including a recent press release reporting positive results from the OlympiAD trial (comparing the PARP inhibitor olaparib to treatment of physicians’ choice for metastatic breast cancer) suggest that PARP inhibitors may 1 day play a significant role in the treatment of many triple-negative tumors.

Based on encouraging preclinical and early-phase data, the combination of the PARP inhibitor talazoparib and irinotecan is being studied as neoadjuvant therapy in the phase II I-SPY2 trial, which previously evaluated the combination of veliparib and carboplatin. Many other studies are ongoing, although the majority have focused on patients with germline mutations inBRCA1/2.

As with nearly any talk about experimental treatments for any tumor type in the past several years, Rugo also discussed immunotherapy, mostly pembrolizumab (Keytruda) and atezolizumab (Tecentriq). There are perhaps a dozen completed or ongoing trials, and at least a dozen more planned trials, of pembrolizumab or atezolizumab, as well as other checkpoint inhibitors, either as monotherapy or in combination with 1 or more additional medications.

“The results patients with triple-negative disease have achieved so far with medications that inhibit the programmed-death-receptor checkpoint have been decidedly mixed,” Rugo said. “Response rates have been low, even by the standards of immunotherapy. No more than 19% of patients have responded in any of the trials to date. However, in patients who have responded, the responses have been generally durable. The major goal that a number of research teams have now is finding ways to increase response rates by using other agents (including chemotherapy) to increase the antitumor immune response as the patients are receiving checkpoint inhibitors.”

Another relatively new treatment type that may prove effective against triple-negative tumors involves antibody-drug conjugates (ADCs) that combine cytotoxins with antibodies that bind to proteins on tumor surfaces. Several of these medications have been used in early-stage trials on patients with triple-negative disease, with encouraging results.

In one of those studies, 69 patients with metastatic triple-negative breast cancer received 10 mg/kg of sacituzumab govitecan (IMMU-132) on days 1 and 8 of ongoing 21-day cycles. Among those relapsed or refractory study patients, who had received a median of 5 prior treatments, there were 2 complete responses (3%) and 19 partial responses (28%), while stable disease was observed in 31 other patients (45%). Median response duration was 8.9 months (but 6 patients were still responding at the data cutoff).

Sacituzumab govitecan, which targets a growth-driving calcium signal transducer called Trop-2, has been awarded breakthrough therapy status by the FDA. This agent is 1 of several ADCs to produce encouraging results in triple-negative patients. A phase III trial with sacituzumab govitecan is planned, and another phase III trial with the ADC glembatumumab vidotin is ongoing.

“In addition to the newer agents that are being tested, there is also work being done on optimizing the timing and dosing of the currently available treatments,” Rugo said. “Which patients can get less therapy? Will the neoadjuvant setting allow us to tailor regimen intensity based on response?

“Unfortunately, we don’t have the answers yet to further improve real-world treatment outcomes,” she added. The main thing that clinical practitioners can do right now is to take advantage of ongoing clinical trials and encourage patient participation. That may change relatively soon, though. Patients with relapsed or refractory triple-negative tumors currently have such poor prognoses that it takes relatively little time to evaluate the performance of new treatment options. A number of experimental treatments being studied in stage III trials could possibly be available in 2 to 3 years, and even those that are just completing early-stage trials could appear a year or 2 later. There is reason for hope,” Rugo said.