David W. Miles, MB BS, BSc, MD, FRCP
Although chemotherapy remains the mainstay of treatment for patients with triple-negative breast cancer (TNBC), promising developments are unfolding on several fronts, including new ways of using existing therapies and the exploration of immunotherapy, novel antibodies, and agents targeting the PI3K/mTOR/AKT pathway. A paucity of biomarkers to predict for responders remains one of the most significant challenges impeding progress, according to David W. Miles, MB BS, BSc, MD, FRCP.
In a presentation during the 1st Annual Paris Breast Cancer Conference hosted by the Physicians Education Resource®
, LLC, Miles, a consultant medical oncologist at West Hertfordshire Hospitals in England, provided his perspective on potential new treatment options for patients with TNBC.
In everyday practice, treatment for patients with TNBC typically includes chemotherapy. “[For] those of us working out in the peripheral hospitals and seeing lots of patients, we are still stuck with chemotherapy,” said Miles. “We say to our patients, ‘I’m sorry the endocrine treatment isn’t going to work, I’m sorry HER2 isn’t a target, so we’re really going to hit as hard as we can with chemotherapy,’ even for those in relatively low-risk situations in the adjuvant setting.”
In the phase II tnAcity study, 3 combinations of these drugs were tested in the frontline setting for patients with metastatic TNBC. The combination of nab-paclitaxel and carboplatin showed the highest progression-free survival (PFS) rate at 7.4 months, compared with 5.4 months with nab-paclitaxel and gemcitabine and gemcitabine plus carboplatin at 6.0 months (Table).1
Overall survival (OS) was also increased with the nab-paclitaxel/carboplatin combination.
Table. Survival Rates of Combinations in the tnAcity Trial1
Miles noted that the trial was not progressing to phase III due to the evolving treatment landscape, but he suggested considering a platinum-containing regimen for these patients.
Miles also argued that there was a role for bevacizumab (Avastin) in TNBC, especially for patients who have received a taxane, based on prior subgroup analyses. In the phase III MERiDiAN trial, patients with HER2-negative metastatic breast cancer, including those with TNBC, received paclitaxel with or without added bevacizumab. In the overall population, the median PFS was 11.0 months with the combination versus 8.8 months with paclitaxel and placebo (hazard ratio [HR], 0.68; 95% CI, 0.51-0.91; P = .0007).2
In searching for a biomarker for response for this regimen, Miles et al tested patients for their plasma VEGF-A levels in the study. Yet the results indicated that baseline plasma VEGF-A levels are not predictive of a clinically relevant difference in treatment effect with the addition of bevacizumab. “Angiogenesis is a very complex behavior, [so] it may be naïve to think that 1 biomarker is going to do it for us,” Miles said.
Immunotherapy and Combinations
“I would have to describe immunotherapy as the dominant strategy at the moment,” commented Miles, as several PD-1/PD-L1 checkpoint inhibitors are currently being tested for patients with TNBC.
In a study of atezolizumab (Tecentriq) in the frontline or in later lines of therapy, patients with TNBC showed an objective response rate (ORR) of 26% (95% CI, 9%-51%) with the PD-L1 inhibitor in the frontline; in the second line and beyond, the ORR was 7%.3 He also noted that with traditional measurements in clinical trials, such as PFS, immunotherapy agents may not demonstrate significant benefit. In this trial of atezolizumab, for example, the median PFS was 1.4 months by RECIST v1.1 criteria and 1.9 months by immune-related response criteria. The benefit seen, however, was much greater when looking at duration of response, which was 21.1 months by both sets of criteria.
Additionally, the study also showed a higher ORR among patients with positive PD-L1 expression compared those with negative expression, yet Miles noted that he found PD-L1 expression to be a transient biomarker of utility. Other biomarkers— tumor-infiltrating lymphocytes, CD8-positive T cells, and PD-L1 expression on immune cells—may be associated with better outcomes, but they are not yet predictive. Instead, he stressed, they may simply identify patients with a better prognosis.