Stand-Alone Adjuvant Immunotherapy for Early TNBC?

The role of adjuvant immunotherapy in triple-negative breast cancer (TNBC) remains uncertain.
Standard therapy for TNBC includes neoadjuvant pembrolizumab with chemotherapy followed by pembrolizumab, with or without chemotherapy, after surgery. 
One lingering uncertainty has been whether continuing immunotherapy after surgery provides any survival benefit (see previous story). 
But there’s another question oncologists continue to wrestle with: How to treat patients with early TNBC who don’t get immunotherapy before surgery? 
Certain women may proceed directly to surgery and skip neoadjuvant immunotherapy because they have smaller tumors with clinically negative lymph nodes. In other instances, patients might receive neoadjuvant chemotherapy without immunotherapy if oncologists are concerned about patients tolerating immunotherapy before surgery.
The issue raised by a recent trial, dubbed A-BRAVE, is what to do if patients who don’t get neoadjuvant immunotherapy have more extensive disease than expected and are left with residual disease after surgery. For these patients, should immunotherapy be added to postoperative chemotherapy?
A-BRAVE, presented at this year’s American Society of Clinical Oncology annual meeting, found a benefit to postoperative immunotherapy in this patient population. The study included 477 women with early TNBC who had not received immunotherapy prior to surgery but had residual disease after surgery. These patients were randomized to the PD-L1 blocker avelumab or observation after receiving adjuvant chemotherapy. 
Those who received adjuvant immunotherapy, instead of adjuvant chemotherapy alone, demonstrated significantly better 3-year overall survival — 85.2% vs 78.2% — with a trend towards improved disease-free survival. 
However, not all data studies to a positive outcome. In fact, another trial, ALEXANDRA/IMpassion030, published earlier this year found the opposite. 
Among 2199 women with stage II or III TNBC who received primary surgery, those randomized to the PD-L1 blocker atezolizumab plus chemotherapy, instead of chemotherapy and observation, demonstrated a trend towards worse disease-free and overall survival at a median of 32 months. The trial was stopped early for futility. 
The reasons for the discrepancies are unclear, and oncologists have been left wondering what to make of them. “It’s a really controversial topic currently,” Lajos Pusztai, MD, a breast cancer specialist at Yale University in New Haven, Connecticut, told Medscape Medical News. 
Pusztai noted that, although similar, the two trials had important differences. For instance, in addition to being a smaller study, all patients in A-BRAVE had residual disease and an overall worse prognosis than those in IMpassion. 
And while patients in A-BRAVE received neoadjuvant chemotherapy, patients in IMpassion went straight to surgery. 
One possible explanation for the different trial outcomes is that neoadjuvant treatment created a favorable immunogenic environment for subsequent immunotherapy. It’s also possible that avelumab was simply a more effective drug than atezolizumab. 
But there’s no way to know for sure what’s behind the different outcomes, Kathy Miller, MD, a breast cancer specialist at Indiana University, Indianapolis, told Medscape Medical News.
How best to treat immunotherapy-naïve patients with early TNBC and residual disease post-surgery is a “question that comes up clinically,” and “we don’t have good data to guide us,” she said. 
Definitive answers may soon come from SWOG-S1418, an ongoing trial led by Pusztai. The trial randomized more than 1000 patients with TNBC who had small residual tumors or positive lymph nodes after neoadjuvant chemotherapy and surgery to a year of pembrolizumab or observation on a background of adjuvant chemotherapy and/or radiation. 
The study is likely “not so amazingly positive,” otherwise topline results would have been reported already, but it’s also not negative because the trial wasn’t halted for futility, said Pusztai, who doesn’t have access to the data.
In melanoma, research has shown that immunotherapy is effective both as adjuvant and neoadjuvant treatment, but it’s more effective if given in the neoadjuvant setting. “Whether this is going to hold up for breast cancer or not is uncertain, but it will become clearer once the SWOG trial reports outcomes,” Pusztai said. 
In keeping with current standards, Pusztai and Miller currently don’t prescribe adjuvant immunotherapy for residual TNBC if patients haven’t had immunotherapy before surgery. In addition to a lack of proven benefit, the oncologists noted the risk for serious long-term side effects. 
Even if people believe in A-BRAVE, Pusztai said, avelumab isn’t approved for the indication and insurance isn’t likely to cover it so he doesn’t expect avelumab to be used in any substantial way for the indication based solely on A-BRAVE. That could change, however, if a group like the National Comprehensive Cancer Network endorses the trial results, he said.
Pusztai disclosed numerous industry ties, including being a consultant for and having research funding form Pfizer, maker of avelumab, and Roche, maker of atezolizumab. Miller disclosed industry as well, including being a consultant for Roche and having research funding from Pfizer. She is also an editorial advisor for Medscape Oncology. 
M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape Medical News. Alex is also an MIT Knight Science Journalism fellow. Email: [email protected].
 
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