Optimizing Checkpoint Inhibitor Use Across Early-Stage and Metastatic Triple-Negative Breast Cancer

Clinical Summary: 

• Tiffany Traina, MD, examines the evolving role of immune checkpoint inhibitors in patients with triple-negative breast cancer, including established indications in early-stage and metastatic disease, biomarker patient selection, and opportunities for treatment de-escalation. 
• Pembrolizumab-based neoadjuvant and adjuvant therapy has demonstrated clinical benefit in patients with stage II/III disease, while first-line immunotherapy in metastatic disease is supported for patients with PD-L1-positive tumors meeting established eligibility criteria. 
• These findings emphasize the importance of individualized treatment selection based on biomarker status, avoiding overtreatment in lower-risk populations, and investigating novel combinations to expand benefit beyond currently eligible patients. 

Tiffany Traina, MD, Memorial Sloan Kettering Cancer Center, New York, New York, discusses the role of immune checkpoint inhibitors in patients with early-stage and metastatic triple-negative breast cancer (TNBC), examining which patients benefit from immunotherapy and where treatment may be unnecessary following her participation in a debate on checkpoint inhibitor use. 

Dr Traina reviews evidence from KEYNOTE-522 supporting neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab in stage II/III TNBC, while highlighting the lack of established benefit for patients with stage I disease or adjuvant-only initiation following upfront surgery. She also discusses PD-L1-guided treatment selection, opportunities for treatment de-escalation, and emerging antibody-drug conjugates being investigated to expand immunotherapy benefit. 

Transcript: 

I'm Dr Tiffany Traina, a breast medical oncologist at Memorial Sloan Kettering Cancer Center in New York. I'm section head of our triple-negative breast cancer clinical research program and vice chair in the department of medicine. 

I had the pleasure to participate in today's debate about whether checkpoint inhibitors should be given to all patients with triple-negative breast cancer– it was an interesting and friendly conversation with my counterpart. 

I think it was clear that there were several reasons why checkpoint inhibitors have great benefit in the treatment of patients with triple-negative breast cancer, but not for all patients as of today. We have compelling evidence for early-stage triple-negative breast cancer. Those patients with stage II/III disease receiving pembrolizumab as part of a chemotherapy backbone in the neoadjuvant setting had higher pathologic complete response rates as well as higher event-free survival and overall survival. That KEYNOTE-522 regimen has really been the mainstay of treatment for stage II/III triple-negative breast cancer as part of an entire package of neoadjuvant therapy followed by adjuvant therapy. 

We made a clear distinction that as of today, we do not have data for incorporating a checkpoint inhibitor purely in the adjuvant setting in those patients who did not see pre-op checkpoint inhibitor. That is supported by data from Impassion130 as well as A-BRAVE. 

There are several ongoing trials, cooperative group trials, trying to really understand how to best manage patients who had a pathologic complete response after seeing neoadjuvant checkpoint inhibitor and chemotherapy. Also, some ongoing studies trying to explore the benefit of checkpoint inhibitor as monotherapy versus observation in the adjuvant setting or residual disease setting.

We then went on to talk about how these data support our existing NCCN guidelines. We talked about the excellent prognosis that patients with early-stage, stage I, triple-negative breast cancer have. For example, large SEER database analysis showed patients with just microinvasive disease, or T1A or T1B triple-negative breast cancer that's node negative, have quite excellent prognosis, even without chemotherapy. 

In those patients who had T1C node-negative triple-negative breast cancer, the absolute benefit from chemotherapy was as small as 3%. When we take that into consideration, the incremental add of immunotherapy is not yet supported by the data and hopefully we'll find subsets of patients that have such an excellent prognosis that perhaps they can deescalate, avoid chemotherapy, and avoid checkpoint inhibitor.

My counterpart, Dr Gatti, made a great point about how biomarkers are so important in our patient selection, but we do need to do a better job. There is tremendous heterogeneity in triple-negative breast cancer. Right now, PD-L1 positivity is our selection criteria for use of checkpoint inhibitors in the metastatic setting, but that only applies to about 30 to 40% of all patients who have metastatic triple-negative breast cancer. 

We would love to see that we can find ways to turn some of these cold tumors hot. This is an area of ongoing research where antibody drug conjugates in combination with checkpoint inhibitors are being explored, even in those tumors that are PD-L1 negative. 

There is a lot of exciting emerging data to explore where else we might find benefit from checkpoint inhibitors. But as of today, it is quite clear that in the metastatic setting, only those patients who have a PD-L1 positive tumor, defined as a CPS of greater than 10, will benefit from a checkpoint inhibitor in the first line setting. In the early-stage triple-negative breast cancer setting, those patients with stage II/III triple-negative breast cancer should receive a checkpoint inhibitor with chemotherapy in the pre-op setting and then continue that on in the adjuvant setting. We really do not have data to support its use in stage I triple-negative breast cancer or in those patients purely receiving adjuvant therapy having undergone upfront surgery.