麻豆传媒

Immune checkpoint inhibitors (ICIs) have demonstrated efficacy in combination with chemotherapy in the treatment of both early- and late-stage triple-negative breast cancer (TNBC).

A recent in JCO Oncology Practice examined the role of immunotherapy in breast cancer. In the following interview, Hope S. Rugo, MD, director of Breast Oncology and Clinical Trials Education and medical director of Cancer Infusion Services at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, outlines the robust data that show ICI successes for TNBC.

Why do ICIs work better in TNBC than other breast cancers?

Rugo: Early preclinical data suggested that TNBCs may be more immune-sensitive. In particular, higher levels of tumor-infiltrating lymphocytes (TILs) were seen in breast tissue of patients with TNBC and HER2+ early-stage breast cancer, and appear to be . This is in contrast to HR+ tumors which have lower levels of TILs. Tumors with high TILs were associated with improved 5-year DFS [disease-free survival] and OS [overall survival] as well as increased rates of pathologic complete response [pCR]. This laid the groundwork for larger clinical trials that ultimately showed a survival benefit with the use of ICIs in TNBC.

ICIs may work very well in subsets of HR+/HER2 negative tumors with more highly proliferative disease, and those with profiles consistent with immune sensitivity, and efficacy in HER2+ disease has been demonstrated. But current trials evaluating ICIs in combination with HER2-targeted therapy are competing against the rapid expansion of the highly effective antibody-drug conjugate trastuzumab deruxtecan.

What is the importance of the KEYNOTE-355 study in metastatic TNBC?

Rugo: KN-355 is a pivotal phase III trial that established a progression-free survival (PFS) and OS benefit with the addition of pembrolizumab to standard chemotherapy in the first-line setting for patients with programmed cell death-ligand 1 (PD-L1)-positive metastatic TNBC. PD-L1 positivity is defined for this purpose as a combined positive score [CPS] of 10 or higher. The chemotherapy partners used in the study were gemcitabine/carboplatin, paclitaxel or nab-paclitaxel.

PFS was 9.7 vs 5.6 months in the placebo group, and OS was 23 vs 16.1 months. Based on these results, adding pembrolizumab to chemotherapy for patients with CPS score >10 in the first-line setting is now standard of care for metastatic TNBC.

The OS for patients diagnosed with metastatic TNBC is unfortunately short, at less than 20 months in most recent studies. Being able to improve OS in these patients is of critical importance, and finding an effective targeted agent has been challenging. For patients with PD-L1-positive disease, this combination therapy offers improved disease response, more durable responses, and improvements in survival.

Another important finding is that a subset of patients will have long-term disease control, or will respond to immunotherapy combinations if pembrolizumab is stopped at 2 years, as it was in KN-355, and then restarted with chemotherapy on progression.

Of course, this benefit needs to be balanced against immune toxicity, but we are much better at both monitoring and treating these autoimmune toxicities now that we use checkpoint inhibitors in the early-stage setting as well.

What is the importance of the KEYNOTE-522 trial in early-stage TNBC?

Rugo: KN-522 is a pivotal phase III trial that demonstrated that the addition of pembrolizumab to a taxane/carboplatin followed by anthracycline/cyclophosphamide neoadjuvant chemotherapy regimen improved by pCR as well as event-free survival (EFS). Pembrolizumab was given for 1 year regardless of response and was compared to placebo.

Patients eligible for this study included patients with stage II or III TNBC. Pembrolizumab improved pCR (64.8% vs 51.2%) and EFS at median follow-up of 39 months (84.5% vs 76.8%). Based on the results of KN-522, adding pembrolizumab to neoadjuvant chemotherapy and continuing pembrolizumab for a total of 1 year of treatment for stage II/III TNBC is now the approved standard of care in the United States and is rapidly achieving approval in other countries.

This is important because TNBC is more common in younger compared with older women, and we have only had chemotherapy to treat this disease. For patients whose tumors do not achieve pCR with standard neoadjuvant chemotherapy, the risk of distant recurrence and subsequent death from disease is high, and recurrence tends to occur early, in the first 3 to 5 years.

Capecitabine after surgery in those with residual disease appears to improve outcomes, but this impact appears to be modest in most aggressive cancers. The addition of pembrolizumab not only improved pCR rates for larger tumors that have lower pCR rates with standard chemotherapy, but it also improved EFS in patients whose cancers did not achieve pCR, an intriguing and encouraging finding. Treatment that improves outcome in patients with early-stage TNBC is a huge step forward.

What novel immunotherapeutic agents are currently under investigation?

Rugo: Novel checkpoints under investigation include LAG3 [lymphocyte-activation gene 3]. Other agents under investigation include cancer vaccines, oncolytic viruses, and adaptive cell therapies, including CAR-T and bispecific T-cell engagers.

What is your main message for practicing oncologists?

Rugo: The addition of pembrolizumab to chemotherapy is associated with survival benefit for patients with stage II/III TNBC and for patients with metastatic TNBC that is CPS-positive at a score of >10 in the first-line setting, and is now the FDA-approved standard of care in the United States.

It is critical that providers be aware of and understand how to monitor for and treat immune-related toxicities, which can be life-threatening. The most commonly reported immune-related toxicities are colitis, dermatitis, and endocrinopathies -- in particular, thyroiditis and hypophysitis/adrenalitis. Depending on the type and severity of the toxicity, systemic steroids may be required. In some cases, further immunomodulating treatments are needed to control severe immune toxicities.

Read the review here.