The management of early-stage triple-negative breast cancer has been evolving at a fast pace, thanks largely to the discovery that immune checkpoint blockade can be effective in this subtype. At the 2023 Miami Breast Cancer Conference, Priyanka Sharma, MD, Professor of Medicine, University of Kansas Medical Center, took a sweeping look at the data that support current management, along with clinical nuances in practice and unanswered questions.¹

How Beneficial Are Platinum Agents?

“Platinum agents have been of interest in triple-negative breast cancer for quite some time and have been studied in the context of neoadjuvant trials. The majority of the studies have added carboplatin to an anthracycline-containing regimen, and all have demonstrated improvement in pathologic complete response rates, but this has come at the expense of increasing toxicity,” she said.

Priyanka Sharma, MD

Dr. Sharma reviewed several of the key studies of platinum agents in the neoadjuvant setting, starting with the large BrighTNess trial.² The three-arm study with an anthracycline, cyclophosphamide, and a taxane (AC→T) backbone evaluated the addition of carboplatin as well as the addition of carboplatin plus low-dose veliparib. Carboplatin increased the pathologic complete response rate over AC→T alone, but veliparib did not. Similarly, the addition of carboplatin, but not veliparib, improved event-free survival—by an absolute 11%.

In a phase III study from Tata Memorial Hospital in India, the addition of a platinum to the neoadjuvant AC→T backbone proved beneficial.³ Of note, compared with other trials, this study had higher proportions of patients younger than age 50 and with a high disease burden. For both event-free and overall survival, the majority of carboplatin’s benefit was in patients aged 50 and younger. In this age group, the addition of carboplatin led to a 12.5% absolute increase in event-free survival (hazard ratio [HR] = 0.642; P = .004) and an 11.2% increase in overall survival (HR = 0.611; P = .003).

“The reasons for carboplatin’s preferential activity in younger vs older patients is not clear. Perhaps treatment compliance and treatment completion rates differed. Perhaps the biology is different for younger vs older patients—older patients may be more likely to have a nonbasal phenotype and, hence, less benefit from carboplatin. We’ll see if the findings hold true in other platinum studies,” Dr. Sharma commented.

An anthracycline-free regimen, on the other hand, was the backbone used in the phase II NeoSTOP study, which Dr. Sharma led.⁴ Patients received eight cycles of a four-drug regimen—carboplatin/paclitaxel followed by doxorubicin/cyclophosphamide (CbP→AC)—or six cycles of a two-drug regimen of carboplatin/docetaxel (CbD). Pathologic complete response rates were similar, 54% per arm, and the rates of residual cancer burden 0+1 were also similar at 67%. The study was not powered to look at long-term outcomes, but event-free and overall survival appeared comparable. The two-drug CbD regimen was associated with a more favorable toxicity profile and lower treatment-related costs, she reported.

Numerous investigations over the years have sought biomarkers of response to chemotherapy. Some factors have indicated general chemosensitivity—including tumor-infiltrating lymphocytes, homologous recombination deficiency, immune signatures, proliferation signatures, and even germline BRCA status. However, to date, none has helped in selecting or excluding patients for treatment, she said.

Immunotherapy for Triple-Negative Disease

Data from four key trials support the use of immune checkpoint blockade in early-stage triple-negative breast cancer: KEYNOTE-522, GeparNuevo, IMpassion031, and NeoTRIPaPDL1. All reported numerical or statistically significant improvements in pathologic complete response rates. Event-free survival outcomes have been reported for KEYNOTE-522 and GeparNuevo but are pending for the other trials.

The results of KEYNOTE-522⁵ led to the 2021 approval by the U.S. Food and Drug Administration (FDA) for pembrolizumab in combination with chemotherapy as neoadjuvant therapy, continuing as adjuvant therapy in high-risk cases of triple-negative breast cancer. Pembrolizumab was given with paclitaxel and carboplatin, then with doxorubicin/epirubicin and cyclophosphamide. Patients received 1 year of pembrolizumab, regardless of residual disease status. The absolute improvement in pathologic complete response rate was 7.5% at the time of pembrolizumab’s approval,⁶ but it was larger (14%) in the original analysis.⁵ Event-free survival at 3 years was improved with pembrolizumab by 7.7% (HR = 0.63; P = .00031).

GeparNuevo was a smaller phase II trial that evaluated the addition of durvalumab to taxane/anthracycline-containing chemotherapy.⁷ The 9.2% numerical improvement in pathologic complete response rate was not statistically significant (P = .287); however, the secondary endpoint of invasive disease–free survival did demonstrate a significant 8.4% absolute improvement with durvalumab (HR = 0.48; P = .0398). Patients received all immunotherapy preoperatively and did not receive adjuvant durvalumab.

Although KEYNOTE-522 and GeparNuevo used anthracycline-based chemotherapy as the backbone for immunotherapy, the NeoPACT trial, presented by Dr. Sharma at the 2022 ASCO Annual Meeting,⁸ evaluated the non–anthracycline-containing regimen of carboplatin/docetaxel plus pembrolizumab. An encouraging pathologic complete response rate of 58% was reported in this single-arm study, and rates exceeded 75% for patients with immune-enriched tumors.

Based on these results, SWOG 2212 (SCARLET) will compare the KEYNOTE-522 regimen with the NeoPACT regimen with event-free survival as the primary endpoint. This important study is joined by several others with pending outcomes in the neoadjuvant and adjuvant settings, including:

• Adjuvant pembrolizumab for patients with residual disease: SWOG S1418/NRG BR006 (n = 1,000) 
• Neoadjuvant plus adjuvant atezolizumab: NSABP B59/GeparDouze (n = 1,520), IMpassion031 (n = 333)
• Adjuvant atezolizumab: IMpassion030 (n = 2,300)
• Neoadjuvant atezolizumab: NeoTRIPaPDL (n = 272), 
• Adjuvant avelumab: A-Brave (n = 335).

“We await their results, as they will frame the future treatment algorithm for patients with early-stage triple-negative breast cancer,” Dr. Sharma commented.

Predicting Benefit to Avoid Unnecessary Toxicity

“The addition of immunotherapy to chemotherapy definitely improves outcomes for patients with early-stage triple-negative breast cancer, but it does come at the cost of toxicity,” Dr. Sharma acknowledged. Immune-related adverse events of any grade have been reported in up to 44% of patients with triple-negative disease, and grades 3 to 5 have been seen in up to 15%. Some effects, such as the endocrinopathies, can be permanent and life-altering, she noted.

For the selection of patients most likely to benefit from immunotherapy, many biomarkers have not panned out, but some that show more promise are emerging. Factors that have not proven predictive of benefit from immunotherapy in early-stage triple-negative breast cancer include PD-L1, tumor-infiltrating lymphocytes, tumor mutational burden, and several immune signatures. Although some of these factors may predict a response to neoadjuvant chemoimmunotherapy, they do not predict for a preferential response to the addition of the checkpoint inhibitor to chemotherapy, Dr. Sharma said.

There have been promising results with the DetermaIO, a 27-gene test that measures both tumor gene expression and tumor immune microenvironment. The DetermaIO score has been associated with preferential benefit from neoadjuvant atezolizumab plus chemotherapy over chemotherapy in NeoTRIP and was associated with pathologic complete response in NeoPACT. Expression of major histocompatibility complex II (MHC-II) on tumor cells has also been correlated with pathologic complete response with neoadjuvant chemotherapy plus durvalumab or pembrolizumab but not to neoadjuvant chemotherapy alone—with some association with event-free survival noted as well.

“We have seen some encouraging results with a couple of biomarkers, and we await their evaluation in larger trials,” she commented.

Adjuvant Treatment of Residual Disease 

For patients with residual disease after neoadjuvant therapy, the CREATE-X trial established the administration of six to eight cycles of capecitabine as beneficial in reducing recurrence risk (HR = 0.58; P = .01) and death (HR = 0.60; P = .01).⁹ Adjuvant capecitabine, therefore, is a standard recommendation for patients with residual disease.

For patients with germline BRCA mutations and high-risk features, the OLYMPIA trial established the benefit of 1 year of adjuvant therapy with olaparib, a PARP inhibitor, based on an 8.8% improvement in 3-year invasive disease–free survival (HR = 0.58; P < .001) and a 3.8% improvement in overall survival (HR = 0.68; P = .009).¹⁰

“Olaparib is certainly a very effective option for patients who have germline BRCA-mutated triple-negative breast cancer and residual disease after preoperative chemotherapy or who start out with stage II or III disease and receive surgery first,” Dr. Sharma said.

Pathologic Response: Highly Prognostic

“It has now been established that pathologic response is highly prognostic, and patients with triple-negative breast cancer who achieve a pathologic complete response do very well. Such patients do not benefit from further adjuvant chemotherapy,” Dr. Sharma said.

In the setting of a pathologic complete response, therefore, is adjuvant pembrolizumab warranted? In KEYNOTE-522, patients who achieved a pathologic complete response had good outcomes regardless of whether they received the checkpoint inhibitor, with a 3-year event-free survival rate of greater than 92% in both arms. In contrast, for patients lacking a pathologic complete response, more than 30% in either arm experienced an event after neoadjuvant therapy. 

“This begs the question: what is the absolute benefit for continuing pembrolizumab in patients with pathologic complete response?” Dr. Sharma asked. “The phase III OptimICE-pCR trial will seek to answer this question in a randomized fashion.”

Other Knowledge Gaps

“Finally, we have made significant progress in treating early-stage triple-negative breast cancer, but knowledge gaps certainly still remain,” Dr. Sharma concluded. She offered questions to be answered, and some of the clinical trials attempting to do so: 

Should all patients be treated with three- to four-drug chemotherapy regimens when immune checkpoint blockade is included as neoadjuvant systemic therapy? With checkpoint blockade on board, can chemotherapy be de-escalated (SWOG 2212)? Could dose-dense AC be used with checkpoint blockade? What is the role of adjuvant checkpoint blockade when these drugs are not used in the neoadjuvant setting? What about in the setting of residual disease (SWOG 1418) or pathologic complete response (OptimICE-pCR)?

Do all patients need chemotherapy and immune checkpoint blockade? Can patients who are unlikely to benefit be identified, and can “cold” tumors be made “hot”? From the patient perspective, what are the long-term side effects of checkpoint blockade in the curative setting? Are there predictors of toxicity, and what is the impact on fertility? 

DISCLOSURE: Dr. Sharma has received consulting fees or honoraria from Pfizer, Merck, Gilead Sciences , Genzyme, Novartis, AstraZeneca, and GSK.

REFERENCES

1. Sharma P: Optimal systemic therapy for early-stage triple-negative breast cancer. Invited Lecture. 2023 Miami Breast Cancer Conference. Presented March 3, 2023.

2. Loibl S et al: Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess). Lancet Oncol 19:497-509, 2018.

3. Gupta S et al: Addition of platinum to sequential taxane-anthracycline neoadjuvant chemotherapy in patients with triple-negative breast cancer. 2022 San Antonio Breast Cancer Symposium. Abstract GS5-01. Presented December 9, 2022.

4. Sharma P et al: Randomized phase II trial of anthracycline-free and anthracycline-containing neoadjuvant carboplatin chemotherapy regimens in stage I-III triple-negative breast cancer (NeoSTOP). Clin Cancer Res 27:975-982, 2021.

5. Schmid P et al: Pembrolizumab for early triple-negative breast cancer. N Engl J Med 382:810-821, 2020.

6. Schmid P et al: Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med 386:556-567, 2022.

7. Loibl S et al: A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer. Ann Oncol 30:1279-1288, 2019.

8. Sharma P et al: Clinical and biomarker results of neoadjuvant phase II study of pembrolizumab and carboplatin plus docetaxel in triple-negative breast cancer (NeoPACT). 2022 ASCO Annual Meeting. Abstract 513.

9. Masuda N et al: Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med 376:2147-2159, 2017.

10. Tutt ANJ et al: Adjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer. N Engl J Med 384:2394-2405, 2021.