Pembrolizumab For Early Triple-negative Breast Cancer

Research Agenda For The Next Decade

The introduction of immunotherapy marks a revolution in the treatment of early-stage TNBC. KEYNOTE-522 has shown that, by unleashing anti-cancer immune responses through ICIs, long-term benefits can be obtained for the treatment of this aggressive BC subtype. However, it represents a starting point rather than a finish line, and additional efforts will be required precisely implement immunotherapy for the treatment of TNBC .

Fig. 1: Next decade research agenda for neo immunotherapy in TNBC.

Abbreviations: IO, immunotherapy, TNBC, triple negative breast cancer TMB, tumor mutational burden ADC, antibody-drug conjugate ER, estrogen receptor CD, cluster of differentiation TILs, tumor infiltrating lymphocytes PD-L1, Programmed death-ligand 1 HLA, human leukocyte antigen PD-1, Programmed cell death protein 1 A, adenosine T, thymine C, cytosine G, guanine BRCA, BReast CAncer gene EFS, event-freee survival RD, residual disease me1, mono-methylated form BC, breast cancer. Created with biorender.com.

The Flip Side Of The Coin: Immune

The price of improving patients outcomes with the addition of immunotherapy is the risk of irAEs beyond the toxicities of traditional chemotherapy. The most common irAEs observed in KEYNOTE-522 were infusion reactions , thyroid impairment , skin toxicities , pneumonitis , hypophysitis , colitis and hepatitis in combined neoadjuvant and adjuvant phases. Importantly, some of these are expected to be irreversible, permanently conditioning the quality of life of patients in this curable setting. Additionally, concern on the impact of immunotherapy on fertility exist, particularly since TNBC often occurs in pre-menopausal patients. In this regards, appropriate training of clinicians in the early identification and management of irAEs will be key for the mitigation of immunotherapy side effects. Concomitantly, these risks should be discussed with patients upfront, to provide a clear overview of the risks/benefits balance of adding immunotherapy to chemotherapy for the treatment of their tumor.

Pivotal Phase 3 Data For Pembrolizumab In High

Results from the Phase 3 KEYNOTE-522 trial have been published in the New England Journal of Medicine.

Results showed that neoadjuvant pembrolizumab, an anti-PD-1 therapy, in combination with chemotherapy followed by adjuvant pembrolizumab as monotherapy, significantly prolonged event-free survival compared with neoadjuvant chemotherapy followed by adjuvant placebo in patients with high-risk early-stage triple-negative breast cancer .

As previously reported, after a median follow-up of 39 months, the pembrolizumab regimen reduced the risk of events or death by 37% versus the chemotherapy-placebo regimen.

A total of 15.7% of patients who received the pembrolizumab regimen had an EFS event compared to 23.8% of patients who received the chemotherapy-placebo regimen.

The estimated three-year EFS rates were 84.5% in the pembrolizumab group compared with 76.8% in the chemotherapy-placebo group.

Event-free survival was defined as the time from randomization to the first occurrence of either disease progression that precluded definitive surgery, a local/distant recurrence, a second primary malignancy, or death from any cause.

The safety profile of the pembrolizumab regimen was consistent with the known profiles of each regimen, and no new safety concerns were identified. Additional detailed efficacy and safety data are also featured in the publication.

Study Design and Additional Data From KEYNOTE-522

The study is continuing to allow for additional follow-up of OS.

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Addition To Neoadjuvant Chemotherapy Reduces Event

byCharles Bankhead, Senior Editor, MedPage Today July 27, 2021

The FDA granted full approval to the PD-1 inhibitor pembrolizumab plus chemotherapy for neoadjuvant treatment of high-risk triple-negative breast cancer , followed by adjuvant pembrolizumab, Merck announced.

The expanded indication represents the first approval of an immunotherapy-containing regimen for early-stage TNBC. Both pembrolizumab and atezolizumab have FDA-approved indications for unresectable/metastatic TNBC.

Earlier this year, the FDA Oncologic Drugs Advisory Committee unanimously recommended the FDA defer an approval decision on the pembrolizumab regimen until more data became available from the phase III KEYNOTE-522 trial. As was recently reported, an updated analysis of KEYNOTE-522 showed the regimen significantly improved event-free survival as compared with chemotherapy alone.

“Even when TNBC is diagnosed early, 30-40% of patients will suffer cancer recurrence after standard neoadjuvant chemotherapy and surgery,” said Joyce O’Shaughnessy, MD, of Baylor University Medical Center in Dallas, in a statement from Merck. “Therefore, there is a high unmet need for new treatment options. Today’s approval is very welcome news and has the potential to change the treatment paradigm by now including an immunotherapy as part of the regimen for patients with high-risk early TNBC.”

The FDA action increases the number of approved indications for pembrolizumab to 30.

Pivotal Phase 3 Data For Keytruda In High

KENILWORTH, N.J.—-Merck , known as MSD outside the United States and Canada, today announced the publication of results from the Phase 3 KEYNOTE-522 trial in the Feb. 10, 2022 edition of the New England Journal of Medicine. Results showed that neoadjuvant KEYTRUDA, Mercks anti-PD-1 therapy, in combination with chemotherapy followed by adjuvant KEYTRUDA as monotherapy , significantly prolonged event-free survival compared with neoadjuvant chemotherapy followed by adjuvant placebo in patients with high-risk early-stage triple-negative breast cancer .

As previously reported, after a median follow-up of 39 months, the KEYTRUDA regimen reduced the risk of events or death by 37% versus the chemotherapy-placebo regimen. A total of 15.7% of patients who received the KEYTRUDA regimen had an EFS event compared to 23.8% of patients who received the chemotherapy-placebo regimen. The estimated three-year EFS rates were 84.5% in the KEYTRUDA group compared with 76.8% in the chemotherapy-placebo group. Event-free survival was defined as the time from randomization to the first occurrence of either disease progression that precluded definitive surgery, a local/distant recurrence, a second primary malignancy, or death from any cause. The safety profile of the KEYTRUDA regimen was consistent with the known profiles of each regimen, and no new safety concerns were identified. Additional detailed efficacy and safety data are also featured in the publication.

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Integrating Immunotherapy Into An Expanding Arsenal Of Treatment Options

Important new data has also recently emerged on neoadjuvant chemotherapy for TNBC. The BrighTNess trial, assessing the addition of veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy for high-risk stage IIIII TNBC, has previously shown that the addition of carboplatin to anthracyclines and taxanes significantly improve pCR rates. Survival results from this trial were recently presented at ESMO Congress 2021: the addition of carboplatin significantly improved 4-year EFS , whereas no benefit was observed with the addition of veliparib. These results appear to confirm a long-term benefit of adding carboplatin, although its still unclear whether the same benefit is retained when adding ICIs: indeed, a survival benefit was also observed in the GeparNuevo trial, which did not include carboplatin in the neoadjuvant regimen. In this setting, the inclusion of carboplatin appears reasonable in fit, high-risk, stage IIIII TNBC patients, but new research efforts to clarify the need for platinum in the presence of pembrolizumab are urgently required, to understand if more flexibility is acceptable regarding the backbone chemotherapy regimen. Similarly, efforts will be needed to clarify if there is any role for associating dose-dense chemotherapy regimens to immunotherapy, based on the benefits observed with this strategy in prior trials.

Pembrolizumab Plus Chemotherapy For Neoadjuvant And Adjuvant Therapy In Early Triple

BACKGROUND: The current standard of care for triple-negative breast cancer is chemotherapy with anthracyclines or taxanes, but the overall survival for this patient population is shorter than the OS in other subtypes of breast cancer, and the risk for disease recurrence or death is high among treatment-naïve patients with stage II or III TNBC. Early data for immune checkpoint inhibitors targeting PD-1 or PD-L1 expression in combination with chemotherapy in patients with TNBC have shown antitumor activity.

METHODS: KEYNOTE-522 was a prospective, randomized, placebo-controlled, phase 3 clinical trial that compared the benefits of the PD-1 inhibitor pembrolizumab plus chemotherapy versus placebo plus chemotherapy in treatment-naïve patients with early-stage TNBC. The study included a neoadjuvant phase and an adjuvant phase, as well as a control group. Patients were randomized to neoadjuvant therapy with 4 cycles of pembrolizumab plus paclitaxel and carboplatin or to placebo plus paclitaxel and carboplatin every 3 weeks, followed by 4 cycles of pembrolizumab plus doxorubicin and cyclophosphamide or epirubicin and cyclophosphamide or to placebo plus these chemotherapies. After undergoing definitive surgery, patients received adjuvant pembrolizumab plus chemotherapy or placebo plus chemotherapy every 3 weeks, for up to 9 cycles. The primary end points were pathologic complete response or event-free survival .

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Preoperative Lenvatinib Plus Pembrolizumab In Early

Biomarkers For Immunotherapy In Tnbc

Despite this deeper understanding of TNBC immunobiology, further development of suitable biomarkers for immunotherapy response and benefit in patients with early-stage TNBC remains an area of significant need. The standardization of biomarker assay implementation and interpretation methodologies before introducing novel biomarkers into the clinical setting will be required. Strategies to identify and target key immune suppression regulators within the tumor microenvironment that could contribute to immunotherapy resistance or predict benefit to checkpoint inhibition and optimize tumor immunogenicity will achieve a more personalized therapeutic approach and balance the risks of immunotherapy-related toxicity.

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Hot Topicmanagement Of Patients With Early

Neoadjuvant pembrolizumab plus chemotherapy is a new standard of care for TNBC.

For residual disease, pembrolizumab, capecitabine, and olaparib are adjuvant therapy options.

We reviewed efficacy and safety data to guide adjuvant therapy selection.

Combinations of pembrolizumab plus capecitabine or olaparib seem safe.

Combination strategies of adjuvant therapy lacks on supportive efficacy data.

Immune Checkpoint Inhibitor Studies In Early

These promising advances in metastatic TNBC therapeutics paved the way for designing clinical trials utilizing immune checkpoint inhibitors in the early-stage setting with varying findings . The phase III IMpassion031 trial demonstrated that administration of atezolizumab every 2 weeks plus anthracycline-cyclophosphamide and taxane-based chemotherapy improved the pathologic complete response rate .28 By contrast, the NeoTRIPaPDL1 trial of neoadjuvant carboplatin plus nab-paclitaxel with or without atezolizumab, followed by surgery and adjuvant anthracycline-based regimen, did not improve the pCR rate in the ITT analysis 1.18 95% CI, 0.74 to 1.89 p=0.48).29 In the Phase II TONIC trial, anthracycline chemotherapy induction in patients with metastatic TNBC prior to administration of nivolumab yielded the highest response rate to immunotherapy compared to other immunomodulating strategies, including other chemotherapeutic agents.30 Collectively, these data suggest that anthracyclines may serve as key chemotherapeutic agents to prime the immune response. In the phase II GeparNuevo trial, 117 patients treated with an initial 2-week window of single-agent durvalumab prior to neoadjuvant chemotherapy had a more pronounced improvement in pCR rate than those who received combination therapy alone .31,32

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Fda Approval Summary: Pembrolizumab For Neoadjuvant And Adjuvant Treatment Of Patients With High

*Corresponding Author:

Note: This is a U.S. Government work. There are no restrictions on its use.

Corresponding Author:

Clin Cancer Res 2022 XX:XXXX

Clin Cancer Res

Mirat Shah, Christy L. Osgood, Anup K. Amatya, Mallorie H. Fiero, William F. Pierce, Abhilasha Nair, Jonathan Herz, Kim J. Robertson, Bronwyn D. Mixter, Shenghui Tang, Richard Pazdur, Julia A. Beaver, Laleh Amiri-Kordestani FDA Approval Summary: Pembrolizumab for Neoadjuvant and Adjuvant Treatment of Patients with High-Risk Early-Stage Triple-Negative Breast Cancer. Clin Cancer Res 2022

Research Progress And Future Questions

After the 2020 approval of the combination of pembrolizumab and chemotherapy for advanced triple-negative breast cancer, FDA approved the combination therapy for people with early-stage disease in 2021.

That approval was based on results from a different trial, KEYNOTE-522. In that study, patients with high-risk, early-stage triple-negative breast cancer benefited from pembrolizumab given with chemotherapy before surgery, and then continued as a single agent as an additional, or adjuvant, treatment after surgery.

This is an exciting time for research on triple-negative breast cancer, said Dr. Lee. We have now seen a benefit from an immune checkpoint inhibitor and chemotherapy in a subgroup of patients in both the advanced and early stages of the disease.

Dr. Lee cautioned, however, that more than half of all patients with triple-negative breast cancer have PD-L1 combined positive scores of less than 10, so more work is needed to find effective treatments for these patients.

In his editorial, Dr. Pivot noted that people diagnosed with triple-negative breast cancer are not a homogeneous group. Future studies, he added, will try to identify which individuals are more or less likely to benefit from pembrolizumab.

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Neoadjuvant Pembrolizumab/chemo Followed By Adjuvant Pembrolizumab Approaches Eu Approval For High

The European Medicines Agencys Committee for Medicinal Products for Human Use has recommended the approval of neoadjuvant pembrolizumab plus chemotherapy, followed by adjuvant pembrolizumab alone after surgery for adult patients with locally advanced or early-stage triple-negative breast cancer who are at a high risk for recurrence.

The European Medicines Agencys Committee for Medicinal Products for Human Use has recommended the approval of neoadjuvant pembrolizumab plus chemotherapy, followed by adjuvant pembrolizumab alone after surgery for adult patients with locally advanced or early-stage triple-negative breast cancer who are at a high risk for recurrence.1

The recommendation from the committee stems from positive findings from the phase 3 KEYNOTE-522 trial . At a median follow-up of 39 months, adjuvant pembrolizumab plus chemotherapy, followed by adjuvant pembrolizumab resulted in a 37% reduction in the risk of events or death compared with neoadjuvant chemotherapy followed by adjuvant placebo .2 The estimated 36-month EFS rate was 84.5% in the investigative arm vs 76.8% in the control arm. The median EFS was not yet reached in either arm.

KEYNOTE-522 enrolled patients with newly diagnosed, previously untreated, nonmetastatic TNBC who had an ECOG performance status of 0 or 1 and acceptable organ function.

Common TRAEs of any grade included nausea , alopecia , anemia , neutropenia , fatigue , diarrhea , and increased alanine aminotransferase .

Identifying Responders To Immunotherapy: Current Status And Future Perspectives

KEYNOTE-522 results prompted a rapid change in clinical practice, leading to the FDA approval of the first immunotherapy agent for early-stage TNBC. This landmark achievement, however, has raised a multitude of scientific questions, requiring a new set of prospective clinical trials.

Besides baseline biomarkers, one established dynamic biomarker, namely the achievement of pCR after neoadjuvant treatment, showed a critical value in KEYNOTE-522. Indeed, a major absolute benefit in terms of EFS was observed among patients not achieving pCR, with a 10% improvement in 3-year EFS for patients receiving pembrolizumab, whereas only a 2% difference was observed in those patients achieving pCR. This finding – together with the results of GeparNuevo showing survival outcomes similar to KEYNOTE-522 with immunotherapy administered only before surgerysupport the experimental testing of strategies to de-escalate adjuvant immunotherapy in patients achieving pCR with chemo-immunotherapy. Nonetheless, until prospective evidence is available, current standards of care should include the adjuvant administration of pembrolizumab to all patients receiving it in the neoadjuvant setting without experiencing concerning irAEs. Moreover, when comparing EFS curves from patients achieving pCR in the two arms, it is important to stress the fact that the addition of pembrolizumab led to more patients achieving pCR, ultimately enriching the population of patients achieving a favorable EFS.

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The Rise Of Immunotherapy For Tnbc

Despite lacking canonical targets for biologic treatment, TNBC is characterized by a relatively high tumor mutational burden compared to other subtypes of BC, a feature which has been linked with increased responsiveness to immunotherapy with immune-checkpoint inhibitors . Indeed, checkpoint inhibition with atezolizumab and with pembrolizumab has been approved for advanced-stage, PD-L1 positive TNBC based on the improvement in outcomes observed when combined with frontline chemotherapy,. Notably, evidence suggest a superior efficacy of ICIs in TNBC when administered early in the disease course, possibly due to the progression of immune escape mechanisms during the advancement of disease,. From this perspective, there was strong rationale for ICI administration to the earliest possible time in the disease course, namely before surgical resection. Results from several randomized trials designed with this purpose are now available, igniting a rapid change of practice in early TNBC.

Table 1 Features and outcomes of the main randomized chemo-immunotherapy trials in early-stage triple negative breast cancer.