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Consensus Statement Regarding Use of Pembrolizumabin Patients With Early-Stage Triple-Negative Breast Cancer

Oncology
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Introduction

Based on the significant improvement in event-free survival (EFS) reported in the phase III Keynote-522 (KN522) trial, on July 26, 2021 the U.S. Food and Drug Administration approved the use of pembrolizumab for high-risk, early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.
The purpose of the Dana-Farber Breast Oncology Center (BOC) multidisciplinary meetings held on August 4, September 3, and October 8, 2021 was to discuss recommendations for the use of pembrolizumab in patients with early-stage TNBC. Data were reviewed from the following randomized phase II and III trials that evaluated the addition of PD-1 or PD-L1 inhibition to neoadjuvant chemotherapy for early-stage TNBC: I-SPY2 (paclitaxel +/- pembrolizumab followed by AC), GeparNuevo, NeoTRIPaPDL1, IMpassion031 and KN522. Use of adjuvant PD-1 or PD-L1 inhibition in the KN522 and IMpassion031 trials, respectively, was reviewed. Data regarding adjuvant capecitabine (CREATE-X) and olaparib (OLYMPIA) for patients with residual disease post-neoadjuvant chemotherapy were also reviewed. Additional relevant data were reviewed to address the questions in this document as noted below.
On June 24, 2022, the BOC updated these recommendations after reviewing data reported from the NeoPACT trial.
This document summarizes the discussions and consensus among the DFCI BOC regarding the following:
  1. Which patients should receive neoadjuvant pembrolizumab?
  2. Neoadjuvant treatment regimen and schedule
  3. Immune-mediated toxicity monitoring and management
  4. Adjuvant treatment recommendations for patients who receive neoadjuvant pembrolizumab
Additional considerations:
  • For all patients presenting with TNBC and being considered for neoadjuvant chemotherapy, radiographic assessment of the axilla is recommended to assess for possible nodal involvement.
    • Additionally for patients with T1c tumors with a clinically negative axilla, axillary US should be considered to assess for potential nodal involvement
  • Potential risks and benefits with pembrolizumab should be considered in an individualized manner and discussed with the patient.
  • Guidelines are subject to change with evolution of data from existing and future trials.

Which patients should receive neoadjuvant pembrolizumab?

The following considerations, including
  • a) clinical stage at diagnosis
  • b) hormone receptor expression, for recommendations on the use of neoadjuvant pembrolizumab are detailed below.
A) Clinical anatomic stage at diagnosis:
After review of the data noted above, the consensus among the group was to consider neoadjuvant pembrolizumab for patients with stage II or III TNBC per the eligibility criteria of the KN522 trial, recognizing that the potential risks and benefits of the addition of pembrolizumab to neoadjuvant chemotherapy should be carefully considered and that the absolute benefits may vary within each stage category.
The potential absolute improvement in EFS with the addition of pembrolizumab will likely be greater for patients at higher risk of recurrence (e.g., larger tumor size, node-positive status).
B) Hormone receptor expression:
Patients with centrally confirmed TNBC in all foci (as defined by ASCO/CAP guidelines) were eligible for KN522. Retrospective studies suggest that hormone receptor (HR)-low tumors (ER and PR 1-<10%) may have similar clinicopathologic and molecular features compared to HR-negative tumors, including similar distribution of histologic grade, prevalence of basal PAM50 subtype, response to neoadjuvant chemotherapy, and survival outcomes in patients with residual disease.
In patients with HR-low/HER2-negative tumors who are considered candidates for neoadjuvant chemotherapy, use of neo-/adjuvant pembrolizumab may be considered.
Patients with HR-low/HER2-negative tumors are considered candidates for endocrine therapy; endocrine therapy plus abemaciclib plus pembrolizumab should not be given in combination due to toxicity concerns.

Neoadjuvant treatment regimen and schedule

The schedule of administration of neoadjuvant chemotherapy and pembrolizumab in KN522 was as follows:
  • First neoadjuvant treatment: 4 cycles of pembrolizumab 200 mg Q3W plus paclitaxel (80 mg/m2 once weekly) plus carboplatin (at AUC 5 mg/mL/min once every 3 weeks or 1.5 mg/mL/min once weekly) in the first 12 weeks, followed by:
  • Second neoadjuvant treatment: 4 cycles of pembrolizumab 200 mg Q3W plus doxorubicin (60 mg/m2) or epirubicin (90 mg/m2) plus cyclophosphamide (600 mg/m2) once every 3 weeks in the subsequent 12 weeks
Considerations regarding the optimal neoadjuvant regimen, including dosing and schedule, are detailed below.
A) Addition of carboplatin to the neoadjuvant chemotherapy backbone:
The impact on long-term outcomes of the addition of carboplatin to an anthracycline-and taxane-based regimen in the neoadjuvant TNBC setting has been investigated in several randomized clinical trials, including the CALGB 40603, GeparSixto, and BrighTNess trials. Differences in survival results with the addition of carboplatin have been observed across these studies. Importantly, these trials were not powered to detect differences in long-term outcomes.
  • In CALGB 40603, patients with TNBC were randomized in a 2×2 factorial design to receive the addition of carboplatin (Q3W) and/or bevacizumab to weekly paclitaxel followed by dose-dense doxorubicin and cyclophosphamide (ddAC). While carboplatin was associated with a significant increase in pathologic complete response (pCR), there was no significant difference in 5-year EFS between patients treated with or without carboplatin.
  • GeparSixto explored the addition of platinum to a non-standard concurrent anthracycline-, taxane-, and bevacizumab-containing regimen. Patients with TNBC received 18 weeks of weekly non-pegylated liposomal doxorubicin and paclitaxel plus every 3-week bevacizumab, with or without weekly carboplatin. The addition of carboplatin significantly improved pCR and disease-free survival, but not overall survival (OS).
  • The BrighTNess trial compared the addition of carboplatin (Q3W) plus veliparib to weekly paclitaxel, and the addition of veliparib to carboplatin (Q3W) plus weekly paclitaxel, followed by AC (dose-dense or Q3W) as neoadjuvant therapy for stage II-III TNBC.

    A significant increase in pCR was observed with the addition of carboplatin and veliparib to paclitaxel followed by AC, but not with the addition of veliparib to carboplatin and paclitaxel.

    Given that both co-primary pCR endpoints were required to be statistically significant to continue formally testing secondary endpoints (EFS and OS), secondary analyses were descriptive.

    At a median follow-up of 4.5 years, improved EFS was reported in each of the carboplatin-containing arms compared to paclitaxel (including a post-hoc analysis comparing carboplatin plus paclitaxel vs. paclitaxel).

    Notably, the rates of distant recurrence were numerically similar across the three treatment arms. No significant differences in OS were reported between treatment arms.
Data from the CALGB 40603 trial suggest that addition of carboplatin (AUC 6 mg/mL/min Q3W) increases the need for dose reductions of both weekly paclitaxel and ddAC, and increases the likelihood of missing two or more doses of paclitaxel. Similarly, treatment discontinuations were higher and the mean relative total dose intensity for all treatments was lower in patients randomized to receive carboplatin (AUC 2 mg/mL/min [or 1.5 mg/mL/min after study amendment due to safety interim analysis] weekly) in GeparSixto.
At the time this statement was written, the consensus within the group was to consider adding carboplatin to the neoadjuvant AC-T chemotherapy backbone in patients with stage II-III TNBC who are candidates for neoadjuvant pembrolizumab, with a strong recommendation to add carboplatin in patients with high-risk (e.g. node-positive or stage III) TNBC.
This recommendation may evolve with future data.
B) Dose intensity of chemotherapy:
Considering the benefit of dose-dense administration of chemotherapy in early-stage ER-negative breast cancer, dose-dense scheduling of AC should be considered in combination with pembrolizumab, recognizing that this differs from the schedule of administration of chemotherapy in KN522.
Prophylactic growth factor support should be administered with dose-dense AC and as needed during neoadjuvant chemotherapy to prevent re-occurrence of severe neutropenia or febrile neutropenia.
C) Dosing of neoadjuvant chemotherapy with pembrolizumab:
  • Carboplatin (Q3W or weekly) + paclitaxel (weekly) + pembrolizumab (Q3W) followed by AC (Q2W) + pembrolizumab (Q3W): TCb-ddAC with pembrolizumab
Both weekly and Q3W versions of carboplatin may be administered in combination with paclitaxel. The risk of hypersensitivity reactions has been shown to increase with cumulative dose and number of cycles of carboplatin. Deleterious mutations in BRCA1 and BRCA2 are also an independent risk factor for hypersensitivity to platinum salts, with potential earlier onset of reactions.
Pembrolizumab is approved with 200 mg Q3W or 400 mg Q6W dosing. The group preferred Q3W dosing during the neoadjuvant portion of therapy (when the risk of immune-mediated toxicity is higher) to allow dose delays and/or discontinuation of pembrolizumab, if needed.
Option A: TCb (Q3W carboplatin/weekly paclitaxel) followed by ddAC
  • Carboplatin (starting dose of AUC 5 mg/mL/min) Q3W x 4 doses.
  • Paclitaxel (80 mg/m2) weekly x 12 doses.
  • Doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) Q2W x 4 doses, with growth factor support.
  • Pembrolizumab 200 mg Q3W x 8 doses in the neoadjuvant portion of treatment.
Option B: TCb (weekly carboplatin/paclitaxel) followed by ddAC
  • Carboplatin (starting dose of AUC 1.5 mg/mL/min) weekly x 12 doses.
  • Paclitaxel (80 mg/m2) weekly x 12 doses.
  • Doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) Q2W x 4 doses, with growth factor support.
  • Pembrolizumab 200 mg Q3W x 8 doses in the neoadjuvant portion of treatment.
  • If anthracyclines are contraindicated: Carboplatin (Q3W) + docetaxel (Q3W) + pembrolizumab (Q3W):
In patients in whom an anthracycline-based regimen is contraindicated, data from the NeoPACT trial support the use of an anthracycline-sparing regimen with carboplatin, docetaxel and pembrolizumab as neoadjuvant therapy. Among all patients enrolled on the trial (stage I-III with tumor size >1.0 cm or node-positive; ER and PR up to 10%), the pCR rate was 58%.
Among patients with stage II-III TNBC defined as ER and PR <1% (similar to KN522), the pCR rate was 59%. In this phase II trial, patients received a total of six cycles of combination therapy prior to surgery:
  • Carboplatin (starting dose of AUC 6 mg/mL/min) IV Q3W x 6 doses
  • Docetaxel (starting dose of 75 mg/m2) IV Q3W x 6 doses
  • Pembrolizumab 200 mg IV Q3W x 6 doses
Alternatively, if paclitaxel-based treatment is preferred (e.g. due to toxicity concerns with docetaxel), weekly paclitaxel may be considered in combination with carboplatin and pembrolizumab:
  • Carboplatin (starting dose of AUC 6 mg/mL/min) IV Q3W x 6 doses
  • Paclitaxel (starting dose of 80 mg/m2) IV weekly x 18 doses
  • Pembrolizumab 200 mg IV Q3W x 6 doses

Immune-mediated toxicity monitoring and management

Toxicity monitoring assessment time points from the KN522 trial were reviewed.
The consensus among the group was to perform the following routine assessments (regardless of whether pembrolizumab is held, delayed or discontinued, and regardless of whether pembrolizumab is continued in the adjuvant setting):
  • Baseline: TSH, fT4
  • Between anthracycline- and taxane-based portions of neoadjuvant therapy: TSH, fT4
  • On day of last dose of neoadjuvant chemotherapy/prior to surgery: Cortisol (am), TSH, fT4
  • First postoperative appointment: TSH, fT4
  • Every 12 weeks while receiving adjuvant systemic therapy (with or without pembrolizumab): TSH, fT4
  • At follow-up visits (e.g. 3-6 months): TSH, fT4 (for at least 12 months post-discontinuation of pembrolizumab)
There are no contraindications for pembrolizumab per FDA label. However, in patients who meet KN522 exclusion criteria, the risks of immune-mediated toxicity should be carefully considered and discussed with the corresponding specialist and patient.
KN522 exclusion criteria included (but were not limited to):
  • Active autoimmune disease for which the patient had received systemic treatment within the previous 2 years
  • Diagnosis of immunodeficiency or use of immunosuppressive therapy within the previous week
  • History of HIV infection
  • History of noninfectious pneumonitis for which the patient had received glucocorticoids or current pneumonitis
  • Active tuberculosis
  • Active HBV or HCV infection
  • Any active infection for which the patient was receiving systemic therapy

Adjuvant treatment recommendations for patients who receive neoadjuvant pembrolizumab

It remains unclear if/how continuation of pembrolizumab in the adjuvant setting, after prior pembrolizumab in the neoadjuvant setting, contributed to the EFS benefit observed in KN522 in patients randomized to the pembrolizumab arm.
Long-term outcome results from the GeparNuevo trial, albeit not powered to detect significant differences in survival, showed higher rates of 3-year invasive disease-free, distant disease-free, and overall survival in patients who received neoadjuvant durvalumab (vs. placebo) in combination with an anthracycline- and taxane-based (non-platinum containing) regimen, without receipt of additional immune checkpoint inhibition in the adjuvant setting.
However, given the significant EFS benefit demonstrated with the schedule of administration of pembrolizumab in KN522 (8 doses Q3W in the neoadjuvant setting followed by 9 doses Q3W in the adjuvant setting to complete a total duration of one year of PD-1 inhibitor therapy), the consensus among the group was that pembrolizumab should be continued in the adjuvant setting in patients who have not experienced significant immune-related toxicity.
Improvements in long-term outcomes with other systemic therapies in patients with residual disease post-neoadjuvant chemotherapy have also been reported (e.g., capecitabine, CREATE-X trial; olaparib in patients with germline BRCA1 or BRCA2 mutation, OLYMPIA trial). Relatively consistent benefits have been observed in long-term outcomes across these trials for TNBC patients with residual disease post neoadjuvant chemotherapy.
To our knowledge, data have not been reported to date on the efficacy of adjuvant pembrolizumab combined with capecitabine or with olaparib (concurrent or sequential administration) in patients with early-stage TNBC. Safety data have been reported for these combinations (capecitabine plus pembrolizumab; olaparib plus pembrolizumab) in the metastatic setting.
A) Adjuvant systemic treatment post neoadjuvant chemotherapy plus pembrolizumab:
Type of neoadjuvant chemotherapy, residual cancer burden, germline BRCA1/BRCA2 status, and individualized risk assessment should be considered when making decisions about systemic therapy in the adjuvant setting.
  • In patients with pCR at surgery after neoadjuvant pembrolizumab + chemotherapy, continuation of pembrolizumab in the adjuvant setting is recommended for patients who have not experienced significant immune-related toxicity.
  • In patients with residual disease at surgery after neoadjuvant pembrolizumab + chemotherapy:
    • For non-germline BRCA carriers:
      • Continuation of pembrolizumab in the adjuvant setting is recommended for patients who have not experienced significant immune-related toxicity.
      • Addition of capecitabine (6-8 cycles; 1000 mg/m2 twice daily on days 1-14 every 3 weeks) is recommended. Decisions regarding the addition of capecitabine to adjuvant pembrolizumab should be made in an individualized manner, with careful consideration of potential residual toxicities from the neoadjuvant regimen.
      • When considering administration of both pembrolizumab and capecitabine, the group favored concurrent administration of both agents, if adequately tolerated.
    • For germline BRCA carriers:
      • Adjuvant olaparib (300 mg twice daily for 52 weeks) is recommended.
      • Addition of pembrolizumab may be considered.
      • When considering administration of both olaparib and pembrolizumab, the group favored concurrent administration of both agents, if adequately tolerated.
B) Additional considerations regarding pembrolizumab use in the adjuvant setting:
Dosing and schedule: The preference among the group was to consider pembrolizumab 400 mg Q6W dosing when administered in the adjuvant setting.
To complete a total duration of one year of pembrolizumab, after 24 weeks of neoadjuvant pembrolizumab (200 mg Q3W x 8 doses), adjuvant pembrolizumab may be administered 400 mg Q6W x 4 doses followed by 200 mg Q3W x 1 dose.
When possible, immune-mediated toxicity monitoring assessments should be aligned with pembrolizumab treatment visits in the adjuvant setting.
Radiation therapy: Concurrent administration of adjuvant radiation therapy with pembrolizumab was allowed in KN522. Per KN522, if postoperative radiation therapy is indicated, adjuvant pembrolizumab may be started either concurrently with radiation therapy or post radiation therapy. Concurrent administration of other systemic therapies (e.g. capecitabine, olaparib) with adjuvant pembrolizumab was not allowed.
When considering adjuvant radiation therapy and pembrolizumab with or without capecitabine or olaparib:
  • If pCR: patients may receive concurrent radiation therapy and pembrolizumab, followed by pembrolizumab alone.
  • If residual disease: patients may receive concurrent radiation therapy and pembrolizumab, followed by pembrolizumab with capecitabine or olaparib.
No prior neoadjuvant IO: Considering the lack of data supporting the use of adjuvant pembrolizumab in patients who have not received neoadjuvant pembrolizumab, for patients with early-stage TNBC who have undergone surgery (without neoadjuvant chemotherapy or with neoadjuvant chemotherapy that did not include pembrolizumab), the group would not routinely recommend treatment with pembrolizumab in the adjuvant setting. This recommendation may evolve with future data.

Development of the Consensus Statements

The preparatory materials for the group discussion were developed initially by Dr Ana Garrido-Castro. Coordination and editorial support were performed by Mr Scorzoni and Ms Bak. The evidence in support and consensus statements were presented for discussion to a multidisciplinary group, which includes physicians, nurses, clinical investigators, lab investigators, translational researchers, administrators, and patient advocates, at the BOC weekly staff meeting, on 8/4/2021, 9/3/2021, 10/8/2021 and 6/24/2022. The discussion and suggestions for improvements continued via email exchanges following the meeting. The final consensus statements were consolidated in July 2022.
The consensus statements can be subject to future variations and periodic updates, based on emerging evidence and new reports from ongoing clinical studies. Therefore, the information provided in this document should not be considered as being complete or inclusive of all proper assessments, treatments or methods of care or as a statement of the standard of care. This information does not mandate any particular course of medical care and is not intended to be a substitute for the independent professional judgment of a health care provider. The document is based on the opinion of a multidisciplinary team at DFCI but does not represent the official institutional position, and overall must be considered as a consensus based on the positions and ideas of the DFCI providers.

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