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Pembrolizumab in combination with nab-paclitaxel for the treatment of patients with early-stage triple-negative breast cancer – A single-arm phase II trial (NeoImmunoboost, AGO-B-041)

Open AccessPublished:January 24, 2023DOI:https://doi.org/10.1016/j.ejca.2023.01.001

      Highlights

      • Neoadjuvant nab-paclitaxel(nP)/anthracycline + pembrolizumab shows a pathological complete response rate of 66%.
      • A pre-chemotherapy pembrolizumab (pembro) dose did not indicate different pathological complete response rates.
      • If platinum is contraindicated nab-paclitaxel could be an alternative to combine with pembro.

      Abstract

      Background

      Pembrolizumab is approved for the neoadjuvant/adjuvant treatment of early triple-negative breast cancer (TNBC) patients in combination with chemotherapy. The Keynote-522 trial used platinum chemotherapy. As neoadjuvant nab-paclitaxel (nP) is also highly effective in triple-negative breast cancer patients, this study investigates the response to nP-containing neoadjuvant chemotherapy in combination with pembrolizumab.

      Patients and methods

      NeoImmunoboost (AGO-B-041/NCT03289819) is a multicenter, prospective single-arm phase II trial. Patients were treated with 12 weekly cycles of nP followed by four three-weekly cycles of epirubicin/cyclophosphamide. Pembrolizumab was given three-weekly in combination with these chemotherapies. The study was planned for 50 patients. After 25 patients, the study was amended to include a pre-chemotherapy single application of pembrolizumab. The primary aim was pathological complete response (pCR), and the secondary aims were safety and quality of life.

      Results

      Of 50 included patients, 33 (66.0%; 95%confidence interval: 51.2%–78.8%) had a (ypT0/is ypN0) pCR. The pCR rate in the per-protocol population (n = 39) was 71.8% (95%confidence interval: 55.1%–85.0%). The most common adverse events of any grade were fatigue (58.5%), peripheral sensory neuropathy (54.7%) and neutropenia (52.8%).
      The pCR rate in the cohort of 27 patients with a pre-chemotherapy pembrolizumab dose was 59.3%, and 73.9% in the 23 patients without pre-chemotherapy dose.

      Conclusions

      pCR rates after NACT with nP and anthracycline combined with pembrolizumab are encouraging. With acceptable side-effect profiles, this treatment might be a reasonable alternative to platinum-containing chemotherapy in cases of contraindications. However, without data from randomised trials and long-term follow up, platinum/anthracycline/taxane-based chemotherapy remains the standard combination chemotherapy for pembrolizumab.

      Keywords

      1. Introduction

      Recently, an anti PD-1 antibody pembrolizumab was approved for the treatment of patients with early stage triple-negative breast cancer (TNBC) [
      • Schmid P.
      • Cortes J.
      • Pusztai L.
      • McArthur H.
      • Kummel S.
      • Bergh J.
      • et al.
      Pembrolizumab for early triple-negative breast cancer.
      ]. It was introduced as a neoadjuvant combination therapy with carboplatinum/paclitaxel and anthracycline/cyclophosphamide.
      In a randomised study, the addition of carboplatin to therapy with solvent paclitaxel increased the pathological complete response (pCR) rate to over 50% compared to a pCR of about 30% in patients treated with solvent paclitaxel [
      • Loibl S.
      • O'Shaughnessy J.
      • Untch M.
      • Sikov W.M.
      • Rugo H.S.
      • McKee M.D.
      • et al.
      Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial.
      ]. Because of high pCR rates and favourable outcomes [
      • Loibl S.
      • Sikov W.
      • Huober J.
      • Rugo H.S.
      • Wolmark N.
      • O'Shaughnessy J.
      • et al.
      Event-free survival (EFS), overall survival (OS), and safety of adding veliparib (V) plus carboplatin (Cb) or carboplatin alone to neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) after ≥4 years of follow-up: BrighTNess, a randomized phase III trial.
      ], platinum-containing chemotherapy can be considered one of the standards for the treatment of patients with early-stage TNBC. Another treatment option, although not approved, is nab-paclitaxel (nP). Treatment of TNBC with nP followed by epirubicin/cyclophosphamide (EC) resulted in a pCR rate of 48% [
      • Untch M.
      • Jackisch C.
      • Schneeweiss A.
      • Conrad B.
      • Aktas B.
      • Denkert C.
      • et al.
      Nab-paclitaxel versus solvent-based paclitaxel in neoadjuvant chemotherapy for early breast cancer (GeparSepto-GBG 69): a randomised, phase 3 trial.
      ].
      The only approved immune checkpoint inhibitor (ICI) for the neoadjuvant treatment of early-stage TNBC patients is pembrolizumab (pembro) [
      • Schmid P.
      • Cortes J.
      • Pusztai L.
      • McArthur H.
      • Kummel S.
      • Bergh J.
      • et al.
      Pembrolizumab for early triple-negative breast cancer.
      ]. Adding pembro to platinum-containing chemotherapy led to an increase in pCR of 64.8% compared to 51.2% in the chemotherapy arm [
      • Schmid P.
      • Cortes J.
      • Pusztai L.
      • McArthur H.
      • Kummel S.
      • Bergh J.
      • et al.
      Pembrolizumab for early triple-negative breast cancer.
      ]. With a median follow-up of 39.1 months, a statistically significant improvement of DFS with a hazard ratio of 0.63 (95%confidence interval (CI): 0.48–0.82, p = 0.0003) was achieved by adding [
      • Schmid P.
      • Cortes J.
      • Dent R.
      • Pusztai L.
      • McArthur H.
      • Kümmel S.
      • et al.
      KEYNOTE-522: phase III study of neoadjuvant pembrolizumab + chemotherapy vs. placebo + chemotherapy, followed by adjuvant pembrolizumab vs. placebo for early-stage TNBC.
      ].
      The GeparNuevo study, which investigated the addition of aPD-L1 inhibitor durvalumab to chemotherapy containing nP followed by EC [
      • Loibl S.
      • Untch M.
      • Burchardi N.
      • Huober J.
      • Sinn B.V.
      • Ju Blohmer
      • et al.
      A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: clinical results and biomarker analysis of GeparNuevo study.
      ], could not show statistically significant superiority of pCR rates in the durvalumab arm (53.4%) compared to the chemotherapy-only arm (44.2%; p = 0.287) [
      • Loibl S.
      • Untch M.
      • Burchardi N.
      • Huober J.
      • Sinn B.V.
      • Ju Blohmer
      • et al.
      A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: clinical results and biomarker analysis of GeparNuevo study.
      ]. This study had a subgroup of patients who received a pre-chemotherapy single dose of durvalumab two weeks before the start of the chemotherapy. In this subgroup, the pCR with durvalumab and chemotherapy was 61.0%, but it was 41.4% in the chemotherapy-only arm [
      • Loibl S.
      • Untch M.
      • Burchardi N.
      • Huober J.
      • Sinn B.V.
      • Ju Blohmer
      • et al.
      A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: clinical results and biomarker analysis of GeparNuevo study.
      ].
      From these two studies with ICI and chemotherapy, it can be concluded that a combination with an nP-containing chemotherapy regimen might be a promising option. Therefore, this study examines the combination of pembro with nP. Furthermore, as this study comprises patients with and without pre-chemotherapy pembro monotherapy, it could also inform about efficacy in relation to this pre-chemotherapy pembro application.

      2. Methods

      2.1 Study design

      NeoImmunoboost (AGO-B-041/NCT03289819) is a multicenter, prospective, open, single-arm phase-II-trial investigating the pCR rate of NACT with nP/pembro followed by EC/pembro in patients with primary non-metastatic TNBC (Supplementary Figure 1). NeoImmunoboost is a study of the AGO-Breast study group. The Ethics Committee and competent authorities approved the study. All patients provided written informed consent.

      2.2 Treatment

      Patients received four cycles of weekly nP (d1, d8, d15, q21d) intravenously (i.v.) at a dose of 125 mg/m2 body surface area (BSA) in combination with four cycles of pembro i.v. with an absolute dose of 200 mg q21d. Similar to the treatment in the Keynote-522 study, nP was followed by four cycles of epirubicin i.v. with 90 mg/m2 BSA and cyclophosphamide i.v. with 600 mg/m2 BSA, q21d in combination with four cycles of pembro i.v. 200 mg q21d. After the publication of the GeparNuevo study [
      • Loibl S.
      • Untch M.
      • Burchardi N.
      • Huober J.
      • Sinn B.V.
      • Ju Blohmer
      • et al.
      A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: clinical results and biomarker analysis of GeparNuevo study.
      ,
      • Loibl S.
      • Untch M.
      • Burchardi N.
      • Huober J.B.
      • Ju Blohmer
      • Grischke E.M.
      • et al.
      Randomized phase II neoadjuvant study (GeparNuevo) to investigate the addition of durvalumab to a taxane-anthracycline containing chemotherapy in triple negative breast cancer (TNBC).
      ], in which a single monotherapy application of an ICI before chemotherapy resulted in a higher pCR rate, the protocol was amended after the inclusion of 27 patients. Then, all patients received an additional dose of 200 mg of pembro three weeks before the start of chemotherapy.

      2.3 Patients

      Patients with previously untreated unilateral or bilateral primary non-metastatic invasive TNBC with stages cT1c or larger, as assessed by a sonography or magnet resonance imaging, could be included. No central pathology was performed; however, oestrogen receptor and progesterone receptor negativity were defined as <1% of the cells expressing hormonal receptors via an IHC analysis. Human epidermal growth factor receptor 2 negativity was defined as either of the following by local laboratory assessment: in situ hybridisation non-amplified (ratio ≤2.2), or Human epidermal growth factor receptor 2 IHC having a score of 0 or IHC 1+, according to ASCO/CAP guidelines [
      • Wolff A.C.
      • Hammond M.E.
      • Hicks D.G.
      • Dowsett M.
      • McShane L.M.
      • Allison K.H.
      • et al.
      Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update.
      ,
      • Wolff A.C.
      • Hammond M.E.H.
      • Allison K.H.
      • Harvey B.E.
      • Mangu P.B.
      • Bartlett J.M.S.
      • et al.
      Human epidermal growth factor receptor 2 testing in breast cancer: American society of clinical oncology/college of American pathologists clinical practice guideline focused update.
      ]. Further relevant inclusion and exclusion criteria are shown in Supplementary Table 1.

      2.4 Objectives and end-points

      The primary end-point was pCR with no invasive tumour residuals in the breast or axillary lymph nodes (ypT0/is ypN0) in patients who received at least one full treatment cycle of q21d nP (d1, d8, d15) and pembro (d1) (full analysis population). Secondary objectives were a pCR rate defined as ypT0 ypN0 as well as pCR rates in the per-protocol population defined as patients, who had completed at least two cycles of nP and two cycles of EC. Treatment compliance is reported as patients with dose reductions, treatment delays, treatment interruptions and permanent treatment discontinuations. Adverse and severe adverse events were reported according to NCI-CTC criteria v4.0, regardless of relatedness, up to 120 days after the last dose of pembro. Quality of life (QoL) was assessed using the EORTC-QLQ-C30 questionnaire. Exploratory end-points included PD-L1 expression in correlation to pCR.

      2.5 Immunohistochemistry of PD-L1

      The PD-L1 assay was performed on a Ventana Benchmark Ultra automated platform (Ventana Medical Systems [VMS] Inc, Oro Valley, AZ, USA). 2 μm-thick sections of formalin-fixed and paraffin-embedded blocks of breast core biopsies were mounted on adhesive glass slides. The human monoclonal anti-PD-L1 antibody (clone: 22C3; host: mouse; code: M3653; dilution 1:50; DAKO, Glostrup, Denmark) was applied for 32 min at 36 °C after a pretreatment for 48 min with Cell Conditioning 1 (VMS). An antibody–antigen binding was visualised using the optiView DAB IHC Detection Kit (VMS), and sections were counterstained with haematoxylin and bluing reagent (VMS). The tonsil tissue served as a positive control. As a negative control, a negative serum (Universal Negative Control Serum, Biocare Medical, LLC) was used instead of an antibody. Stained slides were evaluated with a Zeiss Axio microscope (magnification of 50×, 100×, 200×, and 400×) by a pathologist specialised in breast cancer, and trained in the assessment of the PD-L1 combined positive score (CPS).

      2.6 Statistical considerations and sample size

      The pCR rate is defined as the proportion of patients with pCR among all of the patients included in the efficacy analysis. It was assumed that a pCR rate of 70% could be achieved with the study treatment, and the null hypothesis stated that the pCR rate was 50% at most. A sample size calculation based on a one-sided binomial test with significance level α = 0.05 and a power of 85% indicated that the study size should be 50 patients. All continuous variables were summarised using descriptive statistics (mean, standard deviation, median, 25th percentile and 75th percentile). Frequency and percentages based on the non-missing sample size of observed values were reported for categorical measures. All statistical analyses were performed using the R system for statistical computing (Version 3.6.1, 2019).

      3. Results

      3.1 Patients

      A total of 56 patients were registered between 03/2018 and 10/2019. Fifty-three started treatment (safety analysis population). Later, one patient withdrew their consent, and two patients stopped the trial after the first infusion day of cycle one. Therefore, the full analysis population was 50 patients for whom pCR analysis was conducted. A total of 39 patients completed the predefined requirement for a per-protocol treatment. Patient characteristics are shown in Table 1.
      Table 1Baseline patient characteristics of the full analysis population.
      CharacteristicCategoryNMean (SD) or %
      Age (years)5052.2 (11.5)
      BMI (kg/m2)5027.2 (6.2)
      Time from primary diagnosis to beginning of therapy (days)5030.6 (10.6)
      Time from primary diagnosis to study entry (days)5021.7 (10.1)
      EthnicityCaucasian50100
      Other00
      Menopausal statusPremenopausal/perimenopausal2754
      Postmenopausal2346
      Tumour stagecT1c2448
      cT22346
      cT324
      cT412
      Clinical lymph node statuscN03264
      cN1-31530
      cNX36
      cMcM04998
      cMX12
      GradingG100
      G21020.4
      G33979.6
      Histological subtypeDuctal3675
      Lobular12.1
      Mixed ductal/lobular24.2
      Other918.8
      ECOGECOG 04896
      ECOG 124
      Comorbidities N01632
      11122
      ≥22346
      Initiation boostYes2754
      No2346

      3.2 Efficacy

      A total of 33 (66%; 95%CI: 51.2%–78.8%; P = 0.02, one-sided binomial test; one-sided 95%CI: 53.5%–100%) patients achieved pCR (ypT0/is ypN0). In the per-protocol population, 28 out of 39 patients (71.8%; 95%CI: 55.1%–85.0%) were reported to have pCR. Patients who received a pre-chemotherapy single dose pembro boost had a pCR rate of 59.6% (95%CI: 38.8–77.6%), while patients without the pre-chemotherapy dose had a pCR rate of 73.9% (95%CI: 51.6–89.8). Respective pCR rates in the per-protocol population were 65.2% (95%CI: 42.7–83.6) with a pre-chemotherapy single dose boost, and 81.3% (95%CI: 54.4–96.0) without a pre-chemotherapy single dose boost.
      Further response data according to study populations and pCR definitions are shown in Table 2 and Supplementary Table 2.
      Table 2Pathological response data in the full analysis population.
      pCR definitionPopulationN totalN with pCRpCR rate (%) (95% CI)
      ypT0/is ypN0Total503366.0 (51.2–78.8)
      ypT0/is ypN0Without pre-chemotherapy dose231773.9 (51.6–89.8)
      ypT0/is ypN0With pre-chemotherapy dose271659.3 (38.8–77.6)
      ypT0 ypN0Total503162.0 (47.2–75.3)
      ypT0 ypN0Without pre-chemotherapy dose231669.6 (47.1–86.8)
      ypT0 ypN0With pre-chemotherapy dose271555.6 (35.3–74.5)
      The clinical response six weeks after the beginning of nP showed a partial or complete response in 32 (69.6%) out of 46 patients for whom this information was available. Clinical assessment after six weeks correlated well with the later achievement of pCR (Table 3).
      Table 3Clinical response evaluated six weeks after the initiation of nP/pembro in the full analysis set, showing count and percentage in brackets.
      Clinical responseTotal eventsEvents in patients with later pCREvents in Patients without later pCR
      Complete response2 (100.0)2 (100.0)0 (0.0)
      Partial response30 (100.0)21 (70.0)9 (30.0)
      Stable disease12 (100.0)7 (58.3)5 (41.7)
      Progressive disease1 (100.0)0 (0.0)1 (100.0)
      Not evaluable1 (100.0)0 (0.0)1 (100.0)
      A total of 46 tumour blocks were available for assessment of PD-L1 expression according to the CPS . The pCR rate (ypT0/is ypN0) in patients with a CPS of 0 was 42.9% and 69.2%, 68.2% and 80% for the patient groups with ≥1, ≥10 and ≥20, respectively (Fig. 1). As the CPS clearly influenced the pCR rates, the respective percentages concerning pre-chemotherapy doses (yes or no) and CPS (<10 versus ≥10) are provided in Supplementary Figure 3.
      Fig. 1
      Fig. 1pCR rates (ypT0/is ypN0) according to PD-L1 expression (CPS).

      3.3 Safety

      Within the safety population, relative dose intensity (ratio of administered doses to planned doses) was 89.4% for pembro, 92.6% for nP, 91.1% for epirubicin and 91.4% for cyclophosphamide.
      All of the patients (100%) at any grade had at least one adverse event, and 64.2% of the patients had at least one grade 3/4 adverse event. Adverse events are shown in Table 4. The most commonly reported all-grade adverse events were fatigue (n = 31; 58.5%), peripheral sensory neuropathy (n = 29; 54.7%), neutropenia (n = 28; 52.8%), nausea (n = 23; 43.4%) and skin reactions (n = 19; 35.8%). The most common grade 3/4 adverse events were neutropenia (n = 14; 26.4%), fever (n = 6; 11.3%) and other blood and lymphatic system disorders (n = 5; 9.4%). Five patients had febrile neutropenia (9.4%). Regarding adverse events of interest, there were six cases (11.3%), each of hypothyroidism and hyperthyroidism, and three cases of adrenal insufficiency (5.7%). Adverse events of special interest were in the expected ranges, and no new safety signals were seen (Supplementary Table 3).
      Table 4Adverse events with a frequency of ≥3 patients during the study medication after all patients have completed the safety follow-up (adverse events of interest in bold).
      CTCAE TermAny grade NFrequency in %Grade 3/4 NFrequency in %
      Fatigue3158.523.8
      Peripheral sensory neuropathy2954.723.8
      Neutrophil count decreased2852.81426.4
      Nausea2343.411.9
      Skin and subcutaneous tissue disorders1935.811.9
      Alopecia1528.300.0
      Mucositis oral1426.400.0
      Anaemia1324.547.5
      Diarrhoea1324.523.8
      Dysgeusia1222.600.0
      Insomnia1120.811.9
      Hot flashes1120.800.0
      Fever1018.9611.3
      Anorexia917.035.7
      Headache917.000.0
      Constipation815.100.0
      Back pain815.100.0
      Flu-like symptoms713.200.0
      Alanine aminotransferase increased713.247.5
      Aspartate aminotransferase increased713.235.7
      Rash acneiform713.211.9
      Blood and lymphatic system disorders611.359.4
      Hyperthyroidism611.311.9
      Hypothyroidism611.323.8
      Peripheral motor neuropathy611.311.9
      Epistaxis611.300.0
      Febrile neutropenia59.459.4
      Dry eye59.400.0
      Abdominal pain59.400.0
      Vomiting59.423.8
      Infections and infestations59.423.8
      GGT increased59.447.5
      Myalgia59.400.0
      Dizziness59.400.0
      Breast pain59.400.0
      Gastroesophageal reflux disease47.500.0
      Stomach pain47.511.9
      Chills47.500.0
      Upper respiratory infection47.511.9
      Investigations47.523.8
      Cough47.500.0
      Dry skin47.500.0
      Vertigo35.700.0
      Adrenal insufficiency35.711.9
      Oedema limbs35.700.0
      General disorders and administration site conditions35.723.8
      Pain35.700.0
      Hepatobiliary disorders35.723.8
      Sinusitis35.700.0
      Weight loss35.700.0
      Arthralgia35.700.0
      Pain in extremity35.700.0
      Nervous system disorders35.700.0
      Dyspnoea35.700.0
      Nasal congestion35.700.0
      Nail discolouration35.700.0
      Hypertension35.711.9
      Hypotension35.700.0

      3.4 Quality of life

      QoL according to the EORTC-QLQ-C30 questionnaire is shown in Table 5. QoL at the start of the study were comparable to respective reference populations. However, under therapy, general health scores dropped from 70 to 75 at the start of therapy to between 50 and 60 until the time of surgery. At the time of the safety follow-up, general health scores were at about the same levels as they were before the start of therapy.
      Table 5Quality-of-life subscales assessed by EORTC QLQ-C30, showing mean and standard deviation in the full analysis set.
      Visit
      Pre-chemo pembro1.nbP/Pembro3.nbP/Pembro1.EC/Pembro3.EC/PembroSurgerySafety FU
      Global health70.5 (16.9)74.5 (17.4)59.3 (20.2)52.5 (18.9)54.7 (19.0)56.7 (20.8)70.9 (16.5)
      Physical functioning92.1 (10.5)91.0 (14.5)76.0 (22.3)60.8 (25.0)61.6 (22.0)67.5 (25.0)81.4 (16.7)
      Role functioning82.1 (22.6)84.4 (20.6)59.6 (27.6)45.3 (29.4)43.2 (29.0)49.2 (31.4)68.0 (27.0)
      Emotional functioning60.4 (20.8)65.1 (23.2)69.1 (19.6)65.7 (18.0)65.1 (20.0)64.1 (23.2)75.2 (19.5)
      Cognitive functioning87.2 (16.5)85.5 (19.8)78.9 (25.0)71.7 (19.1)71.2 (26.2)68.3 (25.5)77.6 (24.3)
      Social functioning69.2 (28.2)78.3 (23.3)61.1 (25.1)51.9 (28.7)53.2 (29.6)54.0 (32.3)69.7 (23.2)
      Fatigue22.2 (16.9)24.9 (19.6)50.6 (24.8)59.2 (25.0)55.6 (25.9)47.9 (29.9)31.6 (23.8)
      Nausea and vomiting1.9 (5.4)1.8 (6.3)12.2 (18.9)10.1 (19.6)18.5 (21.4)11.5 (22.2)5.3 (13.5)
      Pain18.6 (20.7)18.1 (21.9)22.6 (26.1)39.5 (28.2)36.9 (24.6)32.9 (28.6)21.9 (24.2)
      Dyspnoea7.7 (17.1)13.0 (21.6)34.1 (29.2)38.8 (28.1)37.8 (29.6)32.5 (29.0)21.1 (30.4)
      Insomnia32.1 (29.0)32.6 (28.5)39.3 (32.0)50.4 (34.4)38.7 (28.9)39.7 (31.4)36.8 (33.6)
      Appetite loss7.7 (14.3)7.2 (17.1)23.0 (30.0)32.6 (31.3)36.0 (32.8)33.3 (37.5)11.4 (23.6)
      Constipation1.3 (6.5)5.1 (15.7)11.9 (22.6)14.7 (25.5)12.6 (19.8)12.7 (26.5)8.8 (18.5)
      Diarrhoea11.5 (16.2)8.0 (14.4)18.2 (30.9)11.6 (17.6)17.1 (24.4)14.3 (29.6)8.8 (21.5)
      Financial difficulties11.5 (18.7)15.2 (25.0)20.7 (26.9)22.5 (28.8)18.0 (24.3)19.8 (23.4)19.3 (27.5)

      4. Discussion

      Neoadjuvant pembro with nP followed by EC showed a pCR rate of 66%. The two cohorts (pre-chemotherapy pembro-boost versus no pre-chemotherapy pembro-boost) had similar pCR rates.
      Carboplatin/paclitaxel followed by anthracycline/cyclophosphamide is the standard combination chemotherapy for neoadjuvant pembrolizumab as established by the Keynote-522-study [
      • Schmid P.
      • Cortes J.
      • Pusztai L.
      • McArthur H.
      • Kummel S.
      • Bergh J.
      • et al.
      Pembrolizumab for early triple-negative breast cancer.
      ,
      • Schmid P.
      • Cortes J.
      • Dent R.
      • Pusztai L.
      • McArthur H.
      • Kümmel S.
      • et al.
      Event-free survival with pembrolizumab in early triple-negative breast cancer.
      ]. Several trials without pembrolizumab have shown high pCR rates for TNBC patients treated neoadjuvantly with platinum between 53% and 58% [
      • Loibl S.
      • O'Shaughnessy J.
      • Untch M.
      • Sikov W.M.
      • Rugo H.S.
      • McKee M.D.
      • et al.
      Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial.
      ,
      • Sikov W.M.
      • Berry D.A.
      • Perou C.M.
      • Singh B.
      • Cirrincione C.T.
      • Tolaney S.M.
      • et al.
      Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance).
      ,
      • von Minckwitz G.
      • Schneeweiss A.
      • Loibl S.
      • Salat C.
      • Denkert C.
      • Rezai M.
      • et al.
      Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial.
      ]. The addition of pembrolizumab resulted in a pCR rate of 64.8% [
      • Schmid P.
      • Cortes J.
      • Pusztai L.
      • McArthur H.
      • Kummel S.
      • Bergh J.
      • et al.
      Pembrolizumab for early triple-negative breast cancer.
      ]. However, a nP-based chemotherapy might be an alternative. In TNBC patients, the GeparSepto study showed a pCR rate of 48% after a NACT of nP followed by EC in TNBC compared to 26% with solvent paclitaxel instead of nP [
      • Untch M.
      • Jackisch C.
      • Schneeweiss A.
      • Conrad B.
      • Aktas B.
      • Denkert C.
      • et al.
      Nab-paclitaxel versus solvent-based paclitaxel in neoadjuvant chemotherapy for early breast cancer (GeparSepto-GBG 69): a randomised, phase 3 trial.
      ]. Disease-free survival also improved with nP compared to solvent paclitaxel [
      • Untch M.
      • Jackisch C.
      • Schneeweiss A.
      • Schmatloch S.
      • Aktas B.
      • Denkert C.
      • et al.
      NAB-paclitaxel improves disease-free survival in early breast cancer: GBG 69-GeparSepto.
      ]. Therefore, this treatment might be considered effective, with similar efficacy compared to platinum-containing chemotherapies.
      The NeoImmunoboost study adds to the knowledge of other studies combining ICI with anthracycline/nP-based chemotherapy regimens [
      • Loibl S.
      • Untch M.
      • Burchardi N.
      • Huober J.
      • Sinn B.V.
      • Ju Blohmer
      • et al.
      A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: clinical results and biomarker analysis of GeparNuevo study.
      ,
      • Loibl S.
      • Schneeweiss A.
      • Huober J.
      • Braun M.
      • Rey J.
      • Ju Blohmer
      • et al.
      Neoadjuvant durvalumab improves survival in early triple-negative breast cancer independent of pathological complete response.
      ,
      • Mittendorf E.A.
      • Zhang H.
      • Barrios C.H.
      • Saji S.
      • Jung K.H.
      • Hegg R.
      • et al.
      Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial.
      ,
      • Foldi J.
      • Silber A.
      • Reisenbichler E.
      • Singh K.
      • Fischbach N.
      • Persico J.
      • et al.
      Neoadjuvant durvalumab plus weekly nab-paclitaxel and dose-dense doxorubicin/cyclophosphamide in triple-negative breast cancer.
      ]. The combination of nP with Durvalumab resulted into a pCR rate of 53.4% in the Geparnuevo study [
      • Loibl S.
      • Untch M.
      • Burchardi N.
      • Huober J.
      • Sinn B.V.
      • Ju Blohmer
      • et al.
      A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: clinical results and biomarker analysis of GeparNuevo study.
      ]. In a smaller Phase I/II study with 55 patients, the combination of Durvalumab with a nP/doxorubicin-based chemotherapy showed a pCR rate of 44% [
      • Foldi J.
      • Silber A.
      • Reisenbichler E.
      • Singh K.
      • Fischbach N.
      • Persico J.
      • et al.
      Neoadjuvant durvalumab plus weekly nab-paclitaxel and dose-dense doxorubicin/cyclophosphamide in triple-negative breast cancer.
      ]. The Impassion031 study investigated the addition of atezolizumab to a nP/doxorubicin-based chemotherapy. In the atezolizumab arm, a pCR rate of 58% was reported [
      • Mittendorf E.A.
      • Zhang H.
      • Barrios C.H.
      • Saji S.
      • Jung K.H.
      • Hegg R.
      • et al.
      Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial.
      ]. Our study is the only study investigating the combination of pembrolizumab with a nP/anthracycline-based chemotherapy. The pCR rate was comparable with the other reported studies.
      The NeoTrip Study investigated the addition atezolizumab to a nP and platinum containing chemotherapy for 8 weeks, Anthracyclines were not given neoadjuvantly [
      • Gianni L.
      • Huang C.S.
      • Egle D.
      • Bermejo B.
      • Zamagni C.
      • Thill M.
      • et al.
      Pathologic complete response (pCR) to neoadjuvant treatment with or without atezolizumab in triple-negative, early high-risk and locally advanced breast cancer: NeoTRIP Michelangelo randomized study.
      ]. There was no significant difference between randomisation arms. The pCR rate in the atezolizumab arm was 48.6% and 44.4% without atezolizumab [
      • Gianni L.
      • Huang C.S.
      • Egle D.
      • Bermejo B.
      • Zamagni C.
      • Thill M.
      • et al.
      Pathologic complete response (pCR) to neoadjuvant treatment with or without atezolizumab in triple-negative, early high-risk and locally advanced breast cancer: NeoTRIP Michelangelo randomized study.
      ]. Together with the inhomogenous data from the metastatic studies Impassion130 [
      • Schmid P.
      • Adams S.
      • Rugo H.S.
      • Schneeweiss A.
      • Barrios C.H.
      • Iwata H.
      • et al.
      Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer.
      ], Impassion131 [
      • Miles D.W.
      • Gligorov J.
      • André F.
      • Cameron D.
      • Schneeweiss A.
      • Barrios C.H.
      • et al.
      Primary results from IMpassion131, a double-blind placebo-controlled randomised phase III trial of first-line paclitaxel (PAC) ± atezolizumab (atezo) for unresectable locally advanced/metastatic triple-negative breast cancer (mTNBC).
      ] and Keynote-355 [
      • Cortes J.
      • Rugo H.S.
      • Cescon D.W.
      • Im S.A.
      • Yusof M.M.
      • Gallardo C.
      • et al.
      Pembrolizumab plus chemotherapy in advanced triple-negative breast cancer.
      ], this study raises the question whether different chemotherapy-ICI-combinations result in different efficacies. The understanding of how chemotherapies interact with the immune system and/or immune therapies still has to be improved [
      • Park Y.H.
      • Lal S.
      • Lee J.E.
      • Choi Y.L.
      • Wen J.
      • Ram S.
      • et al.
      Chemotherapy induces dynamic immune responses in breast cancers that impact treatment outcome.
      ].
      Another aspect to which our study possibly adds information is the question of the role of a pre-chemotherapy single dose of an ICI. The GeparNuevo study indicated that this therapeutic regimen could lead to a higher pCR rate of 61.0% [
      • Loibl S.
      • Untch M.
      • Burchardi N.
      • Huober J.
      • Sinn B.V.
      • Ju Blohmer
      • et al.
      A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: clinical results and biomarker analysis of GeparNuevo study.
      ]. Our study could not confirm this effect. Patients treated without a pre-chemotherapy dose of pembro had a pCR rate of 59.3% (95%CI: 38.8–77.6), while patients with a dose of pembro had a pCR rate of 73.9% (95%CI: 51.6–89.8). With sample sizes of 27 and 23 in both cohorts, our study was very small, and it was not a randomised comparison. Therefore, the results have to be interpreted with caution. However, the trend observed in our study was in the opposite direction, and did not support a pre-chemotherapy dose. A randomized trial dedicated to this question finished recruitment [
      Clinicaltrials.gov
      Study to compare a mono atezolizumab window followed by a atezolizumab - CTX therapy with atezolizuab -CTX therapy (neoMono).
      ]. At the moment, a pre-chemotherapy single dose is not supported.
      KN522 provided extensive data concerning PD-L1 expression according to the CPS and pCR under treatment with and without pembro. While a CPS was not predictive of the effectiveness of pembro + chemo compared to chemotherapy alone, it correlated with the pCR rate in both randomisation arms. pCR rates in the pembro arm were 45.3%, 68.9%, 77.9% and 81.7% for patients with a CPS of <1, ≥1 ≥10, and ≥20, respectively [
      • Schmid P.
      • Park Y.H.
      • Ferreira M.
      • Mouret-Reynier M.-A.
      • Im S.-A.
      • Ahn J.-H.
      • et al.
      KEYNOTE-522 study of neoadjuvant pembrolizumab + chemotherapy vs placebo + chemotherapy, followed by adjuvant pembrolizumab vs placebo for early triple-negative breast cancer: pathologic complete response in key subgroups and by treatment exposure, residual cancer burden, and breast-conserving surgery.
      ]. Although we only had small patient numbers in our study, we could confirm the trend with 42.9%, 69.2%, 68.2% and 80.0% for the same categories.
      Regarding safety, there were some differences in the safety profile compared to Keynote-522. The most frequent all-grade adverse event in the NIB study was fatigue, which was reported for 58.5% of all patients. While the platinum-containing chemotherapy in the KN522 study led to all-grade nausea in 62.7% of patients, this was the case in only 43.4% of patients in the NIB study. However, with nP, there were expectedly more cases of peripheral neuropathy (all-grade: 54.7% in the NIB study, and 19.7% in the KN522 study) [
      • Schmid P.
      • Cortes J.
      • Pusztai L.
      • McArthur H.
      • Kummel S.
      • Bergh J.
      • et al.
      Pembrolizumab for early triple-negative breast cancer.
      ]. Otherwise, safety profiles were comparable.
      Concerning limitations of the small sample size have to be mentioned as it leads to a wide 95% CI of 51.2%–78.8% for pCR rates. Also, it has to be kept in mind that our study was not designed to compare patients with and without a pre-chemotherapy dose. Furthermore, comparisons with Keynote-522 are difficult because our study included 19 patients, who had lower tumour stages than included in Keynote-522. However pCR rates in the group of patients with higher tumour stages (supplementary table 4) were similar to those of the total patient population. Survival data of the NeoImmunoboost population is not yet available and will be analysed in the future.

      5. Conclusions

      In conclusion, we can show that the combination of nP followed by EC and pembro leads to a reasonably high pCR rate of 66%, and might be an individual therapy option in patients in whom platinum-containing chemotherapy is contraindicated. Expectedly a high rate of peripheral neuropathy is most likely the consequence of nP as part of the chemotherapy regimen. No new immune related adverse events were observed.

      Conflict of interest statement

      E.B. received honoraria from Novartis, Hexal AG, BMS, Lilly, Pfizer, Roche, MSD, Bayer, Ipsen, Bluebird, B. Braun and onkowissen.de for consulting, clinical research management or medical education activities.
      R.E. reports institutional research grants from AstraZeneca, Roche, Janssen-Cilag, NanoString Technologies, Novartis, Cepheid and BioNTech.
      P.A.F. received honoraria from Novartis, Pfizer, Roche, Amgen, Celgene, onkowissen.de, Daiichi-Sankyo, AstraZeneca, Merck Sharp and Dohme, Eisai, Puma and Teva. His institution conducts research with funding from Novartis and Biontech.
      T.N.F. has participated on advisory boards for Amgen, Daiichi-Sankyo, Novartis, Pfizer and Roche, and has received honoraria for lectures from Amgen, Celgene, Daiichi-Sankyo, Roche, Novartis and Pfizer.
      A.D.H. received speaker and consultancy honoraria from AstraZeneca, Genomic Health, Roche, Novartis, Celgene, Lilly, MSD, Eisai, Teva, Tesaro, Daiichi-Sankyo, Hexal AG and Pfizer.
      C.C. received honoraria from Novartis and Roche.
      Ar.Ha. reports institutional research grants from AstraZeneca, Roche, Janssen-Cilag, NanoString Technologies, Novartis, Cepheid and BioNTech.
      W.J. has received research grants and/or honoraria from Sanofi-Aventis, Daiichi-Sankyo, Novartis, Roche, Pfizer, Lilly, AstraZeneca, Chugai, GSK, Eisai, Celgene and Johnson & Johnson.
      abrH.-C.K. has received honoraria from Pfizer, Novartis, Roche, Genomic Health/Exact Sciences, Amgen, AstraZeneca, Riemer, Carl Zeiss Meditec AG, Teva, Theraclion, Janssen-Cilag, GSK, LIV Pharma, Lily, SurgVision, Onkowissen and MSD, travel support from Carl Zeiss Meditec AG, LIV Pharma, Novartis, Amgen, Pfizer, Daiichi-Sankyo and Tesaro, and owns stock in Theraclion SA and Phaon Scientific GmbH.
      M.U. reports that all honoraria went to the institution/employer: Abbvie, Amgen, AstraZeneca, Celgene, Daichi Sankyo, Eisai, Lilly, MSD Merck, Mundipharma, Myriad Genetics, Pfizer, Puma Biotechnology, Roche, Sanofi Aventis, Novartis and Pierre Fabre.
      All other authors (M.W.B., S.Y.B., L.H., Al.He., M.R. and S.U.) declare that they do not have a conflict of interest.

      Author contribution

      Conception and design: P.A.F., M.U., A.H. and A.-K.T.
      Collection and assembly of data: P.A.F., A.H., H.C.K., E.B., C.C.H., A.H., R.E., S.Y.B, A.D.H., M.U., S.U. and L.H.
      Data analysis and interpretation: P.A.F., M.U, S.U., L.H. and M.R.
      Manuscript writing: All authors.
      Final approval of manuscript: All Authors.
      Provision of study material or patients: P.A.F., A.H., H.C.K., E.B., C.C.H., A.H., R.E., S.Y.B, A.D.H. and M.U.

      Acknowledgments

      This study was conducted as an investigator-initiated trial. It was partially funded by Merck Sharp & Dohme GmbH, Germany and Bristol-Myers Squibb GmbH & Co. KGaA (Celgene). The funding entities did not have any influence on the conduct of the study or the content of this manuscript.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article.

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