Triple-negative Breast Cancer
Conditions
Keywords
TNBC, Immunotherapy
Brief summary
This is a randomized, open-label, adaptive, two arm, multicentre, Phase II trial comparing a neoadjuvant chemotherapy with PDL1-inhibition (Atezolizumab) and Atezolizumab two-week window to chemotherapy with PDL1-inhibition (Atezolizumab) and identify biomarkers predicting (early) response to or resistance against Atezolizumab (alone and with CTX) allowing patients stratification in future clinical trials
Detailed description
This is a randomized, open-label, adaptive, two arm, multicenter phase II trial that enrolled female and male patients with primary TNBC (defined as ER/PR \< 10% and HER2-negative) with tumor stages cT1c - cT4d (cN0 and cN+). Patients are randomized to Arm A and B. Randomization is stratified by PD-L1 expression on immune cells (IC-status) and anatomic tumor stage (according to the AJCC 8th edition Anatomic Stage Groups I, II andIII). PD-L1 status is determined by central pathology using the VENTANA PD-L1 (SP142) assay and is defined by PD-L1 IC expression. Patients in Arm A receive a 2-week monotherapy of Atezolizumab 840 mg q2w prior to initiation of a 12-week neoadjuvant CTX therapy with Paclitaxel 80 mg/m2 i.v. q1w x 12 doses + Carboplatin AUC of 2 i.v. q1w x 12 doses + Atezolizumab 1200 mg day 1 every 3 weeks for 4 doses followed by Epirubicin 90 mg/m2 + Cyclophosphamide 600 mg/m2, both q3w for 4 cycles + Atezolizumab 1200 mg day 1 every 3 weeks for 4 doses. Patients in Arm B are treated with a neoadjuvant 12-week regimen of Paclitaxel 80 mg/m² i.v. q1w x 12 doses + Carboplatin AUC of 2 i.v. q1w x 12 doses + Atezolizumab 1200 mg day 1 every 3 weeks for 4 doses without a monotherapy window. This is followed by Epirubicin 90 mg/m² + Cyclophosphamide 600 mg/m2, both q3w for 4 cycles + Atezolizumab 1200 mg day 1 every 3 weeks for 4 doses. Patients in both arms undergo surgery after 29 - 30 weeks therapy in total for Arm A and 27 - 28 weeks therapy in total for Arm B (3 - 4 weeks after last dose of neoadjuvant therapy). Safety and toxicities under therapy are supervised via regular DSMB meetings. After surgery, patients are treated according to the local SoC therapy for TNBC and followed-up for 24 months.
Interventions
840 mg Day 1 for two weeks
1200 mg Day 1 every 3 weeks for 8 cycles
DRUGCarboplatin
Dosing according to Area Under the Curve of 2 Intravenous weekly x 12 cycles
DRUGPaclitaxel
Paclitaxel 80 mg/m² IV weekly x 12 cycles
DRUGEpirubicin
90 mg/m2, day 1 for 4 cycles (12 weeks)
DRUGCyclophosphamide
600 mg/m2, day 1 for 4 cycles (12 weeks)
PROCEDUREBiopsy Arm A
1st Biopsy two weeks after Baseline visit. 2nd Biopsy after two weeks of Carboplatin + Paclitaxel + Atezolizumab therapy. 3rd Biopsy with tumor size greater 10 mm in diameter.
PROCEDUREBiopsy Arm B
1st Biopsy after two weeks of Carboplatin + Paclitaxel + Atezolizumab therapy. 2nd Biopsy with tumor size greater 10mm in diameter.
PROCEDURESurgery
After completion of 27-28 weeks (Arm B) or 29-30 weeks (Arm A) of neoadjuvant treatment, surgery is planned for all patients.
Sponsors
Roche Pharma AG
Phaon Scientific GmbH
University Hospital, Essen
University Hospital Erlangen
Palleos Healthcare GmbH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Female and male patients, age at diagnosis 18 years and above * Written informed consent prior to admission to this study * Histologically confirmed unilateral primary invasive carcinoma of the breast * Clinical T1c - T4d * Stage N0-N3 until 21 patients (5%) with stage N3 are randomized, thereafter N0-N2 * Triple negative breast cancer defined by and confirmed by central pathology: * ER negative (\<10% positive cells in IHC) and PR negative (\<10% positive cells on IHC) * HER2 negative breast cancer: * Either defined by IHC: ICH scores of 0-1 or an ICH score of 2 in combination with a negative in-situ-hybridization (ISH) * Or defined by ISH: negative ISH * Identifiable PD-L1 IC-status by central pathology (positive or negative) by means of VENTANA PD-L1 (SP142) assay; positive status is defined by PD-L1 expression on IC on ≥ 1% of the tumor area, negative status is defined by PD-L1 expression on IC on \< 1% of the tumor area * No clinical evidence for distant metastasis (cM0) * Tumor block available for translational research * Performance Status Eastern Cooperative Oncology Group (ECOG) ≤ 1 or KI ≥ 80 % * Negative pregnancy test (urine or serum) within 7 days prior to screening in premenopausal patients * Women of childbearing potential and male patients with partners of childbearing potential must accept to implement a highly effective (less than 1% failure rate according to Pearl index) including at least one non-hormonal contraceptive measures during the study treatment and for 5 months following the last dose of study treatment such as: * Intrauterine device (IUD) * bilateral tubal occlusion * vasectomized partner * sexual abstinence * The patient must be accessible for treatment and follow-up * Normal cardiac function: * Normal electrocardiogram (ECG) (within 6 weeks prior to screening) * Normal left ventricular ejection fraction (LVEF) on echocardiorgraphy * Normal thyroid function o Normal TSH and FT4 * Blood counts within 14 days prior screening: * absolute neutrophile count (ANC) must be ≥ 1,500/mm3 * Platelet count must be ≥ 100,000 / mm3 * Hemoglobin must be ≥ 10 g/dl * Hepatic functions: * Total bilirubin must be ≤ 1 upper limit of normal (ULN) for the lab unless the patient has a bilirubin elevation \> 1 x ULN to 1.5 x ULN due to Gilbert's disease or similar syndrome involving slow conjugation of bilirubin * Alkaline phosphatase must be ≤ 2.5 x ULN for the lab * AST and ALT must be ≤1.5 x ULN for the lab. * Patients with AST and ALT or alkaline phosphatase \> 1 x ULN are eligible for inclusion if liver imaging (computerized tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET-CT, or PET scan) performed within 3 months prior to randomization (and part of standard of care) does not demonstrate metastatic disease and the requirements in criterion (just above) are met * Patients with alkaline phosphatase that is \> 1 x ULN but less than or equal to 2.5 x ULN or with unexplained bone pain are eligible if bone imaging does not demonstrate metastatic disease. * Creatinine clearance ≥ 40 ml/min performed 28 days prior to screening
Exclusion criteria
* Previous history of malign diseases, non-melanoma skin cancer and carcinoma of the cervix are allowed if treated with curative intent * Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that, in the investigator's opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of Paclitaxel, Carboplatin, Epirubicin, Cyclophosphamide or Atezolizumab * Psychological, familial, sociological or geographical conditions that do not permit compliance with the study protocol * Concurrent treatment with other drugs that are contraindicating the use of the study drugs * Existing pregnancy * Breastfeeding * Sequential breast cancer * Concurrent treatment with other experimental drugs and participation in another clinical trial or clinical research project (except registry study) within 30 days prior to study entry * Severe and relevant co-morbidity that would interact with the application of cytotoxic agents or the participation in the study including but not confined to: * Uncompensated chronic heart failure or systolic dysfunction (LVEF \< 55%, congestive heart failure (CHF) New York Heart Association (NYHA) classes II-IV), * unstable arrhythmias requiring treatment i.e., atrial tachycardia with a heart rate ≥ 100/bpm at rest, significant ventricular arrhythmia (ventricular tachycardia) or higher grade AV-block, * Angina pectoris within the last 6 months requiring anti-anginal medication, * Clinically significant valvular heart disease, * Evidence of myocardial infarction on electrocardiogram (ECG), * Poorly controlled hypertension (e.g., systolic \> 180 mmHg or diastolic \> 100 mmHg). * Inadequate organ function including but not confined to: * hepatic impairment as defined by bilirubin \> 1.5 x ULN * pulmonary disease (severe dyspnea at rest requiring oxygen therapy) * Abnormal blood values: * Platelet count below 100,000/mm3 * AST/ALT \> 1.5 x ULN * Hypokalaemia \> CTCAE grade 1 * Neutropenia \> CTCAE grade 1 * Anaemia \> CTCAE grade 1 * Administration of a live, attenuated vaccine within 4 weeks before cycle 1 day 1 or anticipation that such a vaccine will be required during the study * Treatment with systemic immunosuppressive medications (including but not limited to interferons, IL-2) within 28 days or 5 half-lives of the drug, whichever is longer, prior to randomization. * Treatment with systemic immunosuppressive medications (including but not limited to Prednisone, Cyclophosphamide, Azathioprine, Methotrexate, Thalidomide, and anti-tumor necrosis \[anti-TNF\] factor agents) within 14 days prior to screening or anticipation of need for systemic immunosuppressive medications during the study * Patients with prior allogeneic stem cell or solid organ transplantation * Active or history of autoimmune disease or immune deficiency, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis with the following exceptions: * Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible for this study. * Patients with controlled Type 1 diabetes mellitus on a stable dose of insulin regimen may be eligible for this study. * Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are permitted provided all of following conditions are met: Rash must cover \< 10% of body surface area; Disease is well controlled at baseline and requires only low-potency topical corticosteroids; No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, Methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral Corticosteroids within the previous 12 months. * History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan. * History of HIV infection, hepatitis B or hepatitis C infection. * Patients with significant cardiovascular disease * Patients with inadequate hematological and end-organ function * Patients receiving therapeutic anti-coagulants * Stage N3, as soon as 21 patients with stage N3 are randomized
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pathological Complete Response (ypT0/is, ypN0) | after 29-30 weeks in Arm A and after 27-28 weeks in Arm B. | Pathological Complete Response defined as no residual invasive tumor cells in the breast and in the lymph nodes (ypT0/is, ypN0). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pathological Complete Response (ypT0/is, ypN0) (ER/PR Expression of <1%). | after 29-30 weeks in Arm A and after 27-28 weeks in Arm B | Pathological complete response defined as no residual invasive tumor cells in the breast and in the lymph nodes (ypT0/is, ypN0) in patients with an ER/PR expression of \<1% and an ER/PR expression of 1% to 10%. |
| Pathological Complete Response (ypT0/is, ypN0) (ER/PR Between 1 and 10 %). | after 29-30 weeks in Arm A and after 27-28 weeks in Arm B | Pathological complete response defined as no residual invasive tumor cells in the breast and in the lymph nodes (ypT0/is, ypN0) in patients with an ER/PR expression of \<1% and an ER/PR expression of 1% to 10%. |
| Pathological Complete Response (ypT0, ypN0) | after 29-30 weeks in Arm A and after 27-28 weeks in Arm B. | Pathological complete response defined as no tumor cells (invasive and no non-invasive) in the breast but also in the lymph nodes (ypN0, ypT0). |
| Near Pathological Complete Response (Near pCR) | after 29-30 weeks in Arm A and after 27-28 weeks in Arm B. | Near pCR defined as residual tumor \<5 mm in the breast irrespective of in situ and lymph nodes status |
| Pathological Complete Response (no Invasive Tumor) | after 29-30 weeks in Arm A and after 27-28 weeks in Arm B. | Pathological Complete Response defined as no invasive tumor in the breast, irrespective of lymph node status |
| Decrease of Ki-67 Expression by ≥ 30% Compared to Baseline as Continuous Predictor After 14 (Arm A)/28 Days (armB) (+/- 2 Days) of Treatment | after 14/28 days (+/- 2 days) of treatment | Decrease of Ki-67 expression versus baseline after 14/28 days (+/- 2 days) of treatment as continuous predictor. General comment to analysis of secondary biomarker endpoints: biomarker endpoints are analysed as secondary efficacy endpoints. Biomarker endpoints are measured by core biopsy at a central pathology laboratory at two different timepoints. For arm A visit 1 (A1 in tables) corresponds to day 14 in the trial and denotes the measurement after the Atezolizumab monotherapy window. Arm A visit 3 (A3 in tables) corresponds to day 28 and denotes a measurement taken again after two weeks of combined immuno- and chemotherapy. In arm B, only visit 2 (day 14; B2 in tables) is measured after the initial two weeks of combined immuno- and chemotherapy. |
| Decrease of Ki-67 Expression After 28 Days (+/- 2 Days) of Treatment for Arm A and Arm B. | after 28 days (+/- 2 days) of treatment | Decrease of Ki-67 expression versus baseline by 30% or more after 28 days (+/- 2 days) of treatment. See general comments to biomarker endpoints above. Decrease of Ki-67 defined as ≥ 30% compared to baseline. |
| Stromal Tumor-infiltrating Lymphocytes (TILs) ≥ 60% After 14 (Arm A)/28 Days (ArmB) | after 14/28 days (+/- 2 days) of treatment | TILs after 14/28 days (+/- 2 days) of treatment as continuous predictor. See general comments to biomarker endpoints above. |
| Tumor-infiltrating Lymphocytes (TILs) ≥ 60% After 28 Days | after 28 days (+/- 2 days) of treatment | TILs ≥ 60% after 28 days (+/- 2 days) of treatment. Stromal Tumor Infiltrating Lymphocytes (TILs) ≥ 60%. See general comments to biomarker endpoints above. |
| Number of Adverse Events by Grade | from date of randomization up to 24 months | Safety (incidence, relationship, seriousness, and severity of all AEs, SAEs, AESIs coded by medical dictionary for regulatory activities (MedDRA), summarized by Preferred Term and System Organ Class and graded according to common terminology criteria of adverse events (CTCAE V5.0) |
| Complete Cell Cycle Arrest (CCCA) After 28 Days (+/- 2 Days) of Treatment | after 28 days (+/- 2 days) of treatment | CCCA: Ki-67 expression ≤ 2.7%. Complete Cell Cycle Arrest (CCCA) defined as : Ki-67 ≤ 2.7%. See general comments to biomarker endpoints above. |
| Low Cellularity (< 500 Tumor Cells) After 14 (Arm A)/28 Days (Arm B) (+/- 2 Days) of Treatment | after 14/28 days (+/- 2 days) of treatment | Low cellularity: \< 500 tumor cells after 14/28 days (+/- 2 days) of treatment. See general comments to biomarker endpoints above. |
| Low Cellularity (< 500 Tumor Cells) After 28 Days (+/- 2 Days) of Treatment | after 28 days (+/- 2 days) of treatment | Low cellularity: \< 500 tumor cells after 28 days (+/- 2 days) of treatment. See general comments to biomarker endpoints above. |
| Combined Early Response After 14 (Arm A)/28 (Arm B) Days (+/- 2 Days) of Treatment | after 14/28 days (+/- 2 days) of treatment | Combined early response defined by * CCCA (Ki-67 expression \< 2.7%) or * low cellularity or * decrease of Ki-67 expression (versus baseline) by 30% or more or * TILs ≥ 60% See general comments to biomarker endpoints above. |
| Combined Early Response After 28 Days (+/- 2 Days) of Treatment | after 28 days (+/- 2 days) of treatment | Combined early response defined by * CCCA (Ki-67 expression \< 2.7%) or * low cellularity or * decrease of Ki-67 expression (versus baseline) by 30% or more or * TILs ≥ 60% See general comments to biomarker endpoints above. |
| Disease Free Survival (DFS) | from randomization up to 24 months until date of occurrence of no disease to the first occurrence of disease recurrence or death from any cause | Disease free survival (DFS) defined as time from the first date of no disease \[i.e. date of surgery\] to the first occurrence of disease recurrence or death from any cause. |
| Overall Survival (OS). | from randomization up to 24 months until date of death from any cause. | Overall survival (OS) defined as length of time from randomization to death from any cause. Given that novel post-neoadjuvant treatment options (on and off-trial) have emerged such as Pembrolizumab, the post-neoadjuvant treatment in the follow-up phase of this study would have been most certainly highly heterogeneous. Thus, completion of follow-up to 3 years was no longer justified. Therefore, follow-up was limited to 2 years and only clinically significant survival signals were observed. |
| Event Free Survival (EFS) | from randomization up to 24 months until date of death from any cause, failure to achieve remission after induction therapy, relapse in any site, or second malignancy | Event free survival (EFS) defined as length of time after randomization till death from any cause, failure to achieve remission after induction therapy, relapse in any site, or second malignancy |
| Complete Cell Cycle Arrest (CCCA) After 14 (Arm A)/28 Days (armB) (+/- 2 Days) of Treatment | after 14/28 days (+/- 2 days) of treatment | Complete Cell Cycle Arrest (CCCA): Ki-67 expression ≤ 2.7% after 14/28 days (+/- 2 days) of treatment. See general comments to biomarker endpoints above. |
Countries
Germany
Participant flow
Recruitment details
Participants were screened at 34 centers in Germany.The expected number of patients to be recruited was 458. As the study protocol mandated termination of trial recruitment based on the results of the first interim analysis, the final Intention-to-treat (ITT) population was limited to 359 participants.442 participants had been screened, and 2 per arm were excluded from analysis due to protocol violations. First participant enrolled: 2021-03-01; last visit of a participant: 2024-10-02.
Participants by arm
| Arm | Count |
|---|---|
| Arm A 2 weeks Atezolizumab monotherapy before biopsy, followed by a 12-week therapy with Paclitaxel + Carboplatin+ Atezolizumab every 3 weeks for 4 cycles. This will be followed by Epirubicin + Cyclophosphamide + Atezolizumab every 3 weeks for 4 cycles.
Atezolizumab 840 MG in 14 ML Injection: 840 mg Day 1 for two weeks
Atezolizumab 1200 MG in 20 ML Injection: 1200 mg Day 1 every 3 weeks for 8 cycles
Carboplatin: Dosing according to Area Under the Curve of 2 Intravenous weekly x 12 cycles
Paclitaxel: Paclitaxel 80 mg/m² IV weekly x 12 cycles
Epirubicin: 90 mg/m2, day 1 for 4 cycles (12 weeks)
Cyclophosphamide: 600 mg/m2, day 1 for 4 cycles (12 weeks)
Biopsy Arm A: 1st Biopsy two weeks after Baseline visit. 2nd Biopsy after two weeks of Carboplatin + Paclitaxel + Atezolizumab therapy. 3rd Biopsy with tumor size greater 10 mm in diameter.
Surgery: After completion of 27-28 weeks (Arm B) or 29-30 weeks (Arm A) of neoadjuvant treatment, surgery is planned for all patients. | 180 |
| Arm B 12-week therapy with Paclitaxel + Carboplatin + Atezolizumab every 3 weeks for 4 cycles. This will be followed by Epirubicin + Cyclophosphamide + Atezolizumab every 3 weeks for 4 cycles.
Atezolizumab 1200 MG in 20 ML Injection: 1200 mg Day 1 every 3 weeks for 8 cycles
Carboplatin: Dosing according to Area Under the Curve of 2 Intravenous weekly x 12 cycles
Paclitaxel: Paclitaxel 80 mg/m² IV weekly x 12 cycles
Epirubicin: 90 mg/m2, day 1 for 4 cycles (12 weeks)
Cyclophosphamide: 600 mg/m2, day 1 for 4 cycles (12 weeks)
Biopsy Arm B: 1st Biopsy after two weeks of Carboplatin + Paclitaxel + Atezolizumab therapy. 2nd Biopsy with tumor size greater 10mm in diameter.
Surgery: After completion of 27-28 weeks (Arm B) or 29-30 weeks (Arm A) of neoadjuvant treatment, surgery is planned for all patients. | 179 |
| Total | 359 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 23 | 21 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Disease progression | 4 | 8 |
| Overall Study | Physician Decision | 7 | 3 |
| Overall Study | Protocol Violation | 0 | 2 |
| Overall Study | Switched to other therapy. | 0 | 2 |
| Overall Study | Withdrawal by Subject | 11 | 12 |
Baseline characteristics
| Characteristic | Total | Arm A | Arm B |
|---|---|---|---|
| Age, Continuous | 49.27 years STANDARD_DEVIATION 12.01 | 48.57 years STANDARD_DEVIATION 11.66 | 49.98 years STANDARD_DEVIATION 12.34 |
| Cellularity (percentage of tumor volume occupied by invasive tumors cells) | 39.01 percentage STANDARD_DEVIATION 20.5 | 39.22 percentage STANDARD_DEVIATION 20.17 | 38.80 percentage STANDARD_DEVIATION 20.88 |
| ECOG ECOG = 0 | 339 Participants | 169 Participants | 170 Participants |
| ECOG ECOG = 1 | 20 Participants | 11 Participants | 9 Participants |
| HER2 IHC status 0 | 147 Participants | 72 Participants | 75 Participants |
| HER2 IHC status 1+ | 162 Participants | 80 Participants | 82 Participants |
| HER2 IHC status 2+ | 50 Participants | 28 Participants | 22 Participants |
| HER2 status LOW (IHC 1+ or 2+/ISH negative) | 212 Participants | 108 Participants | 104 Participants |
| HER2 status NEGATIVE | 147 Participants | 72 Participants | 75 Participants |
| HER2 status POSITIVE | 0 Participants | 0 Participants | 0 Participants |
| Hormone receptor status Borderline Positive (either ER or PR expression is above 1% and <10%) | 58 Participants | 25 Participants | 33 Participants |
| Hormone receptor status Negative | 301 Participants | 155 Participants | 146 Participants |
| Largest tumor diameter | 25.07 mm STANDARD_DEVIATION 11.99 | 24.79 mm STANDARD_DEVIATION 2.47 | 25.34 mm STANDARD_DEVIATION 11.52 |
| Nodal status cN0 | 249 Participants | 123 Participants | 126 Participants |
| Nodal status cN1 | 84 Participants | 41 Participants | 43 Participants |
| Nodal status cN2 | 17 Participants | 10 Participants | 7 Participants |
| Nodal status cN3 | 9 Participants | 6 Participants | 3 Participants |
| PD-L1 expression | 1.17 percentage STANDARD_DEVIATION 3.18 | 1.12 percentage STANDARD_DEVIATION 2.77 | 1.22 percentage STANDARD_DEVIATION 3.55 |
| Percentage of Positive KI-67 Cells | 69.27 percentage STANDARD_DEVIATION 17.89 | 69.28 percentage STANDARD_DEVIATION 17.97 | 69.26 percentage STANDARD_DEVIATION 17.86 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 16 Participants | 10 Participants | 6 Participants |
| Race (NIH/OMB) White | 339 Participants | 168 Participants | 171 Participants |
| Region of Enrollment Germany | 359 participants | 180 participants | 179 participants |
| Sex: Female, Male Female | 358 Participants | 179 Participants | 179 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 0 Participants |
| TILs (percentage) | 24.89 percentage STANDARD_DEVIATION 19.49 | 24.68 percentage STANDARD_DEVIATION 19.64 | 25.10 percentage STANDARD_DEVIATION 19.38 |
| Tumor grading GRADE 2 | 39 Participants | 21 Participants | 18 Participants |
| Tumor grading GRADE 3 | 320 Participants | 159 Participants | 161 Participants |
| Tumor histology INFILTRATING DUCTAL | 337 Participants | 171 Participants | 166 Participants |
| Tumor histology INFILTRATING LOBULAR | 3 Participants | 3 Participants | 0 Participants |
| Tumor histology Missing | 15 Participants | 5 Participants | 10 Participants |
| Tumor histology MIXED | 3 Participants | 1 Participants | 2 Participants |
| Tumor histology MUCINOUS | 1 Participants | 0 Participants | 1 Participants |
| Tumor stage cT1c | 136 Participants | 73 Participants | 63 Participants |
| Tumor stage cT2 | 198 Participants | 96 Participants | 102 Participants |
| Tumor stage cT3 | 18 Participants | 6 Participants | 12 Participants |
| Tumor stage cT4a | 1 Participants | 1 Participants | 0 Participants |
| Tumor stage cT4b | 2 Participants | 1 Participants | 1 Participants |
| Tumor stage cT4c | 1 Participants | 1 Participants | 0 Participants |
| Tumor stage cT4d | 3 Participants | 2 Participants | 1 Participants |
| Weight (kg) | 71.18 kg STANDARD_DEVIATION 13.6 | 72.00 kg STANDARD_DEVIATION 13.52 | 70.36 kg STANDARD_DEVIATION 13.65 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 180 | 0 / 179 |
| other Total, other adverse events | 178 / 178 | 178 / 178 |
| serious Total, serious adverse events | 86 / 178 | 87 / 178 |
Outcome results
Primary
Pathological Complete Response (ypT0/is, ypN0)
Pathological Complete Response defined as no residual invasive tumor cells in the breast and in the lymph nodes (ypT0/is, ypN0).
Time frame: after 29-30 weeks in Arm A and after 27-28 weeks in Arm B.
Population: The analysis was performed in the ITT population. The analysis population for the primary endpoint encompassed 339 patients with available pCR status (10 missing in each arm).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A | Pathological Complete Response (ypT0/is, ypN0) | pCR = 0 (no pCR) | 58 Participants |
| Arm A | Pathological Complete Response (ypT0/is, ypN0) | pCR = 1 (pCR achieved) | 112 Participants |
| Arm B | Pathological Complete Response (ypT0/is, ypN0) | pCR = 0 (no pCR) | 52 Participants |
| Arm B | Pathological Complete Response (ypT0/is, ypN0) | pCR = 1 (pCR achieved) | 117 Participants |
Comparison: This was a randomized, open-label, adaptive, two arm, multicenter phase II trial that enrolled female and male patients with primary TNBC (defined as ER/PR \< 10% and HER2-negative) with tumor stages cT1c - cT4d (cN0 and cN+). Patients were randomized to Arm A and B, stratified by PD-L1 expression on immune cells (IC-status) and anatomic tumor stage (Anatomic Stage Groups I, II and III). PD-L1 status was determined by central pathology using the VENTANA PD-L1 (SP142) assay.95% CI: [-0.1307, 0.0663]
Secondary
Combined Early Response After 14 (Arm A)/28 (Arm B) Days (+/- 2 Days) of Treatment
Combined early response defined by * CCCA (Ki-67 expression \< 2.7%) or * low cellularity or * decrease of Ki-67 expression (versus baseline) by 30% or more or * TILs ≥ 60% See general comments to biomarker endpoints above.
Time frame: after 14/28 days (+/- 2 days) of treatment
Population: Analyzed were all available samples of participants (19 missing in arm A; 37 missing in arm B).
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A | Combined Early Response After 14 (Arm A)/28 (Arm B) Days (+/- 2 Days) of Treatment | Combined Resp. A1B2 = 0 (not achieved) | 116 Participants |
| Arm A | Combined Early Response After 14 (Arm A)/28 (Arm B) Days (+/- 2 Days) of Treatment | Combined Resp. A1B2 = 1 (achieved) | 45 Participants |
| Arm B | Combined Early Response After 14 (Arm A)/28 (Arm B) Days (+/- 2 Days) of Treatment | Combined Resp. A1B2 = 0 (not achieved) | 53 Participants |
| Arm B | Combined Early Response After 14 (Arm A)/28 (Arm B) Days (+/- 2 Days) of Treatment | Combined Resp. A1B2 = 1 (achieved) | 89 Participants |
95% CI: [-0.447, -0.238]
Secondary
Combined Early Response After 28 Days (+/- 2 Days) of Treatment
Combined early response defined by * CCCA (Ki-67 expression \< 2.7%) or * low cellularity or * decrease of Ki-67 expression (versus baseline) by 30% or more or * TILs ≥ 60% See general comments to biomarker endpoints above.
Time frame: after 28 days (+/- 2 days) of treatment
Population: Analyzed were all available samples of participants (41 missing in arm A; 37 missing in arm B).
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A | Combined Early Response After 28 Days (+/- 2 Days) of Treatment | Combined Resp. A3B2 = 0 (not achieved) | 47 Participants |
| Arm A | Combined Early Response After 28 Days (+/- 2 Days) of Treatment | Combined Resp. A3B2 = 1 (achieved) | 92 Participants |
| Arm B | Combined Early Response After 28 Days (+/- 2 Days) of Treatment | Combined Resp. A3B2 = 1 (achieved) | 89 Participants |
| Arm B | Combined Early Response After 28 Days (+/- 2 Days) of Treatment | Combined Resp. A3B2 = 0 (not achieved) | 53 Participants |
95% CI: [-0.076, 0.146]
Secondary
Complete Cell Cycle Arrest (CCCA) After 14 (Arm A)/28 Days (armB) (+/- 2 Days) of Treatment
Complete Cell Cycle Arrest (CCCA): Ki-67 expression ≤ 2.7% after 14/28 days (+/- 2 days) of treatment. See general comments to biomarker endpoints above.
Time frame: after 14/28 days (+/- 2 days) of treatment
Population: Analyzed were all available samples of participants (20 missing in arm A; 41 missing in arm B).
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A | Complete Cell Cycle Arrest (CCCA) After 14 (Arm A)/28 Days (armB) (+/- 2 Days) of Treatment | CCCA A1B2 = 0 (not achieved) | 160 Participants |
| Arm A | Complete Cell Cycle Arrest (CCCA) After 14 (Arm A)/28 Days (armB) (+/- 2 Days) of Treatment | CCCA A1B2 = 1 (achieved) | 0 Participants |
| Arm B | Complete Cell Cycle Arrest (CCCA) After 14 (Arm A)/28 Days (armB) (+/- 2 Days) of Treatment | CCCA A1B2 = 0 (not achieved) | 138 Participants |
| Arm B | Complete Cell Cycle Arrest (CCCA) After 14 (Arm A)/28 Days (armB) (+/- 2 Days) of Treatment | CCCA A1B2 = 1 (achieved) | 0 Participants |
95% CI: [-0.022, 0.018]
Secondary
Complete Cell Cycle Arrest (CCCA) After 28 Days (+/- 2 Days) of Treatment
CCCA: Ki-67 expression ≤ 2.7%. Complete Cell Cycle Arrest (CCCA) defined as : Ki-67 ≤ 2.7%. See general comments to biomarker endpoints above.
Time frame: after 28 days (+/- 2 days) of treatment
Population: Analyzed were all available samples of participants (43 missing in arm A; 41 missing in arm B).
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A | Complete Cell Cycle Arrest (CCCA) After 28 Days (+/- 2 Days) of Treatment | CCCA A3B2 = 0 (not achieved) | 136 Participants |
| Arm A | Complete Cell Cycle Arrest (CCCA) After 28 Days (+/- 2 Days) of Treatment | CCCA A3B2 = 1 (achieved) | 1 Participants |
| Arm B | Complete Cell Cycle Arrest (CCCA) After 28 Days (+/- 2 Days) of Treatment | CCCA A3B2 = 0 (not achieved) | 138 Participants |
| Arm B | Complete Cell Cycle Arrest (CCCA) After 28 Days (+/- 2 Days) of Treatment | CCCA A3B2 = 1 (achieved) | 0 Participants |
95% CI: [-0.017, 0.034]
Secondary
Decrease of Ki-67 Expression After 28 Days (+/- 2 Days) of Treatment for Arm A and Arm B.
Decrease of Ki-67 expression versus baseline by 30% or more after 28 days (+/- 2 days) of treatment. See general comments to biomarker endpoints above. Decrease of Ki-67 defined as ≥ 30% compared to baseline.
Time frame: after 28 days (+/- 2 days) of treatment
Population: Analyzed were all available samples of participants (43 missing in arm A; 41 missing in arm B).
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A | Decrease of Ki-67 Expression After 28 Days (+/- 2 Days) of Treatment for Arm A and Arm B. | Ki-67 BL Decr. >= 30% A3B2 = 0 (not achieved) | 84 Participants |
| Arm A | Decrease of Ki-67 Expression After 28 Days (+/- 2 Days) of Treatment for Arm A and Arm B. | Ki-67 BL Decr. >= 30% A3B2 = 1 (achieved) | 53 Participants |
| Arm B | Decrease of Ki-67 Expression After 28 Days (+/- 2 Days) of Treatment for Arm A and Arm B. | Ki-67 BL Decr. >= 30% A3B2 = 0 (not achieved) | 90 Participants |
| Arm B | Decrease of Ki-67 Expression After 28 Days (+/- 2 Days) of Treatment for Arm A and Arm B. | Ki-67 BL Decr. >= 30% A3B2 = 1 (achieved) | 48 Participants |
95% CI: [-0.078, 0.15]
Secondary
Decrease of Ki-67 Expression by ≥ 30% Compared to Baseline as Continuous Predictor After 14 (Arm A)/28 Days (armB) (+/- 2 Days) of Treatment
Decrease of Ki-67 expression versus baseline after 14/28 days (+/- 2 days) of treatment as continuous predictor. General comment to analysis of secondary biomarker endpoints: biomarker endpoints are analysed as secondary efficacy endpoints. Biomarker endpoints are measured by core biopsy at a central pathology laboratory at two different timepoints. For arm A visit 1 (A1 in tables) corresponds to day 14 in the trial and denotes the measurement after the Atezolizumab monotherapy window. Arm A visit 3 (A3 in tables) corresponds to day 28 and denotes a measurement taken again after two weeks of combined immuno- and chemotherapy. In arm B, only visit 2 (day 14; B2 in tables) is measured after the initial two weeks of combined immuno- and chemotherapy.
Time frame: after 14/28 days (+/- 2 days) of treatment
Population: Analyzed were available samples of participants (20 missing in arm A; 41 missing in arm B).
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A | Decrease of Ki-67 Expression by ≥ 30% Compared to Baseline as Continuous Predictor After 14 (Arm A)/28 Days (armB) (+/- 2 Days) of Treatment | Ki-67 BL Decr. >= 30% A1B2 = 0 (not achieved) | 142 Participants |
| Arm A | Decrease of Ki-67 Expression by ≥ 30% Compared to Baseline as Continuous Predictor After 14 (Arm A)/28 Days (armB) (+/- 2 Days) of Treatment | Ki-67 BL Decr. >= 30% A1B2 = 1 (achieved) | 18 Participants |
| Arm B | Decrease of Ki-67 Expression by ≥ 30% Compared to Baseline as Continuous Predictor After 14 (Arm A)/28 Days (armB) (+/- 2 Days) of Treatment | Ki-67 BL Decr. >= 30% A1B2 = 0 (not achieved) | 90 Participants |
| Arm B | Decrease of Ki-67 Expression by ≥ 30% Compared to Baseline as Continuous Predictor After 14 (Arm A)/28 Days (armB) (+/- 2 Days) of Treatment | Ki-67 BL Decr. >= 30% A1B2 = 1 (achieved) | 48 Participants |
95% CI: [-0.326, -0.14]
Secondary
Disease Free Survival (DFS)
Disease free survival (DFS) defined as time from the first date of no disease \[i.e. date of surgery\] to the first occurrence of disease recurrence or death from any cause.
Time frame: from randomization up to 24 months until date of occurrence of no disease to the first occurrence of disease recurrence or death from any cause
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A | Disease Free Survival (DFS) | 15 Participants |
| Arm B | Disease Free Survival (DFS) | 10 Participants |
p-value: 0.2995% CI: [0.69, 3.43]Regression, Cox
Secondary
Event Free Survival (EFS)
Event free survival (EFS) defined as length of time after randomization till death from any cause, failure to achieve remission after induction therapy, relapse in any site, or second malignancy
Time frame: from randomization up to 24 months until date of death from any cause, failure to achieve remission after induction therapy, relapse in any site, or second malignancy
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A | Event Free Survival (EFS) | 20 Participants |
| Arm B | Event Free Survival (EFS) | 16 Participants |
p-value: 0.52995% CI: [0.64, 2.38]Regression, Cox
Secondary
Low Cellularity (< 500 Tumor Cells) After 14 (Arm A)/28 Days (Arm B) (+/- 2 Days) of Treatment
Low cellularity: \< 500 tumor cells after 14/28 days (+/- 2 days) of treatment. See general comments to biomarker endpoints above.
Time frame: after 14/28 days (+/- 2 days) of treatment
Population: Analyzed were all available samples of participants (20 missing in arm A; 37 missing in arm B).
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A | Low Cellularity (< 500 Tumor Cells) After 14 (Arm A)/28 Days (Arm B) (+/- 2 Days) of Treatment | Low Cell. A1B2 = 0 (not achieved) | 152 Participants |
| Arm A | Low Cellularity (< 500 Tumor Cells) After 14 (Arm A)/28 Days (Arm B) (+/- 2 Days) of Treatment | Low Cell. A1B2 = 1 (achieved) | 8 Participants |
| Arm B | Low Cellularity (< 500 Tumor Cells) After 14 (Arm A)/28 Days (Arm B) (+/- 2 Days) of Treatment | Low Cell. A1B2 = 0 (not achieved) | 102 Participants |
| Arm B | Low Cellularity (< 500 Tumor Cells) After 14 (Arm A)/28 Days (Arm B) (+/- 2 Days) of Treatment | Low Cell. A1B2 = 1 (achieved) | 40 Participants |
95% CI: [-0.31, -0.148]
Secondary
Low Cellularity (< 500 Tumor Cells) After 28 Days (+/- 2 Days) of Treatment
Low cellularity: \< 500 tumor cells after 28 days (+/- 2 days) of treatment. See general comments to biomarker endpoints above.
Time frame: after 28 days (+/- 2 days) of treatment
Population: Analyzed were all available samples of participants (41 missing in arm A; 37 missing in arm B).
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A | Low Cellularity (< 500 Tumor Cells) After 28 Days (+/- 2 Days) of Treatment | Low Cell. A3B2 = 0 (not achieved) | 92 Participants |
| Arm A | Low Cellularity (< 500 Tumor Cells) After 28 Days (+/- 2 Days) of Treatment | Low Cell. A3B2 = 1 (achieved) | 47 Participants |
| Arm B | Low Cellularity (< 500 Tumor Cells) After 28 Days (+/- 2 Days) of Treatment | Low Cell. A3B2 = 0 (not achieved) | 102 Participants |
| Arm B | Low Cellularity (< 500 Tumor Cells) After 28 Days (+/- 2 Days) of Treatment | Low Cell. A3B2 = 1 (achieved) | 40 Participants |
95% CI: [-0.052, 0.163]
Secondary
Near Pathological Complete Response (Near pCR)
Near pCR defined as residual tumor \<5 mm in the breast irrespective of in situ and lymph nodes status
Time frame: after 29-30 weeks in Arm A and after 27-28 weeks in Arm B.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A | Near Pathological Complete Response (Near pCR) | pCR (ypT0/is/1a) = 0 | 38 Participants |
| Arm A | Near Pathological Complete Response (Near pCR) | pCR (ypT0/is/1a) = 1 | 132 Participants |
| Arm B | Near Pathological Complete Response (Near pCR) | pCR (ypT0/is/1a) = 0 | 31 Participants |
| Arm B | Near Pathological Complete Response (Near pCR) | pCR (ypT0/is/1a) = 1 | 139 Participants |
95% CI: [-0.127, 0.044]
Secondary
Number of Adverse Events by Grade
Safety (incidence, relationship, seriousness, and severity of all AEs, SAEs, AESIs coded by medical dictionary for regulatory activities (MedDRA), summarized by Preferred Term and System Organ Class and graded according to common terminology criteria of adverse events (CTCAE V5.0)
Time frame: from date of randomization up to 24 months
Population: Safety endpoints are based on a subset of the ITT population that actually received treatment. The safety population included 356 patients, 178 from Arm A and 178 from Arm B. Most frequent AEs (\>10% of patients) by system organ class are shown.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A | Number of Adverse Events by Grade | CTCAE grade 2 | 847 Adverse Events |
| Arm A | Number of Adverse Events by Grade | CTCAE grade 3 | 376 Adverse Events |
| Arm A | Number of Adverse Events by Grade | CTCAE grade 4 | 133 Adverse Events |
| Arm A | Number of Adverse Events by Grade | CTCAE grade 1 | 1924 Adverse Events |
| Arm A | Number of Adverse Events by Grade | CTCAE grade 5 | 1 Adverse Events |
| Arm A | Number of Adverse Events by Grade | CTCAE grade - all | 3281 Adverse Events |
| Arm B | Number of Adverse Events by Grade | CTCAE grade 5 | 0 Adverse Events |
| Arm B | Number of Adverse Events by Grade | CTCAE grade - all | 3313 Adverse Events |
| Arm B | Number of Adverse Events by Grade | CTCAE grade 1 | 1937 Adverse Events |
| Arm B | Number of Adverse Events by Grade | CTCAE grade 3 | 368 Adverse Events |
| Arm B | Number of Adverse Events by Grade | CTCAE grade 4 | 159 Adverse Events |
| Arm B | Number of Adverse Events by Grade | CTCAE grade 2 | 849 Adverse Events |
Secondary
Overall Survival (OS).
Overall survival (OS) defined as length of time from randomization to death from any cause. Given that novel post-neoadjuvant treatment options (on and off-trial) have emerged such as Pembrolizumab, the post-neoadjuvant treatment in the follow-up phase of this study would have been most certainly highly heterogeneous. Thus, completion of follow-up to 3 years was no longer justified. Therefore, follow-up was limited to 2 years and only clinically significant survival signals were observed.
Time frame: from randomization up to 24 months until date of death from any cause.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A | Overall Survival (OS). | 5 Participants |
| Arm B | Overall Survival (OS). | 3 Participants |
p-value: 0.49595% CI: [0.39, 6.89]Regression, Cox
Secondary
Pathological Complete Response (no Invasive Tumor)
Pathological Complete Response defined as no invasive tumor in the breast, irrespective of lymph node status
Time frame: after 29-30 weeks in Arm A and after 27-28 weeks in Arm B.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A | Pathological Complete Response (no Invasive Tumor) | pCR (ypT0) = 0 | 63 Participants |
| Arm A | Pathological Complete Response (no Invasive Tumor) | pCR (ypT0) = 1 | 107 Participants |
| Arm B | Pathological Complete Response (no Invasive Tumor) | pCR (ypT0) = 0 | 52 Participants |
| Arm B | Pathological Complete Response (no Invasive Tumor) | pCR (ypT0) = 1 | 118 Participants |
95% CI: [-0.166, 0.034]
Secondary
Pathological Complete Response (ypT0/is, ypN0) (ER/PR Between 1 and 10 %).
Pathological complete response defined as no residual invasive tumor cells in the breast and in the lymph nodes (ypT0/is, ypN0) in patients with an ER/PR expression of \<1% and an ER/PR expression of 1% to 10%.
Time frame: after 29-30 weeks in Arm A and after 27-28 weeks in Arm B
Population: Patients with an ER/PR expression of 1% to 10%. (Data for partients an ER/PR expression of \<1%, see above.)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A | Pathological Complete Response (ypT0/is, ypN0) (ER/PR Between 1 and 10 %). | pCR = 0 (no pCR) | 5 Participants |
| Arm A | Pathological Complete Response (ypT0/is, ypN0) (ER/PR Between 1 and 10 %). | pCR = 1 (pCR achieved) | 18 Participants |
| Arm B | Pathological Complete Response (ypT0/is, ypN0) (ER/PR Between 1 and 10 %). | pCR = 0 (no pCR) | 8 Participants |
| Arm B | Pathological Complete Response (ypT0/is, ypN0) (ER/PR Between 1 and 10 %). | pCR = 1 (pCR achieved) | 23 Participants |
95% CI: [-0.1957, 0.2524]
Secondary
Pathological Complete Response (ypT0/is, ypN0) (ER/PR Expression of <1%).
Pathological complete response defined as no residual invasive tumor cells in the breast and in the lymph nodes (ypT0/is, ypN0) in patients with an ER/PR expression of \<1% and an ER/PR expression of 1% to 10%.
Time frame: after 29-30 weeks in Arm A and after 27-28 weeks in Arm B
Population: Patients with an ER/PR expression of \<1%. (Data for partients and an ER/PR expression of 1% to 10%, see below.)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A | Pathological Complete Response (ypT0/is, ypN0) (ER/PR Expression of <1%). | pCR = 0 (no pCR) | 53 Participants |
| Arm A | Pathological Complete Response (ypT0/is, ypN0) (ER/PR Expression of <1%). | pCR = 1 (pCR achieved) | 94 Participants |
| Arm B | Pathological Complete Response (ypT0/is, ypN0) (ER/PR Expression of <1%). | pCR = 0 (no pCR) | 44 Participants |
| Arm B | Pathological Complete Response (ypT0/is, ypN0) (ER/PR Expression of <1%). | pCR = 1 (pCR achieved) | 94 Participants |
95% CI: [-0.1497, 0.0689]
Secondary
Pathological Complete Response (ypT0, ypN0)
Pathological complete response defined as no tumor cells (invasive and no non-invasive) in the breast but also in the lymph nodes (ypN0, ypT0).
Time frame: after 29-30 weeks in Arm A and after 27-28 weeks in Arm B.
Population: Same as f0r Primary Endpoint.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A | Pathological Complete Response (ypT0, ypN0) | pCR (ypT0, ypN0) = 0 (not achieved) | 67 Participants |
| Arm A | Pathological Complete Response (ypT0, ypN0) | pCR (ypT0, ypN0) = 1 (achieved) | 103 Participants |
| Arm B | Pathological Complete Response (ypT0, ypN0) | pCR (ypT0, ypN0) = 0 (not achieved) | 58 Participants |
| Arm B | Pathological Complete Response (ypT0, ypN0) | pCR (ypT0, ypN0) = 1 (achieved) | 111 Participants |
95% CI: [-0.153, 0.051]
Secondary
Stromal Tumor-infiltrating Lymphocytes (TILs) ≥ 60% After 14 (Arm A)/28 Days (ArmB)
TILs after 14/28 days (+/- 2 days) of treatment as continuous predictor. See general comments to biomarker endpoints above.
Time frame: after 14/28 days (+/- 2 days) of treatment
Population: Analyzed were all available samples of participants (20 missing in arm A; 39 missing in arm B).
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A | Stromal Tumor-infiltrating Lymphocytes (TILs) ≥ 60% After 14 (Arm A)/28 Days (ArmB) | TILs >= 60% A1B2 = 0 (not achieved) | 134 Participants |
| Arm A | Stromal Tumor-infiltrating Lymphocytes (TILs) ≥ 60% After 14 (Arm A)/28 Days (ArmB) | TILs >= 60% A1B2 = 1 (achieved) | 26 Participants |
| Arm B | Stromal Tumor-infiltrating Lymphocytes (TILs) ≥ 60% After 14 (Arm A)/28 Days (ArmB) | TILs >= 60% A1B2 = 0 (not achieved) | 96 Participants |
| Arm B | Stromal Tumor-infiltrating Lymphocytes (TILs) ≥ 60% After 14 (Arm A)/28 Days (ArmB) | TILs >= 60% A1B2 = 1 (achieved) | 44 Participants |
95% CI: [-0.245, -0.054]
Secondary
Tumor-infiltrating Lymphocytes (TILs) ≥ 60% After 28 Days
TILs ≥ 60% after 28 days (+/- 2 days) of treatment. Stromal Tumor Infiltrating Lymphocytes (TILs) ≥ 60%. See general comments to biomarker endpoints above.
Time frame: after 28 days (+/- 2 days) of treatment
Population: Analyzed were all available samples of participants (42 missing in arm A; 39 missing in arm B).
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A | Tumor-infiltrating Lymphocytes (TILs) ≥ 60% After 28 Days | TILs >= 60% A3B2 = 0 (not achieved) | 102 Participants |
| Arm A | Tumor-infiltrating Lymphocytes (TILs) ≥ 60% After 28 Days | TILs >= 60% A3B2 = 1 (achieved) | 36 Participants |
| Arm B | Tumor-infiltrating Lymphocytes (TILs) ≥ 60% After 28 Days | TILs >= 60% A3B2 = 0 (not achieved) | 96 Participants |
| Arm B | Tumor-infiltrating Lymphocytes (TILs) ≥ 60% After 28 Days | TILs >= 60% A3B2 = 1 (achieved) | 44 Participants |
95% CI: [-0.157, 0.055]