Trial Outcomes & Findings for Trial to Evaluate Efficacy and Safety of Pembrolizumab and Gemcitabine in HER2-negative ABC (NCT NCT03025880)

Last Updated: 2023-04-03

Results Overview

DLT was defined as the occurrence of any of the following adverse events (AE) or abnormal laboratory value (graded according to the NCI Common Terminology Criteria for AE (CTCAE) version 4.0), assessed as possibly, probably or definitively related to study drug/medication, occurring within the first cycle of study treatment: any Grade 4 thrombocytopenia or neutropenia lasting \> 7 days; episcleritis, uveitis, or iritis of Grade 2 or higher, any Grade 4 toxicity, any Grade 3 toxicity EXCLUDING: nausea, vomiting, or diarrhea controlled by medical intervention within 72 hours, grade 3 rash in the absence of desquamation, no mucosal involvement, does not require steroids, and resolves to Grade 1 by the next scheduled dose of pembrolizumab, transient Grade 3 Aspartate Transaminase (AST) or Alanine Transaminase (ALT) elevation, defined as no more than 3 days with or without steroid use, discontinuation or delay of more than 2 weeks of any study drug/medication due to treatment-related AE.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

36 participants

Primary outcome timeframe

Up to cycle 1

Results posted on

2023-04-03

Participant Flow

Fourteen patients were enrolled at the Run-in phase, receiving at least one cycle of the combination. All patients were included at Dose Level (DL) 0. Twenty-two patients were included at the phase II.

Participant milestones

Participant milestones
Measure	Run-in Phase Dose Level 0 Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Dose Level 0) or 1,000mg/m2 (Dose Level -1) as a IV infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first. An initial exploratory run-in-phase will be performed to test the safety of the combination and determine the Recommended Phase II Dose (RP2D) of G in combination with fixed doses of P.	Phase II Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Recommended Phase II Dose (RP2D) from the run-in phase) as a IV infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.
Overall Study STARTED	14	22
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	14	22

Reasons for withdrawal

Reasons for withdrawal
Measure	Run-in Phase Dose Level 0 Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Dose Level 0) or 1,000mg/m2 (Dose Level -1) as a IV infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first. An initial exploratory run-in-phase will be performed to test the safety of the combination and determine the Recommended Phase II Dose (RP2D) of G in combination with fixed doses of P.	Phase II Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Recommended Phase II Dose (RP2D) from the run-in phase) as a IV infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.
Overall Study Adverse Event	1	0
Overall Study Death	1	1
Overall Study Withdrawal by Subject	0	1
Overall Study Physician Decision	0	1
Overall Study Progressive Disease	12	19

Baseline Characteristics

Trial to Evaluate Efficacy and Safety of Pembrolizumab and Gemcitabine in HER2-negative ABC

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Run-in Phase Dose Level 0 n=14 Participants Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Dose Level 0) or 1,000mg/m2 (Dose Level -1) as a IV infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first. An initial exploratory run-in-phase will be performed to test the safety of the combination and determine the Recommended Phase II Dose (RP2D) of G in combination with fixed doses of P.	Phase II n=22 Participants Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Recommended Phase II Dose (RP2D) from the run-in phase) as a IV infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.	Total n=36 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	14 Participants n=5 Participants	19 Participants n=7 Participants	33 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	3 Participants n=7 Participants	3 Participants n=5 Participants
Age, Continuous	48.5 years STANDARD_DEVIATION 8 • n=5 Participants	56 years STANDARD_DEVIATION 12.19 • n=7 Participants	51.5 years STANDARD_DEVIATION 10.9 • n=5 Participants
Sex: Female, Male Female	14 Participants n=5 Participants	22 Participants n=7 Participants	36 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	14 Participants n=5 Participants	22 Participants n=7 Participants	36 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment Spain	14 participants n=5 Participants	22 participants n=7 Participants	36 participants n=5 Participants
Menopause Status Postmenopausal	10 Participants n=5 Participants	16 Participants n=7 Participants	26 Participants n=5 Participants
Menopause Status Premenopausal	4 Participants n=5 Participants	6 Participants n=7 Participants	10 Participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) status ECOG 0	7 Participants n=5 Participants	16 Participants n=7 Participants	23 Participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) status ECOG 1	6 Participants n=5 Participants	6 Participants n=7 Participants	12 Participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) status ECOG 2	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Type of Disease for Cohort Purposes Triple negative	9 Participants n=5 Participants	12 Participants n=7 Participants	21 Participants n=5 Participants
Type of Disease for Cohort Purposes Luminal A+B	5 Participants n=5 Participants	10 Participants n=7 Participants	15 Participants n=5 Participants
Ki67 cut-off 20% Ki67 <20%	1 Participants n=5 Participants	4 Participants n=7 Participants	5 Participants n=5 Participants
Ki67 cut-off 20% Ki67 >=20%	8 Participants n=5 Participants	13 Participants n=7 Participants	21 Participants n=5 Participants
Ki67 cut-off 20% Ki67 Not Available/Not Done	5 Participants n=5 Participants	5 Participants n=7 Participants	10 Participants n=5 Participants
Histopathologic Type Ductal	13 Participants n=5 Participants	20 Participants n=7 Participants	33 Participants n=5 Participants
Histopathologic Type Lobular	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Histopathologic Type Other: Squamous Invasive Cancer	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Histologic Grade Grade 1	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Histologic Grade Grade 2	4 Participants n=5 Participants	10 Participants n=7 Participants	14 Participants n=5 Participants
Histologic Grade Grade 3	6 Participants n=5 Participants	10 Participants n=7 Participants	16 Participants n=5 Participants
Histologic Grade Unknown	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Histologic Grade Not done	3 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants

PRIMARY outcome

Timeframe: Up to cycle 1

Population: There was no need to explore the Dose Level -1 (Pembrolizumab 200mg intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine 1,000mg/m2 as a IV infusion on day 1 and 8 of each 21-day cycle.

Outcome measures

Outcome measures
Measure	Run-in Phase Dose Level 0 n=14 Participants Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Dose Level 0) as a IV infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.	Phase II Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Recommended Phase II Dose (RP2D) from the run-in phase) as a IV infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.	Run-in Phase Plus Phase II Patients included in the run-in-phase at the same dose that in the phase II (DL0) were included on the analysis.
Number of Participants With Dose Limiting Toxicity (DLT) Within the First Cycle	1 Participants	—	—

PRIMARY outcome

Timeframe: Up to cycle 1

Population: Run in phase population

The RP2D was decided by the internal committee taken into consideration the information obtained in the study and based on the number of DLT.

Outcome measures

Outcome measures
Measure	Run-in Phase Dose Level 0 n=14 Participants Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Dose Level 0) as a IV infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.	Phase II Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Recommended Phase II Dose (RP2D) from the run-in phase) as a IV infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.	Run-in Phase Plus Phase II Patients included in the run-in-phase at the same dose that in the phase II (DL0) were included on the analysis.
Recommended Phase II Dose (RP2D) of Gemcitabine in Combination With Pembrolizumab	1250 mg/m2	—	—

PRIMARY outcome

Timeframe: Through study treatment, and average of 3 months

Population: Efficacy population: patients that had measurable disease, had received at least one dose of study treatment and had at least one tumor response assessment (unless progression or death or unacceptable toxicity before the first tumor response assessment) and without certain major protocol deviations according to the protocol deviation manual.

Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1). ORR is defined as the percentage of patients with a Complete Response (CR) or Partial Response (PR) out of the patients from the efficacy population. Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an \>=30% decrease in the sum of the longest diameter of target lesions.

Outcome measures

Outcome measures
Measure	Run-in Phase Dose Level 0 n=13 Participants Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Dose Level 0) as a IV infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.	Phase II n=20 Participants Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Recommended Phase II Dose (RP2D) from the run-in phase) as a IV infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.	Run-in Phase Plus Phase II n=33 Participants Patients included in the run-in-phase at the same dose that in the phase II (DL0) were included on the analysis.
Objective Response Rate (ORR)	0 Participants	5 Participants	5 Participants

SECONDARY outcome

Timeframe: Through study treatment, and average of 3 months

Population: Efficacy population

Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1). PFS is defined as the time from enrollment to the first documented progression disease (PD), or death from any cause, whichever occurs first. PD is defined using RECIST, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions

Outcome measures

Outcome measures
Measure	Run-in Phase Dose Level 0 n=13 Participants Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Dose Level 0) as a IV infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.	Phase II n=20 Participants Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Recommended Phase II Dose (RP2D) from the run-in phase) as a IV infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.	Run-in Phase Plus Phase II n=33 Participants Patients included in the run-in-phase at the same dose that in the phase II (DL0) were included on the analysis.
Progression-Free Survival (PFS)	3.1 Months Interval 0.9 to 5.4	2.6 Months Interval 1.9 to 6.1	3.1 Months Interval 2.0 to 4.3

SECONDARY outcome

Timeframe: Through study treatment, and average of 3 months

Population: Efficacy population

Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria. CBR was defined as the percentage of patients with a Complete Response (CR) or Partial Response (PR) plus stable disease (SD) out of the efficacy population. Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an \>=30% decrease in the sum of the longest diameter of target lesions; SD is defined as a failure to meet criteria for CR or PR in the absence of progressive disease. Overall Response (OR) = CR + PR.

Outcome measures

Outcome measures
Measure	Run-in Phase Dose Level 0 n=13 Participants Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Dose Level 0) as a IV infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.	Phase II n=20 Participants Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Recommended Phase II Dose (RP2D) from the run-in phase) as a IV infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.	Run-in Phase Plus Phase II n=33 Participants Patients included in the run-in-phase at the same dose that in the phase II (DL0) were included on the analysis.
Clinical Benefit Rate (CBR)	7 Participants	10 Participants	17 Participants

SECONDARY outcome

Timeframe: 24 weeks

Population: Efficacy population

Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria. CBR was defined as the percentage of patients with a Complete Response (CR) or Partial Response (PR) plus stable disease (SD) lasting at least 24 months out of the efficacy population. Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an \>=30% decrease in the sum of the longest diameter of target lesions; SD is defined as a failure to meet criteria for CR or PR in the absence of progressive disease lasting at least 24 months. Overall Response (OR) = CR + PR.

Outcome measures

Outcome measures
Measure	Run-in Phase Dose Level 0 n=13 Participants Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Dose Level 0) as a IV infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.	Phase II n=20 Participants Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Recommended Phase II Dose (RP2D) from the run-in phase) as a IV infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.	Run-in Phase Plus Phase II n=33 Participants Patients included in the run-in-phase at the same dose that in the phase II (DL0) were included on the analysis.
Clinical Benefit Rate (CBR) at Least 24 Weeks	1 Participants	5 Participants	6 Participants

SECONDARY outcome

Timeframe: Through study treatment, and average of 3 months

Population: There were only 5 Partial Responses on the phase II population.

Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria. RD was defined as the time from the first documentation of objective tumor response (complete response (CR) or partial response (PR)) to the first documented progressive disease (PD), or to death due to any cause, whichever occurs first. Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an \>=30% decrease in the sum of the longest diameter of target lesions; PD is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions

Outcome measures

Outcome measures
Measure	Run-in Phase Dose Level 0 Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Dose Level 0) as a IV infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.	Phase II n=5 Participants Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Recommended Phase II Dose (RP2D) from the run-in phase) as a IV infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.	Run-in Phase Plus Phase II n=5 Participants Patients included in the run-in-phase at the same dose that in the phase II (DL0) were included on the analysis.
Response Duration (RD)	—	4.3 Months Interval 2.3 to 7.4	4.3 Months Interval 2.3 to 7.4

SECONDARY outcome

Timeframe: Up to 2 years

OS is defined as the time from the date of enrollment to the date of death from any cause.

Outcome measures

Outcome measures
Measure	Run-in Phase Dose Level 0 n=13 Participants Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Dose Level 0) as a IV infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.	Phase II n=20 Participants Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Recommended Phase II Dose (RP2D) from the run-in phase) as a IV infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.	Run-in Phase Plus Phase II n=33 Participants Patients included in the run-in-phase at the same dose that in the phase II (DL0) were included on the analysis.
Overall Survival (OS)	6.1 Months Interval 1.3 to 11.7	10.1 Months Interval 7.3 to 17.7	8.7 Months Interval 6.5 to 11.7

SECONDARY outcome

Timeframe: Through study treatment, and average of 3 months

Population: Safety population: patients who were enrolled and had have received at least one dose of the study treatment.

Safety assessments were performed at baseline and during the study: Vital signs assessments (blood pressure, pulse and body temperature), Laboratory assessments (hemoglobin, platelet count, White Blood Cell (WBC), Absolute Neutrophil Count (ANC) and Absolute Lymphocyte Count (ALC), albumin, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, serum creatinine, creatinine clearance (for patients with creatinine levels \> 1.5 x ULN), glucose and urea, International Normalized Ratio (INR)/ Prothrombin time (PT) and activated partial thromboplastin time (aPTT), total or free triiodothyronine (T3 or FT3), free thyroxine (FT4) and Thyroid-stimulating hormone (TSH)) and Urinalysis. A baseline standard 12-lead electrocardiogram (ECG) was mandatory. AEs were graded according to NCI-CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) version 4.03.

Outcome measures

Outcome measures
Measure	Run-in Phase Dose Level 0 n=14 Participants Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Dose Level 0) as a IV infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.	Phase II n=22 Participants Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Recommended Phase II Dose (RP2D) from the run-in phase) as a IV infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.	Run-in Phase Plus Phase II Patients included in the run-in-phase at the same dose that in the phase II (DL0) were included on the analysis.
The Number of Participants Who Experienced Adverse Events (AE) Related to Study Treatment	8 Participants	17 Participants	—

SECONDARY outcome

Timeframe: Through study treatment, and average of 3 months

Tumor response was assessed using Immune-Related Response Evaluation Criteria In Solid Tumors Criteria (irRECIST v 1.0). irORR is defined as the percentage of patients with a Immune-Related Complete Response (irCR) or Immune-Related Partial Response (irPR) out of the patients from the efficacy population. Per irRECIST, irCR is defined as the disappearance of all measurable and non-measurable lesions, and lymph nodes must decrease to \< 10 mm in short axis; irPR is defined as an \>=30% decrease in total measured tumor burden relative to baseline; Immune-Related Overall Response (irOR) = irCR + irPR.

Outcome measures

Outcome measures
Measure	Run-in Phase Dose Level 0 n=13 Participants Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Dose Level 0) as a IV infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.	Phase II n=20 Participants Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Recommended Phase II Dose (RP2D) from the run-in phase) as a IV infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.	Run-in Phase Plus Phase II n=33 Participants Patients included in the run-in-phase at the same dose that in the phase II (DL0) were included on the analysis.
Immune-related Objective Response Rate (irORR)	0 Participants	5 Participants	5 Participants

SECONDARY outcome

Timeframe: Through study treatment, and average of 3 months

Population: Efficacy population

Tumor response was assessed using Immune-Related Response Evaluation Criteria In Solid Tumors Criteria (irRECIST v 1.0). irPFS was defined as the time from enrollment to the first documented progressive disease (PD), or death from any cause, whichever occurs first. PD is defined by irRECIST, as a 20% increase and minimum 5 mm absolute increase in total measured tumor burden compared with nadir, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Outcome measures

Outcome measures
Measure	Run-in Phase Dose Level 0 n=13 Participants Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Dose Level 0) as a IV infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.	Phase II n=20 Participants Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Recommended Phase II Dose (RP2D) from the run-in phase) as a IV infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.	Run-in Phase Plus Phase II n=33 Participants Patients included in the run-in-phase at the same dose that in the phase II (DL0) were included on the analysis.
Immune-related Progression-Free Survival (irPFS)	3.1 Months Interval 1.3 to 7.7	2.6 Months Interval 1.9 to 6.1	3.1 Months Interval 2.0 to 5.4

SECONDARY outcome

Timeframe: Through study treatment, and average of 3 months

Population: Efficacy population

Tumor response was assessed using Immune-Related Response Evaluation Criteria In Solid Tumors Criteria (irRECIST v 1.0). irCBR was defined as the percentage of patients with a Immune Related Complete Response (irCR) or Immune Related Partial Response (irPR) plus Immune Related Stable Disease (irSD) out of the efficacy population. Per irRECIST, irCR is defined as the disappearance of all measurable and non-measurable lesions, and lymph nodes must decrease to \< 10 mm in short axis; irPR is defined as an \>=30% decrease in total measured tumor burden relative to baseline; irSD is defined as a failure to meet criteria for irCR or irPR in the absence of progressive disease.

Outcome measures

Outcome measures
Measure	Run-in Phase Dose Level 0 n=13 Participants Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Dose Level 0) as a IV infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.	Phase II n=20 Participants Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Recommended Phase II Dose (RP2D) from the run-in phase) as a IV infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.	Run-in Phase Plus Phase II n=33 Participants Patients included in the run-in-phase at the same dose that in the phase II (DL0) were included on the analysis.
Immune Related Clinical Benefit Rate (irCBR)	7 Participants	11 Participants	18 Participants

SECONDARY outcome

Timeframe: Through study treatment, and average of 3 months

Population: Efficacy population

Tumor response was assessed using Immune-Related Response Evaluation Criteria In Solid Tumors Criteria (irRECIST v 1.0). irCBR was defined as the percentage of patients with a Immune Related Complete Response (irCR) or Immune Related Partial Response (irPR) plus Immune Related stable disease (irSD) lasting at least 24 months out of the efficacy population. Per irRECIST, irCR is defined as the disappearance of all measurable and non-measurable lesions, and lymph nodes must decrease to \< 10 mm in short axis; irPR is defined as an \>=30% decrease in total measured tumor burden relative to baseline; irSD is defined as a failure to meet criteria for irCR or irPR in the absence of progressive disease at least 24 weeks.

Outcome measures

Outcome measures
Measure	Run-in Phase Dose Level 0 n=13 Participants Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Dose Level 0) as a IV infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.	Phase II n=20 Participants Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Recommended Phase II Dose (RP2D) from the run-in phase) as a IV infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.	Run-in Phase Plus Phase II n=33 Participants Patients included in the run-in-phase at the same dose that in the phase II (DL0) were included on the analysis.
Immune Related Clinical Benefit Rate (irCBR) at Least 24 Weeks	1 Participants	5 Participants	6 Participants

SECONDARY outcome

Timeframe: Through study treatment, and average of 3 months

Population: There were only 5 Partial Responses on the phase II population.

Tumor response was assessed using Immune-Related Response Evaluation Criteria In Solid Tumors Criteria (irRECIST v 1.0). irRD was defined as the time from the first documentation of objective tumor response (immune related complete response (irCR) or immune related partial response (irPR)) to the first documented immune related progressive disease (irPD), or to death due to any cause, whichever occurs first. Per RECIST, irCR is defined as the disappearance of all measurable and non-measurable lesions, and lymph nodes must decrease to \< 10 mm in short axis; irPR is defined as an \>=30% decrease in total measured tumor burden relative to baseline; irPD is defined as a 20% increase and minimum 5 mm absolute increase in total measured tumor burden compared with nadir, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Outcome measures

Outcome measures
Measure	Run-in Phase Dose Level 0 Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Dose Level 0) as a IV infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.	Phase II n=5 Participants Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Recommended Phase II Dose (RP2D) from the run-in phase) as a IV infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.	Run-in Phase Plus Phase II n=5 Participants Patients included in the run-in-phase at the same dose that in the phase II (DL0) were included on the analysis.
Immune Related Response Duration (irRD)	—	4.3 Months Interval 2.3 to 7.4	4.3 Months Interval 2.3 to 7.4

Adverse Events

Run-in Phase Dose Level 0

Serious events: 8 serious events

Other events: 14 other events

Deaths: 12 deaths

Phase II

Serious events: 4 serious events

Other events: 21 other events

Deaths: 19 deaths

Serious adverse events

Serious adverse events
Measure	Run-in Phase Dose Level 0 n=14 participants at risk Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Dose Level 0) as a IV infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.	Phase II n=22 participants at risk Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Recommended Phase II Dose (RP2D) from the run-in phase) as a IV infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.
Infections and infestations Abdominal sepsis	7.1% 1/14 • AEs have been recorded through study treatment, an average of 3 months, and deaths have been recorded through study treatment and up to 2 years of follow up. AE were reported after Informed Consent Document (ICD) and before study drugs until approximately 30 days following the discontinuation of study treatment.	0.00% 0/22 • AEs have been recorded through study treatment, an average of 3 months, and deaths have been recorded through study treatment and up to 2 years of follow up. AE were reported after Informed Consent Document (ICD) and before study drugs until approximately 30 days following the discontinuation of study treatment.
Infections and infestations Bacterial pyelonephritis	7.1% 1/14 • AEs have been recorded through study treatment, an average of 3 months, and deaths have been recorded through study treatment and up to 2 years of follow up. AE were reported after Informed Consent Document (ICD) and before study drugs until approximately 30 days following the discontinuation of study treatment.	0.00% 0/22 • AEs have been recorded through study treatment, an average of 3 months, and deaths have been recorded through study treatment and up to 2 years of follow up. AE were reported after Informed Consent Document (ICD) and before study drugs until approximately 30 days following the discontinuation of study treatment.
Infections and infestations Cellulitis	0.00% 0/14 • AEs have been recorded through study treatment, an average of 3 months, and deaths have been recorded through study treatment and up to 2 years of follow up. AE were reported after Informed Consent Document (ICD) and before study drugs until approximately 30 days following the discontinuation of study treatment.	4.5% 1/22 • AEs have been recorded through study treatment, an average of 3 months, and deaths have been recorded through study treatment and up to 2 years of follow up. AE were reported after Informed Consent Document (ICD) and before study drugs until approximately 30 days following the discontinuation of study treatment.
Infections and infestations Respiratory tract infection	0.00% 0/14 • AEs have been recorded through study treatment, an average of 3 months, and deaths have been recorded through study treatment and up to 2 years of follow up. AE were reported after Informed Consent Document (ICD) and before study drugs until approximately 30 days following the discontinuation of study treatment.	4.5% 1/22 • AEs have been recorded through study treatment, an average of 3 months, and deaths have been recorded through study treatment and up to 2 years of follow up. AE were reported after Informed Consent Document (ICD) and before study drugs until approximately 30 days following the discontinuation of study treatment.
Investigations Anemia Grade 2 and Platelet cound decreased Grade 2	7.1% 1/14 • AEs have been recorded through study treatment, an average of 3 months, and deaths have been recorded through study treatment and up to 2 years of follow up. AE were reported after Informed Consent Document (ICD) and before study drugs until approximately 30 days following the discontinuation of study treatment.	0.00% 0/22 • AEs have been recorded through study treatment, an average of 3 months, and deaths have been recorded through study treatment and up to 2 years of follow up. AE were reported after Informed Consent Document (ICD) and before study drugs until approximately 30 days following the discontinuation of study treatment.
Gastrointestinal disorders Diarrhoea	7.1% 1/14 • AEs have been recorded through study treatment, an average of 3 months, and deaths have been recorded through study treatment and up to 2 years of follow up. AE were reported after Informed Consent Document (ICD) and before study drugs until approximately 30 days following the discontinuation of study treatment.	0.00% 0/22 • AEs have been recorded through study treatment, an average of 3 months, and deaths have been recorded through study treatment and up to 2 years of follow up. AE were reported after Informed Consent Document (ICD) and before study drugs until approximately 30 days following the discontinuation of study treatment.
Nervous system disorders Neurological decompensation	0.00% 0/14 • AEs have been recorded through study treatment, an average of 3 months, and deaths have been recorded through study treatment and up to 2 years of follow up. AE were reported after Informed Consent Document (ICD) and before study drugs until approximately 30 days following the discontinuation of study treatment.	4.5% 1/22 • AEs have been recorded through study treatment, an average of 3 months, and deaths have been recorded through study treatment and up to 2 years of follow up. AE were reported after Informed Consent Document (ICD) and before study drugs until approximately 30 days following the discontinuation of study treatment.
Hepatobiliary disorders Hyperbilirubinaemia	7.1% 1/14 • AEs have been recorded through study treatment, an average of 3 months, and deaths have been recorded through study treatment and up to 2 years of follow up. AE were reported after Informed Consent Document (ICD) and before study drugs until approximately 30 days following the discontinuation of study treatment.	0.00% 0/22 • AEs have been recorded through study treatment, an average of 3 months, and deaths have been recorded through study treatment and up to 2 years of follow up. AE were reported after Informed Consent Document (ICD) and before study drugs until approximately 30 days following the discontinuation of study treatment.
General disorders Pyrexia	7.1% 1/14 • AEs have been recorded through study treatment, an average of 3 months, and deaths have been recorded through study treatment and up to 2 years of follow up. AE were reported after Informed Consent Document (ICD) and before study drugs until approximately 30 days following the discontinuation of study treatment.	0.00% 0/22 • AEs have been recorded through study treatment, an average of 3 months, and deaths have been recorded through study treatment and up to 2 years of follow up. AE were reported after Informed Consent Document (ICD) and before study drugs until approximately 30 days following the discontinuation of study treatment.
Gastrointestinal disorders Abdominal pain upper	7.1% 1/14 • AEs have been recorded through study treatment, an average of 3 months, and deaths have been recorded through study treatment and up to 2 years of follow up. AE were reported after Informed Consent Document (ICD) and before study drugs until approximately 30 days following the discontinuation of study treatment.	0.00% 0/22 • AEs have been recorded through study treatment, an average of 3 months, and deaths have been recorded through study treatment and up to 2 years of follow up. AE were reported after Informed Consent Document (ICD) and before study drugs until approximately 30 days following the discontinuation of study treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour pain	7.1% 1/14 • AEs have been recorded through study treatment, an average of 3 months, and deaths have been recorded through study treatment and up to 2 years of follow up. AE were reported after Informed Consent Document (ICD) and before study drugs until approximately 30 days following the discontinuation of study treatment.	0.00% 0/22 • AEs have been recorded through study treatment, an average of 3 months, and deaths have been recorded through study treatment and up to 2 years of follow up. AE were reported after Informed Consent Document (ICD) and before study drugs until approximately 30 days following the discontinuation of study treatment.
General disorders Oedema peripheral	0.00% 0/14 • AEs have been recorded through study treatment, an average of 3 months, and deaths have been recorded through study treatment and up to 2 years of follow up. AE were reported after Informed Consent Document (ICD) and before study drugs until approximately 30 days following the discontinuation of study treatment.	4.5% 1/22 • AEs have been recorded through study treatment, an average of 3 months, and deaths have been recorded through study treatment and up to 2 years of follow up. AE were reported after Informed Consent Document (ICD) and before study drugs until approximately 30 days following the discontinuation of study treatment.
Investigations Pancytopenia	7.1% 1/14 • AEs have been recorded through study treatment, an average of 3 months, and deaths have been recorded through study treatment and up to 2 years of follow up. AE were reported after Informed Consent Document (ICD) and before study drugs until approximately 30 days following the discontinuation of study treatment.	0.00% 0/22 • AEs have been recorded through study treatment, an average of 3 months, and deaths have been recorded through study treatment and up to 2 years of follow up. AE were reported after Informed Consent Document (ICD) and before study drugs until approximately 30 days following the discontinuation of study treatment.
Investigations Intraabdominal bleeding	7.1% 1/14 • AEs have been recorded through study treatment, an average of 3 months, and deaths have been recorded through study treatment and up to 2 years of follow up. AE were reported after Informed Consent Document (ICD) and before study drugs until approximately 30 days following the discontinuation of study treatment.	0.00% 0/22 • AEs have been recorded through study treatment, an average of 3 months, and deaths have been recorded through study treatment and up to 2 years of follow up. AE were reported after Informed Consent Document (ICD) and before study drugs until approximately 30 days following the discontinuation of study treatment.

Other adverse events

Additional Information

Scientific Director / Medical Lead / Project Manager

Spanish Breast Cancer Research Group

Phone: +34916592870

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60