Breast Cancer Study of Preoperative Pembrolizumab + Radiation

• ClinicalTrials.gov Identifier: NCT03366844
• Recruitment Status: Active, not recruiting
• First Posted: December 8, 2017
• Results First Posted: April 28, 2023
• Last Update Posted: May 30, 2023
• Sponsor: Stephen Shiao
• Collaborator: United States Department of Defense
• Information provided by (Responsible Party): Stephen Shiao, Cedars-Sinai Medical Center

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Breast Cancer
• Interventions: Drug: Pembrolizumab; Radiation: RT Boost
• Enrollment: 66

Participant Flow

Recruitment Details

The trial opened to accrual on 12/14/2017 with first subject enrolled on study 12/22/2017. A total of 85 patients consented, 10 subjects failed screening, 10 withdrew consent prior to starting study intervention and were replaced. 66 subjects completed study intervention but 6 were deemed unevaluable. Total target accrual of 60 subjects was met with the last subject off treatment as of 01/26/2022. Last data collection for primary endpoint confirmed on 03/03/22 as the primary completion date.

Pre-assignment Details

Arm/Group Title	Pembrolizumab With RT Boost
Arm/Group Description	Single Arm with 2 Cohorts: Cohort 1: High-risk, ER-positive and HER2-negative breast cancer patients with primary tumors measuring at least 2cm; Cohort 2: TNBC patients with primary tumors measuring at least 2cm. All subjects receive study intervention: pembrolizumab (checkpoint inhibitor) with the second dose of pembrolizumab given in conjunction with an RT boost ("tumor boost"), consisting of 8 Gy for 3 fractions, before standard of care treatment.
Period Title: Overall Study
Started	66
Phase 1b	10 [1]
Phase II	50 [2]
Completed	60
Not Completed	6
Reason Not Completed
Physician Decision	1
Unevaluable for co-primary endpoint (did not complete all required biopsies)	5
[1] Phase 1b began with 10 TNBC subjects enrolled.; [2] Phase II proceeded with 50 subjects enrolled into the TNBC Cohort and 10 subjects into the HR+ Cohort.

Baseline Characteristics

Arm/Group Title		Pembrolizumab With RT Boost
Arm/Group Description		Single Arm with 2 Cohorts: Cohort 1: High-risk, ER-positive and HER2-negative breast cancer patients with primary tumors measuring at least 2cm; Cohort 2: TNBC patients with primary tumors measuring at least 2cm. All subjects receive study intervention: pembrolizumab (checkpoint inhibitor) with the second dose of pembrolizumab given in conjunction with an RT boost ("tumor boost"), consisting of 8 Gy for 3 fractions, before standard of care treatment.
Overall Number of Baseline Participants		60
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	60 participants
	<=18 years	0 0.0%
	Between 18 and 65 years	45 75.0%
	>=65 years	15 25.0%
Age, Continuous; Median (Full Range); Unit of measure: Years
	Number Analyzed	60 participants
		53; (31 to 93)
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	60 participants
		53 (14)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	60 participants
	Female	60 100.0%
	Male	0 0.0%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	60 participants
	Hispanic or Latino	9 15.0%
	Not Hispanic or Latino	50 83.3%
	Unknown or Not Reported	1 1.7%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	60 participants
	American Indian or Alaska Native	0 0.0%
	Asian	7 11.7%
	Native Hawaiian or Other Pacific Islander	0 0.0%
	Black or African American	8 13.3%
	White	42 70.0%
	More than one race	2 3.3%
	Unknown or Not Reported	1 1.7%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	60 participants
		60

Outcome Measures

1. Primary Outcome

Title	Number of Patients Who do Not Necessitate a Delay in Standard of Care Treatment After Receiving the Investigational Combination of Preoperative Pembrolizumab and Radiation
Description	Feasibility of preoperative radiation and Pembrolizumab in newly diagnosed, non-metastatic patients with triple negative breast cancer.
Time Frame	8 weeks after trial initiation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pembrolizumab With RT Boost
Arm/Group Description:	Single Arm with 2 Cohorts: Cohort 1: High-risk, ER-positive and HER2-negative breast cancer patients with primary tumors measuring at least 2cm; Cohort 2: TNBC patients with primary tumors measuring at least 2cm. All subjects receive study intervention: pembrolizumab (checkpoint inhibitor) with the second dose of pembrolizumab given in conjunction with an RT boost ("tumor boost"), consisting of 8 Gy for 3 fractions, before standard of care treatment.
Overall Number of Participants Analyzed	60
Measure Type: Count of Participants; Unit of Measure: Participants
	36 60.0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab With RT Boost
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Proportion
	Estimated Value	0.60
	Confidence Interval	(2-Sided) 95%; 0.465 to 0.724
	Estimation Comments	95% confidence interval for one proportion were estimated using the Exact (Clopper-Pearson) method.

2. Primary Outcome

Title	Changes in Tumor Infiltrating Lymphocytes (TIL)
Description	An increase in the tumor-infiltrating lymphocyte score (TILs) as measured by Salgado criteria. An increase in TILs is an indicator of immune system engagement (range is 0-100 in percent), therefore increase indicates better outcome. A lead in with pembrolizumab alone followed by the combination of pembrolizumab with RT will allow for serial assessment of TILs. This will establish the contribution of RT to the immune response generated by pembrolizumab. The working group's consensus for Salgado criteria is that TILs may provide more biological relevant information when scored as a continuous variable. The percentage of stromal TILs is a semi quantitative parameter for this assessment (0%-100%). No formal recommendation for a clinically relevant TIL threshold(s) can be given at this stage. The consensus was that a valid methodology is currently more important than issues of thresholds for clinical use, which will be determined once a solid methodology is in place.
Time Frame	8 weeks after trial initiation

Outcome Measure Data Not Reported

3. Secondary Outcome

Title	Pembrolizumab-related Adverse Events
Description	Treatment toxicities. Number of AEs attributed to Pembrolizumab (considered at least possibly related, probably related, or related).
Time Frame	15 weeks after trial initiation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pembrolizumab With RT Boost
Arm/Group Description:	Single Arm with 2 Cohorts: Cohort 1: High-risk, ER-positive and HER2-negative breast cancer patients with primary tumors measuring at least 2cm; Cohort 2: TNBC patients with primary tumors measuring at least 2cm. All subjects receive study intervention: pembrolizumab (checkpoint inhibitor) with the second dose of pembrolizumab given in conjunction with an RT boost ("tumor boost"), consisting of 8 Gy for 3 fractions, before standard of care treatment.
Overall Number of Participants Analyzed	60
Overall Number of Units Analyzed; Type of Units Analyzed: Adverse Events (AEs)	990
Count of Units; Unit of Measure: Adverse Events (AEs)
	453 45.8%

4. Secondary Outcome

Title	Immune-related Adverse Events
Description	Treatment toxicities. Number of immune-related AEs (irAEs).
Time Frame	Assessed up to one year post-treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pembrolizumab With RT Boost
Arm/Group Description:	Single Arm with 2 Cohorts: Cohort 1: High-risk, ER-positive and HER2-negative breast cancer patients with primary tumors measuring at least 2cm; Cohort 2: TNBC patients with primary tumors measuring at least 2cm. All subjects receive study intervention: pembrolizumab (checkpoint inhibitor) with the second dose of pembrolizumab given in conjunction with an RT boost ("tumor boost"), consisting of 8 Gy for 3 fractions, before standard of care treatment.
Overall Number of Participants Analyzed	60
Overall Number of Units Analyzed; Type of Units Analyzed: Adverse Eventss (AEs)	990
Count of Units; Unit of Measure: Adverse Eventss (AEs)
	17 1.7%

5. Secondary Outcome

Title	Invasive Disease-free Survival After Preoperative Radiation and Pembrolizumab
Description	Disease-free survival, as described from time from occurrence of surgery to time from first recurrence from or death from breast cancer
Time Frame	From treatment start date until date of documented recurrence or death from breast cancer, assessed up to 19 weeks after start of treatment

Outcome Measure Data

Analysis Population Description

Median survival estimates not applicable at this moment due to lack of events.

Arm/Group Title	Pembrolizumab With RT Boost
Arm/Group Description:	Single Arm with 2 Cohorts: Cohort 1: High-risk, ER-positive and HER2-negative breast cancer patients with primary tumors measuring at least 2cm; Cohort 2: TNBC patients with primary tumors measuring at least 2cm. All subjects receive study intervention: pembrolizumab (checkpoint inhibitor) with the second dose of pembrolizumab given in conjunction with an RT boost ("tumor boost"), consisting of 8 Gy for 3 fractions, before standard of care treatment.
Overall Number of Participants Analyzed	60
Measure Type: Count of Participants; Unit of Measure: Participants
	53 88.3%

6. Secondary Outcome

Title	Pathological Complete Response Rate
Description	Absence of invasive disease in the breast and lymph nodes at the time of curative-intent surgery.
Time Frame	From treatment start date until the time of curative-intent surgery, approximately 8 weeks.

Outcome Measure Data

Analysis Population Description

The analysis population includes patients starting from Phase II so there are a total of 50 evaluable subjects (40 TNBC; 10 HR+).

Arm/Group Title	PembroRT - Cohort: TNBC	PembroRT - Cohort: HR+
Arm/Group Description:	Single Arm with 2 Cohorts: Cohort: TNBC patients with primary tumors measuring at least 2cm. All subjects receive pembrolizumab with an RT boost, consisting of 8 Gy for 3 fractions, before standard of care treatment.	Single Arm with 2 Cohorts: Cohort: High-risk, ER-positive and HER2-negative breast cancer patients with primary tumors measuring at least 2cm. All subjects receive pembrolizumab with an RT boost, consisting of 8 Gy for 3 fractions, before standard of care treatment.
Overall Number of Participants Analyzed	40	10
Measure Type: Count of Participants; Unit of Measure: Participants
	22 55.0%	3 30.0%

Adverse Events

Time Frame	From week 1 until week 19 for all AEs, and immune-related AEs (irAEs) up until 1 year post treatment, up to 14 months.
Adverse Event Reporting Description	From week 1 until week 19 for all AEs, and immune-related AEs (irAEs) up until 1 year post treatment, up to 14 months.
Arm/Group Title	Pembrolizumab With RT Boost
Arm/Group Description	Single Arm with 2 Cohorts: Cohort 1: High-risk, ER-positive and HER2-negative breast cancer patients with primary tumors measuring at least 2cm; Cohort 2: TNBC patients with primary tumors measuring at least 2cm. All subjects receive study intervention: pembrolizumab (checkpoint inhibitor) with the second dose of pembrolizumab given in conjunction with an RT boost ("tumor boost"), consisting of 8 Gy for 3 fractions, before standard of care treatment.
All-Cause Mortality
	Pembrolizumab With RT Boost
	Affected / at Risk (%)
Total	6/60 (10.00%)
Serious Adverse Events
	Pembrolizumab With RT Boost
	Affected / at Risk (%)	# Events
Total	3/60 (5.00%)
Blood and lymphatic system disorders
Febrile neutropenia † 1	1/60 (1.67%)	1
Cardiac disorders
Syncope † 1	1/60 (1.67%)	1
Endocrine disorders
Adrenal insufficiency † 1	3/60 (5.00%)	3
Gastrointestinal disorders
Colitis † 1	1/60 (1.67%)	1
General disorders
Fever † 1	1/60 (1.67%)	1
Infections and infestations
Lung infection † 1	1/60 (1.67%)	1
Sepsis † 1	1/60 (1.67%)	1
Metabolism and nutrition disorders
Hyponatremia † 1	2/60 (3.33%)	2
Renal and urinary disorders
Urinary tract infection † 1	1/60 (1.67%)	1
Respiratory, thoracic and mediastinal disorders
Pneumonitis † 1	1/60 (1.67%)	1
Skin and subcutaneous tissue disorders
Rash maculo-papular † 1	1/60 (1.67%)	1
Vascular disorders
Hypotension † 1	1/60 (1.67%)	1
1 Term from vocabulary, CTCAE (4.0); † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Pembrolizumab With RT Boost
	Affected / at Risk (%)	# Events
Total	49/60 (81.67%)
Blood and lymphatic system disorders
Anemia Hemoglobin (Hgb) † 1	9/60 (15.00%)	11
Febrile neutropenia † 1	5/60 (8.33%)	7
Cardiac disorders
Palpitations † 1	4/60 (6.67%)	4
Endocrine disorders
Hypothyroidism † 1	4/60 (6.67%)	5
Gastrointestinal disorders
Nausea † 1	49/60 (81.67%)	64
Diarrhea † 1	29/60 (48.33%)	41
Constipation † 1	26/60 (43.33%)	28
Mucositis oral † 1	24/60 (40.00%)	26
Vomiting † 1	8/60 (13.33%)	9
Gastroesophageal reflux † 1	7/60 (11.67%)	7
Abdominal pain † 1	6/60 (10.00%)	6
Hemorrhoids † 1	5/60 (8.33%)	5
Dry mouth † 1	4/60 (6.67%)	4
Dyspepsia † 1	4/60 (6.67%)	4
Flatulence † 1	4/60 (6.67%)	4
Localized edema † 1	4/60 (6.67%)	4
General disorders
Fatigue † 1	49/60 (81.67%)	73
Pain † 1	9/60 (15.00%)	9
Fever † 1	7/60 (11.67%)	7
Chills † 1	5/60 (8.33%)	5
Flu like symptoms † 1	5/60 (8.33%)	5
Edema limbs † 1	4/60 (6.67%)	4
Other † 1 [1]	4/60 (6.67%)	6
Injury, poisoning and procedural complications
Bruising † 1	7/60 (11.67%)	8
Investigations
Alanine aminotransferase increased † 1	6/60 (10.00%)	11
Aspartate aminotransferase increased † 1	6/60 (10.00%)	11
Neutrophil count decreased † 1	5/60 (8.33%)	9
Metabolism and nutrition disorders
Anorexia † 1	13/60 (21.67%)	15
Dehydration † 1	5/60 (8.33%)	6
Hypokalemia † 1	5/60 (8.33%)	5
Musculoskeletal and connective tissue disorders
Myalgia † 1	15/60 (25.00%)	16
Bone pain † 1	14/60 (23.33%)	14
Arthralgia † 1	11/60 (18.33%)	14
Other † 1	5/60 (8.33%)	5
Pain in extremity † 1	5/60 (8.33%)	6
Back pain † 1	4/60 (6.67%)	4
Nervous system disorders
Peripheral sensory neuropathy † 1	26/60 (43.33%)	26
Headache † 1	20/60 (33.33%)	23
Dysgeusia † 1	11/60 (18.33%)	12
Dizziness † 1	9/60 (15.00%)	9
Paresthesia † 1	7/60 (11.67%)	7
Other † 1	4/60 (6.67%)	7
Psychiatric disorders
Insomnia † 1	17/60 (28.33%)	17
Anxiety † 1	8/60 (13.33%)	8
Reproductive system and breast disorders
Breast pain † 1	9/60 (15.00%)	11
Respiratory, thoracic and mediastinal disorders
Dyspnea † 1	11/60 (18.33%)	13
Cough † 1	10/60 (16.67%)	13
Other † 1	6/60 (10.00%)	6
Epistaxis † 1	5/60 (8.33%)	5
Nasal congestion † 1	5/60 (8.33%)	5
Postnasal drip † 1	5/60 (8.33%)	5
Sore throat † 1	4/60 (6.67%)	4
Skin and subcutaneous tissue disorders
Rash maculo-papular † 1	24/60 (40.00%)	29
Alopecia † 1	14/60 (23.33%)	16
Pruritus † 1	13/60 (21.67%)	17
Dry skin † 1	7/60 (11.67%)	7
Other † 1	7/60 (11.67%)	8
Erythema multiforme † 1	4/60 (6.67%)	4
Rash acneiform † 1	4/60 (6.67%)	4
Vascular disorders
Hot flashes † 1	8/60 (13.33%)	9
1 Term from vocabulary, CTCAE (4.0); † Indicates events were collected by systematic assessment; [1] Other

Limitations and Caveats

Co-primary outcome for change in TILs is incomplete at the time of this results submission, as some TILs data not currently available. Current results for this outcome measure is reported according to current available data. Additional data may be reported at a later date.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

Results Point of Contact

• Name/Title: Stephen Shiao, MD, PhD
• Organization: Cedars-Sinai Medical Center
• Phone: 310-423-2836
• EMail: Stephen.Shiao@cshs.org

• Responsible Party: Stephen Shiao, Cedars-Sinai Medical Center
• ClinicalTrials.gov Identifier: NCT03366844
• Other Study ID Numbers: IIT2017-07-HO-PembroRT
• First Submitted: November 25, 2017
• First Posted: December 8, 2017
• Results First Submitted: February 23, 2023
• Results First Posted: April 28, 2023
• Last Update Posted: May 30, 2023