Pembrolizumab After SBRT Versus Pembrolizumab Alone in Advanced NSCLC (PEMBRO-RT)

Randomized Phase II, 2-arm Study of Pembrolizumab After High Dose Radiation (SBRT) Versus Pembrolizumab Alone in Patients With Advanced Non-small Cell Lung Cancer

To evaluate the increase in Overall Response Rate (ORR) in the pembrolizumab alone arm compared to the pembrolizumab after SBRT arm at 12 weeks

Study Overview

• Status: Completed
• Conditions: Non-Small Cell Lung Cancer
• Intervention / Treatment: Drug: pembrolizumab; Radiation: Stereotactic Body Radiation Therapy

Detailed Description

The investigators hypothesize that in a significant subset of patients with recurrent NSCLC immunotherapy after SBRT will be superior to treatment with immunotherapy alone and that SBRT, given to a single metastatic site of the tumor, will augment the immune response to the tumor. Objectives: Disease Control Rate (DCR), defined as the percentage of patients having a complete response, partial response or stable disease at 12 weeks, PFS, defined as time from randomization to disease progression or death, OS, defined as time from randomization to death (of any cause). Toxicity.

• Study Type: Interventional
• Enrollment (Actual): 92
• Phase: Phase 2

Contacts and Locations

Study Locations

• Netherlands
  • Noord-Holland
    • Amsterdam, Noord-Holland, Netherlands, 1066 CX
      • Antoni van Leeuwenhoek (NKI-AVL)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Be willing and able to provide written informed consent/assent for the trial.
2. Be ≥ 18 years of age on day of signing informed consent.
3. Have measurable disease based on RECIST 1.1.
4. Must provide newly obtained tissue from a core or excisional biopsy of a tumor lesion and are willing to have a second biopsy performed form any non-irradiated lesion after the radiation and immune-modulating treatment.
5. Have a performance status of 0 or 1 on the ECOG Performance Scale.
6. Stage IV NSCLC; treated with at least 1 regimen of chemotherapy.
7. Have at least 2 separate (metastatic) lesions of which one is amenable for irradiation with a size of < 5 cm.

8. Demonstrate adequate organ function:

   Absolute neutrophil count (ANC) ≥1,500 /mcL; Platelets ≥100,000 / mcL; Hemoglobin ≥9 g/dL or ≥5.6 mmol/L; Serum creatinine ≤1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≥50 mL/min for subject with creatinine levels > 1.5 X institutional ULN; Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN; AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases; International Normalized Ratio (INR) or Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants.

   All screening labs should be performed within 10 days of treatment initiation.

9. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
10. Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication (Reference Section 5.7.2). Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
11. Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.

Exclusion Criteria:

1. Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment.
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
3. Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.

4. Has had prior chemotherapy or targeted small molecule therapy within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.

   • Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
   • Note: If subjects received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
5. Have had previous radical radiation to any tumor site within 6 months prior to study Day 1.
6. Have known but untreated driver mutations of the EGFR gene or ALK translocation.
7. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy. 8. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least six weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 14 days prior to trial treatment.

9. Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjögren's syndrome will not be excluded from the study.

10. Has evidence of symptomatic interstitial lung disease or an active, non-infectious pneumonitis.

11. Has an active infection requiring systemic therapy. 12. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.

13. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.

14. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.

15. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).

16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

17. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).

18. Has received a live vaccine within 30 days prior to the first dose of trial treatment.

19. Has had major surgery or major blood transfusions (>3 packed cells) in the past 3 months.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SBRT + Pembrolizumab; Stereotactic Body Radiation Therapy (SBRT) followed by pembrolizumab treatment within 7 days of completion. SBRT: 3 x 8 Gy, given 1-2 weeks prior to start of pembrolizumab. Dose of pembrolizumab is 200 mg, every 3 weeks. Patients can continue the pembrolizumab treatment for maximal 2 years.	Drug: pembrolizumab; Other Names: MK3475; Radiation: Stereotactic Body Radiation Therapy; Other Names: SBRT
Active Comparator: Pembrolizumab alone; Dose of pembrolizumab is 200 mg, every 3 weeks.Patients can continue the pembrolizumab treatment for maximal 2 years.	Drug: pembrolizumab; Other Names: MK3475

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate	Patients having a partial response or complete response are considered successes, while all other situations are considered failures.	at 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicity; Incidence of toxicity, graded according to National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 4.0	Toxicity will be analyzed in patients who have received at least one administration of pembrolizumab.	up to 30 days after end of treatment
The percentage of patients having a complete response, partial response or stable disease at 12 weeks		at 12 weeks
Time from randomization to disease progression or death		Until progression, median 5 months
Time from randomization to death (of any cause).		every 12 weeks, median 5 months

Collaborators and Investigators

• Sponsor: The Netherlands Cancer Institute
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Paul Baas, MD, PhD, Antoni van Leeuwenhoek; Principal Investigator: Willemijn Theelen, MD, Antoni van Leeuwenhoek

Publications and helpful links

General Publications

• Theelen WSME, Chen D, Verma V, Hobbs BP, Peulen HMU, Aerts JGJV, Bahce I, Niemeijer ALN, Chang JY, de Groot PM, Nguyen QN, Comeaux NI, Simon GR, Skoulidis F, Lin SH, He K, Patel R, Heymach J, Baas P, Welsh JW. Pembrolizumab with or without radiotherapy for metastatic non-small-cell lung cancer: a pooled analysis of two randomised trials. Lancet Respir Med. 2021 May;9(5):467-475. doi: 10.1016/S2213-2600(20)30391-X. Epub 2020 Oct 20. Erratum In: Lancet Respir Med. 2021 Mar;9(3):e29.
• Theelen WSME, Peulen HMU, Lalezari F, van der Noort V, de Vries JF, Aerts JGJV, Dumoulin DW, Bahce I, Niemeijer AN, de Langen AJ, Monkhorst K, Baas P. Effect of Pembrolizumab After Stereotactic Body Radiotherapy vs Pembrolizumab Alone on Tumor Response in Patients With Advanced Non-Small Cell Lung Cancer: Results of the PEMBRO-RT Phase 2 Randomized Clinical Trial. JAMA Oncol. 2019 Sep 1;5(9):1276-1282. doi: 10.1001/jamaoncol.2019.1478.

Study record dates

Study Major Dates

• Study Start: July 1, 2015
• Primary Completion (Actual): June 1, 2018
• Study Completion (Actual): June 1, 2018

Study Registration Dates

• First Submitted: June 29, 2015
• First Submitted That Met QC Criteria: July 7, 2015
• First Posted (Estimate): July 8, 2015

Study Record Updates

• Last Update Posted (Actual): August 17, 2020
• Last Update Submitted That Met QC Criteria: August 14, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Keywords: NSCLC; SBRT; pembrolizumab; recurrent
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Antineoplastic Agents; Antineoplastic Agents, Immunological; Pembrolizumab
• Other Study ID Numbers: M14PRT; 2014-003935-20 (EudraCT Number); NL51468.031.14 (Other Identifier: Netherlands CCMO)