A randomized, phase 3 trial with anti-PD-1 monoclonal antibody pembrolizumab (MK-3475) versus placebo for patients with early stage NSCLC after resection and completion of standard adjuvant therapy (PEARLS)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Merck Sharp & Dohme LLC

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

6 Nov 2015 → 12 Mar 2026

Decision date (initial)

2024-07-09

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc.

External identifiers

EU CT number

2023-509137-39-00

EudraCT number

2015-000575-27

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacoeconomic, Efficacy, Pharmacokinetic, Pharmacodynamic, Safety, Pharmacogenomic

To prospectively investigate whether adjuvant treatment with pembrolizumab after completion of radical surgery (lobectomy/pneumonectomy) with or without standard adjuvant chemotherapy for stage IB (T ≥ 4 cm) -II-IIIA NSCLC patients improves Disease
Free Survival (DFS), as assessed locally by the investigator, compared to placebo in the PDL1 strong positive subgroup or overall population.

Secondary objectives 6

1. To prospectively compare DFS as assessed by the investigator in the PD-L1 positive population (TPS≥1%)
2. To prospectively determine and compare OS in the PD-L1 strong positive and overall population
3. To prospectively determine and compare OS in the PD-L1 positive population
4. To prospectively determine and evaluate the Lung Cancer Specific Survival (LCSS) in the whole population irrespective of PD-L1 status
5. To prospectively assess the safety of pembrolizumab after radical surgery followed by standard adjuvant chemotherapy
6. ♦ No evidence of disease (NED) at clinical examination and baseline radiological assessment as documented by contrast enhanced chest/upper abdomen CT scan, brain CT/MRI and clinical examination within 12 weeks prior to the randomization date;

Conditions and MedDRA coding

Stage IB (T ≥ 4 cm), II and IIIA NSCLC

Study design 1 period

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 42

1. 1) Registration - step 1 (ORTA step 1) ♦ Before patient registration, written informed consent for tumor testing must be given according to ICH/GCP and national/local regulations. For patients that accept to participate in the translational research, we recommend the informed consent for translational research be signed before registration step 1;
2. ♦ Participants who receive adjuvant chemotherapy must begin adjuvant chemotherapy within 12 weeks of the surgery date. Patients receiving adjuvant chemotherapy must be randomized and dosed with pembrolizumab/placebo at least 3 weeks but no more than 12 weeks from the last dose of chemotherapy (Day 1 of last cycle).
3. ♦ ECOG Performance status 0-1;
4. ♦ Pathological diagnosis of NSCLC confirmed at surgery, any histology is eligible;
5. ♦ Adequate organ function performed within 10 days of treatment initiation;
6. ♦ No prior or planned neoadjuvant or adjuvant radiotherapy and/or neoadjuvant chemotherapy for the current malignancy is allowed;
7. ♦ No prior treatment with an anti-PD-1, anti-PD-L1/2, anti-CD137, CTLA-4 modulators or any other immune-modulating agents ; patients receiving live vaccine within 30 days prior to the first infusion of study treatment are not eligible;
8. ♦No current participation in a interventional clinical trial or treatment with an investigational agent or use of an investigational device within 4 weeks of the first infusion of study treatment;
9. ♦ No known history of Human Immunodeficiency Virus (HIV) (known HIV 1/2 antibodies positive). No known active Hepatitis B or C. Active Hepatitis B is defined as a known positive HBsAg result. Active Hepatitis C is defined by a known positive Hep C Ab result and known quantitative HCV RNA results greater than the lower limits of detection of the assay;
10. ♦ No chronic use of immunosuppressive agents and/or systemic corticosteroids or any use in the last 3 days prior to the first infusion of trial treatment:
11. ♦ Confirmed UICC v7 stage IB with T ≥ 4 cm, II-IIIA NSCLC after complete surgical resection (lobectomy, sleeve lobectomy, bi-lobectomy or pneumonectomy) as documented in the pathology report; (Note: TNM stage according to the 7th edition of the TNM classification for lung cancer)
12. ♦ Availability of tumor sample obtained at surgical resection for PD-L1 Immunohistochemistry (IHC) expression assessment. Patients must submit the tumor sample during screening for PDL1 IHC expression testing at a central pathology laboratory. Patients will be eligible to participate regardless of the level of PD-L1 status, however tissue must be considered satisfactory for characterization of PD-L1 status. Patients whose samples are inadequate for PD-L1 determination will not be randomized;
13. ♦ Resection margins proved microscopically free (R0); Resection margins are evaluated at the bronchial, venous and arterial stumps, peribronchial soft tissue, any peripheral margin near the tumor or of additionally resected tissue;
14. ♦ A systematic complete mediastinal lymph node dissection or a lobe-specific mediastinal lymph node dissection is recommended. At a minimum, the pathology and/or operative report must include the examination of at least two different mediastinal lymph node (N2) levels, one of which is the subcarinal (level 7) and the second of which is lobespecific;
15. ♦ In the uncommon clinical situation where the surgeon thoroughly examines a particular mediastinal lymph node level and does not find any lymph nodes, that mediasintal lymph node level may be counted among the minimum two required levels. However, the surgeon must clearly document in the operative report or in a separate written statement that the lymph node level was explored and no lymph nodes were present. Normal appearing lymph nodes, if present, must be biopsied or/removed; No extracapsular extension of tumor in resected mediastinal (N2) lymph nodes. Extracapsular tumor extension is permitted in resected N1 lymph nodes;
16. ♦ The highest mediastinal node removed can be positive for malignancy;
17. ♦ Carcinoma in situ can be present at bronchial margin;
18. ♦ Patients with two synchronous primary non-small cell lung cancers are excluded from the study;
19. ♦ Corticosteroid use on study for management of ECIs (pembrolizumab Event of Clinical Interest), as premedication for the administration of chemotherapies, and/or a premedication for IV contrast allergies/reactions is allowed;
20. ♦ Corticosteroid use on study for management of ECIs (pembrolizumab Event of Clinical Interest), as premedication for the administration of chemotherapies, and/or a premedication for IV contrast allergies/reactions is allowed;
21. ♦ Daily prednisone at doses of 5-7.5 mg is allowed as an example of replacement therapy. Equivalent hydrocortisone doses are also permitted if administered as a replacement therapy;
22. ♦ Submission of formalin-fixed paraffin embedded tumor tissue sample blocks are preferred; if submitting unstained slides, the slides must be freshly cut and submitted to the central testing laboratory;
23. ♦ At least 18 years;
24. 2) Central confirmation of PD-L1 status - step 2 This central confirmation through EORTC is required for enrolling the patient in step 3.
25. 3) Randomization - step 3 (ORTA step 2) ♦ Before patient randomization, written informed consent (‘Main Study’) for participation in the study must be given according to ICH/GCP, and national/local regulations;
26. ♦ No evidence of disease (NED) at clinical examination and baseline radiological assessment as documented by contrast enhanced chest/upper abdomen CT scan, brain CT/MRI and clinical examination within 12 weeks prior to the randomization date;
27. ♦ Adjuvant chemotherapy is not mandatory but considered for patients with stage IB (T ≥ 4 cm) and strongly recommended for stage II and IIIA, and will be administered according to national and local guidelines. Patients who received more than 4 cycles of adjuvant therapy are not eligible;
28. ♦ Patients not receiving adjuvant chemotherapy must be randomized and dosed with pembrolizumab/placebo within 12 weeks of their surgery date.
29. ♦ No history of interstitial lung disease (ILD) OR a history of (noninfectious) pneumonitis that required oral or IV steroids (other than COPD exacerbation) or current pneumonitis;
30. ♦ No active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Any replacement therapy (i.e., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed. Patients with hyperthyroidism or hypothyroidism but that are stable on hormone replacement are also allowed;
31. ♦ No history of a hematologic or primary solid tumor malignancy, unless in remission for at least 5 years. A pT1-2 prostatic cancer Gleason score < 6, superficial bladder cancer, non melanomatous skin cancer or carcinoma in situ of the cervix is eligible; Note: prior radiotherapy for another malignancy (breast cancer/lymphoma/germ cell tumors, etc.) is not an exclusion criterion, the same applies for prior anti-cancer systemic chemotherapy.
32. ♦ No previous allogeneic tissue/solid organ transplant;
33. ♦ No active infection requiring therapy;
34. ♦ No surgery or chemotherapy related toxicity (non-hematological, toxicity resolved to grade 1 , with the exception of alopecia, fatigue, neuropathy and lack of appetite /nausea);
35. ♦ Female patients with childbearing potential must have a negative urine or serum pregnancy test at screening (within 72 hours of first infusion of study medication). If the urine test cannot be confirmed as negative, a serum pregnancy test will be required. The serum pregnancy test must be negative for the subject to be eligible. Non-childbearing potential is defined as (by other than medical reasons);
36. ♦ ≥45 years of age and has not had menses for greater than 1 year;
37. Amenorrheic for > 2 years without a hysterectomy and oophorectomy and an FSH value in the postmenopausal range upon pretrial (screening) evaluation;
38. ♦ Whose status is post hysterectomy, oophorectomy or tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure otherwise the subject must be willing to use two adequate barrier methods throughout the study, starting with the screening visit through 120 days after the last infusion of study treatment. Information must be captured appropriately within the site's source documents;
39. ♦ If of childbearing potential, female patients must be willing to use two adequate barrier methods throughout the study, starting with the screening visit up to 120 days after last infusion of chemotherapeutic and investigational agents as specified in the protocol; Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
40. ♦ Male patients with a female partner(s) of child-bearing potential must agree to use two adequate barrier methods throughout the trial starting with the screening visit through 120 days after the last infusion of study treatment is received. Males with pregnant partners must agree to use a condom; no additional method of contraception is required for the pregnant partner;
41. ♦ Female patients who are breast feeding must discontinue nursing prior to the first infusion of study treatment and until 120 days after the last study treatment;
42. ♦ Absence of severe comorbidities that in the opinion of the Investigator might hamper the participation to the study and/or the treatment administration;

Exclusion criteria 1

1. Not available. According to study design, all exclusion criteria are included within inclusion criteria.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. ♦ DFS in the PD-L1 strong positive subgroup;
2. ♦ DFS in the overall population.

Secondary endpoints 6

1. ♦ DFS in the PD-L1 positive population;
2. ♦ OS in the overall population;
3. ♦ OS in the PD-L1 strong positive subgroup;
4. ♦ OS in the PD-L1 positive population;
5. ♦ LCSS in the overall population;
6. ♦ Toxicity according to CTCAE version 4.03.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Merck Sharp & Dohme LLC

Sponsor organisation

Merck Sharp & Dohme LLC

Address

126 East Lincoln Avenue, P. O. Box 2000 P. O. Box 2000

City

Rahway

Postcode

07065-4607

Country

United States

Scientific contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

Nazly Shariati

Public contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

Nazly Shariati

Third parties 4

Locations

17 EU/EEA countries · 97 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 96 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications