| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic non-small cell lung cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Metastatic non-small cell lung cancer |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 27.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10059515 |
| E.1.2 | Term | Non-small cell lung cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
1. To compare MK-7684A to pembrolizumab alone with respect to PFS per RECIST 1.1 as assessed by BICR in participants with PD-L1 TPS ≥50% and in participants with PD-L1 TPS ≥1%.
2. To compare MK-7684A to pembrolizumab alone with respect to OS in participants with PD-L1 TPS ≥50%, in participants with PD-L1 TPS ≥1%, and in participants with PD-L1 TPS 1% to 49%.
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|
| E.2.2 | Secondary objectives of the trial |
1. To compare MK-7684A to pembrolizumab alone with respect to PFS per RECIST 1.1 by BICR in participants with PD-L1 TPS 1% to 49%
2. To compare MK-7684A to pembrolizumab alone with respect to objective response rate (ORR) per RECIST 1.1 by BICR in participants with PD-L1 TPS ≥50%, in participants with PD-L1 TPS 1% to 49% and in participants with PD-L1 TPS ≥1%.
3. To evaluate DOR per RECIST 1.1 by BICR for MK-7684A compared to pembrolizumab alone in participants with PD-L1 TPS ≥50%, in participants with PD-L1 TPS 1% to 49% and in participants with PD-L1 TPS ≥1
4. To evaluate the mean change from baseline and TTD in global health status/QoL, physical functioning, dyspnea, cough, and chest pain for MK-7684A compared to pembrolizumab alone in participants with PD-L1 TPS ≥50%, in participants with PD-L1 TPS 1% to 49% and in participants with PD-L1 TPS ≥1%
5. To evaluate the safety and tolerability for MK-7684A compared to pembrolizumab alone |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
A participant will be eligible for inclusion in the study if the participant:
1. Has a histologically or cytologically confirmed diagnosis of NSCLC.
2. Has measurable disease based on RECIST 1.1, as determined by the local site assessment.
3. Has confirmation that EGFR-, ALK-, or ROS1-directed therapy is not indicated as primary therapy.
4. Has provided tumor tissue that demonstrates PD-L1 expression in ≥1% of tumor cells (TPS ≥1%) as assessed by IHC at a central laboratory.
5. Is male or female, ≥ 18 years of age at the time of providing documented informed consent.
6. Has an ECOG PS of 0 or 1 assessed within 7 days prior to randomization.
7. Has a life expectancy of at least 3 months.
8. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
• Is not a WOCBP
OR
• Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis), as described in the protocol during the intervention period and for at least 120 days after the last dose of study intervention. The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention.
• A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours for urine or within 72 hours for serum before the first dose of study intervention.
• If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
• The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
• Contraceptive use by females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study drugs is more stringent than the requirements above, the local label requirements should be followed.
9. The participant (or legally acceptable representative) has provided documented informed consent for the study. The participant may also provide consent for future biomedical research. However, the participant may participate in the main study without participating in future biomedical research.
10. Has adequate organ function as defined in the protocol. Specimens must be collected within 10 days before the start of study intervention.
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| E.4 | Principal exclusion criteria |
The participant must be excluded from the study if the participant:
1. Has a known history of an additional malignancy, except if the participant has undergone potentially curative therapy with no evidence of that disease recurrence for at least 3 years since initiation of that therapy.
2. Has received prior systemic chemotherapy or other targeted or biological antineoplastic therapy for their metastatic NSCLC.
3. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
4. Has received previous treatment with another agent targeting the TIGIT receptor pathway.
5. Has received radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
6. Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention. Administration of killed vaccines is allowed.
7. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention.
8. Has known active or untreated CNS metastases and/or carcinomatous meningitis.
Participants with previously treated brain metastases may participate provided they are radiologically stable (ie, without evidence of progression) for at least 4 weeks by repeat imaging, clinically stable, and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention.
9. Has severe hypersensitivity (≥Grade 3) to MK-7684A or pembrolizumab and/or any of its excipients.
10. Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs).
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
11. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study intervention.
12. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
13. Has a known history of interstitial lung disease. Lymphangitic spread of the NSCLC is not exclusionary.
14. Has an active infection requiring systemic therapy.
15. Has a known history of HIV infection. No HIV testing is required unless mandated by local health authority.
16. Has a known history of Hepatitis B (defined as HBsAg reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
17. Has a history or current evidence of any condition, therapy, or laboratory abnormality that prevents the participant from receiving platinum-doublet chemotherapy for first line NSCLC, or that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
18. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study.
19. If the participant had major surgery, the participant must have recovered adequately from the procedure and/or any complications from the surgery prior to starting study intervention.
20. Has had an allogenic tissue/solid organ transplant. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1.Overall Survival (OS) in Participants With Programmed Cell Death Ligand 1 (PD-L1) Tumor Proportion Score (TPS) ≥50%
2. OS in Participants With PD-L1 TPS ≥1%
3.OS in Participants With PD-L1 TPS 1% to 49%
4. Progression-Free Survival (PFS) in Participants With PD-L1 TPS ≥1%
5. PFS in Participants With PD-L1 TPS ≥50%
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|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to approximately 59 months
2. Up to approximately 59 months
3. Up to approximately 59 months
4. Up to approximately 51 months
5. Up to approximately 51 months |
|
| E.5.2 | Secondary end point(s) |
1. Objective Response Rate (ORR) in Participants With PD-L1 TPS ≥1%
2. PFS in Participants With PD-L1 TPS 1% to 49%
3. ORR in Participants With PD-L1 TPS ≥50%
4. ORR in Participants With PD-L1 TPS 1% to 49%
5. Duration of Response (DOR) in Participants With PD-L1 TPS ≥50%
6. DOR in Participants With PD-L1 TPS 1% to 49%
7. DOR in Participants With PD-L1 TPS ≥1%
8. Change from Baseline in Global Health Status/Quality of Life (QoL) (Items 29, 30) Combined Score on the European Organization for Research and Treatment of Cancer QoL Questionnaire-Core 30 (EORTC QLQ-C30) by PD-L1 TPS Subgroup (≥1%, 1%-49%, ≥50%)
9. Change from Baseline in Physical Functioning (Items 1-5) Combined Score on the EORTC QLQ-C30 by PD-L1 TPS Subgroup (≥1%, 1%-49%, ≥50%)
10. Change from Baseline in Role Functioning (Items 6, 7) Combined Score on the EORTC QLQ-C30 by PD-L1 TPS Subgroup (≥1%, 1%-49%, ≥50%)
11. Change from Baseline in Dyspnea Score (Item 8) on the EORTC QLQ-C30 by PD-L1 TPS Subgroup (≥1%, 1%-49%, ≥50%)
12. Change from Baseline in Cough Score (Item 31) on the European Organization for Research and Treatment of Cancer Quality of Life Lung Cancer-Specific Questionnaire Module (EORTC QLQ-LC13) by PD-L1 TPS Subgroup (≥1%, 1%-49%, ≥50%)
13.Change from Baseline in Chest Pain Score (Item 40) on the EORTC QLQ-LC13 by PD-L1 TPS Subgroup (≥1%, 1%-49%, ≥50%)
14. Time to Deterioration (TTD) in Global Health Status/QoL (Items 29, 30) Combined Score on the EORTC QLQ-C30 by PD-L1 TPS Subgroup (≥1%, 1%-49%, ≥50%)
15. TTD in Physical Functioning (Items 1-5) Combined Score on the EORTC QLQ-C30 by PD-L1 TPS Subgroup (≥1%, 1%-49%, ≥50%)
16. TTD in Role Functioning (Items 6, 7) Combined Score on the EORTC QLQ-C30 by PD-L1 TPS Subgroup (≥1%, 1%-49%, ≥50%)
17. TTD in Dyspnea Score (Item 8) on the EORTC QLQ-C30 by PD-L1 TPS Subgroup (≥1%, 1%-49%, ≥50%)
18. TTD in Cough Score (Item 31) on the EORTC QLQ-LC13 by PD-L1 TPS Subgroup (≥1%, 1%-49%, ≥50%)
19. TTD in in Chest Pain Score (Item 40) on the EORTC QLQ-LC13 by PD-L1 TPS Subgroup (≥1%, 1%-49%, ≥50%)
20. Number of Participants Who Experienced One or More Adverse Events (AEs)
21. Number of Participants Who Discontinued Study Intervention Due to an Adverse Event (AE) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to 2 years
2. Up to 51 months
3. Up to ~2 years
4. Up to ~2 years
5. Up to ~59 months
6. Up to ~59 months
7. Up to ~59 months
8. Baseline and up to 107 weeks
9. Baseline and up to 107 weeks
10. Baseline and up to 107 weeks
11. Baseline and up to 107 weeks
12. Baseline and up to 107 weeks
13. Baseline and up to 107 weeks
14. Baseline and up to 107 weeks
15 Baseline and up to 107 weeks
16. Baseline and up to 107 weeks
17. Baseline and up to 107 weeks
18. Baseline and up to 107 weeks
19. Baseline and up to 107 weeks
20. Baseline and up to 115 weeks
21. Baseline and up to 103 weeks |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 13 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Chile |
| Dominican Republic |
| Guatemala |
| Malaysia |
| Peru |
| Philippines |
| Ukraine |
| Hong Kong |
| Taiwan |
| Brazil |
| Canada |
| China |
| Japan |
| Korea, Republic of |
| Mexico |
| Russian Federation |
| South Africa |
| Thailand |
| United States |
| Hungary |
| Romania |
| Türkiye |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| LVLS - The overall study ends when the last participant completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the participant is unable to be contacted by the investigator). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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