| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced or Metastatic Non-small Cell Lung Cancer (NSCLC) |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 |
- To compare the efficacy of Dato-DXd in combination with pembrolizumab versus pembrolizumab alone, as measured by progression-free survival (PFS) by blinded independent central review (BICR).
- To compare the efficacy of Dato-DXd in combination with pembrolizumab versus pembrolizumab alone, as measured by overall survival (OS). |
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| E.2.2 | Secondary objectives of the trial |
- To evaluate the efficacy of Dato-DXd in combination with pembrolizumab versus pembrolizumab alone, as measured by objective response rate (ORR) by BICR.
- To further evaluate the efficacy of Dato- DXd in combination with pembrolizumab versus pembrolizumab alone.
- To evaluate the patient-reported outcomes (PROs) of Dato-DXd in combination with pembrolizumab and of pembrolizumab alone.
- To further evaluate the safety of Dato- DXd in combination with pembrolizumab.
- To assess the immunogenicity of Dato-DXd in the investigational treatment arm. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet all of the following criteria to be eligible for randomization into the study:
1. Sign and date the Tissue Screening and Main ICFs, prior to the start of any study-specific qualification procedures.
2. Adults ≥18 years or the minimum legal adult age (whichever is greater) at the time of informed consent. (Follow local regulatory requirements if the legal age of adult voluntary consent for study participation is >18 years old.)
3. Histologically documented NSCLC that meets all of the following criteria:
a. Stage IIIB or IIIC disease and not candidates for surgical resection or definitive chemoradiation, or Stage IV NSCLC disease at the time of randomization (based on the American Joint Committee on Cancer, Eighth Edition). Subjects with early-stage NSCLC who have relapsed should be restaged during screening to ensure their eligibility for the study.
b. Documented negative test results for EGFR, ALK, and ROS1 actionable genomic alterations based on analysis of tumor tissue. If test results for EGFR, ALK, and ROS1 are not available, subjects are required to undergo testing performed locally for these genomic alterations.
c. No known actionable genomic alterations in NTRK, BRAF, RET, MET, or other actionable driver kinases with locally approved therapies. (Testing for genomic alterations besides EGFR, ALK, and ROS1 is not required prior to randomization). Subjects with squamous NSCLC are only required to undergo EGFR, ALK, and ROS1 testing if they have no history of tobacco smoking or were diagnosed with NSCLC at <40 years of age. Subjects whose tumors harbor KRAS mutations are eligible for the study.
4. Has provided a formalin-fixed tumor tissue sample (minimum of 4 × 4-micron sections or block equivalent) for the measurement of TROP2 protein expression and for the assessment of other exploratory biomarkers. This tissue requirement is in addition to the tissue required for PD-L1 testing for tissue screening purposes. If a documented law or regulation prohibits (or does not approve) sample collection, then such sample will not be collected.
5. Tumor has high PD-L1 expression (TPS ≥50%) as determined by PD-L1 IHC 22C3 pharmDx assay by central testing (minimum of 6 slides).
6. Has an adequate treatment washout period before Cycle 1 Day 1 as defined in protocol Section 5.1.
7. Measurable disease based on local imaging assessment using RECIST Version 1.1 (see Section 10.4 of the protocol).
8. Has left ventricular ejection fraction (LVEF) ≥50% by either an echocardiogram (ECHO) or multigated acquisition scan (MUGA) within 28 days before randomization.
9. ECOG PS of 0 or 1 at screening.
10. Has a life expectancy of at least 3 months.
11. Adequate bone marrow function within 7 days before randomization as defined in protocol Section 5.1.
12. If the subject is a female of childbearing potential, she must not be pregnant, breastfeeding or intend to become pregnant during the study; she must also have a negative serum pregnancy test at screening and must be willing to use highly effective birth control (as detailed in protocol Section 10.3.4) or avoid heterosexual intercourse upon randomization, during the Treatment Period, for 7 months following the last dose of Dato-DXd, and for 4 months following the last dose of pembrolizumab, whichever occurs later. A female is considered of childbearing potential following menarche and until becoming postmenopausal (no menstrual period for a minimum of 12 months) unless permanently sterile (undergone a hysterectomy, bilateral salpingectomy, or bilateral oophorectomy).
13. If male, the subject must be surgically sterile or must use a condom in addition to their partner using highly effective birth control (Section 10.3.4 of the protocol) if their partner is of reproductive potential or avoid heterosexual intercourse upon enrollment, during the Treatment Period, and for 4 months following the last dose of Dato-DXd.
14. Male subjects must not freeze or donate sperm starting at screening and throughout the study period, and at least 4 months after the last dose of Dato-DXd. Preservation of sperm should be considered prior to enrollment in this study.
15. Female subjects must not donate, or retrieve for their own use, ova from the time of screening and throughout the study treatment period, and for at least 7 months after the last dose of Dato-DXd, or for at least 4 months after the last dose of pembrolizumab, whichever occurs later. Preservation of ova should be considered prior to enrollment in this study.
16. Is willing and able to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions. |
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| E.4 | Principal exclusion criteria |
Subjects who meet any of the following criteria will be disqualified from entering the study:
1. Has received prior systemic treatment for advanced or metastatic NSCLC.
2. Has received prior treatment for NSCLC with any of the following, including in the adjuvant/neoadjuvant setting:
a. Any agent, including an antibody-drug conjugate, containing a chemotherapeutic agent targeting topoisomerase I.
b. TROP2-targeted therapy.
c. Any anti-programmed death receptor-1 (PD-1), anti-PD-L1, or anti-PD-ligand 2 (L2) agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX40, CD137).
d. Any other immune checkpoint inhibitors.
Subjects who received adjuvant or neoadjuvant therapy OTHER than those listed above, are eligible if the adjuvant/neoadjuvant therapy was completed at least 6 months prior to the diagnosis of advanced/metastatic disease.
3. Has spinal cord compression or active and untreated central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are radiologically stable (ie, without evidence of progression) for at least 2 weeks by repeat imaging (note: repeat imaging should be performed during study screening), clinically stable, and without requirement of steroid treatment for at least 7 days before the first dose of study drug. Note: A computed tomography (CT) scan or magnetic resonance imaging (MRI) scan of the brain at baseline (MRI preferred) is required for all subjects. For those subjects in whom CNS metastases are first discovered at the time of screening, the treating investigator should consider delay of study treatment to document stability of CNS metastases with repeat imaging 4 weeks later (in which case, repeat of all screening activity may be required).
4. Has received prior radiotherapy ≤4 weeks of start of study intervention or more than 30 Gy to the lung within 6 months of Cycle 1 Day 1. Subjects must have recovered from all radiation-related toxicities, without requiring corticosteroids. A 2-week washout is permitted for palliative radiation to the non-thoracic region.
5. History of another primary malignancy (beyond NSCLC) except for the following:
- Malignancy treated with curative intent and with no known active disease ≥3 years before the first dose of study treatment and of low potential risk for recurrence
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
- Adequately treated carcinoma in situ without evidence of disease
- Subjects with a history of prostate cancer (tumor/node/metastasis stage) of Stage ≤T2cN0M0 without biochemical recurrence or progression and who in the opinion of the investigator are not deemed to require active intervention.
6. Has a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis including radiation pneumonitis that required steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
7. Clinically severe pulmonary compromise, as judged by the investigator, resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (eg, pulmonary emboli diagnosed within 3 months of Cycle 1 Day 1, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion, etc.), or any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement (eg, rheumatoid arthritis, Sjögren’s syndrome, sarcoidosis, etc.), or prior complete pneumonectomy.
8. Uncontrolled or significant cardiovascular disease, including:
a. Mean QT interval corrected for heart rate using Fridericia’s formula (QTcF) interval >470 msec regardless of sex (based on the average of the 12-lead electrocardiogram determination at screening).
b. Myocardial infarction within 6 months prior to randomization.
c. Uncontrolled angina pectoris within 6 months prior to randomization.
d. LVEF <50% by ECHO or MUGA scan within 28 days before randomization.
e. New York Heart Association Class 2 to 4 congestive heart failure (CHF) at screening. Subjects with a history of Class 2 to 4 CHF prior to screening, must have returned to Class 1 CHF and have LVEF ≥50% (by either an ECHO or MUGA scan within 28 days before randomization) in order to be eligible.
f. Uncontrolled hypertension (resting systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg) within 28 days before randomization.
9. Has clinically significant corneal disease.
For full list of principal exclusion criteria please see Clinical Study Protocol Section 5.2. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
-Progression-free survival (PFS) is defined as the time from randomization to the first documented radiographic disease progression or death due to any cause, whichever occurs first.
-Overall survival (OS) is defined as the time from randomization to death due to any cause.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Subjects will undergo radiographic assessment of tumor response based on Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 every 9 weeks (±7 days) for the first 2 years and then every 12 weeks (±7 days) thereafter, from randomization until radiological disease progression as determined by BICR, death, lost to follow-up, or withdrawal of consent, regardless of discontinuing study treatment or starting a new anticancer therapy (tumor assessment is not restricted to the Treatment Period). |
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| E.5.2 | Secondary end point(s) |
1. Efficacy:
- Objective response rate (ORR) is defined as the proportion of subjects who achieved a best overall response (BOR) of confirmed complete response (CR) or confirmed partial response (PR).
- PFS is defined as the time from randomization to the first documented radiographic disease progression or death due to any cause, whichever occurs first.
- PFS2 is defined as the time from date of randomization to the first documented disease progression on next-line therapy or death due to any cause, whichever occurs first.
- ORR is defined as the proportion of subjects who achieved a BOR of confirmed CR or confirmed PR.
- Duration of response (DoR) is defined as the time from the date of the first documentation of objective response (confirmed CR or confirmed PR) to the date of the first radiographic disease progression or death due to any cause, whichever occurs first.
- Time to response (TTR) is defined as the time from randomization to the date of the first documentation of objective response (confirmed CR or confirmed PR) in responding subjects.
-Disease control rate (DCR) is defined as the proportion of subjects who achieved a BOR of confirmed CR, confirmed PR, or stable disease (SD).
2. Patient-reported outcomes (PROs):
- Time to deterioration (TTD) is defined as the time from randomization to first onset of a ≥10-point increase in cough, chest pain, or dyspnea, confirmed by a second adjacent ≥10- point increase from randomization in the same symptom, or confirmed by death within 21 days of a ≥10-point increase from randomization.
3. Safety:
- Treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), adverse events of special interest (AESIs), Eastern Cooperative Oncology Group performance status (ECOG PS), vital sign measurements, standard clinical laboratory parameters (hematology, clinical chemistry, and urinalysis), electrocardiogram parameters, echocardiogram (ECHO)/multigated acquisition (MUGA) scan findings, and ophthalmologic findings. AEs will be coded by the most recent version of the Medical Dictionary for Regulatory Activities (MedDRA) and both AEs and laboratory test results will be graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0
4. Immunogenicity:
- Anti-drug antibody (ADA) prevalence: the proportion of subjects who are ADA-positive at any point in time (at baseline or post-baseline) ADA incidence: the proportion of subjects having a treatment-emergent ADA Titer and neutralizing antibodies will be determined when the ADA is positive. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Efficacy: Please refer time point of evaluation for Primary end point.
2. PROs: From randomization until EOT.
3. Safety: After the subject signs the Tissue Screening ICF and up to 90 (+7) days after the last dose of study drug (or 30 [+7] days following cessation of study treatment if the subject initiates new anticancer therapy, whichever is earlier).
4. For subjects receiving Dato-DXd: C1 – Day 1 (within 8h before infusion), C2 – Day 1 (within 8h before infusion), C4, C6, C8, and then every 4 cycles (ie, C12, C16 and so on) until EOT
For subjects receiving pembrolizumab: C1 – Day 1 (within 8h before infusion), C2 – Day 1 (within 8h before infusion), and then every 2 cycles (ie, C4, C6) until C8 or pembrolizumab discontinuation, whichever occurs first.
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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 | No |
| 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 | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Patient-reported outcomes (PROs), Immunogenicity, Biomarkers |
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| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Datopotamab deruxtecan (Dato-DXd) in combination with pembrolizumab versus pembrolizumab alone |
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| 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 | 62 |
| 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 |
| Argentina |
| Chile |
| Switzerland |
| Ukraine |
| Hong Kong |
| Taiwan |
| Australia |
| Brazil |
| Canada |
| China |
| Japan |
| Korea, Republic of |
| Mexico |
| Russian Federation |
| Thailand |
| Turkey |
| United Kingdom |
| United States |
| Belgium |
| Czechia |
| France |
| Germany |
| Greece |
| Hungary |
| Italy |
| Netherlands |
| Poland |
| Portugal |
| Romania |
| Spain |
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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
|
Overall EOS will occur after all subjects have discontinued the study or have died; or an alternative study becomes available for subjects continuing to derive benefit from treatment with pembrolizumab and/or Dato-DXd where the drug is offered to these subjects; or the study is discontinued by the Sponsor for other reasons. A final analysis may be conducted at the overall EOS.
The subject’s EOS is the date of their last study visit/contact. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
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