| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Unresectable, locally advanced, or metastatic Non-Small Cell Lung Cancer with HER2 exon 19 or 20 mutations |
|
| E.1.1.1 | Medical condition in easily understood language |
| Locally Advanced/Unresectable/Metastatic HER2 mutant Lung Cancer |
|
| 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 | 24.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10084787 |
| E.1.2 | Term | HER2 mutant non-small cell lung cancer |
| 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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess the efficacy of T-DXd relative to platinum with pemetrexed plus pembrolizumab by assessment of Progression-Free Survival (PFS) by Blinded Independent Central Review (BICR) in participants with unresectable, locally advanced, or metastatic NSCLC harboring HER2 exon 19 or 20 mutations. |
|
| E.2.2 | Secondary objectives of the trial |
-To assess efficacy of T-DXd relative to platinum with pemetrexed plus pembrolizumab by assessment of Overall Survival (OS).
-To assess efficacy of T-DXd relative to platinum with pemetrexed plus pembrolizumab in terms of PFS by investigator assessment, Objective Response Rate (ORR), Duration of Response (DoR), time to second progression or death (PFS2), & landmark analysis of PFS12 and OS24
-To assess efficacy of T-DXd relative to platinum with pemetrexed plus pembrolizumab by assessment of CNS-PFS (per RECIST 1.1).
-To assess safety and tolerability of T-DXd compared to platinum with pemetrexed plus pembrolizumab.
-To assess PK of T-DXd, total anti-HER2 antibody and DXd in serum.
-To investigate immunogenicity of T-DXd.
-To assess benefit of T-DXd relative to platinum with pemetrexed plus pembrolizumab with patient-reported pulmonary symptoms associated with NSCLC.
-To describe patient-reported tolerability of T-DXd as compared to platinum with pemetrexed plus pembrolizumab. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Male and female participants at least 18 years of age
- Locally advanced not amenable to curative therapy, or metastatic disease
- Histologically documented non-squamous NSCLC with HER2 mutation
in exons 19 or 20 by tissue NGS or ctDNA (locally or centrally tested)
- Treatment-naïve for palliative intent systemic therapy for locally advanced or metastatic disease
- Left ventricular ejection fraction (LVEF) ≥ 50%
- Measurable disease assessed by Investigator based on RECIST v1.1
- Protocol-defined adequate organ function including cardiac, renal, hepatic function
- ECOG 0-1
- Having tumour tissue available for central testing |
|
| E.4 | Principal exclusion criteria |
- Tumors with targetable alterations to EGFR (or other targetable mutations including but not limited to ALK, if routinely tested as a targetable alteration with approved available therapy)
- Any clinically active brain metastases; previously treated brain metastases that are asymptomatic and stable are allowed
- Active autoimmune or inflammatory disorders
- Medical history of myocardial infarction within 6 months prior to randomization
- History of non-infectious pneumonitis/ILD, current or suspected ILD
- Lung-specific intercurrent clinical significant severe illness
- Contraindication to platinum-based doublet chemotherapy or pembrolizumab |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression Free Survival (PFS) defined as time from randomization until progression per RECIST 1.1 as assessed by Blinded Independent Central Review (BICR) or death due to any cause. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Until progression or death, assessed up to approximately 12 months. |
|
| E.5.2 | Secondary end point(s) |
1. Overall Survival (OS) defined as time from randomization until date of death due to any cause.
2. PFS by investigator assessment defined as time from randomization until progression as assessed by investigator (per RECIST 1.1) or death due to any cause.
Objective Response Rate (ORR) and Duration of Response (DoR) by BICR and Investigator assessment per RECIST 1.1. ORR is defined as proportion of participants who have a complete response (CR) or partial response (PR).
DoR is defined as time from date of first documented response until date of documented progression.
PFS2 is defined as time from randomization to second progression on next-line of treatment as assessed by investigator or death due to any cause.
PFS12 is the landmark of PFS which is defined as proportion of participants alive and progression-free at 12 months as assessed by BICR and investigator.
OS24 is the landmark of OS defined as proportion of patients alive at 24 months
3. CNS-PFS defined as time from randomization until CNS-progression (RECIST 1.1) as assessed by BICR or death due to any cause in absence of CNS progression.
4. AEs, SAEs, changes from baseline in laboratory parameters, vital signs, ECG, ECHO/MUGA results
5. Pharmacokinetics (PK) of T-DXd and serum concentration of T-DXd, total anti-HER2 antibody and DXd
6. Presence of ADAs for T-DXd
7. Time to sustained deterioration in pulmonary symptoms while on treatment using NSCLC-Symptom Assessment Questionnaire (SAQ)
8. Patient Reported Tolerability will be described among participants using the following outcomes: Symptomatic AEs (assessed by PRO-CTCAE and EORTC Item Library), Overall Side Effect Bother (reported on Patient’s Global Impression of Treatment Tolerability (PGI-TT)), Physical Function (based on EORTC-QLQ-30) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Until death, assessed up to approximately 28 months.
2. PFS by investigator assessment: Until progression, assessed up to approximately 12 months
ORR and DoR: Until progression, assessed up to approximately 12 months
PFS2: Assessed up to approximately 20 months
PFS12: Assessed up to approximately 12 months
OS24: Assessed up to approximately 24 months
3. Until CNS progression or death, assessed up to approximately 12 months
4. Until progression or death, assessed up to approximately 28 months
5. Up to cycle 4, approximately 12 weeks
6. Until progression, assessed up to approximately 13 months
7. Until progression, assessed up to approximately 13 months
8. Until progression, assessed up to approximately 13 months |
|
| 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 | Yes |
| 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 | 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) | 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 52 |
| 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 |
| Hong Kong |
| Taiwan |
| Brazil |
| Canada |
| China |
| India |
| Japan |
| Korea, Republic of |
| Mexico |
| United States |
| Austria |
| Belgium |
| Denmark |
| France |
| Germany |
| Italy |
| Netherlands |
| Poland |
| Spain |
| Türkiye |
|
| 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
|
|
| 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 | 1 |
| E.8.9.1 | In the Member State concerned days | 10 |
| 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 | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 2 |
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