An Open-label, Randomized, Multicenter, Phase 3 Study to Assess the Efficacy and Safety of Trastuzumab Deruxtecan as First-line Treatment of Unresectable, Locally Advanced, or Metastatic NSCLC Harboring HER2 Exon 19 or 20 Mutations (DESTINY-Lung04)

Lung cancer remains the leading cause of cancer-related mortality worldwide
accounting for approximately 18% of all cancer deaths globally in 2018 (Bray et
al 2018). The SoC treatment for patients with metastatic NSCLC is currently
based on molecular characterization and matched targeted therapy for specific
driver-mutated subsets (Heigener et al 2019). For metastatic NSCLC patients
without EGFR or ALK genomic tumor aberrations, platinum-doublet chemotherapy
with anti-PD-1/PD-L1 targeting immunotherapy (including pembrolizumab) is the
current SoC based on results from KEYNOTE189 (Gandhi et al 2018).

There are several driver mutations for which targeted therapies have been
approved, including EGFR, MET, ALK fusions, BRAF, MEK, ROS1, NTRK, RET fusions,
EGFR exon 20 insertion, and KRAS G12C (Mazieres et al 2013, NCCN 2021).
Although HER2 alterations have been widely studied as a predictive biomarker in
breast cancer, with multiple therapeutic options, there have yet to be any
approved therapies (targeted or not) for HER2 alterations in metastatic NSCLC.
Available data suggest that therapies may result in poorer clinical outcomes in
HER2-mutated NSCLC patients compared to NSCLC patients without driver mutations
(Lai et al 2018; Mazieres et al 2019; Dziadziuszko et al 2019).

Study DS8201 A U204 (Smit et al 2020) provided encouraging preliminary clinical
efficacy data for T-DXd as monotherapy in the later-line setting for NSCLC
harboring HER2 mutations. Given the efficacy observed in later-line settings
and the current unmet for targeted therapies in treatment of metastatic NSCLC
harboring HER2 mutations, it is of interest to evaluate the efficacy of T-DXd
compared to currently available standard of care of
platinum doublet chemotherapy with immunotherapy in the first-line setting. In
this Phase 3 study, participants with unresectable, locally advanced, or
metastatic NSCLC harboring a HER2 exon 19 or 20 mutation will be randomized to
T-DXd or platinum with pemetrexed plus pembrolizumab Q3W to evaluate efficacy
in treatment-naïve patients.

This study has been transitioned to CTIS with ID 2023-503674-20-00 check the CTIS register for the current data.

Primary objective: To assess the efficacy of T-DXd relative to platinum with
pemetrexed plus pembrolizumab by assessment of PFS by BICR in participants with
unresectable, locally advanced, or metastatic NSCLC harboring HER2 exon 19 or
20 mutations.

This is a Phase 3, randomized, open-label, 2-arm, multicenter, international
study assessing the efficacy and safety of T-DXd compared with SoC
(platinum-based chemotherapy with pemetrexed in combination with pembrolizumab)
in patients with NSCLC harboring HER2 exon 19 or 20 mutations.

Participants will be randomized in a 1:1 ratio to one of the following
interventions: T-DXd (Arm 1) or platinum (cisplatin or carboplatin; up to 4
cycles) with pemetrexed plus pembrolizumab Q3W (Arm 2). Randomization will be
stratified by smoking history and presence of brain metastasis at baseline.

- Participants in Arm 1 (T-DXd) will receive 5.4 mg/kg of T-DXd as an IV
infusion Q3W until RECIST 1.1-defined progression by investigator, until
unacceptable toxicity, withdrawal of consent, or other discontinuation
criteria. or other discontinuation criteria (with the exception of CNS-PD; see
note below).
- Participants in Arm 2 (active comparator arm) will receive platinum
chemotherapy (cisplatin or carboplatin) with pemetrexed and pembrolizumab Q3W.
Note: Investigator choice of cisplatin or carboplatin (switch from cisplatin to
carboplatin during the treatment period is permitted). Platinum chemotherapy
will be administered for up to 4 cycles. Pembrolizumab and pemetrexed will be
administered until RECIST 1.1-defined progression by investigator, until
unacceptable toxicity, withdrawal of consent, or other discontinuation criteria
(with the exception of CNS-PD; see note below).

Note: In both arms, participants with objective radiological CNS-PD (based on
RECIST 1.1), who in the investigator*s opinion, continue to receive benefit
from their assigned treatment and meet the criteria for treatment in the
setting of CNS-PD may continue to receive therapy on trial for as long as they
are gaining clinical benefit and are without any discontinuation criteria,
until one of the criteria Section 6.1.1.2 is met.

Patients need to come to the hospital more often and visits are longer.
Patients will undergo the following actions during the study:
- History (including medical history)
- Pulmonary function tests at screening and if ILD/pneumonitis is suspected
- ECHO/MUGA scan (LVEF assessment)
- Ophthalmologic assessments
- 12-Lead ECG
- Vital signs (blood pressure, heart rate, body temperature, respiratory rate
and oxygen saturation)
- Height and weight measurement
- ECOG performance status
- Physical examination
- Laboratory assessments (blood / urine / pregnancy test (if applicable))
- Questionnaires
- AE/SAE assessments
- CT/MRI of abdomen, chest and pelvis at screening, Q6W (± 1 week) for 54
weeks, and then Q9W (± 1 week), starting at Week 63, at end of treatment
- Brain metastasis assessments (CT/MRI) at screening, Required Q6W (± 1 week)
for 54 weeks, and then Q9W (± 1 week), starting at Week 63 for participants
with brain metastasis, or as needed based on neurological symptoms for all
participants, at end of treatment
- HRCT of the chest at screening and if ILD/Pneumonitis is suspected
- Study intervention administration
- Biopsy at screening (if no tumor tissue is available or if it is insufficient)
- Biopsy at progression (optional)

The study drugs can also cause side effects. These side effects of T-DXd are
very common (may affect more than 1 in 10 people):
• Nausea
• Feeling tired (Fatigue)
• Vomiting
• Hair loss (Alopecia)
• Constipation
• Feeling less hungry (Anorexia)
• Decrease in the number of red blood cells (Anemia). This may cause you to
feel tired or weak.
• Decrease in the number of white blood cells (includes decrease in neutrophils
(neutropenia), leukocytes (Leukopenia) and lymphocytes (Lymphopenia). White
blood cells help to fight infection.
• Diarrhea
• Decrease in the number of platelets (Thrombocytopenia). Platelets help the
blood to clot
• Coughing
• Stomach (abdominal) pain
• Infections of the upper respiratory tract
• Headache
• Indigestion (Dyspepsia)
• Dry eye
• Dizziness
• Sores in or around your mouth (Stomatitis)
• Abnormal liver enzyme results (Increase in aspartate aminotransferase and
increase in alanine aminotransferase). An enzyme is a type of protein in the
blood. Abnormal levels are not normally associated with symptoms but may
indicate a problem with your liver.
• Difficulty breathing (Dyspnea)
• Severe nose bleeds (Epistaxis)
• Lung problems (Interstitial Lung Disease)
• Low potassium in the blood (Hypokalemia). Potassium is a mineral which helps
your nerves, muscles and heart function normally.
• Rash
• Fever (Pyrexia)
• Swelling of lower legs or hands (Edema peripheral)

These side effects of T-DXd are common (may affect up to 1 in 10 people):
• Reactions related to the infusion of the medicine (described below).
• Fever along with a decrease in the number of neutrophils (Febrile
neutropenia)
• Abnormal liver function
• Abnormal liver enzyme results (Increase in blood alkaline phosphatase). An
enzyme is a type of protein in the blood. Abnormal levels are not normally
associated with symptoms but may indicate a problem with your liver.
• Blood bilirubin increased. Bilirubin is a yellow substance in the blood,
produced by breakdown of red blood cells, which is normally removed by the
liver. Increase may cause yellowing of the skin and might indicate a problem
with your liver.
• Dehydration
• Itching (Pruritis)
• Pneumonia (An infection of the lungs).

The following serious side effect has been reported with the use of T-DXd
• Lung problems (pneumonitis/interstitial lung disease): trastuzumab deruxtecan
may cause lung problems that may be life-threatening or fatal. Symptoms may be
similar to other lung or heart diseases. Contact your doctor right away if you
have any new or worsening lung symptoms, including trouble breathing, shortness
of breath, cough or fever.

The risks described below could possibly be observed with trastuzumab
deruxtecan administration:
• Heart problems: shortness of breath, noticeably rapid, strong or irregular
heartbeat or abnormally rapid heart rate.
• Trastuzumab deruxtecan Allergic reactions/Hypersensitivity: rash, joint pain,
face, lip or tongue swelling, wheezing and difficulty breathing, and/or sudden
drop in blood pressure. A severe allergic reaction could be life threatening.
• Infusion reaction: fever, chills, nausea, vomiting, headache, cough,
dizziness, rash, and/or lower back pain usually of mild to moderate severity
and may lead to shortness of breath and severe lowering of blood pressure.

Risks associated with chemotherapy (cisplatin, carboplatin and pemetrexed):
• Risk of Infection, bruising and bleeding
• Anemia (low number of red blood cells): This may make you feel tired and
breathless.
• Feeling sick and being sick
• Loss of appetite
• Diarrhea or constipation
• Abdominal pain
• Tiredness
• Hair loss
• Changes in the way the liver works
• Changes in the way the kidneys work
• Decreases in the level of sodium, potassium, calcium and magnesium in your
blood
• Numb or tingling hands or feet: due to the effect of carboplatin or cisplatin
on nerves.
• Taste changes
• Changes in hearing: You may get ringing in your ears (tinnitus)
• Skin changes, including rash
• Pain in the joints and muscles
• Blood test abnormalities (low electrolytes)

Risks associated with pembrolizumab:

Most common adverse (reported in >=20% of patients):
• Fatigue
• Musculoskeletal Pain
• Decreased Appetite
• Pruritus
• Diarrhea
• Nausea
• Rash
• Pyrexia
• Cough
• Dyspnea
• Constipation
• Pain
• Abdominal Pain

Risks associated with Pembrolizumab in combination with chemotherapy
• Fatigue/asthenia
• Nausea
• Constipation
• Diarrhea
• Decreased appetite
• Rash
• Vomiting
• Cough
• Dyspnea
• Pyrexia
• Alopecia
• Peripheral neuropathy
• Mucosal Inflammation
• Stomatitis
• Headache