A Clinical study of Trastuzumab Deruxtecan as first line Treatment for Non-Small Cell Lung Cancer
Scientific Title of Study
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)
Senior Director, Oncology Country Head Site Management and Monitoring – India
Affiliation
AstraZeneca Pharma India Limited
Address
AstraZeneca Pharma India Ltd.
Block N1, 12th Floor, Manyata Embassy Business Park
Rachenahalli, Outer Ring Road
Bangalore KARNATAKA 560045 India
Phone
91-9845079472
Fax
08067748857
Email
Sandeep.AV@astrazeneca.com
Source of Monetary or Material Support
AstraZeneca AB, 151 85 Sodertalje, Sweden
Primary Sponsor
Name
AstraZeneca AB
Address
151 85 Sodertalje, Sweden
Type of Sponsor
Pharmaceutical industry-Global
Details of Secondary Sponsor
Name
Address
AstraZeneca Pharma India Limited
Block N1, 12th Floor, Manyata Embassy Business Park
Rachenahalli, Outer Ring Road, Bangalore – 560045, India
Countries of Recruitment
Australia Brazil Bulgaria Canada China Denmark France Germany Hong Kong India Italy Japan Mexico Netherlands Poland Republic of Korea Spain Sweden Taiwan Turkey United States of America
Institutional Ethics Committee Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute
Submittted/Under Review
Institutional Review Board Rajiv Gandhi Cancer Institute & Research Centre
Approved
Intitutional Ethics Committee, Asian Institute of Gastroenterology
Approved
Manavata Clinical Research Institute Ethics Committee
Approved
Regulatory Clearance Status from DCGI
Status
Approved/Obtained
Health Condition / Problems Studied
Health Type
Condition
Patients
(1) ICD-10 Condition: C349||Malignant neoplasm of unspecifiedpart of bronchus or lung,
Intervention / Comparator Agent
Type
Name
Details
Comparator Agent
Cisplatin or carboplatin with pemetrexed and pembrolizumab
Cisplatin or carboplatin with pemetrexed and pembrolizumab every 3 weeks (Q3W). Platinum chemotherapy will be administered for up to 4 cycles. Pembrolizumab and pemetrexed will be administered until RECIST 1.1 defined progression by investigator
Intervention
Trastuzumab Deruxtecan (T-DXd)
Trastuzumab Deruxtecan ((T-DXd) monotherapy by IV administration Q3W until RECIST 1.1 defined progression by investigator
Inclusion Criteria
Age From
18.00 Year(s)
Age To
99.00 Year(s)
Gender
Both
Details
Informed Consent
1.Capable of giving signed informed consent as described in Appendix A, which includes compliance with the requirements and restrictions listed in the ICF and in this CSP.
2.Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports the Genomic Initiative (see Appendix D)
3.Provision of signed and dated written ICF prior to any mandatory study‑specific procedures, sampling, or analyses. Note: Participants without a qualifying HER2-mutation status result will be required to sign a pre-screening ICF to permit blood sample collection for HER2 exon 19 or 20 mutation testing. Main study informed consent and assessment of the main study eligibility is only to be completed following confirmation of a study-qualifying HER2 mutation
Age
4.Male and female participants must be ≥ 18 years of age at the time of signing the ICF. Other age restrictions may apply as per local regulations.
Type of Participant and Disease Characteristics
5.Histologically documented non-squamous Stage 3 locally advanced and unresectable NSCLC not amenable to treatment with curative intent (surgery or chemoradiotherapy) or Stage 4 or recurrent metastatic NSCLC (according to Version 8 of the IASLC Staging Manual in Thoracic Oncology). Participants with mixed histology are eligible if adenocarcinoma is the predominant histology.
6.Participants must be treatment-naïve for palliative intent systemic therapy in locally advanced or metastatic disease and medically fit to receive first-line treatment. Prior local or systemic (neo-adjuvant or adjuvant) treatment for early-stage disease is permitted.
7.Documented qualifying HER2 exon 19 or 20 mutation (Appendix O lists qualifying activating HER2 exon 19 or 20 mutations):
a.From an archival tumor tissue sample (Appendix O details the study requirements for qualifying requirements for laboratories).
b.From a local plasma ctDNA test (Appendix O lists the acceptable assays for meeting this criterion).
c.Participants without a known qualifying HER2-mutation status result will be required to sign a pre-screening ICF to permit blood sample collection for HER2 exon 19 or 20 mutation testing. The main ICF and other study procedures may not be started until the qualifying central laboratory test result is obtained.
8.A FFPE tumor sample must be available for central testing. If there is no written confirmation of the availability of an archived tumor sample (preferred) or alternatively from a recently obtained biopsy (provided it was performed as part of their routine clinical care pathway, see Section 8.6.1.1), the participant is not eligible for the study.
9.A WHO/ECOG performance score of 0 or 1, with no deterioration over the previous 2 weeks prior to baseline or day of first dosing.
10.At least one measurable lesion by RECIST 1.1. Note: A previously irradiated lesion can be considered a target lesion if the lesion is well defined, measurable per RECIST, and has clearly progressed.
11.Adequate organ and bone marrow function within 14 days before randomization/enrollment as follows:
Parameters for Adequate Organ and Bone Marrow Function
Adequate bone marrow function
Platelet count- ≥ 100,000/mm3. (Platelet transfusion is not allowed within 1 week prior to screening assessment)
Hemoglobin- ≥ 9.0 g/dL NOTE: Participants requiring ongoing transfusions or growth factor support to maintain hemoglobin ≥ 9.0 g/dL are not eligible (red blood cell transfusion is not allowed within 1 week prior to screening assessment)
Absolute neutrophil count- ≥ 1,500/mm3. (Granulocyte-colony stimulating factor administration is not allowed within 1 week prior to screening assessment)
Adequate blood clotting function
International normalized ratio or PT and either partial thromboplastin or activated partial thromboplastin time ≤ 1.5 × ULN
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CrCL, calculated creatinine clearance; PT, prothrombin time; ULN, upper limit of normal.
12.Left ventricular ejection fraction ≥ 50% within 28 days before randomization/enrollment.
13.Minimum life expectancy of at least 12 weeks
14.Adequate treatment washout period before randomization/enrollment, as defined below:
Adequate treatment washout periods
Major Surgery (as defined by the investigator) ≥ 4 weeks prior to first dose or still recovering from prior surgery. Note: Local surgeries are allowed if completed prior to the administration of the first dose of study intervention
Radiation therapy including palliative stereotactic radiation therapy to chest ≥ 4 weeks
Palliative stereotactic radiation therapy to other anatomic areas (except as specified for CNS radiation, see exclusion criterion 4)≥ 2 weeks
Anti-cancer chemotherapy [immunotherapy (non-antibody based therapy)], retinoid therapy, hormonal therapy ≥ 3 weeks
Antibody based anti-cancer therapy- ≥ 4 weeks
Targeted agents and small molecules (such as 5 fluorouracil based agents, folinate agents, weekly paclitaxel) ≥ 2 weeks or 5 half-lives, whichever is longer
Nitrosoureas or mitomycin C- ≥ 6 weeks
TKIs approved for treatment of NSCLC- ≥ 1 week
Chloroquine/Hydroxychloroquine- ≥ 14 days
Cell-free and CART, peritoneal shunt or drainage of pleural effusion, ascites or pericardial effusion- ≥ 2 weeks prior to screening assessment
Reproduction
15.Evidence of post-menopausal status or negative serum pregnancy test for females of childbearing potential who are sexually active with a non-sterilized male partner.
a.For women of childbearing potential, a negative result for serum pregnancy test (test must have a sensitivity of at least 25 mIU/mL) must be available at the screening visit and urine β-HCG pregnancy test prior to each administration of study intervention.
b.Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
16.Female participants of childbearing potential who are sexually active with a non-sterilized male partner must use at least one highly effective method of contraception from the time of screening and must agree to continue using such precautions for 7 months after the last dose of T-DXd and for as long as is indicated in the relevant product label for the other study treatment/interventions. Not engaging in sexual activity for the duration of the study and drug washout period is an acceptable practice; however, periodic or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. Not all methods of contraception are highly effective (see Table 23 for complete list of highly effective birth control methods). Female participants must not donate, or retrieve for their own use, ova from the time of screening and throughout the study intervention period, and for at least 7 months after the final dose of T-DXd and for as long as is indicated in the relevant product label for the other study interventions.
17.Non sterilized male participants who are sexually active with a female partner of childbearing potential must use a condom with spermicide from screening to 4 months after the final dose of T DXd and for as long as is indicated in the relevant product label for the other study interventions. Not engaging in sexual activity for the duration of the study and drug washout period is an acceptable practice; however, periodic, or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable. It is strongly recommended for the female partners of a male participant to also use at least one highly effective method of contraception throughout this period. Male participants should refrain from fathering a child or donating sperm during the study and for 4 months after the last dose of IP
ExclusionCriteria
Details
Medical Conditions
1.Mixed small-cell lung cancer, squamous histology NSCLC, and sarcomatoid histology variant NSCLC.
2.Tumors that harbor 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).
3.Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, uncontrolled hypertension, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs, or compromise the ability of the participant to give written informed consent.
4.Any spinal cord compression, leptomeningeal disease, or clinically active CNS metastases. Note: Clinically active CNS metastases are defined as untreated AND symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Participants with CNS metastases must have previously completed local therapy.
- Participants with previously treated CNS metastases are allowed if asymptomatic or neurologically stable and have recovered from the acute toxic effects of prior therapy.
- Participants with CNS metastases treated by radiation must be:
a ≥ 7 days since stereotactic radiosurgery or gamma knife prior to enrollment.
b ≥ 14 days since whole brain radiation therapy prior to enrollment
5. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn’s disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, sarcoidosis, granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, autoimmune pneumonitis and autoimmune myocarditis). The following are exceptions to this criterion:
- Participants with vitiligo or alopecia.
- Participants with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement.
- Any chronic skin condition that does not require systemic therapy.
- Participants without active disease in the last 5 years may be included but only after consultation with the AstraZeneca Study Physician.
- Participants with coeliac disease controlled by diet alone.
6.A pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or Cell-free and Concentrated Ascites Reinfusion Therapy.
7.Has a concomitant medical condition that would increase the risk of toxicity in the opinion of the investigator.
8.Multiple primary malignancies within 3 years, except adequately resected non-melanoma skin cancer, curatively treated in-situ disease, other solid tumors curatively treated.
9.Participants with a medical history of myocardial infarction within 6 months before randomization/enrollment or symptomatic congestive heart failure (NYHA Class II to IV). Note: Participants with troponin levels above ULN at screening (as defined by the manufacturer), and without any myocardial related symptoms, should have a cardiologic consultation before enrollment to rule out myocardial infarction.
10.QTcF prolongation to > 470 msec (females) or > 450 msec (males) based on average of the screening triplicate 12-lead ECG.
11.History of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
12.Lung criteria:
- Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (eg, pulmonary emboli within 3 months of study enrollment, severe asthma, severe COPD, restrictive lung disease, pleural effusion, etc).
- Any autoimmune, connective tissue or inflammatory disorders (ie, rheumatoid arthritis, Sjogren’s, sarcoidosis, etc) where there is documented, or a suspicion of pulmonary involvement at the time of screening. Full details of the disorder should be recorded in the eCRF for participants who are included in the study.
- Prior complete pneumonectomy. Note: Prior lobar or segmental resection is permitted.
13.Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals or active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination, and radiographic findings, and tuberculosis testing in line with local practice).
14.Active primary immunodeficiency, known HIV infection, or active hepatitis B or C infection. Note: Participants positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Participants should be tested for HIV prior to randomization/enrollment if required by local regulations or institutional review board/ethics committee
15.Receipt of live, attenuated vaccine within 30 days prior to the first dose of T-DXd. Note: Participants, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of study intervention.
Prior/Concomitant Therapy
16.Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤ 1 or baseline. Note: Participants may be enrolled with chronic, stable Grade 2 toxicities (defined as no worsening to > Grade 2 for at least 3 months prior to enrollment and managed with standard of care treatment) that the investigator deems related to previous anticancer therapy, for example:
- Chemotherapy-induced neuropathy
- Fatigue
- Residual toxicities from prior IO treatment: Grade 1 or Grade 2 endocrinopathies which may include:
a Hypothyroidism/hyperthyroidism
b Type 1 diabetes
c Hyperglycemia
d Adrenal insufficiency
e Adrenalitis
f Skin hypopigmentation (vitiligo).
17.Medical contraindication to platinum-based doublet chemotherapy or pembrolizumab.
18.Is unable or unwilling to take folic acid or vitamin B12 supplementation
Prior/Concurrent Clinical Study Experience
19.Previous randomization in the present study.
20.Randomization into a prior T-DXd study regardless of treatment assignment.
21.Concurrent enrollment in another therapeutic clinical study. Note: Enrollment in observational studies will be allowed.
22.Known allergy or hypersensitivity to study intervention or any of the study drug excipients or other mAbs.
Other Exclusions
23.Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
24.Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions and requirements.
25.Pregnant (confirmed with positive pregnancy test) or breastfeeding female participants or participants who are planning to become pregnant.
26.Has substance abuse or any other medical conditions such as clinically significant cardiac or psychological conditions, that may, in the opinion of the investigator, interfere with the participant’s participation in the clinical study or evaluation of the clinical study results.
Method of Generating Random Sequence
Stratified block randomization
Method of Concealment
Centralized
Blinding/Masking
Open Label
Primary Outcome
Outcome
TimePoints
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
38 months after the first participant is randomized
Secondary Outcome
Outcome
TimePoints
1 To assess the efficacy of T-DXd relative to platinum with pemetrexed plus pembrolizumab by assessment of OS (overall survival).
63 months after the first participant is randomized
2. To further assess the efficacy of T-DXd relative to platinum with pemetrexed plus pembrolizumab in terms of PFS by investigator assessment, ORR (objective response rate), DoR (duration of response), PFS2 (time to second progression or death), and landmark analysis of PFS12 (proportion of participants alive and progression free at 12 months) and OS24 (proportion of participants alive at 24 months)
63 months after the first participant is randomized
To further assess the efficacy of T-DXd relative to platinum with pemetrexed plus pembrolizumab in terms of PFS by investigator assessment, ORR (objective response rate), DoR (duration of response), PFS2 (time to second progression or death), and landmark analysis of PFS12 (proportion of participants alive and progression free at 12 months) and OS24 (proportion of participants alive at 24 months)
63 months after the first participant is randomized
Further assess the efficacy of T-DXd relative to platinum with pemetrexed plus pembrolizumab in terms of PFS by investigator assessment, ORR (objective response rate), DoR (duration of response), PFS2 (time to second progression or death), and landmark analysis of PFS12 (proportion of participants alive and progression free at 12 months) and OS24 (proportion of participants alive at 24 months)
63 months after the first participant is randomized
Assess the efficacy of T-DXd relative to platinum with pemetrexed plus pembrolizumab in terms of PFS by investigator assessment, ORR (objective response rate), DoR (duration of response), PFS2 (time to second progression or death), and landmark analysis of PFS12 (proportion of participants alive and progression free at 12 months) and OS24 (proportion of participants alive at 24 months)
63 months after the first participant is randomized
To Assess the efficacy of T-DXd relative to platinum with pemetrexed plus pembrolizumab in terms of PFS by investigator assessment, ORR (objective response rate), DoR (duration of response), PFS2 (time to second progression or death), and landmark analysis of PFS12 (proportion of participants alive and progression free at 12 months) and OS24 (proportion of participants alive at 24 months)
63 months after the first participant is randomized
To assess the efficacy of T-DXd relative to platinum with pemetrexed plus pembrolizumab by assessment of CNS-PFS (per RECIST 1.1).
63 months after the first participant is randomized
To assess the safety and tolerability of T-DXd as compared to platinum with pemetrexed plus pembrolizumab
63 months after the first participant is randomized
To assess the PK of T-DXd, total anti-HER2 antibody and DXd in serum
63 months after the first participant is randomized
To investigate the immunogenicity of T-DXd.
63 months after the first participant is randomized
To assess the benefit of T-DXd relative to platinum with pemetrexed plus pembrolizumab with patient reported pulmonary symptoms associated with NSCLC.
63 months after the first participant is randomized
To describe patient-reported tolerability of T-DXd as compared to platinum with pemetrexed plus pembrolizumab
63 months after the first participant is randomized
Target Sample Size
Total Sample Size="264" Sample Size from India="12" Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials" Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials"
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Response - NO
Brief Summary
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. Approximately 5500 participants with non-squamous NSCLC will be screened in order to randomize approximately 264 participants from around 150 sites across 21 countries globally.
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. 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