Study of Datopotamab Deruxtecan (Dato-DXd) for first line treatment of patients with locally advanced or metastatic NSCLC

Phase 3

Recruiting

• Conditions: Malignant neoplasm of unspecifiedpart of bronchus or lung,

• Registration Number: CTRI/2023/05/052218
• Lead Sponsor: AstraZeneca AB

Brief Summary

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|This is a Phase III, Randomised, Open-label, Multicentre, Global Study of Datopotamab Deruxtecan (Dato-DXd) in Combination With Durvalumab and Carboplatin Versus Pembrolizumab in Combination With Platinum-based Chemotherapy for the First-line Treatment of Patients With Locally Advanced or Metastatic NSCLC Without Actionable Genomic Alterations (D926NC00001; AVANZAR)

 Approximately 1000 patients will be randomized in a 1:1: ratio in 2 treatment arms

 At study start, mandatory tumour samples will be collected for retrospective assessment of TROP2 expression in a sponsor-designated central laboratory using the TROP2 IHC clinical trial assay (Ventana Medical Systems, Inc., Tucson, Arizona) until prospective assay availability.

 All the patients randomized into study will be followed for survival follow up.

 Participants will be stratified based on tumour histology (squamous versus non-squamous), centrally determined PD-L1 expression (TC < 1%, TC 1% to 49%, and TC ≥ 50%), smoking status (current/former smoker versus never smoker) and TROP2 biomarker status (positive or negative) to ensure that there is a balanced distribution of these important prognostic/predictive factors between treatment arms.

 Tumor evaluation using RECIST 1.1 will be conducted at screening (within 28 days prior to randomization); thereafter every 7 weeks ±1 week (after randomization) up to Week 12, then every 9 weeks (± 7 days) up to Week 48 and then every 12 weeks (± 7 days) thereafter, relative to the date of randomisation and until RECIST 1.1-defined radiological PD plus an additional follow-up scan at least 4 weeks later and no later than the next scheduled imaging visit.

 **Follow-up of Participants Post Discontinuation of Study Intervention**

 After study intervention discontinuation, all participants will undergo an end-of-treatment visit (within 97 days of discontinuation) and will be followed up for safety assessments up to 97 days after their last dose of study intervention (ie, the safety follow-up visit). If the day of discontinuation is over 97 days from last study intervention administration, follow-up assessment is not needed.

 Participants who have discontinued study intervention prior to objective RECIST 1.1-defined radiological progression will be followed up with tumour assessments as indicated in the SoA until the follow-up scan at least 4 weeks later and no later than the next scheduled imaging visit (if clinically feasible), or death regardless of whether or not the participant started a subsequent anti-cancer therapy unless they have withdrawn all consent to study-related assessments.

 All participants will be followed up for survival status after intervention discontinuation every 3 months (± 7 days) until death, withdrawal of consent, or the end of the study, per the SoA. Participants will also be followed up for PFS2 after every 3 months (± 7 days) after initial objective PD until death, withdrawal of consent, or the end of the study, per the SoA.

Detailed Description

Not available

Study Timeline

• Study Start: 2023-06-18
• Last Update Posted: 2024-02-24

Recruitment & Eligibility

• Status: Open to Recruitment
• Sex: All
• Target Recruitment: 1000

Inclusion Criteria

• Participant must be ≥ 18 years at the time of screening.
• Type of Participant and Disease Characteristics 2.
• Histologically or cytologically documented NSCLC that: a) Is Stage IIIB or IIIC disease not amenable for surgical resection or definitive chemoradiation, or Stage IV metastatic NSCLC disease at the time of randomisation who have not received prior chemotherapy or other systemic therapy for first-line Stage IIIB, IIIC or IV NSCLC.
• Participants who have received prior platinum-containing adjuvant, neoadjuvant, or definitive chemoradiation for early stage disease (Stage I to IIIA) are eligible, provided that progression has occurred 6 months from the last dose of checkpoint inhibitor, chemotherapy, or other systemic anti-cancer therapy.
• b) Lacks sensitising EGFR tumour tissue mutation (eg, exon 19 deletion or exon 21 L858R, exon 21 L861Q, exon 18 G719X, or exon 20 S768I mutation), as well as ALK and ROS1 rearrangements.
• c) Has no documented tumour genomic alteration results in NTRK, BRAF, RET, MET or any other actionable driver oncogenes for which there are locally approved and available targeted first-line therapies.
• Note: Participants whose tumours harbour KRAS mutations are eligible for the study.
• ECOG PS of 0 or 1 with no deterioration over the previous 2 weeks prior to day of first dosing.
• FFPE tumour sample collected prior to signing of informed consent, ie, the start of screening.
• Tumour PD-L1 status defined as TC 1%, TC 1% to 49%, or TC 50%, determined using the VENTANA PD-L1 (SP263) IHC Assay by a central laboratory.
• Participants with unknown central PD L1 status are not eligible for the study.
• TROP2 biomarker status as determined retrospectively using the VENTANA TROP2 IHC QCS Assay (clinical trial assay), or prospectively once a TROP2 IHC QCS assay is validated in a CAP/CLIA laboratory.
• Participants with unknown central TROP2 biomarker status are not eligible for the study once prospective testing is implemented.
• At least 1 lesion, not previously irradiated, that qualifies as a target lesion (TL) per RECIST 1.1 at baseline and can be accurately measured at baseline as 10 mm in the longest diameter (except lymph nodes, which must have short axis 15 mm) with CT or MRI and is suitable for accurate repeated measurements.
• Adequate bone marrow reserve and organ function within 7 days before randomisation defined as: Haemoglobin 9.0 g/dL (red blood cell/plasma transfusion is not allowed within 1 week prior to screening assessment).
• Absolute neutrophil count 1.5 109/L (granulocyte colony stimulating factor administration is not allowed within 1 week prior to screening assessment).
• Platelet count 100 109/L (platelet transfusion is not allowed within 1 week prior to screening assessment).
• International normalised ratio/prothrombin time and either partial thromboplastin time or activated partial thromboplastin time 1.5 ULN.
• TBL 1.5 ULN or 3 ULN in the presence of documented Gilbert’s syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline.
• ALT and AST 3 ULN (5 ULN in participants with liver metastases).
• Calculated CrCL 40 mL/min as determined by Cockcroft Gault (using actual body weight).
• Minimum life expectancy of 12 weeks.
• Male and/or female.
• Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• Reproduction: 11.
• Negative pregnancy test (serum) for women of childbearing potential who are sexually active with a non-sterilised male partner.
• 12.Female participants must be 1 year postmenopausal, surgically sterile, or using 1 highly effective form of birth control (a highly effective method of contraception is defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly).
• For women who are on HRT please refer to Appendix G.
• Women of childbearing potential who are sexually active with a non sterilised male partner must agree to use 1 highly effective method of birth control (see Appendix G for complete list of highly effective birth control methods).
• Male participants who intend to be sexually active with a female partner of childbearing potential must be surgically sterile or using an acceptable method of contraception (see Appendix G) from the time of screening throughout the total duration of the study and the drug washout period (90 days after the last dose of durvalumab or 180 days after the last dose of tremelimumab, whichever is longer) to prevent pregnancy in a partner.
• Male participants must not donate or bank sperm during this same time period.
• Informed Consent 14.
• 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 protocol.

Exclusion Criteria

• Exclusion criteria Medical conditions 1.As judged by the investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, including active bleeding diseases, active systemic infection (except for HBV infection or HCV infection), active interstitial lung disease (ILD) pneumonitis, serious chronic gastrointestinal conditions associated with diarrhea, psychiatric illness/social situations) or history of allogeneic organ transplant that, in the investigator’s opinion, makes it undesirable for the participant to participate in the study or that would jeopardize compliance with the protocol.
• 2.Uncontrolled arterial hypertension defined by a systolic pressure 150 mm Hg or diastolic pressure 90 mm Hg or other hypertensive cardiovascular complications despite standard medical management.
• 3.Refractory nausea and vomiting, chronic gastrointestinal disease, inability to swallow a formulated product, or previous significant bowel resection that would preclude adequate absorption, distribution, metabolism, or excretion of Lenvatinib.
• 4.History of another primary malignancy.
• Exceptions include: 1) malignancy treated with curative intent or has low potential risk for recurrence with no known active disease 5 years before the first dose of study intervention; 2) malignancy which occurred 5 years before the first dose of study intervention, is not active, and not expected to recur or be clinically relevant in the next 5 years (may be considered pending further to discussion with the study physician prior to randomization).
• 5.Persistent toxicities (Common Terminology Criteria for Adverse Events [CTCAE] Grade 2) caused by previous anticancer therapy; alopecia and vitiligo are excluded toxicities.
• Participants with irreversible toxicity that is not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included (eg, hearing loss) after consultation with the AstraZeneca study clinical lead.
• 6.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, etc), 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.
• Participants with coeliac disease controlled by diet alone.
• 7.History of leptomeningeal carcinomatosis.
• 8.Co-infection with HBV and hepatitis D virus (HDV).
• (The HBV infection is indicated by the presence of HBsAg and/or anti-HBcAb with detectable HBV DNA 10 IU/mL or above the limit of detection per local lab standard; HDV positive infection is indicated by the presence of anti-HDV antibodies.) 9.Known to have tested positive for human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies) or tuberculosis infection (clinical evaluation that may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice).
• 10.History of symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia.
• Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted upon discussion with the study clinical lead.
• 11.Any history of nephrotic or nephritic syndrome.
• 12.Known fibrolamellar HCC, sarcomatoid HCC, infiltrative-type HCC, or mixed cholangiocarcinoma and HCC.
• 13.History of hepatic encephalopathy or porto-systemic shunt within past 12 months or requirement for medications to prevent or control encephalopathy (ie, no lactulose, rifaximin, etc, if used for purposes of hepatic encephalopathy).
• 14.Clinically meaningful ascites, defined as ascites requiring non-pharmacologic intervention (eg, paracentesis) to maintain symptomatic control, within 6 months prior to the first scheduled dose.
• •Participants with ascites that has required pharmacologic intervention (eg, diuretics) and who have been on stable doses of diuretics for ascites for 2 months are eligible.
• 15.Major portal vein thrombosis visible on baseline/eligibility imaging.
• 16.Evidence by investigator assessment of varices at risk of bleeding on upper endoscopy undertaken at the screening visit, or within 6 months (24 weeks) of randomization.
• Prior/Concomitant Therapy 17.Receipt of prior systemic anticancer therapies for HCC.
• 18.Receipt of more than 1 prior embolization treatment/procedure with palliative intent (embolization procedures as part of curative therapy are not restricted).
• Prior radiotherapy (eg, transarterial radioembolization [TARE], SBRT) is permitted if > 6 months prior to randomization.
• Prior exposure to immune-mediated therapy including, but not limited to, other antiCTLA-4, anti-PD-1, anti-PD-L1, antiPD-L2, and anti-VEGF antibodies, excluding therapeutic anticancer vaccines.
• 20.Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab, tremelimumab, or lenvatinib.
• The following are exceptions to this criterion: •Intranasal, inhaled, topical steroids or local steroid injections (eg, intra-articular injection).
• •Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent.
• • Steroids as premedication for hypersensitivity reactions or as an anti-emetic (eg, CT scan premedication).
• 21.Receipt of live attenuated vaccine within 30 days prior to the first dose of study intervention .
• 22.Major surgical procedure or significant traumatic injury within 4 weeks of the first dose of study intervention or an anticipated need for major surgery during the study.
• Prior/Concurrent Clinical Study Experience 23.Previous randomization in the present study or a previous durvalumab and/or tremelimumab clinical study regardless of treatment arm assignment.
• 25.Participants with a known hypersensitivity to durvalumab, tremelimumab, and/or lenvatinib or any of the excipients of the products.
• Other Exclusions: 26.Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
• 27.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.
• 28.Female participants who are pregnant or breastfeeding or male or female participants of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy or 180 days after the last dose of tremelimumab, whichever is longer.

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
To demonstrate the superiority of Dato-DXd in combination with durvalumab and carboplatin relative to pembrolizumab in combination with platinum based chemotherapy by assessment of PFS by BICR in first line treatment of TROP2 biomarker positive participants with locally advanced or metastatic NSCLC	PFS using BICR assessments according to RECIST 1.1 will be assessed at Baseline followed by every 6 weeks (± 7 days) up to Week 12, then every 9 weeks (± 7 days) up to Week 48 and then every 12 weeks (± 7 days) thereafter, relative to the date of randomisation and until RECIST 1.1 defined radiological PD plus an additional follow-up scan at least 4 weeks later
To demonstrate the superiority of Dato-DXd in combination with durvalumab and carboplatin relative to pembrolizumab in combination with platinum based chemotherapy by assessment of OS in first-line treatment of TROP2 biomarker positive participants with locally advanced or metastatic NSCLC	PFS using BICR assessments according to RECIST 1.1 will be assessed at Baseline followed by every 6 weeks (± 7 days) up to Week 12, then every 9 weeks (± 7 days) up to Week 48 and then every 12 weeks (± 7 days) thereafter, relative to the date of randomisation and until RECIST 1.1 defined radiological PD plus an additional follow-up scan at least 4 weeks later

Secondary Outcome Measures

Name	Time	Method
To demonstrate the superiority of Dato-DXd in combination with durvalumab and carboplatin relative to pembrolizumab in combination with platinum based chemotherapy by assessment of PFS by BICR in first line treatment of participants with locally advanced or metastatic NSCLC (ITT population)	PFS using BICR assessments according to RECIST 1.1 will be assessed at Baseline followed by every 6 weeks (± 7 days) up to Week 12, then every 9 weeks (± 7 days) up to Week 48 and then every 12 weeks (± 7 days) thereafter, relative to the date of randomisation and until RECIST 1.1 defined radiological PD plus an additional follow-up scan at least 4 weeks later
To demonstrate the superiority of Dato-DXd in combination with durvalumab and carboplatin relative to pembrolizumab in combination with platinum based chemotherapy by assessment of OS in first-line treatment of participants with locally advanced or metastatic NSCLC (ITT population)	Assessments for survival after intervention discontinuation will be conducted every 3 months (± 7 days) until death, withdrawal of consent or the end of study
To demonstrate the superiority of Dato-DXd in combination with durvalumab and carboplatin relative to pembrolizumab in combination with platinum based chemotherapy by assessment of PFS by BICR in first line treatment of TROP2 biomarker negative participants with locally advanced or metastatic NSCLC	PFS using BICR assessments according to RECIST 1.1 will be assessed at Baseline followed by every 6 weeks (± 7 days) up to Week 12, then every 9 weeks (± 7 days) up to Week 48 and then every 12 weeks (± 7 days) thereafter, relative to the date of randomisation and until RECIST 1.1 defined radiological PD plus an additional follow-up scan at least 4 weeks later
To demonstrate the superiority of Dato-DXd in combination with durvalumab and carboplatin relative to pembrolizumab in combination with platinum based chemotherapy by assessment of OS in first-line treatment of TROP2 biomarker negative participants with locally advanced or metastatic NSCLC	Assessments for survival after intervention discontinuation will be conducted every 3 months (± 7 days) until death, withdrawal of consent or the end of study
To demonstrate the effectiveness of Dato-DXd in combination with durvalumab and carboplatin relative to pembrolizumab in combination with platinum based chemotherapy by assessment of ORR in first-line treatment of participants with locally advanced or metastatic NSCLC	Evaluation of CR or PR as determined by BICR and investigator per RECIST 1.1 assessed at Baseline, every 6 weeks (± 7 days) up to Week 12, then every 9 weeks (± 7 days) up to Week 48 and then every 12 weeks (± 7 days) thereafter, relative to the date of randomisation
Safety objective	To assess the safety and tolerability of Dato-DXd in combination with durvalumab and carboplatin as compared with pembrolizumab in combination with platinum based chemotherapy in first-line treatment of participants with locally advanced or metastatic NSCLC.
To demonstrate the effectiveness of Dato-DXd in combination with durvalumab and carboplatin relative to pembrolizumab in combination with platinum based chemotherapy by assessment of DoR in first line treatment of participants with locally advanced or metastatic NSCLC	DoR is defined as the time from the date of first documented confirmed response until date of documented progression per RECIST 1.1, as assessed by BICR and investigator assessment or death due to any cause. This will be based on the radiology assessments performed at Baseline and then every 6 weeks up to Week 12, then every 9 weeks up to Week 48 and then every 12 weeks thereafter
To demonstrate the effectiveness of Dato-DXd in combination with durvalumab and carboplatin relative to pembrolizumab in combination with platinum based chemotherapy by assessment of PFS in first line treatment of participants with locally advanced or metastatic NSCLC by investigator’s assessment	PFS using Investigator’s assessments according to RECIST 1.1 will be assessed at Baseline followed by every 6 weeks (± 7 days) up to Week 12, then every 9 weeks (± 7 days) up to Week 48 and then every 12 weeks (± 7 days) thereafter, relative to the date of randomisation and until RECIST 1.1 defined radiological PD plus an additional follow-up scan at least 4 weeks later
To assess participant-reported pulmonary symptoms of NSCLC in participants treated with Dato-DXd in combination with durvalumab and carboplatin relative to pembrolizumab in combination with platinum based chemotherapy	TTD in pulmonary symptoms (dyspnoea, cough and chest pain) as measured by the NSCLC-SAQ at Baseline and Every 3 weeks from C1 Day 1 for the first 51 weeks and every 6 weeks thereafter until EoT, at EoT, and then every 6 weeks (relative to C1 Day 1) after EoT until 18 weeks after PD
To assess participant-reported physical functioning in participants treated with Dato-DXd in combination with durvalumab and carboplatin relative to pembrolizumab in combination with platinum based chemotherapy	Time to Deterioration in physical functioning as measured by PROMIS Physical Function short form 8c at Baseline and Every 3 weeks from C1 Day 1 for the first 51 weeks and every 6 weeks thereafter until EoT, at EoT, and then every 6 weeks (relative to C1 Day 1) after EoT until 18 weeks after PD
To assess the PK of Dato-DXd when combined with durvalumab and carboplatin	Concentration of Dato-DXd, total anti TROP2 antibody, and MAAA 1181a (payload deruxtecan) in plasma and PK parameters collected at C1D1 followed by C4D1 and C8D1
To investigate the immunogenicity of Dato DXd when combined with durvalumab and carboplatin	Presence of Antidrug Antibody for Dato-DXd. Samples will be collected from patient randomized on Dato-Dxd arm. Pre-dose at Cycles 1, 2, 4, and 8, and every 4 cycles thereafter until PD, the EoT visit and the first safety follow-up visit 30 (± 3) days after the last dose of Dato-DXd in combination with durvalumab and Carboplatin

Trial Locations

Locations (7)

All India Institute of Medical Sciences; 🇮🇳 Delhi, DELHI, India

Bhagwan Mahaveer Hospital and Research Centre; 🇮🇳 Jaipur, RAJASTHAN, India

Jawaharlal Institute of Postgraduate Medical Education & Research; 🇮🇳 Pondicherry, PONDICHERRY, India

Meenakshi Mission Hospital and Research Centre; 🇮🇳 Madurai, TAMIL NADU, India

MVR Cancer Hospital & Research Institute; 🇮🇳 Kozhikode, KERALA, India

Rajiv Gandhi Cancer Institute and Research Centre; 🇮🇳 Delhi, DELHI, India

Tata Medical Center, Kolkata; 🇮🇳 Kolkata, WEST BENGAL, India

All India Institute of Medical Sciences

🇮🇳Delhi, DELHI, India

Dr Sachin Khurana

Principal investigator

9769030180

dr.sachinkhurana@gmail.com