A trial to learn how well Dato-DXd works and how safe it is with other anticancer drugs in adults with TROP2 NMR-positive non-small cell lung cancer

Trial details

Who runs it

AstraZeneca AB

Trial code

EU 2025-524836-21-00

Record updated

10 November 2026

Original description

- To estimate the PFS of Dato-DXd + durvalumab in participants with non-squamous, non-AGA, TROP2 NMR+, a/mNSCLC. - To estimate the PFS of Dato-DXd + durvalumab + carboplatin in participants with non-squamous, non-AGA, TROP2 NMR+ a/mNSCLCRead full original descriptionShow less

A Global, Multicentre, Phase II Platform Study of Datopotamab Deruxtecan (Dato-DXd)-based Combinations in Adult Patients With TROP2 NMR-positive Non-small Cell Lung Cancer (NSCLC) (PATAGONIA)

- To estimate the PFS of Dato-DXd + durvalumab in participants with non-squamous, non-AGA, TROP2 NMR+, a/mNSCLC. - To estimate the PFS of Dato-DXd + durvalumab + carboplatin in participants with non-squamous, non-AGA, TROP2 NMR+ a/mNSCLC

Inclusion: Participant must be ≥ 18 years of age at the time of signing the ICF (or the statutory age of majority stipulated by local regulatory requirements); Male and/or female assigned at birth, inclusive of all gender identities. Contraceptive use by participants or participant partners should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies; see Appendix G for further details. a. Male participants: i. Use of a condom plus an additional contraceptive method, or avoid intercourse from randomisation and throughout study and the drug washout period (see Appendix G for further details), in addition to the female partner using a highly effective contraceptive method. ii. Starting at the first dose of study intervention, male participants must not freeze or donate sperm at any time during this study and the drug washout period (see Appendix G for further details). Preservation of sperm should be considered prior to the first dose of study intervention in this study. b. Female participants: Females not of child-bearing potential, see Appendix G for definition. i. Females receiving HRT and whose menopausal status is in doubt will be required to use one of the contraception methods outlined for WOCBP if they wish to continue using HRT during the study. Otherwise, HRT must be discontinued to allow confirmation of post-menopausal status prior to randomisation; see Appendix G for further details. ii. WOCBP must use one highly effective form of contraception or avoid intercourse from randomization throughout the study and the drug washout period; see Appendix G for further details. All WOCBP must have a negative serum pregnancy test documented during screening. iii. Starting at the first dose of study intervention, female participants must not donate, or retrieve for their own use, ova at any time during this study and the drug washout period; see Appendix G for further details. Preservation of ova should be considered prior to the first dose of study intervention in this study; 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; Provision of signed and dated Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports the Genomic Initiative; Pathologically documented NSCLC that: a. Has documented NSQ histology b. Is TROP2 NMR+ as determined using the investigational TROP2 REDACTED c. Documented lack of sensitising EGFR 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 on tumour tissue; Stage IIIB or IIIC disease not amenable to surgical resection or definitive chemoradiation, or Stage IV metastatic NSCLC at the time of randomisation, as per the American Joint Committee on Cancer Staging System, 9th Edition. Participants must not have received prior chemotherapy or other systemic therapy for first-line Stage IIIB, IIIC, or IV NSCLC. Participants who have received prior adjuvant, neoadjuvant, or definitive chemoradiation for early stage disease (Stage I to III) are eligible, provided that progression has occurred REDACTED from the last dose of checkpoint inhibitor, chemotherapy, other systemic anti-cancer therapy, or radiation therapy; The REDACTED capped to REDACTED of total randomized patients, with no deterioration over the previous 2 weeks prior to the day of first dosing. Participants with ECOG PS 2 are eligible if they meet the following criteria: a. Serum albumin ≥ 2.5 g/dL b. Do not have significant third-space fluid retention (for example, ascites or pleural effusion) that requires repeated drainage; Known tumour PD-L1 status; Minimum life expectancy of 12 weeks; Provision of acceptable FFPE tumour sample from a lesion not previously irradiated. All participants must be able to provide an available FFPE tumour sample collected REDACTED prior to eligibility testing for the study. For non-EU countries: If such a sample is not available, then an FFPE tumour sample will be collected at biomarker screening (if applicable) or main screening for mandatory eligibility testing; At least 1 lesion, not previously irradiated, that qualifies as a RECIST 1.1 TL 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 (see Appendix F). If only 1 measurable lesion exists, it is acceptable to be used (as a TL) as long as it has not been previously irradiated and as long as it has not been biopsied within 14 days prior to the baseline tumour assessment scans; Adequate bone marrow reserve and organ function as follows: a. Haemoglobin ≥ 9.0 g/dL (red blood cell transfusion is not allowed within 1 week prior to screening assessment) b. Absolute neutrophil count ≥ 1.5 × 109/L (granulocyte colony stimulating factor administration is not allowed within 1 week prior to screening assessment) c. Platelet count ≥ 100 × 109/L (platelet transfusion is not allowed within 1 week prior to screening assessment) d. INR/prothrombin time and either partial thromboplastin time or aPTT ≤ 1.5 × ULN. e. TBL ≤ 1.5 × ULN (or ≤ 3 × ULN in the presence of documented Gilbert’s syndrome [unconjugated hyperbilirubinaemia] or liver metastases at baseline). f. Except in the setting of HBV, ALT and AST ≤ 2.5 × ULN (for participants with liver metastases at baseline, ALT and AST ≤ 5 × ULN). See Exclusion Criterion 10 for requirements in the setting of HBV. g. Calculated CrCL ≥ 40 mL/min as determined by Cockcroft Gault (using actual body weight) or measured by 24-hour urine collection per local guidelines.

Exclusion: As judged by the investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, including active bleeding diseases, ongoing or active infection, active ILD/pneumonitis, serious chronic gastrointestinal conditions associated with diarrhoea, psychiatric illness/social situations, or significant cardiac conditions), chronic diverticulitis or previous complicated diverticulitis, or history of allogenic organ transplant, which, in the investigator’s opinion, makes it undesirable for the participant to participate in the study or that would jeopardise compliance with the protocol; Prior exposure to: a. Any agent, including ADC, containing a chemotherapeutic agent targeting topoisomerase I b. Chemotherapy or any other systemic therapy for first-line Stage IIIB, IIIC, or IV NSCLC c. TROP2-targeted therapy d. Chloroquine/hydroxychloroquine without an adequate treatment washout period of REDACTED prior to randomisation; Participants who have received any prior adjuvant, neoadjuvant, or defi nitive chemoradiation for early stage disease (Stage I to III) are eligible, provided that progression has occurred REDACTED from the time of the last dose of checkpoint inhibitor, chemotherapy, or other systemic anti-cancer therapy or radiation therapy. However, for participants who have received immune checkpoint inhibitors (not limited to prior anti-PD-1, anti-PD-L1, or anti-CTLA4 in the adjuvant or neoadjuvant setting): a. Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy b. All AEs whilst receiving prior immunotherapy must have completely resolved or resolved to baseline prior to screening for this study. c. Must not have experienced a Grade ≥ 3 immune-related AE or an immune-related Neurologic or ocular AE of any grade whilst receiving prior immunotherapy Note: Participants with an endocrine AE of Grade ≤ 2 are eligible if they are stably maintained on appropriate replacement therapy and are asymptomatic. d. Must not have required the use of additional immunosuppression other than corticosteroids for the management of an immune-related AE, not have experienced recurrence of an AE if re-challenged, and not currently require doses of REDACTED or equivalent per day; History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 3 years before the first dose of study intervention and of low potential risk for recurrence, adequately resected basal cell carcinoma of the skin or squamous cell carcinoma of the skin, lentigo maligna that has undergone potentially curative therapy, or adequately treated in situ disease without evidence of disease; Current or prior use of immunosuppressive medication within 14 days before the fi rst dose of study intervention. The following are exceptions to this criterion: a. Intranasal, inhaled, topical steroids or local steroid injections. Corticosteroid mouthwash formulations are permitted to prevent and manage certain AEs. b. Systemic corticosteroids at physiologic doses not to exceed REDACTED or its equivalent c. Steroids as premedication for hypersensitivity reactions or as an antiemetic d. Use of steroids for known CNS metastases; Any concurrent anti-cancer treatment (including cytotoxic, biologic, targeted agents, immunotherapy, antibody, retinoid or anti-cancer hormonal treatment) other than those under investigation in this study (including curative radiotherapy and radiotherapy to the thorax). Concurrent use of hormonal therapy for non-cancer-related conditions (eg, HRT) is allowed; Any concomitant medication known to be associated with Torsades de Pointes; Receipt of live, attenuated vaccine within 30 days prior to the first dose of study intervention; Received prior radiotherapy to the brain within 2 weeks of start of study intervention or received palliative radiotherapy to the chest within 4 weeks of start of study intervention or has ongoing radiation-related toxicities requiring corticosteroids. Ongoing radiation toxicities should resolve to Grade 1 or baseline prior to first dose of study intervention; Major surgical procedure (excluding placement of vascular access) or significant traumatic injury within ≤ 4 weeks of the first dose of study intervention or an anticipated need for major surgery during the study. Note: Local surgery of isolated lesions for palliative intent is acceptable; Participation in another clinical study with a study intervention or investigational medicinal device administered in the last 4 weeks prior to randomisation or concurrent participation in another clinical study (unless the study is observational [non-interventional] or the participant is in the follow-up period of an interventional study); Persistent toxicities caused by previous anti-cancer therapy, excluding alopecia or vitiligo, not yet improved to Grade ≤ 1 or baseline. Note: Participants may be randomised with some chronic, stable Grade 2 toxicities (defined as no worsening to > Grade 2 for at least 3 months prior to randomisation and managed with SoC treatment) which the investigator deems related to previous anti-cancer therapy, including (but not limited to): a. Chemotherapy-induced neuropathy b. Fatigue c. Residual toxicities from prior immunotherapy treatment: Grade 1 or Grade 2 endocrinopathies, which may include but are not limited to hypothyroidism/hyperthyroidism, Type I diabetes, hyperglycaemia, adrenal insufficiency, or adrenalitis; and skin hypopigmentation (vitiligo) Note: Participants with irreversible toxicity that is not reasonably expected to be exacerbated by study intervention in the opinion of the investigator may be included; Active or prior documented autoimmune, connective tissue or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn’s disease], systemic lupus erythematosus, Sjögren’s syndrome, sarcoidosis, granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, etc), autoimmune pneumonitis, or autoimmune myocarditis. The following are exceptions to this criterion: a. Participants with vitiligo or alopecia b. Participants with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement c. Any chronic skin condition that does not require systemic therapy d. Participants without active disease in the last 5 years may be included but only after consultation with the study clinical lead e. Participants with coeliac disease controlled by diet alone; Spinal cord compression or CNS metastases, unless asymptomatic, stable, and not requiring treatment with corticosteroids or anticonvulsants for at least 7 days prior to randomisation. Participants who have been stabilised after completion of local therapy (ie, radiation and/or surgery) and have a stable neurological status for at least 2 weeks after completion of the local therapy (confirmed by brain MRI) and who require no treatment with corticosteroids or anticonvulsants can be randomised. Participants must have recovered from the acute toxic effect of radiotherapy (eg, dizziness and signs of increased intracranial pressure). A minimum of 2 weeks must have elapsed between the end of brain radiotherapy and randomisation. For those participants 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 at least 4 weeks later (in which case, repeat of all screening activity may be required); Uncontrolled infection requiring systemic antibiotics, antivirals, or antifungals, suspected infections (eg, prodromal symptoms), or inability to rule out infections (participants with localised fungal infections of skin or nails are eligible), or use of systemic antibiotics within 14 days of randomisation; Known to have active tuberculosis infection (clinical evaluation that may include clinical history, physical examination, and radiographic findings, or tuberculosis testing in line with local practice); History of ILD/pneumonitis, including radiation pneumonitis (apart from radiation pneumonitis that did not require steroids), or drug-induced ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening. Examples of suspected ILD/pneumonitis by imaging include the presence of lung parenchymal fibrosis, such as combined pulmonary fibrosis and emphysema , and any radiographic features consistent with interstitial lung abnormalities, including but not limited to extensive ground glass opacities, reticular opacities, traction bronchiectasis, and honeycombing. Investigator should assess whether these radiographic features present in imaging are suggestive of suspected ILD/pneumonitis at baseline; Has clinically REDACTED compromise resulting from intercurrent pulmonary illnesses, including but not limited to any underlying pulmonary disorder (eg, pulmonary emboli within 3 months of signed main informed consent, severe asthma, severe COPD, restrictive lung disease, symptomatic pleural effusion, etc); Participants with a known history of severe hypersensitivity reactions to study intervention or any excipients of these products (including but not limited to polysorbate 80); Participants with a known history of severe hypersensitivity reactions to other monoclonal antibodies; Squamous histology or mixed small-cell lung cancer and NSCLC histology, or sarcomatoid variant of NSCLC, or lung neuroendocrine tumours ; History of leptomeningeal carcinomatosis or metastasis; Clinically significant corneal disease; Has active or uncontrolled HBV or HCV infection. Hepatitis B and C testing are required at screening Part 2. Participants are eligible if they: a. Have a history of hepatitis C infection and the HCV viral load is below the level of detection in the absence of antiviral therapy during the previous 4 weeks and have normal transaminase values or, if liver metastases are present, abnormal transaminases with a result of AST/ALT REDACTED, which are not attributable to HCV infection b. Have received HBV vaccination with only anti-HBs positivity and no clinical signs of hepatitis c. Are HBsAg- and anti-HBc+ and meet conditions i-iii of criterion “d” below d. Are HBsAg+ with chronic HBV infection (lasting 6 months or longer) and meet criteria i-iii below: i. HBV DNA viral load REDACTED ii. Have normal transaminase values, or, if liver metastases are present, abnormal transaminases, with a result of AST/ALT REDACTED, which are not attributable to HBV infection iii. Start or maintain antiviral treatment if clinically indicated as per the investigator; Known HIV infection that is not well controlled. All of the following criteria are required to define an HIV infection that is well controlled: REDACTED, CD4+ count of REDACTED, no history of AIDS-defining opportunistic infection within the past 12 months, and stable for at least 4 weeks on the same anti-HIV medications. If an HIV infection meets the above criteria, monitoring of viral RNA load and CD4+ count is recommended and should be performed per local SoC in order to determine whether the infection is controlled and whether the participant is eligible for inclusion into the study. Participants must be tested for HIV during the screening period if acceptable by local regulations or an IRB/IEC; Uncontrolled or significant cardiac disease including: a. Myocardial infarction or uncontrolled/unstable angina within 6 months prior to randomisation b. Congestive heart failure (New York Heart Association Class II to IV) c. Uncontrolled hypertension (resting systolic blood pressure > 180 mmHg or diastolic blood pressure > 110 mmHg) d. Cardiac arrhythmia requiring treatment (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. e. History of QT prolongation associated with other medications that required discontinuation of that medication], or any current concomitant medication known to prolong the QT interval and cause Torsades de Pointes (TdP) f. Congenital long QT syndrome], family history of long QT syndrome, or unexplained sudden cardiac death under 40 years of age in first-degree relatives g. Unstable angina pectoris; For females only: Is pregnant (confi rmed with positive serum pregnancy test), or- breastfeeding, or planning to become pregnant during the intervention period and up to REDACTED after the last dose of Dato-DXd; Has documented tumour genomic alterations in EGFR, ALK, ROS1(see inclusion criteria 2c) NTRK, BRAF V600E, RET, MET exon 14, 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; Mean resting QTcF > 470 ms, regardless of gender, obtained from triplicate 12-lead ECGs performed at screening; Allocation to a stratum that has reached the cap; Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site); 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.

EU CTIS 2025-524836-21-00