Phase Ib Study of the Safety of T-DXd and Immunotherapy Agents With and Without Chemotherapy in Advanced or Metastatic HER2+, Non-squamous NSCLC (DL03)

Phase Ib Study of the Safety of T-DXd and Immunotherapy Agents With and Without Chemotherapy in Advanced or Metastatic HER2+, Non-squamous NSCLC

A Phase Ib Multicenter, Open-label Study to Evaluate the Safety and Tolerability of Trastuzumab Deruxtecan (T-DXd) and Immunotherapy Agents With and Without Chemotherapy Agents in First-line Treatment of Patients With Advanced or Metastatic Non-squamous Non-small Cell Lung Cancer (NSCLC) and Human Epidermal Growth Factor Receptor 2 (HER2) Overexpression (OE) (DESTINY-Lung03)

DESTINY-Lung03 will investigate the safety and tolerability of trastuzumab deruxtecan in combination with Immunotherapy Agents with and without chemotherapy in patients with HER2 over-expressing non-small cell lung cancer. The efficacy will be also analyzed as a secondary endpoint.

Part 1 is a dose escalation study by design, allowing the assessment of safety, tolerability and recommended dose levels of the combination of T-DXd and durvalumab plus cisplatin, carboplatin or pemetrexed. No more patients will be enrolled in this part of the study. Part 2, expansions in the treatment naïve setting on any recommended dose level will not be initiated. The evaluation of T-DXd combination treatment with immunotherapy continues in Part 3, assessing T-DXd and MEDI5752 with or without carboplatin (Arms 3A and 3B, respectively), using a dose confirmation and expansion design. For Part 3, patients will be randomized 1:1 to Arms 3A and 3B, beginning with the cohorts receiving the MEDI5752 starting dose (SD). A total of 6 DLT-evaluable patients will be enrolled to the SD cohorts in each arm. If the combination of T-DXd with MEDI5752 at the starting dose is deemed safe, a dose escalation (E1) cohort will be opened for 6 DLT-evaluable patients. Once all open dose confirmation cohorts have 6 DLT-evaluable patients, the SRC will convene to select the MEDI5752 RP2D to be used in the dose-expansion (DE) cohorts of each arm (n=34). The target population of interest (for Part 3) are patients with advanced or metastatic non-small cell lung cancer measurable disease by RECIST criteria, HER2 overexpression, ECOG PS of 0 to 1, patients who are treatment naïve for recurrent, unresectable or metastatic disease. Patients with tumors that harbor a known genomic alteration or driver for which approved therapies are available are excluded.

HER2+, HER2 expression, DS-8201a, T-DXd, Trastuzumab Deruxtecan, MEDI5752, Volrustomig, Carboplatin, First line, Locally advanced and unresectable non-squamous NSCLC, Metastatic non-squamous NSCLC, Non-small cell lung cancer

The study will consist of 2 parts: Dose-escalation part and monotherapy arm (Part 1 second-line and third-line patients). The dose of T-DXd and chemotherapeutic components on Arms 1A, 1B and 1C (cisplatin, carboplatin or pemetrexed) will be modified during the dose-escalation part in order to find the RP2D. Durvalumab dose will remain fixed on the dose escalation part of the study. Arm 1D is the T-DXd monotherapy arm. Dose-expansion part (Part 2 treatment naïve patients for metastatic disease) will not be initiated. Dose-expansion part (Part 3 treatment naïve patients with metastatic disease) will consist of 2 Arms (3A and 3B) utilizing T-DXd in combination with MEDI5752 with or without carboplatin (first 4 cycles in Arm 3B only). The initial portion of Part 3 will assess two different doses of MEDI5752 for safety and tolerability. In addition to safety & tolerability, the study will also assess preliminary efficacy based upon ORR, DoR, DCR, OS, PFS among treatment groups.

Drug: T-DXd and MEDI5752 T-DXd: administered as an IV infusion Other Name: DS-8201a, Trastuzumab deruxtecan Biological/Vaccine: MEDI5752 MEDI5752: administered as an IV infusion Other Name: Volrustomig

Drug: T-DXd, MEDI5752 and Carboplatin T-DXd: administered as an IV infusion Other Name: DS-8201a, Trastuzumab deruxtecan Biological/Vaccine: MEDI5752 MEDI5752: administered as an IV infusion Other Name: Volrustomig Drug: Carboplatin Carboplatin: administered as an IV infusion

Confirmed ORR per RECIST 1.1 is the percentage of patients with Complete Response or Partial Response that is subsequently confirmed, based on investigator assessment

DOR is defined as the time from the date of first documented response until the date of documented progression or death, based on RECIST assessment

DCR is the percentage of patients who have a best overall response of complete response (CR) or partial response (PR) or stable disease (SD), based on RECIST assessment

PFS is the time from first dose of study treatment until the date of objective disease progression or death, based on RECIST assessment

Pharmacokinetics (PK) assessed by the serum concentration of T-DXd, total anti-HER2 antibody, and MAAA-1181 in all arms

Individual patient data and descriptive statistics will be provided for serum concentration data at each time point for T-DXd, total anti-HER2 antibody and MAAA-1181a

Pharmacokinetics (PK) assessed by the serum concentration of durvalumab in study arms including T-DXd in combination with durvalumab

Individual patient data and descriptive statistics will be provided for serum concentration data at each time point for durvalumab, including T-DXd in combination with durvalumab

Pharmacokinetics (PK) assessed by the serum concentration of MEDI5752 in study arms including T-DXd in combination with MEDI5752

Individual patient data and descriptive statistics will be provided for serum concentration data at each time point for MEDI5752, including T-DXd in combination with MEDI5752

The immunogenicity of T-DXd, durvalumab and MEDI5752 assessed by the presence of ADAs for T-DXd,durvalumab and MEDI5752

Individual participant data and descriptive statistics will be provided for data at each time point for each dose level for T-DXd, durvalumab and MEDI5752

Inclusion criteria: Histologically documented unresectable locally advanced/metastatic non-squamous NSCLC Part 1: Progression after 1 or 2 lines of systemic therapy for recurrent or metastatic setting. Part 3: Treatment-naïve for non curative treatment for locally advanced or metastatic NSCLC. Part 3: Patients must have tumors without known genomic alterations or actionable driver kinases, as determined by existing local test results, for which approved therapies are available are allowed. Patients who received prior adjuvant, neoadjuvant chemotherapy, or definitive chemoradiation for advanced disease are eligible, provided that progression has occurred > 6 months from end of last therapy HER2overexpression status as determined by central review of tumor tissue WHO / ECOG performance status of 0 or 1 Measurable target disease assessed by the investigator using RECIST 1.1 Has protocol defined adequate organ and bone marrow function Part 3: Minimum body weight of 35 kg. Exclusion criteria: HER2 mutation if previously known Has a 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 Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder and prior pneumonectomy Active primary immunodeficiency known HIV infection, or active hepatitis B (positive hepatitis B virus surface antigen or hepatitis B virus core antibody) or hepatitis C infection Active infection including tuberculosis and uncontrolled infection requiring IV antibiotics, antivirals, or antifungals Spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms Medical history of myocardial infarction within 6 months before treatment assignment, symptomatic CHF (New York Heart Association Class II to IV), clinically important cardiac arrhythmias, or a recent (< 6 months) cardiovascular event including stroke Cardiomyopathy of any etiology, symptomatic CHF (as defined by New York Heart Association Class > II), unstable angina pectoris, history of MI within the past 12 months, or cardiac arrhythmia (Part 3). A pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or CART (Concentrated Ascites Reinfusion Therapy) Unresolved toxicities not yet resolved to Grade ≤ 1 or baseline from previous anticancer therapy OR prior discontinuation of any planned study therapy due to toxicity. must not have any medical contraindication to platinum-based chemotherapy. Part 3 patients must not have had prior exposure to anti-PD-1, anti-PD-L1, anti-CTLA-4, anti-TIGIT or any other experimental immunotherapy in any setting.

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