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

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, Part 4, and Part 5. In Part 3, T-DXd is assessed in combination with volrustomig, with carboplatin (Arm 3B) or without carboplatin (Arm 3A). Part 4 examines T-DXd with rilvegostomig, either with carboplatin (Arm 4B) or without carboplatin (Arm 4A). In Part 5, T-DXd is evaluated with volrustomig, given with or without a priming dose followed by a fixed dose in Arm 5A. There is also an optional Arm 5B at the Sponsor's discretion. These parts focus on further dose optimization for first-line HER2-overexpressing NSCLC.

For Part 3, patients will be randomized to Arms 3A and 3B, beginning with the cohorts receiving the volrustomig 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 volrustomig 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 volrustomig RP2D to be used in the dose-expansion (DE) cohorts of each arm (n=34). Part 3 is now permanently closed to recruitment; no further patients will be enrolled.

In Part 4, once a total of 6 DLT-evaluable patients/arm have been enrolled into Arm 4A and Arm 4B safety-run in (SR) cohorts and deemed safe, an additional 34 patients per arm will be enrolled in Arms 4A and 4B in dose expansion cohorts.

Part 5 involves additional dosing regimens of T-DXd in combination with volrustomig. The objective of Part 5 is to evaluate the safety and efficacy of priming and flat dosing regimens in 2 different cohorts of up to 30 patients per arm.

The target population of interest (for Part 3, 4 and 5) are patients with advanced or metastatic non-small cell lung cancer measurable disease by RECIST 1.1 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.

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, Part 4 and Part 5: Patients must have tumors that do not harbor known genomic alterations or actionable driver kinases, for which approved therapies are available are allowed.
• Part 3, Part 4 and Part 5: Patient must be treatment-naïve for advanced or metastatic NSCLC. Patients who have received prior adjuvant, or 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, Part 4 and Part 5: 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 chronic and resolved hepatitis B (positive hepatitis B virus surface antigen [HBsAg+ve] or hepatitis B virus core antibody (anti-HBc +ve) regardless of HBV DNA level)) or hepatitis C infection. Patients positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Patients should be tested for HIV prior to treatment assignment if required by local regulations or IRB/EC
• 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
• For Part 3, Part 4 and Part 5: 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 are to be excluded. Patients with troponin levels above ULN at screening (as defined by the manufacturer), and without any myocardial related symptoms, should have a cardiologic consultation before treatment assignment to rule out acute cardiopulmonary events.
• Ascites or pericardial effusion that requires drainage, peritoneal shunt, Pleuroperitoneal shunt or CART (Concentrated Ascites Reinfusion Therapy)
• For Part 3, Part 4 and Part 5: Active non-infectious skin disease (including any grade rash, urticarial, dermatitis, ulceration, or psoriasis) requiring systemic treatment, active or prior documented autoimmune or inflammatory disorders requiring chronic treatment with steroids or other immunosuppressive treatment.
• 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, Part 4 and Part 5 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.
• For Part 3, Part 4 and Part 5: History of substance abuse or any other medical or psychological conditions that may, in the opinion of the Investigator, interfere with the subject's participation in the clinical study or evaluation of the clinical study results
• For Part 3, Part 4 and Part 5: History of thromboembolic events within 3 months before the first dose of IP (limited to pulmonary embolism, deep vein thrombosis, or cerebral venous sinus thrombosis).