An International, Multicentre, Open-label Randomised Phase III Trial to Evaluate the Benefit of Adding Adjuvant Durvalumab After Neoadjuvant Chemotherapy Plus Durvalumab in Patients With Stage IIB-IIIB (N2) Resectable NSCLC

Official Summary

ADOPT-lung is an international, multicentre, open-label randomised phase III trial. Protocol treatment consists of 3-4 cycles of neoadjuvant durvalumab in combination with platinum-based doublet chemotherapy, followed by surgery. Patients with R0 and R1 only resection will be randomised to receive either adjuvant durvalumab for 12 cycles (experimental arm) or observation (control arm). The primary objective of the study is to determine whether additional adjuvant immunotherapy with durvalumab after neoadjuvant chemo-immunotherapy has an effect on disease-free survival (DFS) in patients who do not achieve complete pathological response (pCR) as per local assessment according to the IASLC recommendations.

Eligibility Requirements

• Minimum Age: 18 Years

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: NONE
• Enrollment: 290 participants

Study Arms

• Durvalumab (EXPERIMENTAL)
  Protocol treatment in the adjuvant phase consists of adjuvant durvalumab
• Observation (NO_INTERVENTION)
  Observation only

Interventions

• DRUG: Adjuvant durvalumab — Durvalumab is given at a fixed dose of 1500 mg i.v. every 4 weeks (±1 week) until relapse or unacceptable toxicity, for a maximum of 12 cycles after surgery.

Primary Outcomes

• Disease-free survival (DFS) (From the date of randomisation until last patient last visit (approximately 60 months after randomisation of the first patient))

Secondary Outcomes

• DFS in patients with pCR (From the date of randomisation until last patient last visit (approximately 60 months after randomisation of the first patient))
• Overall survival (OS) in patients with/without pCR (From the date of randomisation until last patient last visit (approximately 60 months after randomisation of the first patient))
• DFS in patients with/without ctDNA clearance (From the date of randomisation until last patient last visit (approximately 60 months after randomisation of the first patient))
• Time to recurrence (TTR) in patients with/without pCR (From the date of randomisation until last patient last visit (approximately 60 months after randomisation of the first patient))
• Time to treatment discontinuation (TTD) in patients with/without pCR (From the date of randomisation until last patient last visit (approximately 60 months after randomisation of the first patient))

Eligibility Criteria

Inclusion Criteria for enrolment:

* Histologically confirmed NSCLC.
* Stage IIB-IIIB (T1-4 N0-2) according to 8th edition of the TNM staging system of lung cancer.

Stage III assessment should include samples of lymph nodes at levels 4, bilaterally, and level 7 to rule out stage IIIB N3 disease.

T4 tumours will only be eligible if they are defined as T4 based only on their size (\>7cm); any other reason will be considered ineligible.

* Known PD-L1 status, as tested locally using a validated assay. To ensure comparability of results, it is strongly encouraged that PD-L1 testing is done with the Ventana PD-L1 (SP263) assay.
* Absence of EGFR mutation or ALK translocation, as tested locally.
* Primary tumour resectable and functionally operable as assessed per local multidisciplinary tumour board (cardiac evaluation, pulmonary function and diffusion capacity, comorbidity).
* Adequate haematological function:

Haemoglobin ≥90 g/L, Absolute neutrophil count (ANC) ≥1.0× 109/L, Platelet count ≥75× 109/L.

\- Adequate renal function: Measured creatinine clearance (CL) \>40 mL/min or calculated CL \>40 mL/min calculated by the Cockcroft-Gault.

\- Adequate liver function: ALT and AST ≤2.5× institutional ULN, Total serum bilirubin ≤1.5× institutional ULN (patients with Gilbert's syndrome may be allowed to be enrolled after consultation with the Medical Affairs Team at the ETOP IBCSG Partners Foundation.

* Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
* Age ≥18 at the time of enrolment.
* Body weight \>30 kg.
* Life expectancy of at least 12 weeks.
* Women of childbearing potential, including women who had their last menstruation in the last 2 years, must have a negative urinary or serum pregnancy test at screening before enrolment. Pregnancy test must be repeated within 3 days before the first dose of protocol treatment.
* Written IC for study participation must be signed and dated by the patient and the investigator prior to any study-related intervention.

Eligibility Criteria for randomisation:

* Surgical resection must have been completed. Note: Participants who have had only had segmentectomy or wedge resections are not eligible for randomisation.
* Patients must have complete resection: R0 or R1 resection.
* Patients must be fit to receive adjuvant treatment with durvalumab.
* Patients must have no evidence of metastatic disease as assessed by CT scan.
* Documentation of pathological response as per local review must be available.

Exclusion Criteria for enrolment:

* T4 with invasion of heart, great vessels, carina, trachea, oesophagus, or spine.
* Any previous or concurrent treatments for NSCLC.
* Any previous immunotherapy.
* Major surgical procedure (as per investigators assessment) within 28 days before enrolment.
* History of allogenic organ transplantation.
* Active or prior documented autoimmune disease or inflammatory disorders (including inflammatory bowel disease \[e.g., colitis or Crohn's disease\], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome \[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.\]). The following are exceptions to this criterion:

Patients with vitiligo or alopecia. Patients with type I diabetes. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement.

Any chronic skin condition that does not require systemic therapy. Patients without active disease in the last 5 years may be included but only after consultation with the Medical Affairs Team at the ETOP IBCSG Partners Foundation.

Patients with celiac disease controlled by diet alone.

* Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease (ILD), or serious chronic gastrointestinal conditions associated with diarrhoea.
* Psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
* History of another primary malignancy except for:

Malignancy treated with curative-intent and with no known active disease 5 years before the first dose of durvalumab and of low potential risk for recurrence.

Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.

Adequately treated carcinoma in situ without evidence of disease.

* History of leptomeningeal carcinomatosis.
* History of active primary immunodeficiency.
* Active hepatitis infection, positive hepatitis C virus (HCV) antibody, hepatitis B virus (HBV) surface antigen (HbsAg) or HBV core antibody (anti-HBc).

Participants with a past or resolved HBV infection (defined as the presence of anti-HBc and absence of HbsAg) are eligible.

Participants positive for HCV antibody are only eligible if pol

Trial Locations

• Chris O'Brien Lifehouse, Camperdown, New South Wales, Australia
• Nepean Hospital, Penrith, New South Wales, Australia
• Royal North Shore Hospital, St Leonards, New South Wales, Australia
• Princess Alexandra Hospital, Woolloongabba, Queensland, Australia
• Flinders Medical Centre, Bedford Park, South Australia, Australia
• Royal Hobart Hospital, Hobart, Tasmania, Australia
• Eastern Health, Box Hill, Victoria, Australia
• Alfred Hospital, Melbourne, Victoria, Australia
• Peter MacCallum Cancer Centre, Parkville, Victoria, Australia
• Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
• ...and 10 more locations

Contact Information

• Heidi Roschitzki, PhD — CONTACT
  Phone: +41 31 511 94 00
  Email: heidi.roschitzki@etop.ibcsg.org
• Susanne Roux — CONTACT
  Phone: +41 31 511 94 00
  Email: ADOPT-lung@etop.ibcsg.org

Study Officials

• Solange Peters, MD-PhD — STUDY_CHAIR
  Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland
• Sabine Schmid, MD — STUDY_CHAIR
  Inselspital, Universitätsspital Bern, 3010 Bern, Switzerland
• Paul Van Schil, MD-PhD — STUDY_CHAIR
  Antwerp University Hospital, Antwerp, Belgium,
• Stephen Finn, MD-PhD — STUDY_CHAIR
  St. James's Hospital, Dublin 8, Ireland

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