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Design and Rationale for a Phase III, Double-Blind, Placebo-Controlled Study of Neoadjuvant Durvalumab + Chemotherapy Followed by Adjuvant Durvalumab for the Treatment of Patients With Resectable Stages II and III non-small-cell Lung Cancer: The AEGEAN Trial
Address for correspondence: John V. Heymach; Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, 1515 Holcombe Blvd, TX 77030.
For patients with resectable, early-stage non-small-cell lung cancer (NSCLC), surgery is the primary treatment; however, 5-year survival rates remain poor. Postoperative adjuvant platinum-doublet chemotherapy is associated with a statistically significant but modest improvement in survival of ∼5% at 5 years and is widely accepted as standard of care in patients with resectable, Stage II-III NSCLC. Neoadjuvant chemotherapy has been associated with similar improvements in overall survival to adjuvant therapy in this setting. Durvalumab, a high-affinity PD-L1 inhibitor, has become the standard of care for patients with unresectable, Stage III NSCLC following chemoradiotherapy based on improved progression-free and overall survival in the phase III PACIFIC trial. AEGEAN is a phase III, double-blind, placebo-controlled, international study that will assess pathological and clinical outcomes of durvalumab plus chemotherapy prior to surgery, followed by durvalumab monotherapy after surgery in adults with resectable, Stage II-III NSCLC. Approximately 800 patients will be randomized (1:1) to receive durvalumab or placebo every 3 weeks (q3w) alongside platinum-based chemotherapy (≤4 cycles) prior to surgery, followed by durvalumab or placebo monotherapy q4w, for an additional 12 cycles post surgery, stratified by disease stage (IASLC 8th Edition, Stage II vs. Stage III) and PD-L1 tumor cell expression levels (<1% vs. ≥1%). Primary endpoints include pathological complete response and event-free survival for patients with wild-type EGFR and ALK. Key secondary efficacy endpoints include major pathologic response, disease-free survival and overall survival.
For patients diagnosed with early stage (Stages I-IIIA) non-small-cell lung cancer (NSCLC), surgery is the primary curative treatment in patients where resection is possible.
The IASLC lung cancer staging project: proposals for revision of the TNM stage groupings in the forthcoming (Eighth) edition of the TNM classification for lung cancer.
Preoperative versus postoperative chemotherapy in patients with resectable non-small cell lung cancer: systematic review and indirect comparison meta-analysis of randomized trials.
The advantages of a neoadjuvant treatment approach include the timely treatment of subclinical micrometastatic disease, reduction in tumor bulk prior to surgery, increased tumor T-cell infiltration, improved R0 resection rate, increased knowledge of drug sensitivity, along with higher treatment compliance and drug delivery rates compared with adjuvant therapy.
Neoadjuvant chemotherapy followed by surgery versus upfront surgery in non-metastatic non-small cell lung cancer: systematic review and meta-analysis of randomized controlled trials.
Systemic anticancer therapy may also be more effective when the blood supply to the tumor remains intact prior to resection, and may be better tolerated if patients are not recovering from major surgery.
Finally, neoadjuvant CT is not associated with increased postoperative complications or death, and also allows for an in vivo assessment of early treatment response, through the use of surrogate endpoints such as pathologic response.
Pathological response after neoadjuvant chemotherapy in resectable non-small-cell lung cancers: proposal for the use of major pathological response as a surrogate endpoint.
Neoadjuvant immunotherapy may have the further advantage of leveraging the tumor as an antigen source, potentially enhancing antitumor T-cell response, leading to antitumor immunity which could reduce metastatic spread
Emerging clinical data from exploratory, single-arm, and randomized studies of patients with NSCLC receiving neoadjuvant treatment with immune checkpoint inhibitors (ICIs) prior to resection, have demonstrated promising antitumor efficacy, with major pathological response (mPR; ≤10% residual viable tumor tissue in the lung primary tumor at time of surgery) rates of 20% to 45%, increasing to 57% to 83% when combined with CT.
Neoadjuvant atezolizumab and chemotherapy in patients with resectable non-small-cell lung cancer: an open-label, multicentre, single-arm, phase 2 trial.
Recent data from the phase 3 CheckMate 816 trial demonstrated a statistically significant improvement in pathological complete response (pCR; absence of any viable tumor cells after complete evaluation in resected lung tissue and all sampled regional lymph nodes) in patients with early-stage, resectable NSCLC following neoadjuvant treatment with the programmed cell death-1 (PD-1) inhibitor nivolumab in combination with CT, versus CT alone.
Nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo as neoadjuvant treatment (tx) for resectable (IB-IIIA) non-small cell lung cancer (NSCLC) in the phase 3 CheckMate 816 trial (CT003).
These findings further support the rationale for combining ICIs targeting the PD-1/programmed cell death ligand-1 (PD-L1) pathway with CT in the neoadjuvant setting. Surrogate endpoints such as mPR and pCR enable earlier assessment of efficacy following neoadjuvant treatment and have shown promising potential as surrogate endpoints for OS.
Phase II trial of neoadjuvant bevacizumab plus chemotherapy and adjuvant bevacizumab in patients with resectable nonsquamous non-small-cell lung cancers.
Furthermore, the utility of immunotherapy in the adjuvant setting for patients with resectable NSCLC has recently been demonstrated in data from the phase 3 IMpower010 trial, which randomized patients to either atezolizumab or best supportive care following standard-of-care adjuvant chemotherapy.
IMpower010: Primary results of a phase III global study of atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB-IIIA non-small cell lung cancer (NSCLC).
Adjuvant atezolizumab was associated with statistically significant improvements in disease-free survival (DFS; hazard ratio [HR] = 0.79; 95% CI, 0.64-0.96; P = 0.02). This benefit was more pronounced in the subgroup with PD-L1 expression on tumor cells (TC) ≥1%.
IMpower010: Primary results of a phase III global study of atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB-IIIA non-small cell lung cancer (NSCLC).
The phase III, placebo-controlled PACIFIC trial of patients with unresectable, Stage III NSCLC whose disease had not progressed following concurrent chemoradiotherapy (CRT) demonstrated that up to 12 months’ of the anti-PD-L1 monoclonal antibody durvalumab, 10 mg/kg every 2 weeks, significantly prolonged progression-free survival (PFS; stratified HR = 0.52; 95% confidence interval [CI], 0.42–0.65; P < 0.0001) and overall survival (OS; stratified HR = 0.68; 95% CI, 0.53–0.87; P = 0.00251), with a manageable safety profile.
Consequently, the ‘PACIFIC regimen’ (consolidation durvalumab following platinum-based CRT) is now standard of care (SoC) in this disease setting.
Durvalumab is also being investigated for use as neoadjuvant and/or adjuvant therapy in patients with resectable NSCLC. The AEGEAN trial (NCT03800134) will assess whether neoadjuvant durvalumab plus CT followed by surgical resection and adjuvant durvalumab monotherapy will improve pathologic and clinical outcomes versus neoadjuvant placebo plus CT followed by surgical resection and adjuvant placebo, in patients with resectable Stage II/III NSCLC. In this manuscript we describe the design and rationale of the study.
Materials and Methods
Study Design
AEGEAN is a phase III, double-blind, placebo-controlled, multicenter, international trial designed to assess pathological and long-term clinical outcomes of durvalumab plus CT prior to surgery, followed by durvalumab monotherapy after surgery in adults with resectable, Stage II/III NSCLC. The study will enroll patients from ∼275 locations across >25 countries globally. Approximately 800 patients will be randomized (1:1) to receive durvalumab plus platinum-based doublet CT (carboplatin/paclitaxel, cisplatin/gemcitabine, pemetrexed/cisplatin, or pemetrexed/carboplatin) prior to surgery followed by durvalumab monotherapy post surgery (Arm 1) or placebo plus platinum-based doublet CT prior to surgery, followed by placebo alone post surgery (Arm 2) (Figure 1). This sample size was calculated to provide adequate statistical power to demonstrate statistically significant improvements in the primary endpoints.
Figure 1Study Design. EFS defined as the time from randomization to PD (determined by blinded independent central review [BICR] per RECIST v1.1), death due to any cause, PD that precludes surgery, or PD discovered while attempting surgery. DFS is defined as the time from resection until local or distant disease recurrence (determined by BICR per RECIST v1.1) in the subpopulation of patients who were disease free following resection, or death due to any cause, whichever occurred first. ALK = anaplastic lymphoma kinase; BICR = blinded independent central review; DFS = disease-free survival; EFS = event-free survival, EGFR = epidermal growth factor receptor; HRQoL = health-related quality of life; mPR = major pathological response; NSCLC = non-small-cell lung cancer; OS = overall survival; pCR = pathological complete response; PD = progression of disease; PD-L1 = programmed cell death ligand-1; PD-L1 TC ≥1% = expression of PD-L1 on tumor membrane, at any intensity, in ≥1% of tumor cells; PRO = patient-reported outcome; Q3W = every 3 weeks; Q4W = every 4 weeks; R = randomization; RECIST = Response Evaluation Criteria in Solid Tumors; TC = tumor cell; wt = wild-type.
Patients will receive 1500 mg durvalumab or placebo via intravenous infusion, plus platinum-based doublet CT every 3 weeks (q3w) for a maximum of 4 cycles followed by surgery, either lobectomy, bilobectomy, or sleeve resection as determined by the attending surgeon. Utilizing a dose and regimen of durvalumab 1500 mg q3w during the neoadjuvant phase aligns with the standard chemotherapy schedule for this disease setting (q3w for 4 cycles),
and is consistent with other studies that have evaluated durvalumab in combination with chemotherapy in both metastatic NSCLC and small-cell-lung cancer.
Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial.
Pharmacokinetic modeling has also previously shown no clinically meaningful differences in drug levels between q3w and q4w dosing regimens (data on file). Following surgery, patients will receive an additional 12 cycles of durvalumab (1500 mg)/placebo q4w, which is consistent with other studies that incorporate a durvalumab monotherapy portion of the regimen and minimizes the number of patient visits required.
Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial.
Durvalumab with or without tremelimumab vs standard chemotherapy in first-line treatment of metastatic non-small cell lung cancer: the MYSTIC phase 3 randomized clinical trial.
Treatment will commence as soon as clinically feasible post surgery. Interim safety reviews of unblinded data will be carried out by an independent data monitoring committee.
Key Eligibility Criteria
Patients must be ≥18 years old, with previously untreated resectable Stage IIA to select (N2) IIIB NSCLC (per the American Joint Committee on Cancer Staging Manual, 8th edition
), have at least one lesion not previously irradiated at baseline, and no prior exposure to immune-mediated therapy. Confirmation of tumor PD-L1 status must occur prior to randomization using the Ventana PD-L1 (SP263) immunohistochemistry assay. Additionally, confirmation of EGFR and ALK status must be available prior to randomization; patients with documented evidence of an EGFR mutation or ALK translocation are excluded, based in part on recent data demonstrating a significant improvement in DFS in patients with EGFR mutations treated with adjuvant osimertinib in the phase 3 ADAURA trial.
Patients with a history of allogeneic organ transplantation, active primary immunodeficiency, another primary malignancy, prior/active documented autoimmune or inflammatory disorders are also excluded. Full inclusion/exclusion criteria are provided in Table 1.
Table 1Key Inclusion and Exclusion Criteria
Inclusion Criteria
•
Age ≥18 years and the ability to provide informed consent
•
Newly diagnosed and previously untreated, histologically or cytologically documented NSCLC with resectable (Stage IIA to select [ie, N2] Stage IIIB) disease per IASLC Staging Manual in Thoracic Oncology version 8
•
WHO/ECOG PS of 0 or 1 at enrollment
•
At least 1 lesion, not previously irradiated, that qualifies as a RECIST 1.1 TL at baseline
•
No prior exposure to immune-mediated therapy including, but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-PD-L2 antibodies, excluding therapeutic anti cancer vaccines
•
Adequate organ and marrow function
•
Confirmation of patient's tumor PD-L1 status
•
Provision of sufficient tumor biopsy sample for evaluation and confirmation of EGFR and ALK status
•
Planned surgery must comprise lobectomy, sleeve resection, or bilobectomy
•
Life expectancy ≥12 weeks
•
Body weight >30 kg
Exclusion Criteria
•
History of allogeneic organ transplantation
•
Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease, diverticulitis, systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome)
•
Uncontrolled intercurrent illness
•
Medical contraindication to treatment with platinum-based doublet chemotherapy
•
History of another primary malignancy
•
History of active primary immunodeficiency
•
Active infection including tuberculosis, hepatitis B and C, or human immunodeficiency virus
•
Deemed unresectable NSCLC by multidisciplinary evaluation
•
Patients who have preoperative radiotherapy treatment as part of their care plan
•
Patients who have brain metastases or spinal cord compression
•
Stage IIIB N3 and Stages IIIC, IVA, and IVB NSCLC
•
Known allergy or hypersensitivity to any of the study drugs or excipients
•
Existence of more than one primary tumor, such as mixed small-cell and NSCLC histology
•
Patients who are candidates to undergo only pneumonectomy, segmentectomies, or wedge resections
•
Documented evidence of EGFR mutation or ALK translocation
Abbreviations: ALK = anaplastic lymphoma kinase; CTLA-4 = cytotoxic T-lymphocyte-associated protein 4; ECOG = Eastern Cooperative Oncology Group; EGFR = epidermal growth factor receptor; IASLC = International Association for the Study of Lung Cancer; NSCLC = non-small-cell lung cancer; PD-1 = programmed cell death-1; PD-L1/2 = programmed cell-death ligand 1/2; PS = performance status; RECIST = Response Evaluation Criteria in Solid Tumors; TL = target lesion; WHO = World Health Organization.
The dual primary endpoints are pCR and event-free survival (EFS; defined as the time from randomization to progression of disease [PD], determined by blinded independent central review [BICR] per RECIST v1.1, death due to any cause, PD that precludes surgery, or PD discovered while attempting surgery) (Figure 1). Key secondary efficacy endpoints include mPR; DFS (time from resection until local or distant disease recurrence in the subpopulation of patients who were disease free following resection, or death due to any cause, whichever occurs first); and OS (time from randomization until death due to any cause). Analyses of EFS, pCR, DFS, mPR, and OS will be repeated in the subpopulation of patients with PD-L1 TC ≥1%.
Additional secondary endpoints include safety and tolerability; health-related quality of life (HRQoL) measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30, version 3) and the lung cancer symptom specific questionnaire QLQ-LC13; pharmacokinetics; and immunogenicity.
Study Assessments
Pathologic assessments will be performed and determined by a blinded central pathology review following the IASLC (2020) recommendations
for pathologic assessment of lung cancer resection specimens after neoadjuvant therapy. Radiologic tumor assessments will be performed by BICR and investigator assessment according to RECIST v1.1 guidelines. Tumor evaluation will be conducted at baseline, prior to randomization; after completion of neoadjuvant treatment, prior to surgery; post surgery and prior to the first dose of adjuvant durvalumab/placebo; every 12 weeks for the first year post surgery; and every 24 to 48 weeks thereafter until RECIST 1.1-defined radiological PD, consent withdrawal, or death.
Safety and tolerability will be assessed in terms of reported adverse events (AEs) and serious AEs, deaths, laboratory data, vital signs, electrocardiograms, and exposure to assigned study treatment. Immunogenicity will be assessed by measuring serum for the presence of antidrug antibodies.
Ethical Considerations
AEGEAN is being conducted in accordance with the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines, and International Conference of Harmonisation Good Clinical Practice Guidelines. The initial protocol and all subsequent amendments were approved by an independent ethics committee (IEC)/international review board (IRB). All patients will provide written informed consent before study enrollment. It will be possible to obtain data underlying the findings described in the final report for this study in accordance with AstraZeneca's data sharing policy (https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure).
Conclusions
Despite surgery and adjuvant CT, recurrence rates remain high across all stages of resectable NSCLC and additional treatments are required. AEGEAN is designed to assess the efficacy and tolerability of neoadjuvant durvalumab in combination with CT followed by surgery and adjuvant durvalumab in patients with resectable Stage IIA to select (N2) IIIB NSCLC. The rationale for this study is supported by emerging clinical data that suggest PD-1/PD-L1 ICIs, as monotherapy and in combination with CT, demonstrate clinical benefit and tolerable safety profiles in the neoadjuvant and adjuvant settings.
Neoadjuvant atezolizumab and chemotherapy in patients with resectable non-small-cell lung cancer: an open-label, multicentre, single-arm, phase 2 trial.
Nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo as neoadjuvant treatment (tx) for resectable (IB-IIIA) non-small cell lung cancer (NSCLC) in the phase 3 CheckMate 816 trial (CT003).
IMpower010: Primary results of a phase III global study of atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB-IIIA non-small cell lung cancer (NSCLC).
Randomized double-blind placebo-controlled phase 2 study of bemarituzumab combined with modified FOLFOX6 (mFOLFOX6) in first-line (1L) treatment of advanced gastric/gastroesophageal junction adenocarcinoma (FIGHT).
The authors would like to thank the patients, their families and caregivers, and all investigators involved in this study. Medical writing support, under the direction of the authors, was provided by Connor Keating, BSc, of Ashfield MedComms (Manchester, UK), an Ashfield Health company, and was funded by AstraZeneca.
Disclosures
JVH has received grants or contracts outside the submitted work from AstraZeneca, GlaxoSmithKline and Spectrum, Royalties or licenses from Spectrum, consulting fees from AstraZeneca, Boehringer-Ingelheim, Catalyst, Genentech, GlaxoSmithKline, Guardant Health, Foundation medicine, Hengrui Therapeutics, Eli Lilly, Novartis, Spectrum, EMD Serono, Sanofi, Takeda, Mirati Therapeutics, BMS, BrightPath Biotherapeutics, Janssen Global Services, Nexus Health Systems, EMD Serono, Pneuma Respiratory, Kairos Venture Investments, Roche, Leads Biolabs and RefleXion, Payment or honoraria from Medlinker, Peerview, Nexus Health Medicine, Targeted Oncology and MJH Events, support for attending meetings and/or travel from IASLC Targeted Therapies and IASLC World Conference on Lung Cancer, has served on scientific advisory boards for AstraZeneca, Genentech, EMD Serono, BMS, Lilly, Regeneron, and Sanofi, and has a leadership role with Mechanisms of Cancer Therapeutics-1 (MCT1) Study Section - Chair; TM has received institutional grants or contracts from Boehringer Ingelheim, Chugai, Ono, MSD and Pfizer, consulting fees from AstraZeneca, honoraria from AstraZeneca, Chugai, Boehringer Ingelheim, Pfizer, Taiho, Eli Lilly, Daiichi-Sankyo, Thermofisher, MSD, BMS, Ono, Merck Biopharma and Novartis, has participated in advisory boards for AstraZeneca, MSD, Boehringer Ingelheim, Novartis, Chugai, Pfizer, BMS, Ono, Taiho, Takeda, Amgen and Janssen, and has a leadership role with the IASLC as president; DH has participated in advisory boards for AstraZeneca and Medtronic; MA is an employee of AstraZeneca; SJ works as a contractor on behalf of AstraZeneca; HM is an employee of AstraZeneca and reports share ownership for AstraZeneca; TMF is an employee of AstraZeneca and lead study physician for the AEGEAN trial; MR has received honoraria from, and has participated in a DSMB or advisory board with, Amgen, AstraZeneca, BMS, Boehringer-Ingelheim, Eli Lilly, Mirati, MSD, Novartis, Merck, Roche, Pfizer and Sanofi.
The IASLC lung cancer staging project: proposals for revision of the TNM stage groupings in the forthcoming (Eighth) edition of the TNM classification for lung cancer.
Preoperative versus postoperative chemotherapy in patients with resectable non-small cell lung cancer: systematic review and indirect comparison meta-analysis of randomized trials.
Neoadjuvant chemotherapy followed by surgery versus upfront surgery in non-metastatic non-small cell lung cancer: systematic review and meta-analysis of randomized controlled trials.
Pathological response after neoadjuvant chemotherapy in resectable non-small-cell lung cancers: proposal for the use of major pathological response as a surrogate endpoint.
Neoadjuvant atezolizumab and chemotherapy in patients with resectable non-small-cell lung cancer: an open-label, multicentre, single-arm, phase 2 trial.
Nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo as neoadjuvant treatment (tx) for resectable (IB-IIIA) non-small cell lung cancer (NSCLC) in the phase 3 CheckMate 816 trial (CT003).
Phase II trial of neoadjuvant bevacizumab plus chemotherapy and adjuvant bevacizumab in patients with resectable nonsquamous non-small-cell lung cancers.
IMpower010: Primary results of a phase III global study of atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB-IIIA non-small cell lung cancer (NSCLC).
Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial.
Durvalumab with or without tremelimumab vs standard chemotherapy in first-line treatment of metastatic non-small cell lung cancer: the MYSTIC phase 3 randomized clinical trial.
Randomized double-blind placebo-controlled phase 2 study of bemarituzumab combined with modified FOLFOX6 (mFOLFOX6) in first-line (1L) treatment of advanced gastric/gastroesophageal junction adenocarcinoma (FIGHT).
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