AEGEAN Trial Shows a 32% Reduction in the Risk of Disease Recurrence or Progression in NSCLC

Patients with treatment-naïve resectable non-small cell lung cancer (NSCLC) who received neoadjuvant durvalumab (Imfinzi®; AstraZeneca; previously known as MEDI4736)* plus chemotherapy and adjuvant durvalumab monotherapy had improved event-free survival (EFS) and pathological complete response (pCR) compared with those who received neoadjuvant chemotherapy alone, according to results from the phase III placebo-controlled AEGEAN clinical trial, which were presented at the annual meeting of the American Association for Cancer Research (AACR), being held April 14-19, 2023 at the Orange County Convention Center in Orlando, Florida. [1]

Each year there are an estimated 2.2 million people diagnosed with lung cancer globally with 80-85% of patients diagnosed with NSCLC, the most common form of lung cancer. [2][3][4]

Approximately 25-30% of all patients with NSCLC are diagnosed early enough to have surgery with curative intent.[5][6] However, only around 56-65% of patients with Stage II disease will survive for five years.[7] This decreases to 41% for patients with Stage IIIA and 24% for patients with Stage IIIB disease, reflecting a high unmet medical need. [7]

Early-stage lung cancer diagnoses are often only made when the cancer is found on imaging for an unrelated condition.[8][9] For patients with resectable tumors, the majority eventually develop recurrence despite complete tumor resection and adjuvant chemotherapy.[10]

“Non-small cell lung cancer remains the leading cause of cancer mortality, and historically, about half of patients who undergo resection experience recurrence,” said presenter John V. Heymach, MD, chair of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center.

“Anything we can do to increase cure rates for these patients could potentially be a tremendous advance,” Heymach added.

Recent studies indicate the benefit from the use of an adjuvant immune checkpoint inhibitor in NSCLC, especially in patients with PD-1-positive tumors, but whether a more comprehensive approach could improve outcomes has yet to be established, Heymach explained.

In AEGEAN study, a randomized, double-blind, placebo-controlled trial, 802 patients with treatment-naïve resectable NSCLC (Stage IIA-IIIB (Eighth Edition AJCC Cancer Staging Manual), irrespective of PD-L1 expression, were randomly assigned (1:1) to receive either neoadjuvant durvalumab (a 1500 mg fixed dose) plus platinum-based chemotherapy or neoadjuvant placebo plus platinum-based chemotherapy every three weeks (Q3W) for four cycles for 4 cycles; following surgery, patients continued to receive either durvalumab or placebo every four weeks for up to 12 cycles.

Patients were stratified by disease stage (II vs III) and PD–L1 tumor cell expression (<1% vs ≥1%, Ventana SP263) and patients with known EGFR or ALK genomic tumor aberrations were excluded from the primary efficacy analyses.

After excluding patients whose tumors had EGFR/ALK alterations, 740 patients in the modified intent-to-treat population were assessed in this planned interim analysis evaluating the primary endpoint of EFS, defined as the length of time from randomization to an event, such as disease progression precluding definitive surgery, disease recurrence, or death. Final analyses for the additional primary endpoint of pCR, defined as no viable tumor left in the surgical specimen (including lymph nodes) following neoadjuvant therapy, was also evaluated.

Following neoadjuvant treatment, pCR was 17.2% in the treatment arm, versus 4.3% in the placebo arm, a difference of 13.0%.

Overall, 77.6% of patients in the treatment arm and 76.7% of patients in the placebo arm underwent surgery following neoadjuvant therapy.

“Before the study started, there was a concern that giving neoadjuvant immunotherapy might make it harder for some patients to get to surgery. But in fact, we were happy to see that almost an identical number of patients were able to get surgery in both arms, suggesting that the inclusion of neoadjuvant immunotherapy does not reduce the number of patients who can go on to complete surgery,” Heymach said.

After a median follow-up time of 11.7 months, median EFS was not reached in the durvalumab-based regimen arm, versus 25.9 months in the chemotherapy alone arm. Patients in the durvalumab-based regimen arm showed a 32% reduction in the risk of disease progression precluding definitive surgery, disease recurrence, or death compared with those in the chemotherapy alone arm.

Grade 3-4 any cause adverse events occurred in 42.3% and 43.4% of patients in the durvalumab-based regimen arm and the chemotherapy alone arm, respectively. Heymach noted that the data on adverse events were consistent with earlier studies, and no unexpected adverse events related to the treatment were observed.

“We are excited to see that the trial has achieved both its primary endpoints of improving pCR and significantly reducing the likelihood of disease progression, recurrence, or death,” Heymach said.

“The good news for patients with NSCLC is there are now multiple different regimens that have shown improvements in outcomes. This study has laid the foundation that we can build on by designing new combination regimens on top of this effective backbone,” he added.

“This is a new treatment paradigm for this patient population, but one that requires investment from multidisciplinary teams—a greater integration of medical oncology, molecular pathology, and surgical oncology teams all working together to improve clinical outcomes,” Heymach explained.

Data on secondary endpoints, including overall survival, will be needed in the future to understand the full impact of this treatment approach for patients with treatment-naïve resectable non-small cell lung cancer, Heymach concluded.

The study was conducted by AstraZeneca.

Note:
* Durvalumab is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumor’s immune-evading tactics and releasing the inhibition of immune responses. Durvalumab is the only approved immunotherapy and the global standard of care in the curative-intent setting of unresectable, Stage III NSCLC in patients whose disease has not progressed after chemo-radiation therapy based on the PACIFIC Phase III trial. In addition to its indications in lung cancer, durvalumab is also approved in combination with chemotherapy in locally advanced or metastatic biliary tract cancer in the US, EU, Japan and several other countries. Since the first approval in May 2017, more than 150,000 patients have been treated with durvalumab.

Clinical trials
A Study of Neoadjuvant/Adjuvant Durvalumab for the Treatment of Patients With Resectable Non-small Cell Lung Cancer (AEGEAN) – NCT03800134
A Global Study to Assess the Effects of MEDI4736 Following Concurrent Chemoradiation in Patients With Stage III Unresectable Non-Small Cell Lung Cancer (PACIFIC) – NCT02125461
Durvalumab vs Placebo With Stereotactic Body Radiation Therapy in Early Stage Unresected Non-small Cell Lung Cancer (NSCLC) Patients / Osimertinib Following SBRT in Patients With Early Stage Unresected NSCLC Harboring an EGFR Mutation (PACIFIC-4) – NCT03833154
A Study of Durvalumab as Consolidation Therapy in Non-Small Cell Lung Cancer Patients (PACIFIC-5) – NCT03706690
A Global Study to Assess the Effects of Durvalumab + Domvanalimab Following Concurrent Chemoradiation in Participants With Stage III Unresectable NSCLC (PACIFIC-8) – NCT05211895
A Global Study to Assess the Effects of Durvalumab With Oleclumab or Durvalumab With Monalizumab Following Concurrent Chemoradiation in Patients With Stage III Unresectable Non-Small Cell Lung Cancer (PACIFIC-9) – NCT05221840
Study of Durvalumab Given With Chemoradiation Therapy in Patients With Unresectable Non-small Cell Lung Cancer – NCT03519971

Highlights of Prescribing Information
Durvalumab (Imfinzi®; AstraZeneca) [Prescribing Information]

Reference
[1] Heymach JV, Harpole D, Mitsudomi T, Taube JM, Galffy G, Hochmair M, Winder T, Zukov R, Garbaos G, Gao S, Kuroda H, You J, Lee KY, Antonuzzo L, Aperghis M, Doherty GJ, Mann H, Fouad TM, Reck M. AEGEAN: A phase 3 trial of neoadjuvant durvalumab + chemotherapy followed by adjuvant durvalumab in patients with resectable NSCLC. In: Proceedings of the 114th Annual Meeting of the American Association for Cancer Research; 2023 April 14-19; Orlando, FL. Philadelphia (PA): AACR; 2023. Abstract nr CT005.
[2] World Health Organisation. International Agency for Research on Cancer. Lung Fact Sheet. Online. Last accessed on April 14, 2023. 
[3]  Types of Lung Cancer. LUNGevity Foundation. Online. Last accessed on April 14, 2023. 
[4] Cheema PK, et al. Perspectives on treatment advances for stage III locally advanced unresectable non-small-cell lung cancer. Curr Oncol. 2019;26(1):37-42.
[5] Cagle PT, et al. Lung Cancer Biomarkers: Present Status and Future Developments. Arch Pathol Lab Med. 2013;137(9):1191-1198.
[6] Le Chevalier T. Adjuvant Chemotherapy for Resectable Non-Small-Cell Lung Cancer: Where is it Going? Ann Oncol. 2010;21:vii196-198.
[7] Goldstraw P, et al. 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. J Thorac Oncol. 2016;11(1):39-51.
[8] Sethi S, et al. Incidental Nodule Management – Should There Be a Formal Process? J Thorac Onc. 2016:8;S494-S497.
[9] Screening and Early Detection. LUNGevity Foundation. Online. Last accesses on April 14, 2023. 
[10] Pignon JP, et al. Lung Adjuvant Cisplatin Evaluation: A Pooled Analysis by the LACE Collaborative Group. J Clin Oncol. 2008;26(21):3552-3559.

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