Perioperative Durvalumab for Resectable Non–Small-Cell Lung Cancer

Author(s): John V. Heymach, M.D., Ph.D., David Harpole, M.D., Tetsuya Mitsudomi, M.D., Ph.D., Janis M. Taube, M.D., Gabriella Galffy, M.D., Ph.D., Maximilian Hochmair, M.D., Thomas Winder, M.D., Ph.D., Ruslan Zukov, M.D., Ph.D., Gabriel Garbaos, M.D., Shugeng Gao, M.D., Ph.D., Hiroaki Kuroda, M.D., Ph.D., Gyula Ostoros, M.D., Tho V. Tran, M.D., Jian You, M.D., Ph.D., Kang-Yun Lee, M.D., Ph.D., Lorenzo Antonuzzo, M.D., Ph.D., Zsolt Papai-Szekely, M.D., Hiroaki Akamatsu, M.D., Ph.D., Bivas Biswas, M.B., B.S., M.D., Alexander Spira, M.D., Ph.D., Jeffrey Crawford, M.D., Ha T. Le, M.D., Ph.D., Mike Aperghis, Ph.D., Gary J. Doherty, M.D., Ph.D., Helen Mann, M.Sc., Tamer M. Fouad, M.D., Ph.D., and Martin Reck, M.D., Ph.D. for the AEGEAN Investigators*

Source: DOI: 10.1056/NEJMoa2304875

Dr. Maen Hussein's Thoughts

Adding Durvalumab to chemotherapy preop improved CR (17.2 vs4.3%) regardless of PLD -1 status. We already have approval for neoadjuvant chemotherapy and immunotherapy combinations in resectable lung cancer, so not sure if this regimen will be favored. The unique thinkg about this one is that durva was also given post op ( not in the opidvo trial) but you can give pembrolizumab as adjuvant in those pts who had opdivo preop, and now pembrolizumab just got its approval in the neoadjuvant setting (last month) in which nit is given post op too.

BACKGROUND

Neoadjuvant or adjuvant immunotherapy can improve outcomes in patients with resectable non–small-cell lung cancer (NSCLC). Perioperative regimens may combine benefits of both to improve long-term outcomes.

METHODS

We randomly assigned patients with resectable NSCLC (stage II to IIIB [N2 node stage] according to the eighth edition of the AJCC Cancer Staging Manual) to receive platinum-based chemotherapy plus durvalumab or placebo administered intravenously every 3 weeks for 4 cycles before surgery, followed by adjuvant durvalumab or placebo intravenously every 4 weeks for 12 cycles. Randomization was stratified according to disease stage (II or III) and programmed death ligand 1 (PD-L1) expression (≥1% or <1%). Primary end points were event-free survival (defined as the time to the earliest occurrence of progressive disease that precluded surgery or prevented completion of surgery, disease recurrence [assessed in a blinded fashion by independent central review], or death from any cause) and pathological complete response (evaluated centrally).

RESULTS

A total of 802 patients were randomly assigned to receive durvalumab (400 patients) or placebo (402 patients). The duration of event-free survival was significantly longer with durvalumab than with placebo; the stratified hazard ratio for disease progression, recurrence, or death was 0.68 (95% confidence interval [CI], 0.53 to 0.88; P=0.004) at the first interim analysis. At the 12-month landmark analysis, event-free survival was observed in 73.4% of the patients who received durvalumab (95% CI, 67.9 to 78.1), as compared with 64.5% of the patients who received placebo (95% CI, 58.8 to 69.6). The incidence of pathological complete response was significantly greater with durvalumab than with placebo (17.2% vs. 4.3% at the final analysis; difference, 13.0 percentage points; 95% CI, 8.7 to 17.6; P<0.001 at interim analysis of data from 402 patients). Event-free survival and pathological complete response benefit were observed regardless of stage and PD-L1 expression. Adverse events of maximum grade 3 or 4 occurred in 42.4% of patients with durvalumab and in 43.2% with placebo. Data from 62 patients with documented EGFR or ALK alterations were excluded from the efficacy analyses in the modified intention-to-treat population.

CONCLUSIONS

In patients with resectable NSCLC, perioperative durvalumab plus neoadjuvant chemotherapy was associated with significantly greater event-free survival and pathological complete response than neoadjuvant chemotherapy alone, with a safety profile that was consistent with the individual agents. (Funded by AstraZeneca; AEGEAN ClinicalTrials.gov number, NCT03800134. opens in new tab.)

Author Affiliations

From the Department of Thoracic–Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston (J.V.H.), and US Oncology Research, the Woodlands (A.S.) — both in Texas; the Department of Surgery, Duke University Medical Center (D.H.), and Duke Cancer Institute (J.C.) — both in Durham, NC; the Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama (T.M.), the Department of Thoracic Surgery, Aichi Cancer Center Hospital, Aichi (H.K.), and Internal Medicine III, Wakayama Medical University, Wakayama (H.A.) — all in Japan; the Bloomberg–Kimmel Institute for Cancer Immunotherapy, Johns Hopkins Kimmel Cancer Center, Baltimore (J.M.T.); Törökbalint Institute of Pulmonology, Törökbálint (G. Galffy), Koranyi National Institute for TB and Pulmonology, Budapest (G.O.), and the University Teaching Hospital of Fejér County, Székesfehérvár (Z.P.-S.) — all in Hungary; the Department of Respiratory and Critical Care Medicine, Karl Landsteiner Institute of Lung Research and Pulmonary Oncology, Klinik Floridsdorf, Vienna (M.H.), and the Department of Hematology, Oncology, Gastroenterology and Infectiology, Landeskrankenhaus Feldkirch, Feldkirch (T.W.) — both in Austria; Krasnoyarsk State Medical University, Krasnoyarsk, Russia (R.Z.); Fundación Estudios Clínicos, Santa Fe, Argentina (G. Garbaos); the Thoracic Surgery Department, National Cancer Center–National Clinical Research Center for Cancer–Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (S.G.), and the Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin (J.Y.) — both in China; the Oncology and Chemotherapy Department, University Medical Center of Ho Chi Minh City, Ho Chi Minh City (T.V.T.), and No. 1 Medical Oncology Department, Hanoi Oncology Hospital, Hanoi (H.T.L.) — both in Vietnam; the Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan (K.-Y.L.); the Clinical Oncology Unit, Careggi University Hospital, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy (L.A.); Tata Medical Center, Kolkata, India (B.B.); Virginia Cancer Specialists Research Institute, Fairfax (A.S.); AstraZeneca, Cambridge, United Kingdom (M.A., G.J.D., H.M.); AstraZeneca, New York (T.M.F.); and Lung Clinic Grosshansdorf, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany (M.R.).

Simultaneous Durvalumab and Platinum-Based Chemoradiotherapy in Unresectable Stage III Non–Small Cell Lung Cancer: The Phase III PACIFIC-2 Study

PACIFIC-2 was a phase III trial testing durva given concurrently with cCRT (and continued as consolidation) versus placebo + cCRT in unresectable stage III NSCLC, and it did not meet its primary endpoint. The overall response rate (ORR) was essentially identical (60.7% vs 60.6%), and pneumonitis rates were similar (any grade 28.8% vs 28.7%; grade ≥3: 4.6% vs 5.6%), but adverse events (AEs) leading to discontinuation and fatal AEs were higher with durva (25.6% vs 12.0%; 13.7% vs 10.2%), especially early on. Starting IO up front with cCRT didn’t improve outcomes and added early toxicity—consolidation durva after cCRT is still the way to go.

Sevabertinib in Advanced HER2-Mutant Non–Small-Cell Lung Cancer

Sevabertinib shows strong efficacy in HER2-mutant NSCLC, with an overall response rate (ORR) of 64% and median progression-free survival (PFS) of 8.3 months in previously treated, HER2-TKI–naive patients, and an overall response rate (ORR) of 71% with a duration of response (DOR) of 11.0 months in first-line therapy. Activity is highest in TKD mutations, especially Y772_A775dupYVMA, and intracranial responses are seen. Safety is manageable: diarrhea is common but mostly low grade, with grade ≥3 in 5–23% and rare discontinuations. Notably, interstitial lung disease (ILD) was not observed. These data position sevabertinib as a viable oral TKI alongside ADCs for HER2-mutant NSCLC, particularly for TKD/YVMA disease.

Overall Survival with Amivantamab–Lazertinib in EGFR-Mutated Advanced NSCLC

The combination therapy demonstrated improved overall survival (a 25% reduction in mortality) but was associated with increased toxicity, including skin rash and venous thromboembolic events (VTEs). Single-agent osimertinib may lose its role as monotherapy for EGFR-mutated NSCLC, as the FLAURA2 trial showed that combining osimertinib with chemotherapy yielded better outcomes than osimertinib alone.

Neoadjuvant Osimertinib for Resectable EGFR-Mutated Non–Small Cell Lung Cancer

The phase III NeoADAURA trial evaluated neoadjuvant osimertinib (OSI) with or without platinum-based chemotherapy (CT) versus CT alone in resectable, EGFR-mutated stage II-IIIB non-small cell lung cancer (NSCLC). Both OSI+CT and OSI monotherapy significantly improved major pathologic response (MPR: 26% and 25% vs 2%), and 12-month event-free survival (EFS) rates were higher with OSI-containing regimens (OSI+CT 93%, OSI 95%, CT 83%). Nodal downstaging was also more frequent with OSI arms (53% vs 21%). Neoadjuvant OSI—with or without CT—looks like a real step forward for our EGFR-mutant NSCLC patients, especially given the robust pathologic responses and high rates of surgical completion.

Phase III Study of Mediastinal Lymph Node Dissection for Ground Glass Opacity–Dominant Lung Adenocarcinoma

This large, well-done study compared systematic mediastinal lymph node dissection (LND) versus no LND in patients with GGO-dominant invasive lung adenocarcinoma (CTR ≤0.5, ≤3 cm, cT1N0M0). Interim analysis of 302 patients showed no lymph node metastases in either arm, with both groups achieving 3-year disease-free survival (DFS) and overall survival (OS) of 100% at the time of analysis. The no LND arm had significantly shorter surgery duration (74 vs 109 min), less blood loss (44 vs 82 mL), shorter hospital stays (3.9 vs 4.5 days), and fewer grade ≥2 complications (3.3% vs 9.3%). Based on these findings, the trial was terminated early for nonmaleficence, and the authors recommend omitting systematic mediastinal LND in this population. In short, for carefully selected GGO-dominant lung adenocarcinoma, skipping mediastinal LND appears safe and spares patients’ unnecessary morbidity—this could be a real practice-changer for our early-stage, node-negative cases.