Letter to the Editor Open Access
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Oncol. Sep 24, 2022; 13(9): 758-761
Published online Sep 24, 2022. doi: 10.5306/wjco.v13.i9.758
Neoadjuvant immunotherapy in non-small-cell lung cancer: Times are changing—and fast
Carlos Aguado, Unai Jiménez Maestre, Xabier Mielgo-Rubio
Carlos Aguado, Department of Medical Oncology, Hospital Universitario Clínico San Carlos, Madrid 28040, Spain
Unai Jiménez Maestre, Department of Thoracic Surgery, Hospital Universitario Cruces, Barakaldo 48903, Bizkaia, Spain
Xabier Mielgo-Rubio, Department of Medical Oncology, Hospital Universitario Fundación Alcorcón, Alcorcón 28922, Madrid, Spain
ORCID number: Carlos Aguado (0000-0002-5624-8035); Unai Jiménez Maestre (0000-0001-5034-4723); Xabier Mielgo-Rubio (0000-0002-0985-6150).
Author contributions: Aguado C, Maestre UJ, and Mielgo-Rubio X wrote and revised the letter.
Conflict-of-interest statement: All authors declare no conflict of interests related to this article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Carlos Aguado, MD, Consultant Physician-Scientist, Medical Oncology, Hospital Universitario Clínico San Carlos, Calle del Prof Martín Lagos, Madrid 28040, Spain. carlos.aguado84@gmail.com
Received: May 9, 2022
Peer-review started: May 9, 2022
First decision: June 16, 2022
Revised: July 6, 2022
Accepted: August 30, 2022
Article in press: August 30, 2022
Published online: September 24, 2022

Abstract

Recent data from a phase 3 trial have shown that the addition of immunotherapy to neoadjuvant chemotherapy improves event-free survival in patients with non-small-cell lung cancer (NSCLC). This is the first positive phase 3 trial in this setting, although several phase 3 trials are currently investigating the efficacy of neoadjuvant and adjuvant immunotherapy in resectable NSCLC.

Key Words: Neoadjuvant, Immunotherapy, NSCLC, Perioperative, Checkmate-816, nivolumab, Chemo-immunotherapy

Core Tip: Recent data from a phase 3 trial show that the addition of immunotherapy to neoadjuvant chemotherapy in patients with non-small-cell lung cancer (NSCLC) improves pathologic complete response and event-free survival. This is the first positive phase 3 trial in this setting, although several other phase 3 studies are currently investigating the efficacy of neoadjuvant and adjuvant immunotherapy in resectable NSCLC. We describe the results of the CheckMate-816 phase 3 trial, which found that neoadjuvant chemoimmunotherapy was superior to chemotherapy alone. We also briefly review the main phase 3 studies currently underway to evaluate the role of immunotherapy in the perioperative setting of NSCLC.



TO THE EDITOR

The management of localized non-small-cell lung cancer (NSCLC) is set to undergo an important change in the first few months of this year (2022) due to the recent publication of the second primary endpoint—event-free survival (EFS)—from the Checkmate-816 trial. The data show that the combination of chemotherapy + nivolumab yielded a mean disease-free survival of 31.6 m in the experimental arm vs 20.8 m [hazard ratio (HR): 0.63] in the control arm (chemotherapy alone), with a 2 year-EFS rate of 64% vs 45%, respectively[1]. These results, in addition to previously reported results showing an improvement in pathological complete response (pCR) of 24% vs 2%, confirm the combination of three cycles of chemotherapy + neoadjuvant nivolumab as the new standard of care in resectable NSCLC[2].

This is the first time that pCR has been validated as a surrogate marker for survival in a randomized trial. In the experimental arm, the median EFS was 26.6 m in patients without pCR and not reached in those with pCR (HR: 0.13). Although the results in terms of overall survival are still immature, a trend towards better survival was observed in the experimental arm, in which 12% more patients were alive at 2 years (HR: 0.57).

This new change in clinical practice comes with several questions that need be resolved in the next few years, including the following: The role of adjuvant therapy; the selection of the most suitable candidates; comparison with adjuvant chemoimmunotherapy; the optimal approach in stage I-II disease; standardization of pathological response assessment; changes in resectability criteria; and changes in the preoperative algorithm.

The perioperative management of NSCLC will undoubtedly undergo a major transformation in the coming years due to the arrival of targeted therapy in this clinical setting, mainly the incorporation of pre- or post-operative immunotherapy[3]. The CheckMate 816 study was the first phase 3 trial to report positive results for the addition of immunotherapy to neoadjuvant chemotherapy[1]. However, other ongoing phase 3 trials evaluating other PD-1 axis inhibitors are expected to report results soon, such as the Impower-030 trial (atezolizumab)[4], KeyNote-671 trial (pembrolizumab)[5], and the Aegean trial (durvalumab)[6] (Table 1). Likewise, atezolizumab has already obtained FDA approval for use in the adjuvant setting in patients with resected PD-L1 positive stage II-IIIA NSCLC[7], and positive results have also been reported from an interim analysis of the KeyNote-091 trial, showing the benefits of pembrolizumab in resected stage IB-IIIA NSCLC[8]. Nivolumab and durvalumab are also being evaluated in the adjuvant setting in several other phase 3 trials (ANVIL, NADIM-Adjuvant, Mermaid-1)[9-11] (Table 2). As a result, the panorama for the treatment of early-stage NSCLC is becoming increasingly interesting, and the data suggest that it will be crucial to personalize treatment to offer the best treatment scheme for each individual patient.

Table 1 Main phase 3 trials evaluating neoadjuvant chemoimmunotherapy in non-small-cell lung cancer.
Neoadjuvant NSCLC
Study
IO agent
Strategy
Objective
Status
CheckMate-816[1]Nivolumab (anti-PD1)ChT + IOEFS and pCRFDA approved
Impower-030[4]Atezolizumab (anti-PD-L1)ChT + IOPFS and OSCompleted. Results pending
KeyNote-671[5]Pembrolizumab (anti-PD1)ChT + IOEFS and OSActive, not recruiting
Aegean[6]Durvalumab (anti-PD-L1)ChT+ IOpCR and EFSRecruiting
Table 2 Main phase 3 trials evaluating adjuvant immunotherapy in non-small-cell lung cancer.
Adjuvant NSCLC
Study
IO agent
Strategy
Objective
Status
Impower-010[7]Atezolizumab (anti-PD-L1)IO monoOS in selected PD-L1 populationFDA approved in II-IIIA NSCLC PD-L1+
KeyNote-091 (PEARLS)[8]Pembrolizumab (anti-PD-L1)IO monoDFSInterim analysis: positive in IB-IIIA NSCLC all corners
ANVIL[9]Nivolumab (anti-PD1)IO monoOS and DFSActive, not recruiting
NADIM-Adjuvant[10]Nivolumab (anti-PD-1)ChT + IODFSRecruiting
Mermaid-1[11]Durvalumab (anti-PD-L1)ChT + IODFS in MRD+Recruiting

These new options bring hope of a cure to a greater number of patients, but also new challenges for the multidisciplinary team and other professionals involved in the treatment of these patients. Once again, coordinated multidisciplinary work will be essential, especially among medical oncology, thoracic surgery, and radiation oncology.

Footnotes

Provenance and peer review: Unsolicited article; Externally peer reviewed.

Peer-review model: Single blind

Specialty type: Oncology

Country/Territory of origin: Spain

Peer-review report’s scientific quality classification

Grade A (Excellent): A

Grade B (Very good): B

Grade C (Good): 0

Grade D (Fair): 0

Grade E (Poor): 0

P-Reviewer: Preziosi F, Italy; Suda K, Japan S-Editor: Liu JH L-Editor: A P-Editor: Liu JH

References
1.  Forde PM, Spicer J, Lu S, Provencio M, Mitsudomi T, Awad MM, Felip E, Broderick SR, Brahmer JR, Swanson SJ, Kerr K, Wang C, Ciuleanu TE, Saylors GB, Tanaka F, Ito H, Chen KN, Liberman M, Vokes EE, Taube JM, Dorange C, Cai J, Fiore J, Jarkowski A, Balli D, Sausen M, Pandya D, Calvet CY, Girard N; CheckMate 816 Investigators. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N Engl J Med. 2022;386:1973-1985.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 87]  [Cited by in F6Publishing: 109]  [Article Influence: 87.0]  [Reference Citation Analysis (0)]
2.  Forde PM, Spicer J, Lu S, Provencio M, Mitsudomi T, Awad MM, Felip E, Broderick S, Brahmer J, Swanson SJ, Kerr K, Wang C, Saylors GB, Tanaka F, Ito H, Chen K-N, Dorange C, Cai J, Fiore J, Girard N. Abstract CT003: 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. Cancer Res. 2021;81:CT003-CT003.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 48]  [Cited by in F6Publishing: 48]  [Article Influence: 48.0]  [Reference Citation Analysis (0)]
3.  Mielgo-Rubio X, Calvo V, Luna J, Remon J, Martín M, Berraondo P, Jarabo JR, Higuera O, Conde E, De Castro J, Provencio M, Hernando Trancho F, López-Ríos F, Couñago F. Immunotherapy Moves to the Early-Stage Setting in Non-Small Cell Lung Cancer: Emerging Evidence and the Role of Biomarkers. Cancers (Basel). 2020;12.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 8]  [Cited by in F6Publishing: 10]  [Article Influence: 4.0]  [Reference Citation Analysis (0)]
4.  Peters S, Kim AW, Solomon B, Gandara DR, Dziadziuszko R, Brunelli A, Garassino MC, Reck M, Wang L, To I, Sun SW, Gitlitz BJ, Sandler A, Rizvi N. IMpower030: Phase III study evaluating neoadjuvant treatment of resectable stage II-IIIB non-small cell lung cancer (NSCLC) with atezolizumab (atezo) + chemotherapy. Ann Oncol. 2019;30 Suppl 2: ii30.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 18]  [Cited by in F6Publishing: 19]  [Article Influence: 6.0]  [Reference Citation Analysis (0)]
5.  Tsuboi M, Luft A, Ursol G, Kato T, Levchenko E, Eigendorff E, Berard H, Zurawski B, Demedts I, Garassino MC, Yang J, Makarious K, Keller SM, Wakelee HA. 1235TiP Perioperative pembrolizumab + platinum-based chemotherapy for resectable locally advanced non-small cell lung cancer: The phase III KEYNOTE-671 study. Ann Oncol. 2020;31:S801-S802.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 6]  [Cited by in F6Publishing: 6]  [Article Influence: 3.0]  [Reference Citation Analysis (0)]
6.  Heymach JV, Mitsudomi T, Harpole D, Aperghis M, Jones S, Mann H, Fouad TM, Reck M. 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. Clin Lung Cancer. 2022;23:e247-e251.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3]  [Cited by in F6Publishing: 3]  [Article Influence: 3.0]  [Reference Citation Analysis (0)]
7.  Herbst RS, Giaccone G, de Marinis F, Reinmuth N, Vergnenegre A, Barrios CH, Morise M, Felip E, Andric Z, Geater S, Özgüroğlu M, Zou W, Sandler A, Enquist I, Komatsubara K, Deng Y, Kuriki H, Wen X, McCleland M, Mocci S, Jassem J, Spigel DR. Atezolizumab for First-Line Treatment of PD-L1-Selected Patients with NSCLC. N Engl J Med. 2020;383:1328-1339.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 444]  [Cited by in F6Publishing: 500]  [Article Influence: 222.0]  [Reference Citation Analysis (0)]
8.  Paz-Ares L, O’Brien MER, Mauer M, Dafni U, Oselin K, Havel L, Esteban Gonzalez E, Isla D, Martinez-Marti A, Faehling M, Tsuboi M, Lee J-S, Nakagawa K, Yang J, Keller SM, Jha N, Marreaud SI, Stahel RA, Peters S, Besse B. VP3-2022: Pembrolizumab (pembro) vs placebo for early-stage non-small cell lung cancer (NSCLC) following complete resection and adjuvant chemotherapy (chemo) when indicated: Randomized, triple-blind, phase III EORTC-1416-LCG/ETOP 8-15 – PEARLS/KEYNOTE-091 study. Ann Oncol. 2022;.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 20]  [Cited by in F6Publishing: 19]  [Article Influence: 20.0]  [Reference Citation Analysis (0)]
9.  Chaft JE, Dahlberg SE, Khullar OV, Edelman MJ, Simone CB, Heymach J, Rudin CM, Ramalingam SS. EA5142 adjuvant nivolumab in resected lung cancers (ANVIL). J Clin Oncol. 2018;36:TPS8581-TPS8581.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 9]  [Cited by in F6Publishing: 9]  [Article Influence: 2.3]  [Reference Citation Analysis (0)]
10.  Calvo V, Domine M, Sullivan I, Gonzalez-Larriba J-L, Ortega AL, Bernabé R, Sala MA, Campos B, De Castro J, Martín-Martorell P, Bosch-Barrera J, Mielgo X, Vilà L, Casal J, Ros S, Martinez Aguillo M, Padilla A, Sandiego S, Aires Machado J, Provencio-Pulla M. A phase III clinical trial of adjuvant chemotherapy vs chemoimmunotherapy for stage IB-IIIA completely resected non-small cell lung cancer (NSCLC) patients nadim-adjuvant: New adjuvant trial of chemotherapy vs chemoimmunotherapy. J Clin Oncol. 2021;39:TPS8581-TPS8581.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 5]  [Cited by in F6Publishing: 5]  [Article Influence: 5.0]  [Reference Citation Analysis (0)]
11.  Peters S, Spigel D, Ahn M, Tsuboi M, Chaft J, Harpole D, Goss G, Barlesi F, Abbosh C, Poole L, May R, Dennis PA, Swanton C. P03.03 MERMAID-1: A phase III study of adjuvant durvalumab plus chemotherapy in resected NSCLC patients with MRD+ post-surgery. J Thorac Oncol. 2021;16:S258-S259.  [PubMed]  [DOI]  [Cited in This Article: ]