NEOSTAR trial and the current status of neoadjuvant therapy in non–small cell lung cancer

Central MessageAdvancements in neoadjuvant therapy of NSCLC will depend on novel drug combinations, biomarkers and the ability to modulate intrinsic and extrinsic factors associated with therapy response.This Invited Expert Opinion provides a perspective on the following paper: Nat Med. 2023;29(3):593-604. http://doi.org/10.1038/s41591-022-02189-0.See Commentary on page XXX. Advancements in neoadjuvant therapy of NSCLC will depend on novel drug combinations, biomarkers and the ability to modulate intrinsic and extrinsic factors associated with therapy response. This Invited Expert Opinion provides a perspective on the following paper: Nat Med. 2023;29(3):593-604. http://doi.org/10.1038/s41591-022-02189-0. See Commentary on page XXX. Feature Editor's Introduction—Non–small cell lung cancer (NSCLC) is an insidious disease. Even among those most likely to be cured by surgery (≤2 cm, peripheral, node-negative tumors), NSCLC recurs in nearly one-third of patients (CALGB 140503). Responsible are the micrometastases that escape the primary tumor before it is removed. To impact the unflattering survival curves of early-stage NSCLC requires effective systemic therapy, and these therapies, before our eyes, have revolutionized the management of resectable NSCLC. The advancement of immune checkpoint blockade (ICB) into the neoadjuvant space has been rapid yet rigorous, incremental yet exponential, and driven in large part by surgeon innovators. In their recent Nature Medicine article, Sepesi and colleagues report the results of their single-center NEOSTAR trial that demonstrated an escalating degree of killing of NSCLC tumors (pathologic response) after single-agent neoadjuvant ICB (nivolumab), dual-agent ICB (nivolumab plus ipilimumab), and then a 3-agent regimen of chemotherapy plus nivolumab plus ipilimumab. Although I prefer the reader to experience firsthand the remarkability of the Feature Expert Opinion that follows, it is impossible for me to not mention that the median percent residual viable tumor was 4.5% following chemoimmunotherapy in EGFR/ALK wild-type tumors. In other words, 94.5% of the tumor was dead at the time of surgery. Please continue to read this Feature Expert Opinion article to experience for yourself the innovation and grit that is required to advance our field. As a bonus, you will receive a condensed, tabled summary of key metrics from the randomized neoadjuvant trials that have changed practice (CheckMate 816, AEGEAN, Neo-Adjuvant Immunotherapy [NADIM] II, and KEYNOTE-671). Please bring these data to your clinic and to your multidisciplinary conferences. And please stay abreast. By the time this article is published, the results of even another practice-changing randomized trial will have been presented. CheckMate 77 T showed improved event-free survival for patients with resectable stage IIA to IIIB treated by neoadjuvant nivolumab plus chemotherapy followed by adjuvant nivolumab, compared with neoadjuvant chemotherapy plus adjuvant placebo. As you begin to dig in and recognize that some of these neoadjuvant trials also contain an adjuvant component, you will naturally begin to wonder about how patients should be selected for the growing number of available regimens. Know that the entire field is dissecting this same question and know that another Feature Expert Opinion article addressing question this is in progress. Stay tuned, stay collaborative, and stay excited. —Bryan M. Burt, MD, FACS The phase 2 platform NEOSTAR trial of neoadjuvant chemotherapy plus nivolumab with or without ipilimumab in operable non–small cell lung cancer (NSCLC) was published online March 16, 2023, in Nature Medicine.1Cascone T. Leung C.H. Weissferdt A. Pataer A. Carter B.W. Godoy M.C.B. et al.Neoadjuvant chemotherapy plus nivolumab with or without ipilimumab in operable non–small cell lung cancer: the phase 2 platform NEOSTAR trial.Nat Med. 2023; 29: 593-604Crossref PubMed Scopus (25) Google Scholar The novelty of this publication was the last study arm D of this overall 4-arm trial, which administered 3 cycles of neoadjuvant therapy consisting of chemotherapy plus nivolumab with a single dose of ipilimumab at cycle one. The primary outcome of the trial was major pathologic response (MPR) in the intention-to-treat (ITT) population, and complete pathologic response (pCR) was evaluated as a secondary outcome. In the study arm of nivolumab plus chemotherapy (Nivo+CT), the MPR was 32.1% with pCR of 18.2%. When patients with known tumor EGFR/ALK alterations were excluded, MPR and pCR rates increased to 41.2% and 23.5%, respectively. When ipilimumab, nivolumab, and chemotherapy were combined (Ipi+Nivo+CT), the MPR rate was 50% with pCR of 18.2%. When excluding patients with known tumor EGFR/ALK alterations, MPR and pCR rates increased to 62.5% and 25%, respectively. The impact of adding ipilimumab was most notable upon evaluation of median percent residual viable tumor (%RVT); in the final pathologic specimens of Nivo+CT arm, the median RVT was 50.5% and in the Ipi+Nivo+CT the median RTV was 4.5%. No new clinical safety signals were observed. This study evaluated a number of exploratory translational end points using single-cell RNA-sequencing of resected samples, multiplatform immune profiling of immune cells and phenotypes, as well as baseline fecal microbiome as candidate biomarkers associated with treatment arm and pathological response.1Cascone T. Leung C.H. Weissferdt A. Pataer A. Carter B.W. Godoy M.C.B. et al.Neoadjuvant chemotherapy plus nivolumab with or without ipilimumab in operable non–small cell lung cancer: the phase 2 platform NEOSTAR trial.Nat Med. 2023; 29: 593-604Crossref PubMed Scopus (25) Google Scholar Herein, we discuss the NEOSTAR trial in the context of the rapidly evolving field of neoadjuvant immune-based therapy in NSCLC. The benefit of immunotherapy in metastatic lung cancer encouraged the initiation of a number of phase 1/2 trials that tested immunotherapy before surgery for patients with resectable NSCLC, with the hypothesis that the stimulation of the intact immune system against tumor antigen presentation will induce measurable radiologic and pathologic responses. At that time, most trials selected MPR as the primary outcome measure, defined as 10% or less viable cancer cells within the primary tumor bed in the final pathologic specimen. This outcome was selected based on the evidence of the relationship between MPR and long-term survival outcomes, including recurrent-free survival and overall survival (OS), from neoadjuvant chemotherapy trials, and the fact that the probability of MPR following neoadjuvant chemotherapy ranged between 15% and 19%.2Pataer A. Kalhor N. Correa A.M. Raso M.G. Erasmus J.J. Kim E.S. et al.Histopathologic response criteria predict survival of patients with resected lung cancer after neoadjuvant chemotherapy.J Thorac Oncol. 2012; 7: 825-832Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar The event rate for pCR was generally less than 5% with chemotherapy and, therefore, pCR was not a suitable statistical end point. With the early trials, it was also unclear how many cycles of immunotherapy should be administered and when definitive operations should occur relative to the last cycle. The first study of 21 patients included stages I-IIIA NSCLC and administered only 2 cycles of nivolumab.3Forde P.M. Chaft J.E. Smith K.N. Anagnostou V. Cottrell T.R. Hellmann M.D. et al.Neoadjuvant PD-1 blockade in resectable lung cancer.N Engl J Med. 2018; 378: 1976-1986Crossref PubMed Scopus (1231) Google Scholar There were no delays to surgery, and despite of a few conversions from minimally invasive to open procedures, perioperative outcomes and side effect profiles were acceptable. Mainly, the MPR rate was an unprecedented 45%, and authors also observed expansion of neoantigen specific T-cell clones in the blood, suggestive of systemic antitumor response.3Forde P.M. Chaft J.E. Smith K.N. Anagnostou V. Cottrell T.R. Hellmann M.D. et al.Neoadjuvant PD-1 blockade in resectable lung cancer.N Engl J Med. 2018; 378: 1976-1986Crossref PubMed Scopus (1231) Google Scholar To build on this initial result, the randomized portion of the phase 2 NEOSTAR trial tested neoadjuvant nivolumab versus nivolumab plus ipilimumab in patients with stage I-IIIA (N2 single-station, American Joint Committee on Cancer 7th edition) NSCLC. NEOSTAR administered 3 cycles of checkpoint inhibition, comparable with an accepted standard for neoadjuvant chemotherapy.4Cascone T. William W.N. Weissferdt A. Leung C.H. Lin H.Y. Pataer A. et al.Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non–small cell lung cancer: the phase 2 randomized NEOSTAR trial.Nat Med. 2021; 27: 504-514Crossref PubMed Scopus (304) Google Scholar The primary end point of the intention-to-treat (ITT) MPR had a preset efficacy threshold if ≥ 6 MPRs were observed in each arm relative to the historical 15% MPR rate following platinum-based chemotherapy. A total of 23 patients were randomized to the nivolumab arm and 21 to the nivolumab plus ipilimumab group. In the ITT population, the MPR was 22% after nivolumab and 38% following nivolumab plus ipilimumab. When analyzing only the 37 patients who underwent resection and had specimen for final pathologic analysis, the MPR rates increased to 24% and 50%, with pCR rates of 10% versus 38%, in the nivolumab and the nivolumab plus ipilimumab arms, respectively. This trial demonstrated that the addition of a single dose of ipilimumab to nivolumab increases pathologic response rates.4Cascone T. William W.N. Weissferdt A. Leung C.H. Lin H.Y. Pataer A. et al.Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non–small cell lung cancer: the phase 2 randomized NEOSTAR trial.Nat Med. 2021; 27: 504-514Crossref PubMed Scopus (304) Google Scholar The largest trial with single agent atezolizumab was organized by the Lung Cancer Mutation Consortium and administered 2 doses of immune checkpoint inhibitor before surgical resection.5Chaft J.E. Oezkan F. Kris M.G. Bunn P.A. Wistuba I.I. Kwiatkowski D.J. et al.Neoadjuvant atezolizumab for resectable non–small cell lung cancer: an open-label, single-arm phase II trial.Nat Med. 2022; 28: 2155-2161Crossref PubMed Scopus (66) Google Scholar The trial enrolled 181 patients. In total, 159 patients underwent resection and 143 were used in the final analysis. The MPR and pCR rates were 20% and 6%, respectively, which were overall similar to the NEOSTAR nivolumab monotherapy arm.5Chaft J.E. Oezkan F. Kris M.G. Bunn P.A. Wistuba I.I. Kwiatkowski D.J. et al.Neoadjuvant atezolizumab for resectable non–small cell lung cancer: an open-label, single-arm phase II trial.Nat Med. 2022; 28: 2155-2161Crossref PubMed Scopus (66) Google Scholar These initial chemotherapy-sparing immunotherapy trials demonstrated feasibility but also early efficacy in the neoadjuvant setting. Results demonstrated that there are patient subgroups who respond well even to only 2 cycles of immunotherapy, and that the addition of a single dose of anti-CTLA4 blockade nearly doubles the MPR rates. It should be noted that immunotherapy alone can induce a false-positive nodal flare in 16% of treated cases, which manifests radiologically as apparent disease progression in the lymph nodes. However, invasive pathologic examination of biopsies or resection specimens from the “progressed” lymph nodes demonstrate de novo sarcoid-like reactions (noncaseating granulomas), characterized by an enriched immune microenvironment without evidence of cancer. This phenomenon has been named “nodal immune flare,” or NIF, and should be recognized by clinicians in order to avoid erroneous treatment changes.6Cascone T. Weissferdt A. Godoy M.C.B. William W.N. Leung C.H. Lin H.Y. et al.Nodal immune flare mimics nodal disease progression following neoadjuvant immune checkpoint inhibitors in non–small cell lung cancer.Nat Commun. 2021; 12: 5045Crossref PubMed Scopus (36) Google Scholar The idea of tumor “priming” or sensitization with low-dose radiation therapy is another concept of chemotherapy-sparing neoadjuvant immunotherapy regimen. This paradigm was tested in a phase 2 trial, which enrolled 60 patients with stage I-IIIA NSCLC.7Altorki N.K. McGraw T.E. Borczuk A.C. Saxena A. Port J.L. Stiles B.M. et al.Neoadjuvant durvalumab with or without stereotactic body radiotherapy in patients with early-stage non–small-cell lung cancer: a single centre, randomised phase 2 trial.Lancet Oncol. 2021; 22: 824-835Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar Patients received either 2 cycles of durvalumab alone or durvalumab with three 8-Gy fractions of stereotactic body radiation therapy (SBRT) to the primary tumor. The hypothesis for the low-dose radiation was to induce a proinflammatory tumor environment, cell death, and neoantigen presentation and avoid potential toxicity when combined with immunotherapy. SBRT was administered to the primary tumor only either before or on the same day as the first dose of durvalumab. This combined treatment of SBRT and durvalumab achieved an MPR rate of 53% versus 6.7% with durvalumab alone, which was highly encouraging for the treatment group but arguably lower for the single-agent immunotherapy control group relative to other trials. Importantly, the pCR rate with combined therapy was 24%, similar to the results observed in the CheckMate 816 trial.8Forde P.M. Spicer J. Lu S. Provencio M. Mitsudomi T. Awad M.M. et al.Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer.N Engl J Med. 2022; 386: 1973-1985Crossref PubMed Scopus (638) Google Scholar This study was the first of its kind to establish the concept of low-dose radiation priming of the tumor microenvironment in neoadjuvant setting of resectable NSCLC7Altorki N.K. McGraw T.E. Borczuk A.C. Saxena A. Port J.L. Stiles B.M. et al.Neoadjuvant durvalumab with or without stereotactic body radiotherapy in patients with early-stage non–small-cell lung cancer: a single centre, randomised phase 2 trial.Lancet Oncol. 2021; 22: 824-835Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar (Table 1).Table 1Phase 2 neoadjuvant immunotherapy trials without chemotherapyTrialNivoNEOSTAR ANivoNEOSTAR BNivo-IpiLCMC3SBRT DurvaPhase1-22222Patients21232118160End pointMPRMPRMPRMPRMPRMPR45%24%50%20%53%pCR10%10%38%6%6.7%LCMC3, Lung Cancer Mutation Consortium; SBRT, stereotactic body radiation therapy; MPR, major pathologic response; pCR, complete pathologic response. Open table in a new tab LCMC3, Lung Cancer Mutation Consortium; SBRT, stereotactic body radiation therapy; MPR, major pathologic response; pCR, complete pathologic response. The highly encouraging clinical benefit achieved by chemotherapy combined with immunotherapy in metastatic NSCLC gave impetus for several single-arm phase 2 trials of neoadjuvant chemoimmunotherapy such as Neoadjuvant immunotherapy (NADIM),9Provencio M. Nadal E. Insa A. García-Campelo M.R. Casal-Rubio J. Dómine M. et al.Neoadjuvant chemotherapy and nivolumab in resectable nonsmall-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial.Lancet Oncol. 2020; 21: 1413-1422Abstract Full Text Full Text PDF PubMed Scopus (402) Google Scholar NADIM II,10Provencio M. Serna-Blasco R. Nadal E. Insa A. García-Campelo M.R. Casal Rubio J. et al.Overall survival and biomarker analysis of neoadjuvant nivolumab plus chemotherapy in operable stage IIIA non–small-cell lung cancer (NADIM phase II trial).J Clin Oncol. 2022; 40: 2924-2933Crossref PubMed Scopus (99) Google Scholar SAKK 16/14,11Rothschild S.I. Zippelius A. Eboulet E.I. Savic Prince S. Betticher D. Bettini A. et al.SAKK 16/14: durvalumab in addition to neoadjuvant chemotherapy in patients with stage IIIA(N2) non–small-cell lung cancer—a multicenter single-arm phase II trial.J Clin Oncol. 2021; 39: 2872-2880Crossref PubMed Scopus (133) Google Scholar and the Columbia trial,12Shu C.A. Gainor J.F. Awad M.M. Chiuzan C. Grigg C.M. Pabani A. et al.Neoadjuvant atezolizumab and chemotherapy in patients with resectable non–small-cell lung cancer: an open-label, multicentre, single-arm, phase 2 trial.Lancet Oncol. 2020; 21: 786-795Abstract Full Text Full Text PDF PubMed Scopus (343) Google Scholar and eventually culminating in the phase 3 randomized CheckMate 816 trial.8Forde P.M. Spicer J. Lu S. Provencio M. Mitsudomi T. Awad M.M. et al.Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer.N Engl J Med. 2022; 386: 1973-1985Crossref PubMed Scopus (638) Google Scholar NADIM,9Provencio M. Nadal E. Insa A. García-Campelo M.R. Casal-Rubio J. Dómine M. et al.Neoadjuvant chemotherapy and nivolumab in resectable nonsmall-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial.Lancet Oncol. 2020; 21: 1413-1422Abstract Full Text Full Text PDF PubMed Scopus (402) Google Scholar conducted in multiple centers in Spain, included 46 patients with stage IIIA NSCLC, of whom 74% had evidence of clinical N2 mediastinal nodal disease. Patients received 3 cycles of chemotherapy with paclitaxel and carboplatin plus nivolumab, and 41 of 46 patients underwent surgical resection. Nivolumab was also administered in the adjuvant setting for 1 year. This trial stunned the “neoadjuvant community” with unprecedented 83% MPR and 63% pCR rates, meeting the primary progression-free survival end point of 77% at 24 months and OS of 89.9% at 24 months. In an updated publication, OS at 3 years remained at commanding 81.9%, supporting durable therapeutic effect.9Provencio M. Nadal E. Insa A. García-Campelo M.R. Casal-Rubio J. Dómine M. et al.Neoadjuvant chemotherapy and nivolumab in resectable nonsmall-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial.Lancet Oncol. 2020; 21: 1413-1422Abstract Full Text Full Text PDF PubMed Scopus (402) Google Scholar The Columbia trial,12Shu C.A. Gainor J.F. Awad M.M. Chiuzan C. Grigg C.M. Pabani A. et al.Neoadjuvant atezolizumab and chemotherapy in patients with resectable non–small-cell lung cancer: an open-label, multicentre, single-arm, phase 2 trial.Lancet Oncol. 2020; 21: 786-795Abstract Full Text Full Text PDF PubMed Scopus (343) Google Scholar conducted in New York and Boston, included 30 patients with stage IB-IIIA NSCLC, with the majority (77%) having clinical IIIA disease. Patients received 2 cycles of nab-paclitaxel, carboplatin, and atezolizumab with 2 additional cycles if there was no evidence of disease progression at radiologic evaluation. The primary end point was met with MPR rate of 57% and pCR of 33%.12Shu C.A. Gainor J.F. Awad M.M. Chiuzan C. Grigg C.M. Pabani A. et al.Neoadjuvant atezolizumab and chemotherapy in patients with resectable non–small-cell lung cancer: an open-label, multicentre, single-arm, phase 2 trial.Lancet Oncol. 2020; 21: 786-795Abstract Full Text Full Text PDF PubMed Scopus (343) Google Scholar The SAKK 16/14 trial,11Rothschild S.I. Zippelius A. Eboulet E.I. Savic Prince S. Betticher D. Bettini A. et al.SAKK 16/14: durvalumab in addition to neoadjuvant chemotherapy in patients with stage IIIA(N2) non–small-cell lung cancer—a multicenter single-arm phase II trial.J Clin Oncol. 2021; 39: 2872-2880Crossref PubMed Scopus (133) Google Scholar conducted in Switzerland, enrolled 67 patients with stage IIIA, all with pathologically confirmed N2 disease. This trial used a sequential approach of 3 cycles of chemotherapy followed by 2 cycles of durvalumab before surgery and 1 more year of durvalumab after surgery. The primary end point of event-free survival (EFS) at 1 year was met at 73%. The MPR and pCR rates were 62% and 18%, respectively.11Rothschild S.I. Zippelius A. Eboulet E.I. Savic Prince S. Betticher D. Bettini A. et al.SAKK 16/14: durvalumab in addition to neoadjuvant chemotherapy in patients with stage IIIA(N2) non–small-cell lung cancer—a multicenter single-arm phase II trial.J Clin Oncol. 2021; 39: 2872-2880Crossref PubMed Scopus (133) Google Scholar Following these encouraging results from single-arm phase 2 studies of neoadjuvant chemoimmunotherapy and recognition that EGFR and ALK alterations should be excluded from chemoimmunotherapy regimen due the lack of encouraging responses in this population, the Spanish group conducted a randomized NADIM II trial,10Provencio M. Serna-Blasco R. Nadal E. Insa A. García-Campelo M.R. Casal Rubio J. et al.Overall survival and biomarker analysis of neoadjuvant nivolumab plus chemotherapy in operable stage IIIA non–small-cell lung cancer (NADIM phase II trial).J Clin Oncol. 2022; 40: 2924-2933Crossref PubMed Scopus (99) Google Scholar which once again included only operable stage IIIA (N2 multistation) NSCLC. Eighty-seven patients were randomized to paclitaxel, carboplatin, plus nivolumab versus paclitaxel and carboplatin. Those who underwent complete R0 resection received additional nivolumab in the adjuvant setting for 6 months. NADIM II was one of the first trials to use pCR as the primary end point in the ITT population, instead of MPR, since the pCR event rate increased with chemoimmunotherapy and pathologic readout of pCR is considered more consistent compared with MPR. The pCR rate in NADIM II was 36.2% versus 6.8% for chemoimmunotherapy versus chemotherapy, with MPR rate of 52% versus 14% in the 2 treatment groups, respectively.10Provencio M. Serna-Blasco R. Nadal E. Insa A. García-Campelo M.R. Casal Rubio J. et al.Overall survival and biomarker analysis of neoadjuvant nivolumab plus chemotherapy in operable stage IIIA non–small-cell lung cancer (NADIM phase II trial).J Clin Oncol. 2022; 40: 2924-2933Crossref PubMed Scopus (99) Google Scholar Results from these successful phase 2 trials culminated in the practice-changing phase 3 CheckMate 8168Forde P.M. Spicer J. Lu S. Provencio M. Mitsudomi T. Awad M.M. et al.Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer.N Engl J Med. 2022; 386: 1973-1985Crossref PubMed Scopus (638) Google Scholar international (North America, Europe, Asia) randomized trial, which enrolled patients with stage IB-IIIA (American Joint Committee on Cancer 7th edition) NSCLC and excluded patients with EGFR and ALK aberrations. The trial enrolled 773 patients, of whom 505 were randomized, and 358 (179 in each arm) eventually underwent treatment with platinum-based chemotherapy plus nivolumab versus chemotherapy alone. Clinical stage IIIA was present in 64% of patients. The co-primary end points of the trial were pCR and EFS rates. The rate of patients who completed neoadjuvant therapy was 93.8% versus 84.7%, and the completion of curative-intent surgery was achieved in 83.2% and 75.4% of patients in the chemoimmunotherapy and chemotherapy arms, respectively. Both co-primary end points were ultimately met. First reported, pCR rate was 24% following chemoimmunotherapy as compared with 2.2% after chemotherapy in the ITT population; pCR rate increased to 41% when analyzing only patients who underwent resection. The benefit of pCR was independent of age, smoking, stage, histology, or biomarkers such as programmed death-ligand 1 (PD-L1) expression status or tumor mutation burden. As data matured, EFS also met its primary end point, favoring chemoimmunotherapy. Median EFS was 31.6 months after chemoimmunotherapy versus 20.8 months after chemotherapy, with HR of 0.63. Although EFS benefit was observed across subgroups, greater benefit from the addition of nivolumab to chemotherapy was seen in patients with stage III disease, nonsquamous histology, and high PD-L1 expression. CheckMate 816 chemotherapy plus nivolumab regimen was approved for all subgroups and became a standard of care neoadjuvant regimen for patients with resectable NSCLC8Forde P.M. Spicer J. Lu S. Provencio M. Mitsudomi T. Awad M.M. et al.Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer.N Engl J Med. 2022; 386: 1973-1985Crossref PubMed Scopus (638) Google Scholar (Tables 2 and 3).Table 2Phase 2 single-arm neoadjuvant immunotherapy trials with chemotherapyTrialNADIMChemo-NivoNEOSTAR CChemo-NivoNEOSTAR DChemo-Nivo-IpiSAKK 16/14Chemo-DurvaColumbiaChemo-AtezoPhase22222Patients4622226730StagesIIIA AJCC 7thII-IIIB AJCC 8thII-IIIB AJCC 8thIIIA AJCC 7thIB-IIIA AJCC 7thEnd pointMPRMPRMPREFSMPRMPR83%32%50%62%57%pCR63%18%18%18%33%NADIM, Neo-Adjuvant Immunotherapy; AJCC, American Joint Committee on Cancer; MPR, major pathologic response; EFS, event-free survival; pCR, complete pathologic response. Open table in a new tab Table 3Randomized trials completed, published, or presented at major conferencesTrialCM 816Chemo-NivoNADIM 2Chemo-NivoAEGEANChemo-DurvaNeotorchChemo-ToriKN 671Chemo-PembroPhase32333Randomizationno. and type3521:1902:18021:14041:17971:1End pointspCR, EFSpCR, PFS, OSpCR, EFSMPR, EFSEFS, OSStagesII-IIIB AJCC 8thIIIA-IIIB AJCC 8thII-IIIB AJCC 8thIII AJCC 8thII-IIIB AJCC 8thSystemic therapyNeoadjuvant onlyNeoadjuvantAdjuvantNeoadjuvantAdjuvantNeoadjuvantAdjuvantNeoadjuvantAdjuvantSurgery83%93%81%82%82%R0 rate83%93%95%96%92%EFS 2 y65%66% (PFS)63%67%62%OS 2 yHR83%0.5785%0.40NA81%82%0.73NADIM, Neo-Adjuvant Immunotherapy; pCR, complete pathologic response; PFS, progression free survival; EFS, event-free survival; OS, overall survival; MPR, major pathologic response; AJCC, American Joint Committee on Cancer; HR, hazard ratio; NA, not applicable. Open table in a new tab NADIM, Neo-Adjuvant Immunotherapy; AJCC, American Joint Committee on Cancer; MPR, major pathologic response; EFS, event-free survival; pCR, complete pathologic response. NADIM, Neo-Adjuvant Immunotherapy; pCR, complete pathologic response; PFS, progression free survival; EFS, event-free survival; OS, overall survival; MPR, major pathologic response; AJCC, American Joint Committee on Cancer; HR, hazard ratio; NA, not applicable. Although NADIM and NADIM II included adjuvant nivolumab in their protocols, CheckMate 816 evaluated 3 cycles of chemoimmunotherapy in the neoadjuvant setting, with adjuvant therapy being left to the investigator's discretion and specifically omitted adjuvant checkpoint blockade. There remains a debate about the most optimal number of neoadjuvant and adjuvant doses of systemic therapy, as well as about who should receive neoadjuvant or adjuvant therapy only. Presently, there are 5 major phase 3 trials with very similar design, using 4 cycles of neoadjuvant chemoimmunotherapy followed by surgical resection and adjuvant immunotherapy alone for approximately 1 year. They include IMpower030 with atezolizumab,13Peters S. Kim A.W. Solomon B. Gandara D. Dziadziuszko R. Brunelli A. et al.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: ii30Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar KEYNOTE-671 with pembrolizumab,14Tsuboi M. Luft A. Ursol G. Kato T. Levchenko E. Eigendorff E. et al.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-S802Abstract Full Text Full Text PDF Google Scholar AEGEAN with durvalumab,15Heymach J. Taube J. Mitsudomi T. Harpole D. Aperghis M. Trani L. et al.P1.18-02 the AEGEAN phase 3 trial of neoadjuvant/adjuvant durvalumab in patients with resectable stage II/III NSCLC.J Thorac Oncol. 2019; 14: S625-S626Abstract Full Text Full Text PDF Google Scholar and CheckMate 77T with nivolumab,16Cascone T. Provencio M. Sepesi B. Lu S. Aanur N. Li S. et al.Checkmate 77T: a phase III trial of neoadjuvant nivolumab (NIVO) plus chemotherapy (chemo) followed by adjuvant nivo in resectable early-stage NSCLC.J Clin Oncol. 2020; 38: TPS9076Crossref Google Scholar and the NEOTORCH trial (Chinese population only)17Lu S. Wu L. Zhang W. Zhang P. Wang W. Fang W. et al.Perioperative toripalimab + platinum-doublet chemotherapy vs chemotherapy in resectable stage II/III non-small cell lung cancer (NSCLC): interim event-free survival (EFS) analysis of the phase III Neotorch study.J Clin Oncol. 2023; 41: 425126Crossref Google Scholar (Tables 1 and 2). KEYNOTE-67118Wakelee H. Liberman M. Kato T. Tsuboi M. Lee S.H. Gao S. et al.KEYNOTE-671 Investigators. Perioperative pembrolizumab for early-stage non–small-cell lung cancer.N Engl J Med. 2023; 389: 491-503Crossref PubMed Scopus (52) Google Scholar is the first published trial of the prespecified interim analysis, as it met one (EFS) of its dual primary end points consisting of EFS and OS. The trial randomized 397 patients to the pembrolizumab group and 400 to the placebo group. Tumors with EGFR/ALK alterations were not excluded. At the median follow-up of 25.2 months, EFS at 24 months was significantly better with chemotherapy plus pembrolizumab (62.4%) as compared with chemotherapy and placebo (40.6%). OS at 24 months was 80.9% and 77.6%, and the pCR rate was 18.1% versus 4.0% in the pembrolizumab versus placebo groups, respectively.18Wakelee H. Liberman M. Kato T. Tsuboi M. Lee S.H. Gao S. et al.KEYNOTE-671 Investigators. Perioperative pembrolizumab for early-stage non–small-cell lung cancer.N Engl J Med. 2023; 389: 491-503Crossref PubMed Scopus (52) Google Scholar The interim analysis of the AEGEAN trial19Heymach JV, Harpole D, Mitsudomi T, Taube JM, Galffy G, Hochmair M, et al: Abstract CT005: AEGEAN: a phase 3 trial of neoadjuvant duvalumab + chemotherapy followed by adjuvant durvalumab in patients with resectable NSCLC. Paper presented at: American Association for Cancer Research Annual Meeting 2023; April 16, 2023; Orlando, Florida.Google Scholar was reported at the 2023 American Association of Cancer Research Annual meeting. At the median follow-up of 11.7 months, the median EFS was not reached in durvalumab arm versus 25.9 months in the chemotherapy arm. This difference represents a 32% reduction in the risk of the combined EFS outcome of disease progression and death with the use of immunotherapy along with chemotherapy. The analysis of pCR demonstrated a 17.2% pCR rate with chemoimmunotherapy versus 4.3% with chemotherapy alone. The benefit was again seen mainly in stage IIIA disease, but patients who were smokers or with other stages IIB and IIIB benefited as well. Tumors expressing PD-L1 ≥50% responded best to the therapy19Heymach JV, Harpole D, Mitsudomi T, Taube JM, Galffy G, Hochmair M, et al: Abstract CT005: AEGEAN: a phase 3 trial of neoadjuvant duvalumab + chemotherapy followed by adjuvant durvalumab in patients with resectable NSCLC. Paper presented at: American Association for Cancer Research Annual Meeting 2023; April 16, 2023; Orlando, Florida.Google Scholar (Tables 3 and 4).Table 4Ongoing randomized trials, not yet read out or presentedTrialIMpower030Chemo-AtezoCM 77TChemo-NivoBGB-A317-315Chemo-TislePhase333Randomizationno. and type4501:14521:14531:1End pointsEFSEFSMPR/EFSStagesII-IIIB AJCC 8thII-IIIB AJCC 8thII-IIIA AJCC 8thSystemic therapyNeoadjuvantAdjuvantNeoadjuvantAdjuvantNeoadjuvantAdjuvantEFS, Event-free survival; MPR, major pathologic response; AJCC, American Joint Committee on Cancer. Open table in a new tab EFS, Event-free survival; MPR, major pathologic response; AJCC, American Joint Committee on Cancer. The introduction of neoadjuvant chemoimmunotherapy for patients with operable stage II-IIIB NSCLC without EGFR and ALK alterations is a tremendous advancement in clinical care. As phase 3 and 2 trials demonstrate, the benefit is rather consistent and reproducible in approximately 25% to 30% of patients. However, many unanswered questions remain. Responses vary among patients, and although some predictive markers such as smoking, high PD-L1 expression, or stage III disease suggest a greater magnitude of effect, the need for more accurate biomarkers, and patient selection remains. There are patients who achieve major or complete responses to single-agent immunotherapy alone, some to dual-checkpoint inhibition, and some to SBRT tumor priming. We still do not have an absolute answer about the number of neoadjuvant cycles necessary and who needs adjuvant therapy, and what kind, depending on the %RVT in the specimen. The curative intent resections occurred in 81% to 83% of patients in large studies like AEGEAN and CheckMate816 and KEYNOTE-671, which is deemed “acceptable,” but it means that 1 of 5 patients does not complete planned indicated therapy. Can we improve on this trend through better patient selection or different therapeutic strategy? We need more trials to answer these questions, as the importance of biomarker discovery and novel drug testing becomes ever more relevant. The emergence of perioperative therapy, now escalating care to well over a year of checkpoint blockade, may bring even more profound survival benefits. Nevertheless, we are likely uselessly escalating therapy and attendant morbidity for a large proportion of patients already destined for cure. The corollary is also true: we are lacking clear biomarkers to support the use of adjuvant checkpoint blockade after neoadjuvant chemoimmunotherapy when the availability of this approach is required to salvage unaddressed micrometastatic disease. Arm D of the NEOSTAR trial1Cascone T. Leung C.H. Weissferdt A. Pataer A. Carter B.W. Godoy M.C.B. et al.Neoadjuvant chemotherapy plus nivolumab with or without ipilimumab in operable non–small cell lung cancer: the phase 2 platform NEOSTAR trial.Nat Med. 2023; 29: 593-604Crossref PubMed Scopus (25) Google Scholar builds on the current best evidence. It tested the addition of one dose of ipilimumab to the current standard of care regimen of chemotherapy and nivolumab. The responses were significantly improved, so much so that the median tumor viability was 4.5% overall, and patients with stage IIIA were16 times more likely to achieve an MPR compared with chemotherapy plus nivolumab. In both arms combined, patients who were smokers had 23.6 times greater odds of response than those who did not smoke, and contrary to other trials, the odds of MPR were 9.6 times greater in squamous than nonsquamous histology. Greater pathologic responses were also observed in KRAS and TP53 tumors with dual checkpoint and chemotherapy use, as were the responses with low PD-L1 expression, although the overall population was mostly composed by chance of low or negative PD-L1 tumors at baseline. Translational studies with multiplatform immune profiling revealed enrichment immune cell populations and phenotypes, including effector memory CD8+ T, B, and myeloid cells and markers of tertiary lymphoid structures, that were preferentially increased in the ipilimumab plus nivolumab plus chemotherapy cohort.1Cascone T. Leung C.H. Weissferdt A. Pataer A. Carter B.W. Godoy M.C.B. et al.Neoadjuvant chemotherapy plus nivolumab with or without ipilimumab in operable non–small cell lung cancer: the phase 2 platform NEOSTAR trial.Nat Med. 2023; 29: 593-604Crossref PubMed Scopus (25) Google Scholar The exploratory analysis of fecal microbiome demonstrated the associations between “favorable” gut microbiome composition, with Rhodospirillales and Akkermansia being associated with MPR.1Cascone T. Leung C.H. Weissferdt A. Pataer A. Carter B.W. Godoy M.C.B. et al.Neoadjuvant chemotherapy plus nivolumab with or without ipilimumab in operable non–small cell lung cancer: the phase 2 platform NEOSTAR trial.Nat Med. 2023; 29: 593-604Crossref PubMed Scopus (25) Google Scholar Overall, the findings from NEOSTAR and other completed trials stimulate critical thinking for additional and novel opportunities to improve responses to systemic neoadjuvant therapy either via novel drug testing, manipulation of the intrinsic immune system, extrinsic environment, diet, or other yet-unmeasured factors, which may affect tumor biology and antitumor responses, and hopefully result in another leap forward toward the curative treatments of NSCLC. The engagement of thoracic surgeons in the development and conduct of such translational trials is of paramount importance. Perhaps the greatest achievement of NEOSTAR is that it definitively proved that we can manipulate and evaluate the tumor microenvironment and host immune response in a manner that favors cancer eradication and produces the data to individualize therapy. B.S. received speaker fees from Medscape, Astra Zeneca, and PeerView and consultation fees from Astra Zeneca T.C. reports speaker fees/honoraria from the Society for Immunotherapy of Cancer, Mark Foundation for Cancer Research, Bristol Myers Squibb, Roche, Medscape, IDEOlogy Health, OncLive, Physicians' Education Resource, and PeerView; advisory role/consulting fees from MedImmune/AstraZeneca, Bristol Myers Squibb, Merck, Genentech, Arrowhead Pharmaceuticals, and Regeneron; travel, food, and/or beverage expenses/reimbursement from the Parker Institute for Cancer Immunotherapy (PICI), Physicians’ Education Resource, Dava Oncology, IDEOlogy Health, International Association for the Study of Lung Cancer, Society for Immunotherapy of Cancer, AstraZeneca, and Bristol Myers Squibb; and institutional research funding from MedImmune/AstraZeneca, Bristol Myers Squibb, and EMD Serono. J.S. reports speaker fees/honoraria/advisory/consulting fees from Bristol Myers Squibb, MSD, Roche, AstraZeneca, IDEOlogy Health, Medscape, PeerView, Eisai, Novartis, Regeneron, AMGEN Protalix Biotherapeutics, and Xenetic Biosciences; and grants to institution from AstraZeneca, MSD, Roche, CLS Therapeutics, Bristol Myers Squibb, and Protalix Biotherapeutics. R.M. reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest. We acknowledge Nicolas Zhou, MD, for the help with the central figure, and Hong Cheuk Leung for the help with manuscript editing.