Perioperative considerations for neoadjuvant immunotherapy in non–small cell lung cancer

Central MessageIntense interest exists in preoperative immunotherapy for patients with surgically resectable lung cancer. Surgeons should be actively involved in trial design, patient selection, and outcome evaluation.See Commentary on page 1383. Intense interest exists in preoperative immunotherapy for patients with surgically resectable lung cancer. Surgeons should be actively involved in trial design, patient selection, and outcome evaluation. See Commentary on page 1383. Feature Editor's Introduction—The mortality of lung cancer has declined over the past decade at record rates of up to 4.3% per year,1Siegel R.L. Miller K.D. Jemal A. Cancer statistics, 2020.CA Cancer J Clin. 2020; 70: 7-30Crossref PubMed Scopus (12764) Google Scholar and immune checkpoint inhibitors (ICIs) are at least partly responsible for this trend. On the basis of efficacy, ICIs have rapidly increased from investigational agents to standard of care for metastatic non–small cell lung cancer (NSCLC). Not long after demonstrating improved survival compared with standard chemotherapy in patients with stage IV disease, ICIs entered clinical trials for earlier stage lung cancer. For example, the programmed death ligand 1 inhibitor durvalumab has recently been adopted as standard of care for patients with locally advanced (stage IIIB) NSCLC after its addition to chemoradiation was shown to improve survival. These and other promising data in advanced NSCLC data have ushered ICIs into the neoadjuvant setting, and clinical trials for stage IB to IIIA NSCLC have completed or are accruing. On the basis of the early output of these trials (reviewed herein) and the track record of ICIs in advanced NSCLC, it is reasonable to suspect that there will be a place for ICIs in the standard of care for early-stage disease. This is a new frontier in thoracic surgery, and operating on patients who have received immunotherapy is becoming commonplace in many institutions. However, there are challenges with neoadjuvant ICI therapy that are not obvious and that are directly relevant to thoracic surgeons. Aside from operative considerations such as the hilar fibrosis that can result from ICIs, and choosing the optimal approach, there are new concepts such as nodal immune flare and pseudo-progression that must be understood and considered in restaging and surgical decision-making. There are new immune-related adverse events and complications germane to preoperative risk stratification and postoperative management (eg, pneumonitis). In the following Expert Opinion article, thoracic surgical oncologists at the forefront of this field offer a succinct and practical primer on preoperative, intraoperative, and postoperative considerations for neoadjuvant ICI therapy in NSCLC. Included also is an expert summary of published and presented neoadjuvant ICI efficacy data that should rally our discipline to pile on to the lung cancer mortality curve and lead its next record decline. Bryan, M. Burt, MD Given the success of immune checkpoint blockade (ICB) in patients with metastatic lung cancer, intense interest exists in moving these therapeutics into earlier stage disease. In particular, based on the success of early investigator-initiated trials in which major pathologic response (MPR) rates of between 17% and 45% have been reported for ICB alone,2Forde P.M. Chaft J.E. Smith K.N. Anagnostou V. Cottrell T.R. Hellman M.D. et al.Neoadjuvant PD-1 blockade in resectable lung cancer.N Engl J Med. 2018; 378: 1976-1986Crossref PubMed Scopus (1045) Google Scholar, 3Cascone T. William W.N. Weissferdt A. Lin H.Y. Leung C.H. Carter B.W. et al.Neoadjuvant nivolumab or nivolumab plus ipilimumab for resectable non-small cell lung cancer (NSCLC): clinical and correlative results from the NEOSTAR study.J Clin Oncol. 2019; 37 (presented at ASCO 2019): 8504Crossref Google Scholar, 4Kwiatkowski D.J. Rusch V.W. Chaft J.E. Johnson B.E. Nicholas A. Wistuba I.I. et al.Neoadjuvant atezolizumab in resectable non-small cell lung cancer (NSCLC): interim analysis and biomarker data from a multicenter study (LCMC3).J Clin Oncol. 2019; 37 (presented at ASCO 2019): 8503Crossref Google Scholar, 5Altorki N. Borczuk A. Saxena A. Port J. Stiles B. Lee B. et al.Neoadjuvant durvalumab with or without subablative stereotactic radiotherapy in patients with resectable NSCLC (NCT02904954).J Thorac Oncol. 2019; 14: S746Abstract Full Text Full Text PDF Google Scholar several large neoadjuvant trials are under way (Table 1). Despite the promise of neoadjuvant ICB, several challenges exist that merit discussion. It is critical that thoracic surgeons participate actively in the design and implementation of neoadjuvant trials, because the outcomes of these trials will depend heavily on patient selection and surgical expertise. Additionally, neoadjuvant trials present an excellent opportunity for surgeons to engage with and lead translational research. We present a brief overview of important considerations for surgeons regarding neoadjuvant ICB trials.Table 1Published manuscripts or abstracts describing early experiences with neoadjuvant immunotherapy followed by surgical resection for patients with non–small cell lung cancerTrial or seriesInstitutionNeoadjuvant treatmentPublished vs abstractNo. of patients enrolled/randomizedMedian time to surgery after completion of neoadjuvant therapyNo. of patients undergoing resection (%)Grade 3 or 4 complicationsMPR (intention-to-treat and surgically resected)NCT022596212Forde P.M. Chaft J.E. Smith K.N. Anagnostou V. Cottrell T.R. Hellman M.D. et al.Neoadjuvant PD-1 blockade in resectable lung cancer.N Engl J Med. 2018; 378: 1976-1986Crossref PubMed Scopus (1045) Google Scholar,6Bott M.J. Yang S.C. Park B.J. Adusumilli P.S. Rusch V.W. Isbell J.M. et al.Initial results of pulmonary resection after neoadjuvant nivolumab in patients with resectable non-small cell lung cancer.J Thorac Cardiovasc Surg. 2019; 158: 269-276Abstract Full Text Full Text PDF PubMed Scopus (144) Google ScholarMSK/JHMINivolumabPublished2118 d (11-29)20 (95%)50% (any morbidity)9 (43%, 45%)NCT03158129 (NEOSTAR3Cascone T. William W.N. Weissferdt A. Lin H.Y. Leung C.H. Carter B.W. et al.Neoadjuvant nivolumab or nivolumab plus ipilimumab for resectable non-small cell lung cancer (NSCLC): clinical and correlative results from the NEOSTAR study.J Clin Oncol. 2019; 37 (presented at ASCO 2019): 8504Crossref Google Scholar)MD Anderson Cancer CenterNivolumab vs Nivolumab + ipilimumabAbstract ASCO 2019/WCLC 20194431 d (21-87)39 (89%)NR11 (25%, 30%)19% N vs 44% N + INCT03081689 (NADIM7Provencio M. Nadal E. Insa A. Garcia-Campelo R. Rubio J.C. Domine M. et al.Neoadjuvant chemo-immunotherapy for the treatment of stage IIIA resectable non-small-cell lung cancer (NSCLC): a phase II multicenter exploratory study—final data of patients who underwent surgical assessment.J Clin Oncol. 2019; 37 (presented at ASCO 2019): 8509Crossref Google Scholar)Spanish Lung Cancer GroupNivolumab + paclitaxel and carboplatinAbstract ASCO 201946NR (target 3-4 wk after last dose)41 (89%)17%35 (76%, 85%)NCT02927301 (LCMC34Kwiatkowski D.J. Rusch V.W. Chaft J.E. Johnson B.E. Nicholas A. Wistuba I.I. et al.Neoadjuvant atezolizumab in resectable non-small cell lung cancer (NSCLC): interim analysis and biomarker data from a multicenter study (LCMC3).J Clin Oncol. 2019; 37 (presented at ASCO 2019): 8503Crossref Google Scholar)MulticenterAtezolizumabAbstract ASCO 2019/AATS 2019101NR (17% with delays to surgery)90 (89%)6%15 (15%, 17%)NCT029049545Altorki N. Borczuk A. Saxena A. Port J. Stiles B. Lee B. et al.Neoadjuvant durvalumab with or without subablative stereotactic radiotherapy in patients with resectable NSCLC (NCT02904954).J Thorac Oncol. 2019; 14: S746Abstract Full Text Full Text PDF Google ScholarWeill CornellDurvalumab vs durvalumab + 8 Gy × 3Abstract WCLC 2019/AATS 201934NR (target 1-2 wk after last dose)30 (88%)17%11 (32%, 37%)6% D vs 53% D + SBRTNCT01820754(TOP12018Yang C.J. McSherry F. Mayne N.R. Wang X. Berry M.F. Tong B. et al.Surgical outcomes after neoadjuvant chemotherapy and ipilimumab for non-small cell lung cancer.Ann Thorac Surg. 2018; 105: 924-929Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar)DukeChemotherapy + IpilimumabPublished24NR13 (54%)NR by grade2 (8%, 15%)Only reported CPRMPR, Major pathologic response; MSK/JHMI, Memorial Sloan Kettering/Johns Hopkins Medicine Institution; ASCO, American Society of Clinical Oncology; WCLC, World Conference on Lung Cancer; NR, not reported; AATS, American Association for Thoracic Surgery; SBRT, stereotactic body radiotherapy. Open table in a new tab MPR, Major pathologic response; MSK/JHMI, Memorial Sloan Kettering/Johns Hopkins Medicine Institution; ASCO, American Society of Clinical Oncology; WCLC, World Conference on Lung Cancer; NR, not reported; AATS, American Association for Thoracic Surgery; SBRT, stereotactic body radiotherapy. Because the aim of the early phase I and II neoadjuvant trials has been mainly to establish safety and early efficacy, generally measured by MPR, inclusion criteria for enrollment have been rather broad. Trials have typically included patients older than 18 years with histologically or cytologically proven NSCLC of adenocarcinoma or squamous cell carcinoma histology. Although carcinoid tumors or small cell lung cancers have not been eligible, some trials allowed enrollment of carcinomas with neuroendocrine differentiation. Surgical resectability as judged by treating surgeons has been of paramount importance for inclusion. Therefore, most trials enrolled patients with resectable stages IB to IIIA NSCLC according to the American Joint Committee on Cancer 7th or 8th edition. Given the suboptimal overall survival of these patients, we support the concept of enrolling patients with stage II and III and even consider patients with stage IB disease. We strongly recommend that all patients undergo invasive mediastinal staging before enrollment on a trial with endobronchial ultrasound or mediastinoscopy. Performance status should be good (Eastern Cooperative Oncology Group 0-1), and patients must have adequate organ and bone marrow function. Major exclusion criteria for ICB on current trials include common criteria such as history and treatment of lung cancer, pregnancy or lactation, other active malignancy within the last 2 years, and any other serious medical or psychologic illnesses. In particular, patients should also be questioned and excluded for immune-related disorders, including autoimmune diseases, pneumonitis, hepatitis B or C infection, human immunodeficiency virus or acquired immunodeficiency syndrome, and corticosteroid use (doses >10 mg per day) or prior treatment with any immunotherapy. Considering the cost and selective efficacy of ICBs in the metastatic setting, there has been an intense search for predictive biomarkers of response. Many metastatic lung cancer trials stratified patients according to programmed death ligand 1 (PD-L1) expression on tumor cells or tumor mutation burden.9Gandhi L. Rodríguez-Abreu D. Gadgeel S. Esteban E. Felip E. De Angelis F. et al.Pembrolizumab plus chemotherapy in metastatic non-small cell lung cancer.N Engl J Med. 2018; 378: 2078-2092Crossref PubMed Scopus (3588) Google Scholar, 10Mok T.S.K. Wu Y.L. Kudaba I. Kowalski D.M. Cho B.C. Turna H.Z. et al.Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial.Lancet. 2019; 393: 1819-1830Abstract Full Text Full Text PDF PubMed Scopus (1678) Google Scholar, 11Hellmann M.D. Ciuleanu T.E. Pluzanski A. Lee J.S. Otterson G.A. Audigier-Valette C. et al.Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden.N Engl J Med. 2018; 378: 2093-2104Crossref PubMed Scopus (2010) Google Scholar Current neoadjuvant studies do not require percent PD-L1 expression or tumor mutation burden for enrollment; however, a myriad of biomarkers have been intensely studied in these trials. Questions remain whether patients with targetable mutations such as EGFR, ALK, ROS1, or BRAF should be enrolled on neoadjuvant immunotherapy trials. Although there is evidence in the metastatic setting that cancers with these mutations respond well to targeted therapies and poorly to immunotherapy,12Lisberg A. Cummings A. Goldman J.W. Bornazyan K. Reese N. Wang T. et al.A Phase II study of pembrolizumab in EGFR-mutant, PD-L1+, tyrosine kinase inhibitor naïve patients with advanced NSCLC.J Thorac Oncol. 2018; 13: 1138-1145Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar,13Mhanna L. Guibert N. Milia J. Mazieres J. When to consider immune checkpoint inhibitors in oncogene-driven non-small cell lung cancer?.Curr Treat Options Oncol. 2019; 20: 60Crossref PubMed Scopus (27) Google Scholar evidence in an early-stage or locally advanced setting is lacking. Despite the fact that there are other ongoing trials testing targeted therapies in the neoadjuvant setting, many ongoing immunotherapy neoadjuvant therapy trials also include these patients, mainly because mutation testing in early-stage disease is currently not considered standard of care and not routinely covered by insurance companies. However, 2 phase III randomized placebo controlled trials mandate testing for EGFR mutation. For example, the AEGEAN (NCT03800134) multicenter international phase III randomized trial of neoadjuvant chemotherapy plus durvalumab versus chemotherapy alone requires EGFR and ALK testing as well as tumor PD-L1 status; however, the trial will allow 20% of patients with EGFR mutation to be accrued. On the contrary, the phase III Checkmate 77T (NCT04025879) randomized, double-blind, placebo-controlled trial of neoadjuvant chemotherapy plus nivolumab versus chemotherapy alone requires EGFR and ALK targetable mutation testing and excludes these patients from enrollment; this trial enrolls those with clinical stage IIA to IIIB according to the American Joint Committee on Cancer 8th edition. Notably, in the LCMC3 and Cornell single-agent trials, no patients with EGFR mutations had an MPR in early reports.4Kwiatkowski D.J. Rusch V.W. Chaft J.E. Johnson B.E. Nicholas A. Wistuba I.I. et al.Neoadjuvant atezolizumab in resectable non-small cell lung cancer (NSCLC): interim analysis and biomarker data from a multicenter study (LCMC3).J Clin Oncol. 2019; 37 (presented at ASCO 2019): 8503Crossref Google Scholar,5Altorki N. Borczuk A. Saxena A. Port J. Stiles B. Lee B. et al.Neoadjuvant durvalumab with or without subablative stereotactic radiotherapy in patients with resectable NSCLC (NCT02904954).J Thorac Oncol. 2019; 14: S746Abstract Full Text Full Text PDF Google Scholar These tumors may simply be less antigenic because of lower mutation burden. Therefore, we recommend excluding them from similar single-agent trials. It remains to be seen whether patients with driver mutations may respond to ICB with combination chemotherapy in the neoadjuvant setting, but consideration should be made to at least limiting inclusion similar to the AEGEAN study. Further analyses from ongoing trials are needed to discover potential biomarkers that may be used in the future to stratify patients for neoadjuvant immunotherapy alone or concomitant chemotherapy and immunotherapy. The likely next step for improved patient selection for neoadjuvant strategies will be mandatory driver mutation testing. In the neoadjuvant setting, a balance needs to be struck to allow patients enough time to respond to preoperative therapy, but not to overly delay loco-regional disease control and potentially curative surgical therapy in those patients who do not respond. We believe that the optimal duration depends on whether or not ICB is given as stand-alone therapy versus given in conjunction with cytotoxic therapy. For patients receiving mono or dual immunotherapy alone, published or presented trials have generally given only 2 to 3 cycles of neoadjuvant ICB.2Forde P.M. Chaft J.E. Smith K.N. Anagnostou V. Cottrell T.R. Hellman M.D. et al.Neoadjuvant PD-1 blockade in resectable lung cancer.N Engl J Med. 2018; 378: 1976-1986Crossref PubMed Scopus (1045) Google Scholar, 3Cascone T. William W.N. Weissferdt A. Lin H.Y. Leung C.H. Carter B.W. et al.Neoadjuvant nivolumab or nivolumab plus ipilimumab for resectable non-small cell lung cancer (NSCLC): clinical and correlative results from the NEOSTAR study.J Clin Oncol. 2019; 37 (presented at ASCO 2019): 8504Crossref Google Scholar, 4Kwiatkowski D.J. Rusch V.W. Chaft J.E. Johnson B.E. Nicholas A. Wistuba I.I. et al.Neoadjuvant atezolizumab in resectable non-small cell lung cancer (NSCLC): interim analysis and biomarker data from a multicenter study (LCMC3).J Clin Oncol. 2019; 37 (presented at ASCO 2019): 8503Crossref Google Scholar, 5Altorki N. Borczuk A. Saxena A. Port J. Stiles B. Lee B. et al.Neoadjuvant durvalumab with or without subablative stereotactic radiotherapy in patients with resectable NSCLC (NCT02904954).J Thorac Oncol. 2019; 14: S746Abstract Full Text Full Text PDF Google Scholar With such a regimen, it is possible to get patients to the operating room within 4 to 6 weeks after starting therapy. Surgery soon after completion of therapy may have the advantage of avoiding or at least decreasing the intraoperative fibrosis that has been described after prolonged ICB or after long delays between completion of therapy and surgery.6Bott M.J. Yang S.C. Park B.J. Adusumilli P.S. Rusch V.W. Isbell J.M. et al.Initial results of pulmonary resection after neoadjuvant nivolumab in patients with resectable non-small cell lung cancer.J Thorac Cardiovasc Surg. 2019; 158: 269-276Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar With neoadjuvant regimens that incorporate chemotherapy with or without radiation, preoperative treatment can be extended because potential nonresponders are at least receiving standard-of-care neoadjuvant cytotoxic treatment. The NADIM trial (NCT03081689) gave 3 cycles of neoadjuvant ICB and chemotherapy, and patients underwent operation 3 to 4 weeks after the final cycle.7Provencio M. Nadal E. Insa A. Garcia-Campelo R. Rubio J.C. Domine M. et al.Neoadjuvant chemo-immunotherapy for the treatment of stage IIIA resectable non-small-cell lung cancer (NSCLC): a phase II multicenter exploratory study—final data of patients who underwent surgical assessment.J Clin Oncol. 2019; 37 (presented at ASCO 2019): 8509Crossref Google Scholar Recently completed or accruing trials, the CheckMate-816, Impower030, and KEYNOTE-671, all have similar structures. The optimal combination of neoadjuvant therapy remains to be determined. Clearly, on the basis of MPR rates in early trials with ICB alone, many patients will respond as well or better than historical chemotherapy controls, which achieved MPR rates of approximately 15%. However, in view of the unpublished results of the NADIM trial, which reported an unprecedented 83% MPR rate (which still needs to be validated), we anticipate that overall MPR rates will be higher with combination therapy.7Provencio M. Nadal E. Insa A. Garcia-Campelo R. Rubio J.C. Domine M. et al.Neoadjuvant chemo-immunotherapy for the treatment of stage IIIA resectable non-small-cell lung cancer (NSCLC): a phase II multicenter exploratory study—final data of patients who underwent surgical assessment.J Clin Oncol. 2019; 37 (presented at ASCO 2019): 8509Crossref Google Scholar The results of other phase II trials of combination chemo-immunotherapy are eagerly anticipated. Whether the MPR rate will translate to a long-term survival advantage is not currently known, and the Food and Drug Administration does not yet recognize the MPR rate as a sufficiently powerful surrogate of survival to approve neoadjuvant drug regimens based on MPR. For now, we will need to wait for event-free, disease-free, or overall survival readout from these trials. Given the historically small survival benefit (5%) of neoadjuvant and adjuvant chemotherapy for surgically resectable patients, we encourage continued patient enrollment on investigator-initiated and cooperative group trials with arms using ICB alone to better understand which patients may be able to completely avoid chemotherapy.14Blumenthal G.M. Bunn Jr., P.A. Chaft J.E. McCoach C.E. Perez E.A. Scagliotti G.V. et al.Current status and future perspectives on neoadjuvant therapy in lung cancer.J Thorac Oncol. 2018; 13: 1818-1831Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar Overall, ICIs are well tolerated. The most common side effect noted in neoadjuvant trials to date has been fatigue. However, ICB disinhibition of T cells may result in off-target effects due to immune activation and inflammation. Clinical sequelae of these effects are termed “immune-related adverse events” and may manifest in various organ systems. The majority of data regarding immune-related adverse events come from medical oncology studies of patients with advanced disease. Data regarding immune-related adverse events in the neoadjuvant setting are limited but will be augmented by forthcoming large prospective trials. Pneumonitis is the most common pulmonary toxicity of ICB therapy and is the most relevant to patients receiving ICB therapy in the neoadjuvant setting because severe pneumonitis could potentially exclude patients from operative therapy. Large retrospective series and meta-analyses report an overall pneumonitis rate of approximately 5% with slightly higher rates in the setting of dual checkpoint inhibition versus monotherapy.15Naidoo J. Wang X. Woo K.M. Iyriboz T. Halpenny D. Cunningham J. et al.Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy.J Clin Oncol. 2017; 35: 709-717Crossref PubMed Scopus (662) Google Scholar,16Nishino M. Giobbie-Hurder A. Hatabu H. Ramaiya N.H. Hodi F.S. Incidence of programmed cell death 1 inhibitor-related pneumonitis in patients with advanced cancer: a systematic review and meta-analysis.JAMA Oncol. 2016; 2: 1607-1616Crossref PubMed Scopus (462) Google Scholar However, single-center studies within these analyses have reported rates as high as 19%. Time to onset of pneumonitis is variable, and clinical risk factors remain to be elucidated. Generally, pneumonitis tends to occur after multiple ICB doses; however, it can occur even after a single dose. Significant pneumonitis has been rare in neoadjuvant trials to date, but in some cases has caused significant hypoxia requiring high-dose steroids and a delay in surgery. Additional immune-related adverse events in patients treated with ICB for NSCLC include endocrinopathies (hypothyroidism, hypopituitarism, and adrenal insufficiency), gastrointestinal toxicities (colitis, hepatitis), and cardiovascular (myocarditis and pericarditis). The National Comprehensive Cancer Network and American Society of Clinical Oncology have issued guidelines for recognition and management of immune-related adverse events.17Thompson J.A. New NCCN guidelines: recognition and management of immunotherapy-related toxicity.J Natl Compr Canc Netw. 2018; 16: 594-596Crossref PubMed Scopus (104) Google Scholar,18Brahmer J.R. Lacchetti C. Schneider B.J. Atkins M.B. Brassil K.J. Caterino J.M. et al.Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline.J Clin Oncol. 2018; 36: 1714-1768Crossref PubMed Scopus (1989) Google Scholar The mainstay of treatment of immune-related adverse events is corticosteroids, with few patients requiring additional immunosuppression. Despite the wide range of possible immune-related side effects, in neoadjuvant ICB studies to date most patients have completed neoadjuvant treatment and undergone resection. General “falloff” in ICB trials is approximately 10%, which is similar to that with neoadjuvant chemotherapy alone. In the study by Forde and colleagues,2Forde P.M. Chaft J.E. Smith K.N. Anagnostou V. Cottrell T.R. Hellman M.D. et al.Neoadjuvant PD-1 blockade in resectable lung cancer.N Engl J Med. 2018; 378: 1976-1986Crossref PubMed Scopus (1045) Google Scholar in which patients received 2 doses of single-agent nivolumab, 20 of 21 patients underwent resection (1 patient was unresectable at exploration) without any delays to planned surgery. A single patient received only 1 dose of nivolumab and was taken to surgery early because of postobstructive pneumonia. The NEOSTAR investigators at the American Society of Clinical Oncology annual meeting in 2019 reported that 5 of 44 patients (1 in the single-agent nivolumab arm and 4 in nivolumab/ipilimumab arm) did not undergo resection, with grade 3 hypoxia in the patients with nivolumab only.3Cascone T. William W.N. Weissferdt A. Lin H.Y. Leung C.H. Carter B.W. et al.Neoadjuvant nivolumab or nivolumab plus ipilimumab for resectable non-small cell lung cancer (NSCLC): clinical and correlative results from the NEOSTAR study.J Clin Oncol. 2019; 37 (presented at ASCO 2019): 8504Crossref Google Scholar In the LCMC3 study, 90 of 101 patients (89%) (neoadjuvant atezolizumab) underwent planned resection.4Kwiatkowski D.J. Rusch V.W. Chaft J.E. Johnson B.E. Nicholas A. Wistuba I.I. et al.Neoadjuvant atezolizumab in resectable non-small cell lung cancer (NSCLC): interim analysis and biomarker data from a multicenter study (LCMC3).J Clin Oncol. 2019; 37 (presented at ASCO 2019): 8503Crossref Google Scholar Most patients not undergoing resection demonstrated progressive disease (n = 5) or withdrew consent (n = 4). Likewise, in the Weill-Cornell neoadjuvant durvalumab/stereotactic body radiotherapy study, the majority of patients (30/34) underwent planned resection.5Altorki N. Borczuk A. Saxena A. Port J. Stiles B. Lee B. et al.Neoadjuvant durvalumab with or without subablative stereotactic radiotherapy in patients with resectable NSCLC (NCT02904954).J Thorac Oncol. 2019; 14: S746Abstract Full Text Full Text PDF Google Scholar In the NADIM trial, 41 of 46 patients (89%) underwent resection after chemo-immunotherapy.7Provencio M. Nadal E. Insa A. Garcia-Campelo R. Rubio J.C. Domine M. et al.Neoadjuvant chemo-immunotherapy for the treatment of stage IIIA resectable non-small-cell lung cancer (NSCLC): a phase II multicenter exploratory study—final data of patients who underwent surgical assessment.J Clin Oncol. 2019; 37 (presented at ASCO 2019): 8509Crossref Google Scholar Data from published studies and those presented in abstract form do not suggest undue delays to surgery or frequent treatment toxicities precluding surgical resection. As larger scale prospective studies report surgical outcomes, more data regarding this concern will become available. At this time, all patients enrolled in neoadjuvant immunotherapy trials should have “resectable” disease as judged by a thoracic surgeon before trial enrollment. Hope or assumption that marginally resectable patients will be “downstaged” after 3 or 4 cycles of immunotherapy with or without chemotherapy and become “resectable” should be resisted until more data are available. Radiographic restaging is a component of all neoadjuvant immunotherapy trials and generally includes both computed tomography and combined positron emission tomography computed tomography. The aim of radiographic restaging is to measure therapeutic response within the primary tumor and lymph nodes and to ensure there is no disease progression, which would result in treatment plan change. Criteria for the response evaluation are according to the revised Response Evaluation Criteria in Solid Tumors guidelines version 1.1.19Eisenhauer E.A. Therasse P. Bogaerts J. Schwartz L.H. Sargent D. Ford R. et al.New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).Eur J Cancer. 2009; 45: 228-247Abstract Full Text Full Text PDF PubMed Scopus (18242) Google Scholar Considering the fact that most checkpoint inhibitor drugs are infused every 2 or 3 weeks for just 2 or 3 doses, it is biologically unlikely that the primary cancer would significantly progress during the time of neoadjuvant therapy, even if there is no response to therapy. However, there have been reports of both pseudo-progression and hyper-progression on immunotherapy for lung cancer, mainly in the metastatic setting.20Fujimoto D. Yoshioka H. Kataoka Y. Morimoto T. Hata T. Kim Y.H. et al.Pseudoprogression in previously treated patients with non-small cell lung cancer who received nivolumab monotherapy.J Thorac Oncol. 2019; 14: 468-474Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, 21Frelaut M. Le Toruneau C. Borcoman E. Hyperprogression under immunotherapy.Int J Mol Sci. 2019; 20: 2674Crossref Scopus (79) Google Scholar, 22Ferrara R. Mezquita L. Texier M. Lahmar J. Audigier-Valette C. Tessonnier L. et al.Hyperprogressive disease in patients with advanced non-small cell lung cancer treated with PD-1/PD-L1 inhibitors or with single-agent chemotherapy.JAMA Oncol. 2018; 4: 1543-1552Crossref PubMed Scopus (463) Google Scholar. Pseudo-progression is defined as an initial tumor enlargement followed by tumor regression and was observed in approximately 3% of patients with NSCLC treated with nivolumab monotherapy. As one can imagine, pseudo-progression is difficult to report in the neoadjuvant setting because the majority of patients undergo resection soon after completing therapy; therefore, there is only a brief period to observe tumor regression/progression. However, it should be noted that patients with primary tumor pseudo-progression may experience better long-term outcomes. Hyperprogression is defined as a true rapid disease progression associated with patients' clinical deterioration. It has been reported with immunotherapy in lung and