The Role of Immunotherapy or Immuno-Chemotherapy in Non-Small Cell Lung Cancer: A Comprehensive Review

Many new treatment modalities for non-small-cell carcinoma (NSCLC) have been described in the last two decades. Surgical resections remain the gold standard for early stages and may be considered for locally advanced tumors. Medical treatment has changed drastically in recent years, especially for advanced stages, for which the development of immunotherapy and molecular targeted therapy significantly increased survival and quality of life. The addition of radical surgical resection following immunotherapy or immuno-chemotherapy is feasible and safe with low surgical-related mortality and morbidity in selected patients with initially unresectable NSCLC. However, data from multiple ongoing trials with overall survival as the primary endpoint should be awaited before this strategy is introduced into the standard of care.

[1]  T. Mok,et al.  LBA8 Nivolumab (NIVO) + chemotherapy (chemo) vs chemo in patients (pts) with EGFR-mutated metastatic non-small cell lung cancer (mNSCLC) with disease progression after EGFR tyrosine kinase inhibitors (TKIs) in CheckMate 722 , 2022, Annals of Oncology.

[2]  J. Bosch-Barrera,et al.  PL03.12 Progression Free Survival and Overall Survival in NADIM II Study , 2022, Journal of Thoracic Oncology.

[3]  M. Tsuboi,et al.  Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomised, triple-blind, phase 3 trial. , 2022, The Lancet. Oncology.

[4]  U. Dafni,et al.  930MO PD-L1 expression and outcomes of pembrolizumab and placebo in completely resected stage IB-IIIA NSCLC: Subgroup analysis of PEARLS/KEYNOTE-091 , 2022, Annals of Oncology.

[5]  A. Chella,et al.  PL03.09 IMpower010:Overall Survival Interim Analysis of a Phase III Study of Atezolizumab vs Best Supportive Care in Resected NSCLC , 2022, Journal of Thoracic Oncology.

[6]  Juliana Guarize,et al.  The Interdisciplinary Management of Lung Cancer in the European Community , 2022, Journal of clinical medicine.

[7]  Robert W. Hsieh,et al.  Tiragolumab plus atezolizumab versus placebo plus atezolizumab as a first-line treatment for PD-L1-selected non-small-cell lung cancer (CITYSCAPE): primary and follow-up analyses of a randomised, double-blind, phase 2 study. , 2022, The Lancet. Oncology.

[8]  R. Herbst,et al.  COAST: An Open-Label, Phase II, Multidrug Platform Study of Durvalumab Alone or in Combination With Oleclumab or Monalizumab in Patients With Unresectable, Stage III Non–Small-Cell Lung Cancer , 2022, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  N. Girard,et al.  Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. , 2022, The New England journal of medicine.

[10]  A. Chella,et al.  80O Atezolizumab (atezo) vs best supportive care (BSC) in stage II-IIIA NSCLC with high PD-L1 expression: Sub-analysis from the pivotal phase III IMpower010 study , 2022, Annals of Oncology.

[11]  D. Planchard,et al.  Five-Year Survival Outcomes From the PACIFIC Trial: Durvalumab After Chemoradiotherapy in Stage III Non–Small-Cell Lung Cancer , 2022, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  A. Addeo,et al.  Role and impact of immune checkpoint inhibitors in neoadjuvant treatment for NSCLC. , 2022, Cancer treatment reviews.

[13]  K. Kerrigan,et al.  Role of CTLA Inhibition in Management of Non-Small Cell Lung Cancer , 2022, Current Oncology Reports.

[14]  N. Reinmuth,et al.  PL02.01 Durvalumab ± Tremelimumab + Chemotherapy as First-line Treatment for mNSCLC: Results from the Phase 3 POSEIDON Study , 2021, Journal of Thoracic Oncology.

[15]  J. Heymach,et al.  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. , 2021, Clinical lung cancer.

[16]  A. Chella,et al.  Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB–IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial , 2021, The Lancet.

[17]  D. Planchard,et al.  1172MO Durvalumab consolidation in patients with stage III non-resecable NSCLC with driver genomic alterations , 2021, Annals of Oncology.

[18]  N. Girard,et al.  1171MO PACIFIC-R real-world study: Treatment duration and interim analysis of progression-free survival in unresectable stage III NSCLC patients treated with durvalumab after chemoradiotherapy , 2021, Annals of Oncology.

[19]  D. de Ruysscher,et al.  CheckMate 73L: A Phase 3 Study Comparing Nivolumab Plus Concurrent Chemoradiotherapy Followed by Nivolumab With or Without Ipilimumab Versus Concurrent Chemoradiotherapy Followed by Durvalumab for Previously Untreated, Locally Advanced Stage III Non-Small-Cell Lung Cancer. , 2021, Clinical lung cancer.

[20]  Keunchil Park,et al.  Pembrolizumab Plus Concurrent Chemoradiation Therapy in Patients With Unresectable, Locally Advanced, Stage III Non–Small Cell Lung Cancer , 2021, JAMA oncology.

[21]  N. Girard,et al.  Surgical outcomes from the phase 3 CheckMate 816 trial: Nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo alone as neoadjuvant treatment for patients with resectable non-small cell lung cancer (NSCLC). , 2021 .

[22]  N. Sanfilippo,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. , 2021, The Lancet. Oncology.

[23]  James D. Murphy,et al.  Cost-effectiveness of Nivolumab-Ipilimumab Combination Therapy for the Treatment of Advanced Non–Small Cell Lung Cancer , 2021, JAMA network open.

[24]  D. Harpole,et al.  Perioperative outcomes of pulmonary resection after neoadjuvant pembrolizumab in patients with non-small cell lung cancer. , 2021, The Journal of thoracic and cardiovascular surgery.

[25]  M. Tsuboi,et al.  93TiP MERMAID-2: Phase III study of durvalumab in patients with resected, stage II-III NSCLC who become MRD+ after curative-intent therapy , 2021 .

[26]  C. Faivre-Finn,et al.  78MO Early safety assessment of durvalumab after sCRT in patients with stage III, unresectable NSCLC (PACIFIC-6) , 2021 .

[27]  M. Kris,et al.  PS01.05 Surgical and Clinical Outcomes With Neoadjuvant Atezolizumab in Resectable Stage IB–IIIB NSCLC: LCMC3 Trial Primary Analysis , 2021 .

[28]  M. Tsuboi,et al.  P03.03 MERMAID-1: A Phase III Study of Adjuvant Durvalumab plus Chemotherapy in Resected NSCLC Patients with MRD+ Post-Surgery , 2021 .

[29]  Summer S. Han,et al.  Durvalumab for Stage III EGFR-Mutated Non-Small Cell Lung Cancer After Definitive Chemoradiotherapy. , 2021, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[30]  Keunchil Park,et al.  Pembrolizumab Plus Ipilimumab or Placebo for Metastatic Non–Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score ≥ 50%: Randomized, Double-Blind Phase III KEYNOTE-598 Study , 2021, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[31]  M. Kriegsmann,et al.  Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. , 2021, Lung cancer.

[32]  A. Shaw,et al.  First-Line Lorlatinib or Crizotinib in Advanced ALK-Positive Lung Cancer. , 2020, The New England journal of medicine.

[33]  U. Dafni,et al.  Progression-free and overall survival for concurrent nivolumab with standard concurrent chemo-radiotherapy in locally advanced stage IIIA/B NSCLC: Results from the European Thoracic Oncology Platform NICOLAS phase II trial (ETOP 6-14). , 2020, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[34]  I. Wistuba,et al.  Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial. , 2020, The Lancet. Oncology.

[35]  M. Tsuboi,et al.  Osimertinib in Resected EGFR-Mutated Non-Small-Cell Lung Cancer. , 2020, The New England journal of medicine.

[36]  C. Chiu,et al.  1269P EMPOWER-lung 4: Phase II, randomized, open-label high dose or standard dose cemiplimab alone/plus ipilimumab in the second-line treatment of advanced non-small cell lung cancer (NSCLC) , 2020 .

[37]  B. Milleron,et al.  1214O Neoadjuvant durvalumab in resectable non-small cell lung cancer (NSCLC): Preliminary results from a multicenter study (IFCT-1601 IONESCO) , 2020 .

[38]  E. Fadel,et al.  1215O - SC Neoadjuvant atezolizumab (A) for resectable non-small cell lung cancer (NSCLC): Results from the phase II PRINCEPS trial , 2020 .

[39]  M. Tsuboi,et al.  1235TiP Perioperative pembrolizumab + platinum-based chemotherapy for resectable locally advanced non-small cell lung cancer: The phase III KEYNOTE-671 study , 2020 .

[40]  M. Provencio,et al.  Checkmate 77T: A phase III trial of neoadjuvant nivolumab (NIVO) plus chemotherapy (chemo) followed by adjuvant nivo in resectable early-stage NSCLC. , 2020 .

[41]  N. Hanna,et al.  Consolidation nivolumab/ipilimumab versus nivolumab following concurrent chemoradiation in patients with unresectable stage III NSCLC: A planned interim safety analysis from the BTCRC LUN 16-081 trial. , 2020 .

[42]  D. Carbone,et al.  Nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of platinum-doublet chemotherapy (chemo) vs 4 cycles chemo as first-line (1L) treatment (tx) for stage IV/recurrent non-small cell lung cancer (NSCLC): CheckMate 9LA. , 2020 .

[43]  P. Jänne,et al.  ALCHEMIST: Adjuvant targeted therapy or immunotherapy for high-risk resected NSCLC. , 2020 .

[44]  M. Lanuti,et al.  Neoadjuvant atezolizumab and chemotherapy in patients with resectable non-small-cell lung cancer: an open-label, multicentre, single-arm, phase 2 trial. , 2020, The Lancet. Oncology.

[45]  Edward S. Kim,et al.  Durvalumab With or Without Tremelimumab vs Standard Chemotherapy in First-line Treatment of Metastatic Non–Small Cell Lung Cancer , 2020, JAMA oncology.

[46]  Yibo Gao,et al.  Neoadjuvant PD-1 inhibitor (Sintilimab) in Non-Small Cell Lung Cancer. , 2020, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[47]  G. Rossi,et al.  Diagnosis and treatment of early and locally advanced non-small-cell lung cancer: The 2019 AIOM (Italian Association of Medical Oncology) clinical practice guidelines. , 2020, Critical reviews in oncology/hematology.

[48]  P. Fournel,et al.  Efficacy and safety of anti-PD-1 immunotherapy in patients with advanced Non Small Cell Lung Cancer with BRAF, HER2 or MET mutation or RET-translocation. GFPC 01-2018. , 2020, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[49]  D. Planchard,et al.  Three-Year Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC—Update from PACIFIC , 2019, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[50]  K. Syrigos,et al.  Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer. , 2019, The New England journal of medicine.

[51]  K. Boucher,et al.  Phase I Trial of Targeted EGFR or ALK Therapy with Ipilimumab in Metastatic NSCLC with Long-Term Follow-Up , 2019, Targeted Oncology.

[52]  A. Drilon,et al.  Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry , 2019, Annals of oncology : official journal of the European Society for Medical Oncology.

[53]  Ying Cheng,et al.  Erlotinib Versus Gemcitabine Plus Cisplatin as Neoadjuvant Treatment of Stage IIIA-N2 EGFR-Mutant Non-Small-Cell Lung Cancer (EMERGING-CTONG 1103): A Randomized Phase II Study. , 2019, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[54]  L. Trani,et al.  PACIFIC-2: Phase 3 study of concurrent durvalumab and platinum-based chemoradiotherapy in patients with unresectable, stage III NSCLC. , 2019, Journal of Clinical Oncology.

[55]  D. Gandara,et al.  IMpower030: Phase III study evaluating neoadjuvant treatment of resectable stage II-IIIB non-small cell lung cancer (NSCLC) with atezolizumab (atezo) + chemotherapy. , 2019, Annals of oncology : official journal of the European Society for Medical Oncology.

[56]  J. Goldman,et al.  KEYNOTE-021 cohorts D and H suggest modest benefit in combining ipilimumab with pembrolizumab in second-line or later advanced non-small cell lung cancer treatment. , 2019, Translational lung cancer research.

[57]  B. Han,et al.  Erlotinib as Neoadjuvant Therapy in Stage IIIA (N2) EGFR Mutation‐Positive Non‐Small Cell Lung Cancer: A Prospective, Single‐Arm, Phase II Study , 2018, The oncologist.

[58]  David R. Jones,et al.  Initial results of pulmonary resection after neoadjuvant nivolumab in patients with resectable non-small cell lung cancer. , 2019, The Journal of thoracic and cardiovascular surgery.

[59]  W. Mao,et al.  Erlotinib versus vinorelbine plus cisplatin as adjuvant therapy in Chinese patients with stage IIIA EGFR mutation-positive non-small-cell lung cancer (EVAN): a randomised, open-label, phase 2 trial. , 2018, The Lancet. Respiratory medicine.

[60]  C. Rudin,et al.  EA5142 adjuvant nivolumab in resected lung cancers (ANVIL). , 2018 .

[61]  Ying Cheng,et al.  Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC (ADJUVANT/CTONG1104): a randomised, open-label, phase 3 study. , 2018, The Lancet. Oncology.

[62]  E. Felip,et al.  Nivolumab Versus Docetaxel in Previously Treated Patients With Advanced Non-Small-Cell Lung Cancer: Two-Year Outcomes From Two Randomized, Open-Label, Phase III Trials (CheckMate 017 and CheckMate 057). , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[63]  Tarek Mekhail,et al.  Durvalumab after Chemoradiotherapy in Stage III Non–Small‐Cell Lung Cancer , 2017, The New England journal of medicine.

[64]  V. Rusch,et al.  Initial Experience With Lung Cancer Resection After Treatment With T-Cell Checkpoint Inhibitors. , 2017, The Annals of thoracic surgery.

[65]  R. Govindan,et al.  Phase III Trial of Ipilimumab Combined With Paclitaxel and Carboplatin in Advanced Squamous Non-Small-Cell Lung Cancer. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[66]  Li Zhang,et al.  Clinical Characteristics and Prognostic Factors in Bone Metastases from Lung Cancer , 2017, Medical science monitor : international medical journal of experimental and clinical research.

[67]  F. Petrella,et al.  Salvage Surgery After Definitive Chemoradiotherapy for Non-small Cell Lung Cancer. , 2017, Seminars in thoracic and cardiovascular surgery.

[68]  M. Stuschke,et al.  Definitive radiochemotherapy versus surgery within multimodality treatment in stage III non-small cell lung cancer (NSCLC) - a cumulative meta-analysis of the randomized evidence , 2017, Oncotarget.

[69]  H. Asamura,et al.  The Lung Cancer Surgical Study Group of the Japan Clinical Oncology Group: past activities, current status and future direction. , 2017, Japanese journal of clinical oncology.

[70]  S. Gettinger,et al.  Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. , 2017, The Lancet. Oncology.

[71]  Frank C. Detterbeck,et al.  The Eighth Edition Lung Cancer Stage Classification , 2017, Chest.

[72]  P. Stephens,et al.  Comprehensive Genomic Profiling Facilitates Implementation of the National Comprehensive Cancer Network Guidelines for Lung Cancer Biomarker Testing and Identifies Patients Who May Benefit From Enrollment in Mechanism-Driven Clinical Trials. , 2016, The oncologist.

[73]  C. Rudin,et al.  Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. , 2015, The New England journal of medicine.

[74]  L. Crinò,et al.  Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. , 2015, The New England journal of medicine.

[75]  W. Curran,et al.  Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. , 2015, The Lancet. Oncology.

[76]  B. Hutton,et al.  The incidence and clinical impact of bone metastases in non-small cell lung cancer. , 2015, Lung cancer.

[77]  Jeffrey W. Clark,et al.  Crizotinib in ROS1-rearranged non-small-cell lung cancer. , 2014, The New England journal of medicine.

[78]  Chris Sander,et al.  Copy number alteration burden predicts prostate cancer relapse , 2014, Proceedings of the National Academy of Sciences.

[79]  P. Thomas,et al.  Surgical management of advanced non-small cell lung cancer. , 2014, Journal of thoracic disease.

[80]  E. Smit,et al.  Changes in non-surgical management of stage III non-small cell lung cancer at a single institution between 2003 and 2010 , 2014, Acta oncologica.

[81]  C. Drake,et al.  Ipilimumab: An Anti-CTLA-4 Antibody for Metastatic Melanoma , 2011, Clinical Cancer Research.

[82]  Jeffrey W. Clark,et al.  Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. , 2010, The New England journal of medicine.

[83]  S. Gabriel,et al.  EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy , 2004, Science.