Online first
Review paper
Published online: 2024-06-24
Advancements in non-small cell lung cancer treatment: from early to advanced stages
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DOI: 10.5603/ocp.100477
Abstract
Over the past years, tremendous progress has been made in the treatment available for non-small cell lung cancer patients (NSCLC), both in the early and advanced stages of the disease. In early-stage NSCLC, perioperative immunotherapy is emerging as a promising approach. Several studies in preoperative chemoimmunotherapy showed a significant increase in the rate of complete pathologic response and prolonged event-free survival in resectable NSCLC patients. Similarly, atezolizumab and osimertinib are the standard of care in some patients after complete resection in EGFR-mutated or programmed cell death ligand 1 (PD-L1) high-expressing tumors. In locally advanced disease, durvalumab consolidation therapy following chemoradiotherapy improved progression-free survival (PFS) and overall survival (OS) in unresectable NSCLC while other immunotherapies in combination with chemotherapy showed promising results. In advanced NSCLC, novel immunotherapies or immunoconjugates such as trastuzumab deruxtecan are also demonstrating efficacy. Furthermore, molecularly targeted therapy targeting KRAS, EGFR, and other genetic aberrations, guided by next-generation sequencing, offers new treatment options. However, challenges remain, including patient selection, sequencing, and reimbursement. This article reviews the latest treatments for patients with NSCLC in the early and advanced stages of the disease.
Keywords: non-small cell lung cancertreatmentimmunotherapytargeted therapyimmunoconjugates
References
- Forde PM, Spicer J, Lu S, et al. CheckMate 816 Investigators. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N Engl J Med. 2022; 386(21): 1973–1985.
- EMA. Opdivo.Product Information. https://www.ema.europa.eu/en/medicines/human/EPAR/opdivo (24.04.2024).
- Felip E, Altorki N, Zhou C, et al. IMpower010 Investigators. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial. Lancet. 2021; 398(10308): 1344–1357.
- Felip E, Altorki N, Zhou C, et al. Overall survival with adjuvant atezolizumab after chemotherapy in resected stage II-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase III trial. Ann Oncol. 2023; 34(10): 907–919.
- Wakelee H, Liberman M, Kato T, et al. KEYNOTE-671 Investigators. Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer. N Engl J Med. 2023; 389(6): 491–503.
- Wu YL, Tsuboi M, John T, et al. ADAURA Investigators. Osimertinib in Resected -Mutated Non-Small-Cell Lung Cancer. N Engl J Med. 2020; 383(18): 1711–1723.
- Tsuboi M, Herbst R, John T, et al. Overall Survival with Osimertinib in Resected EGFR -Mutated NSCLC. N Engl J Med. 2023; 389(2): 137–147.
- Majem M, Goldman JW, John T, et al. Health-Related Quality of Life Outcomes in Patients with Resected Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer Who Received Adjuvant Osimertinib in the Phase III ADAURA Trial. Clin Cancer Res. 2022; 28(11): 2286–2296.
- Herbst RS, Wu YL, John T, et al. Adjuvant Osimertinib for Resected EGFR-Mutated Stage IB-IIIA Non-Small-Cell Lung Cancer: Updated Results From the Phase III Randomized ADAURA Trial. J Clin Oncol. 2023; 41(10): 1830–1840.
- Tsuboi M, Weder W, Escriu C, et al. Neoadjuvant osimertinib with/without chemotherapy versus chemotherapy alone for -mutated resectable non-small-cell lung cancer: NeoADAURA. Future Oncol. 2021; 17(31): 4045–4055.
- Tsutani Y, Goldman JW, Dacic S, et al. Adjuvant Osimertinib vs. Placebo in Completely Resected Stage IA2-IA3 EGFR-Mutated NSCLC: ADAURA2. Clin Lung Cancer. 2023; 24(4): 376–380.
- Efficacy and Safety of Almonertinib Combined With or Without Chemotherapy as an Adjuvant Treatment for Stage II–IIIA Non-small Cell Lung Carcinoma Following Complete Tumour Resection (APEX). https://clinicaltrials.gov/ct2/show/NCT04762459.
- To Assess the Efficacy and Safety of Furmonertinib Versus Placebo, in Patients With Epidermal Growth Factor Receptor Mutation Positive Stage II-IIIA Non-small Cell Lung Carcinoma, Following Complete Tumour Resection With or Without Adjuvant Chemotherapy (FORWARD). https://clinicaltrials.gov/study/NCT04853342.
- Solomon B, Ahn J, Dziadziuszko R, et al. LBA2 ALINA: Efficacy and safety of adjuvant alectinib versus chemotherapy in patients with early-stage ALK+ non-small cell lung cancer. Ann Oncol. 2023; 34(suppl 2): S1295–S1296.
- Goldman J, Besse B, Wu Y, et al. P01.01 LIBRETTO-432: A Placebo-Controlled Phase 3 Study of Adjuvant Selpercatinib in Stage IB-IIIA RET Fusion-Positive NSCLC. J Thorac Oncol. 2021; 16(10_suppl): S975–S976.
- Socinski MA, Özgüroğlu M, Villegas A, et al. PACIFIC Investigators. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med. 2017; 377(20): 1919–1929.
- Spigel DR, Faivre-Finn C, Gray JE, et al. Five-Year Survival Outcomes From the PACIFIC Trial: Durvalumab After Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. J Clin Oncol. 2022; 40(12): 1301–1311.
- Jabbour SK, Lee KiH, Frost N, et al. Pembrolizumab Plus Concurrent Chemoradiation Therapy in Patients With Unresectable, Locally Advanced, Stage III Non-Small Cell Lung Cancer: The Phase 2 KEYNOTE-799 Nonrandomized Trial. JAMA Oncol. 2021 [Epub ahead of print]; 7(9): 1–9.
- Reck M, Lee K, Frost N, et al. Two-year update from KEYNOTE-799: Pembrolizumab plus concurrent chemoradiation therapy (cCRT) for unresectable, locally advanced, stage III NSCLC. J Clin Oncol. 2022; 40(16_suppl).
- Zhou Q, Chen M, Jiang Ou, et al. Sugemalimab versus placebo after concurrent or sequential chemoradiotherapy in patients with locally advanced, unresectable, stage III non-small-cell lung cancer in China (GEMSTONE-301): interim results of a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2022; 23(2): 209–219.
- Wu Y, Zhou Q, Chen M, et al. OA02.05 sugemalimab vs placebo after cCRT or sCRT in pts with unresectable stage III NSCLC: final PFS analysis of a phase 3 study. J Thorac Oncol. 2022; 17(9_suppl): S7–S8.
- Naidoo J, Antonia SJ, Wu YL, et al. 8541 Durvalumab (durva) after chemoradiotherapy (CRT) in unresectable, , EGFR mutation-positive (EGFRm) NSCLC: A post hoc subgroup analysis from PACIFIC. J Clin Oncol. 2022; 40(16_suppl).
- Hellyer JA, Aredo JV, Das M, et al. Role of Consolidation Durvalumab in Patients With EGFR- and HER2-Mutant Unresectable Stage III NSCLC. J Thorac Oncol. 2021; 16(5): 868–872.
- Lu S, Casarini I, Kato T, et al. Osimertinib Maintenance After Definitive Chemoradiation in Patients With Unresectable EGFR Mutation Positive Stage III Non-small-cell Lung Cancer: LAURA Trial in Progress. Clin Lung Cancer. 2021; 22(4): 371–375.
- A Study Evaluating the Efficacy and Safety of Multiple Therapies in Cohorts of Participants With Locally Advanced, Unresectable, Stage III Non-Small Cell Lung Cancer (NSCLC). https://clinicaltrials.gov/ct2/show/NCT05170204.
- Sezer A, Kilickap S, Gümüş M, et al. Cemiplimab monotherapy for first-line treatment of advanced non-small-cell lung cancer with PD-L1 of at least 50%: a multicentre, open-label, global, phase 3, randomised, controlled trial. Lancet. 2021; 397(10274): 592–604.
- Özgüroğlu M, Kilickap S, Sezer A, et al. First-line cemiplimab monotherapy and continued cemiplimab beyond progression plus chemotherapy for advanced non-small-cell lung cancer with PD-L1 50% or more (EMPOWER-Lung 1): 35-month follow-up from a mutlicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2023; 24(9): 989–1001.
- Gogishvili M, Melkadze T, Makharadze T, et al. Cemiplimab plus chemotherapy versus chemotherapy alone in non-small cell lung cancer: a randomized, controlled, double-blind phase 3 trial. Nat Med. 2022; 28(11): 2374–2380.
- Makharadze T, Gogishvili M, Melkadze T, et al. Cemiplimab Plus Chemotherapy Versus Chemotherapy Alone in Advanced NSCLC: 2-Year Follow-Up From the Phase 3 EMPOWER-Lung 3 Part 2 Trial. J Thorac Oncol. 2023; 18(6): 755–768.
- Johnson ML, Cho BC, Luft A, et al. POSEIDON investigators. Durvalumab With or Without Tremelimumab in Combination With Chemotherapy as First-Line Therapy for Metastatic Non-Small-Cell Lung Cancer: The Phase III POSEIDON Study. J Clin Oncol. 2023; 41(6): 1213–1227.
- Garon EB, Cho BC, Luft A, et al. POSEIDON investigators. Durvalumab With or Without Tremelimumab in Combination With Chemotherapy as First-Line Therapy for Metastatic Non-Small-Cell Lung Cancer: The Phase III POSEIDON Study. J Clin Oncol. 2023; 41(6): 1213–1227.
- Peters S, Cho BC, Luft A. LBA3 – Durvalumab ± Tremelimumab + Chemotherapy in First-Line Metastatic NSCLC: 5-Year Overall Survival Update from the POSEIDON Study. Abstract presented at ESMO Immuno-Oncology Congress. 2023.
- Li BT, Shen R, Buonocore D, et al. Ado-Trastuzumab Emtansine for Patients With HER2-Mutant Lung Cancers: Results From a Phase II Basket Trial. J Clin Oncol. 2018; 36(24): 2532–2537.
- Li BT, Michelini F, Misale S, et al. HER2-Mediated Internalization of Cytotoxic Agents in Amplified or Mutant Lung Cancers. Cancer Discov. 2020; 10(5): 674–687.
- Li BT, Smit EF, Goto Y, et al. DESTINY-Lung01 Trial Investigators. Trastuzumab Deruxtecan in -Mutant Non-Small-Cell Lung Cancer. N Engl J Med. 2022; 386(3): 241–251.
- Jänne PA, Baik C, Su WC, et al. Efficacy and Safety of Patritumab Deruxtecan (HER3-DXd) in EGFR Inhibitor-Resistant, -Mutated Non-Small Cell Lung Cancer. Cancer Discov. 2022; 12(1): 74–89.
- Merle G, Friedlaender A, Desai A, et al. Antibody Drug Conjugates in Lung Cancer. Cancer J. 2022; 28(6): 429–435.
- Cardillo TM, Govindan SV, Sharkey RM, et al. Sacituzumab Govitecan (IMMU-132), an Anti-Trop-2/SN-38 Antibody-Drug Conjugate: Characterization and Efficacy in Pancreatic, Gastric, and Other Cancers. Bioconjug Chem. 2015; 26(5): 919–931.
- Heist RS, Guarino MJ, Masters G, et al. Therapy of Advanced Non-Small-Cell Lung Cancer With an SN-38-Anti-Trop-2 Drug Conjugate, Sacituzumab Govitecan. J Clin Oncol. 2017; 35(24): 2790–2797.
- Bardia A, Messersmith WA, Kio EA, et al. Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate, for patients with epithelial cancer: final safety and efficacy results from the phase I/II IMMU-132-01 basket trial. Ann Oncol. 2021; 32(6): 746–756.
- Levy BP, Felip E, Reck M, et al. TROPION-Lung08: phase III study of datopotamab deruxtecan plus pembrolizumab as first-line therapy for advanced NSCLC. Future Oncol. 2023; 19(21): 1461–1472.
- Strickler JH, Weekes CD, Nemunaitis J, et al. First-in-Human Phase I, Dose-Escalation and -Expansion Study of Telisotuzumab Vedotin, an Antibody-Drug Conjugate Targeting c-Met, in Patients With Advanced Solid Tumors. J Clin Oncol. 2018; 36(33): 3298–3306.
- Waqar SN, Redman MW, Arnold SM, et al. A Phase II Study of Telisotuzumab Vedotin in Patients With c-MET-positive Stage IV or Recurrent Squamous Cell Lung Cancer (LUNG-MAP Sub-study S1400K, NCT03574753). Clin Lung Cancer. 2021; 22(3): 170–177.
- de Langen AJ, Johnson ML, Mazieres J, et al. CodeBreaK 200 Investigators. Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRAS mutation: a randomised, open-label, phase 3 trial. Lancet. 2023; 401(10378): 733–746.
- Jänne PA, Riely GJ, Gadgeel SM, et al. Adagrasib in Non-Small-Cell Lung Cancer Harboring a Mutation. N Engl J Med. 2022; 387(2): 120–131.
- Zhou C, Tang KJ, Cho BC, et al. PAPILLON Investigators. Amivantamab plus Chemotherapy in NSCLC with Exon 20 Insertions. N Engl J Med. 2023; 389(22): 2039–2051.
- Demetri GD, De Braud F, Drilon A, et al. Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Patients With NTRK Fusion-Positive Solid Tumors. Clin Cancer Res. 2022; 28(7): 1302–1312.
- Drilon A, Chiu CH, Fan Y, et al. trial investigators, trial investigators. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020; 21(2): 271–282.
- Waguespack SG, Drilon A, Lin JJ, et al. Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N Engl J Med. 2018; 378(8): 731–739.
- Hendriks LE, Kerr KM, Menis J, et al. ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org. Non-oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023; 34(4): 358–376.