Abstract

Research Article

Induction therapy with Erlotinib (E) and Gemcitabine/Platinum (GP) in stage III NSCLC

Tobias R Overbeck*, Stefan HP Wenleder*, Bernhard C Danner, Wolfgang Körber, Karin Toepelt, Bernhard Hemmerlein, Christina Perske, Markus Falk, Markus Tiemann, Claudia Tomala, Elke Stitz and Frank Griesinger

Published: 28 January, 2021 | Volume 5 - Issue 1 | Pages: 001-018

Background: In 2004 we started a phase II trial in non-small lung cancer (NSCLC), stage III, with erlotinib followed by a combination with a platinum-based doublet in unselected patients to identify molecular subgroups benefitting from an EGFR targeting approach.

Patients and methods: Induction with erlotinib (E, 150 mg, d1-42) was followed by three cycles of gemcitabine (G, 1250 mg/m², d1+d8, q3w) and cisplatin (P, 80 mg/m², d1, q3w). Patients with at least stable disease after E were treated with a GP + E combination. Induction was followed by surgery and radiation. The trial was conducted as a prospective, multi-center, open label, exploratory phase II study to determine pathological response rate (pRR), as well as secondary endpoints disease free survival (DFS) and overall survival (OS).

Results: Of 38 prescreened patients 16 were included in the main study. Due to slow recruitment the study had to be terminated early. Combination of E and GP was well tolerated, surgery was feasible after induction therapy in 12 of 16 patients, 7/12 (58%) patients had a major pathological response (MPR). Median overall survival for patients with MPR was 57.7 months (confidence interval (CI), 37.4 to 78.0; n = 7) and for patients without MPR 11.9 months (CI, 6.4 to 17.4; n = 5). 2/16 patients had an epidermal growth factor receptor (EGFR) mutation.

Conclusion: Before discovery of distinct molecular mechanisms in NSCLC our study was an attempt to identify clinical and pathological subgroups that would benefit from E induction. Two patients with an EGFR mutation were identified. MPR was a predictor of long term disease free and overall survival.

Read Full Article HTML DOI: 10.29328/journal.jprr.1001018 Cite this Article Read Full Article PDF

Keywords:

Induction; Erlotinib; NSCLC; Stage III; Lung cancer

References

  1. NSCLC Meta-analyses Collaborative Group. Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: two meta-analyses of individual patient data. Lancet. 2010; 375: 1267–1277. PubMed: https://pubmed.ncbi.nlm.nih.gov/20338627/
  2. Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, et al. Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. N Engl J Med. 2018; 379: 2342–2350. PubMed: https://pubmed.ncbi.nlm.nih.gov/30280658/
  3. Provencio M, Nadal E, Insa A, García-Campelo MR, Casal-Rubio J, et al. Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol. 2020; 21: 1413–1422. PubMed: https://pubmed.ncbi.nlm.nih.gov/32979984/
  4. Cascone T, William WN, Weissferdt A, Lin HY, Leung CH, et al. Neoadjuvant nivolumab (N) or nivolumab plus ipilimumab (NI) for resectable non-small cell lung cancer (NSCLC): Clinical and correlative results from the NEOSTAR study. J Clin Oncol. 2019; 37(15_suppl): 8504.
  5. Forde PM, Chaft JE, Smith KN, Anagnostou V, Cottrell TR, et al. Neoadjuvant PD-1 Blockade in Resectable Lung Cancer. N Engl J Med. 2018; 378: 1976–1986. PubMed: https://pubmed.ncbi.nlm.nih.gov/29658848/
  6. Roth JA, Atkinson EN, Fossella F, Komaki R, Bernadette Ryan M, et al. Long-term follow-up of patients enrolled in a randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer. Lung Cancer. 1998; 21: 1–6. PubMed: https://pubmed.ncbi.nlm.nih.gov/9792048/
  7. Roth JA, Fossella F, Komaki R, Ryan MB, Putnam JB, et al. A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer. J Natl Cancer Inst. 1994; 86: 673–680. PubMed: https://pubmed.ncbi.nlm.nih.gov/8158698/
  8. Rosell R, Gomez-Codina J, Camps C, Maestre J, Padille J, et al. A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer. New Engl J Med.1994; 330: 153–158. PubMed: https://pubmed.ncbi.nlm.nih.gov/8043059/
  9. Pass HI, Pogrebniak HW, Steinberg SM, Mulshine J, Minna J. Randomized trial of neoadjuvant therapy for lung cancer: interim analysis. Ann Thorac Surg. 1992; 53: 992–998. https://pubmed.ncbi.nlm.nih.gov/1317697/
  10. Thomas M, Rube C, Hoffknecht P, Macha HN, Freitag L, et al. Effect of preoperative chemoradiation in addition to preoperative chemotherapy: a randomised trial in stage III non-small-cell lung cancer. Lancet Oncol. 2008; 9: 636–648. PubMed: https://pubmed.ncbi.nlm.nih.gov/18583190/
  11. NSCLC Meta-analysis Collaborative Group. Preoperative chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual participant data. Lancet. 2014; 383: 1561–1571. PubMed: https://pubmed.ncbi.nlm.nih.gov/24576776/
  12. Horita N, Miyazawa N, Morita S, Kojima R, Kimura N, et al. Preoperative Chemotherapy Is Effective for Stage III Resectable Non–Small-Cell Lung Cancer: Metaanalysis of 16 Trials. Clin Lung Cancer. 2013; 14: 488–494. PubMed: https://pubmed.ncbi.nlm.nih.gov/23664722/
  13. Pignon JP, Tribodet H, Scagliotti GV, Douillard JY, Shepherd FA, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol. 2008; 26: 3552–3559. PubMed: https://pubmed.ncbi.nlm.nih.gov/18506026/
  14. Felip E, Rosell R, Maestre JA, Rodríguez-Paniagua JM, Morán T, et al. Preoperative chemotherapy plus surgery versus surgery plus adjuvant chemotherapy versus surgery alone in early-stage non-small-cell lung cancer. J Clin Oncol. 2010; 28: 3138–3145. PubMed: https://pubmed.ncbi.nlm.nih.gov/20516435/
  15. Junker K, Langner K, Klinke F, Bosse U, Thomas M. Grading of tumor regression in non-small cell lung cancer: morphology and prognosis. Chest. 2001; 120: 1584–1591. PubMed: https://pubmed.ncbi.nlm.nih.gov/11713138/
  16. Betticher DC, Hsu Schmitz SF, Totsch M, Hansen E, Joss C, et al. Mediastinal lymph node clearance after docetaxel-cisplatin neoadjuvant chemotherapy is prognostic of survival in patients with stage IIIA pN2 non-small-cell lung cancer: a multicenter phase II trial. J Clin Oncol. 2003; 21: 1752–1759. PubMed: https://pubmed.ncbi.nlm.nih.gov/12721251/
  17. Cerfolio RJ, Bryant AS, Winokur TS, Ohja B, Bartolucci AA. Repeat FDG-PET after neoadjuvant therapy is a predictor of pathologic response in patients with non-small cell lung cancer. Ann Thorac Surg. 2004; 78:1903-1909. PubMed: https://pubmed.ncbi.nlm.nih.gov/15560998/
  18. Gatzemeier U, Pluzanska A, Szczesna A, Kaukel E, Roubec J, et al. Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial. J Clin Oncol. 2007; 25: 1545–1552. PubMed: https://pubmed.ncbi.nlm.nih.gov/17442998/
  19. Hidalgo M, Siu LL, Nemunaitis J, Rizzo J, Hammond LA, et al. Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol. 2001; 19: 3267–3279. PubMed: https://pubmed.ncbi.nlm.nih.gov/11432895/
  20. Ratain MJ, George CM, Janisch L, et al. Phase I trial of erlotinib (OSI-774) in combination with gemcitabine (G) and cisplatin (P) in patients with advanced solid tumors. Proc Am Soc Clin Oncol. 2002; 21: 76b.
  21. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. New Engl J Med. 2004; 350: 2129–2139. PubMed: https://pubmed.ncbi.nlm.nih.gov/15118073/
  22. Yang JCH, Shih JY, Su WC, Hsia TC, Tsai CM, et al. Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial. Lancet Oncol. 2012; 13: 539–548. PubMed: https://pubmed.ncbi.nlm.nih.gov/22452895/
  23. Kelly K, Chansky K, Gaspar LE, Albain KS, Jett J, et al. Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023. J Clin Oncol. 2008; 26: 2450–2456. PubMed: https://pubmed.ncbi.nlm.nih.gov/18378568/
  24. Goss GD, O'Callaghan C, Lorimer I, Tsao MS, Masters GA, et al. Gefitinib versus placebo in completely resected non-small-cell lung cancer: results of the NCIC CTG BR19 study. J Clin Oncol. 2013; 31: 3320–3326. PubMed: https://pubmed.ncbi.nlm.nih.gov/23980091/
  25. Janjigian YY, Park BJ, Zakowski MF, Ladanyi M, Pao W, et al. Impact on disease-free survival of adjuvant erlotinib or gefitinib in patients with resected lung adenocarcinomas that harbor EGFR mutations. J Thorac Oncol. 2011; 6: 569–575. PubMed: https://pubmed.ncbi.nlm.nih.gov/21150674/
  26. Kelly K, Altorki NK, Eberhardt WEE, O'Brien MER, Spigel DR, et al. Adjuvant Erlotinib Versus Placebo in Patients With Stage IB-IIIA Non-Small-Cell Lung Cancer (RADIANT): A Randomized, Double-Blind, Phase III Trial. J Clin Oncol. 2015; 33: 4007–4014. PubMed: https://pubmed.ncbi.nlm.nih.gov/26324372/
  27. Zhong WZ, Wang Q, Mao WM, Xu ST, Wu L, 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. Lancet Oncol. 2018; 19: 139–148. PubMed: https://pubmed.ncbi.nlm.nih.gov/29174310/
  28. Wu YL, Tsuboi M, He J, John T, Grohe C, et al. Osimertinib in Resected EGFR-Mutated Non-Small-Cell Lung Cancer. N Engl J Med. 2020; 383: 1711–1723. PubMed: https://pubmed.ncbi.nlm.nih.gov/32955177/
  29. Rosell R, Maestre J, Font A, Moreno I, Molina F, et al. A randomized trial of mitomycin/ifosfamide/cisplatin preoperative chemotherapy plus surgery versus surgery alone in stage IIIA non-small cell lung cancer. Semin Oncol. 1994; 21(3 Suppl 4): 28–33. PubMed: https://pubmed.ncbi.nlm.nih.gov/8209274/
  30. Daly BDT, Cerfolio RJ, Krasna MJ. Role of surgery following induction therapy for stage III non-small cell lung cancer. Surg Oncol Clin N Am. 2011; 20: 721–732. PubMed: https://pubmed.ncbi.nlm.nih.gov/21986268/
  31. Herse B, Dalichau H, Wormann B, Hemmerlein B, Schmidberger H, et al. Induction combination chemotherapy with docetaxel and carboplatin in advanced non-small-cell lung cancer. Thorac Cardiovasc Surg. 1998; 46: 298–302. PubMed: https://pubmed.ncbi.nlm.nih.gov/27517545/
  32. Poettgen C, Theegarten D, Eberhardt W, Levegruen S, Gauler T, et al. Correlation of PET/CT findings and histopathology after neoadjuvant therapy in non-small cell lung cancer. Oncology. 2007; 73: 316–323. PubMed: https://pubmed.ncbi.nlm.nih.gov/18497503/
  33. Liu M, Jiang G, He W, Zhang P, Song N. Surgical resection of locally advanced pulmonary adenocarcinoma after gefitinib therapy. Ann Thorac Surg. 2011; 92: e11-2. PubMed: https://pubmed.ncbi.nlm.nih.gov/21718818/
  34. Lara-Guerra H, Waddell TK, Salvarrey MA, Joshua AM, Chung CT, et al. Phase II study of preoperative gefitinib in clinical stage I non-small-cell lung cancer. J Clin Oncol. 2009; 27: 6229–6236. PubMed: https://pubmed.ncbi.nlm.nih.gov/19884551/
  35. Lara-Guerra H, Chung CT, Schwock J, Pintilie M, Hwang DM, et al. Histopathological and immunohistochemical features associated with clinical response to neoadjuvant gefitinib therapy in early stage non-small cell lung cancer. Lung Cancer. 2012; 76: 235–241. PubMed: https://pubmed.ncbi.nlm.nih.gov/22112291/
  36. Rizvi NA, Rusch V, Pao W, Chaft JE, Ladanyi M, et al. Molecular characteristics predict clinical outcomes: prospective trial correlating response to the EGFR tyrosine kinase inhibitor gefitinib with the presence of sensitizing mutations in the tyrosine binding domain of the EGFR gene. Clin Cancer Res. 2011; 17: 3500–3506. PubMed: https://pubmed.ncbi.nlm.nih.gov/21558399/
  37. Gandara D, Narayan S, Lara PN, JR, Goldberg Z, Davies A, et al. Integration of novel therapeutics into combined modality therapy of locally advanced non-small cell lung cancer. Clin Cancer Res. 2005; 11: 5057s-5062s. PubMed: https://pubmed.ncbi.nlm.nih.gov/16000614/
  38. Eberhard DA, Johnson BE, Amler LC, Goddard AD, Heldens SL, et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol. 2005; 23: 5900–5999. PubMed: https://pubmed.ncbi.nlm.nih.gov/16043828/
  39. Bell DW, Lynch TJ, Haserlat SM, Harris PL, Okimoto RA, et al. Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: molecular analysis of the IDEAL/INTACT gefitinib trials. J Clin Oncol. 2005; 23: 8081–8092. PubMed: https://pubmed.ncbi.nlm.nih.gov/16204011/
  40. Sangha R, Davies AM, Lara PN, JR, Mack PC, Beckett LA, et al. Intercalated erlotinib-docetaxel dosing schedules designed to achieve pharmacodynamic separation: results of a phase I/II trial. J Thorac Oncol. 2011; 6: 2112–2119. PubMed: https://pubmed.ncbi.nlm.nih.gov/21892109/
  41. Davies AM, Ho C, Beckett L, Lau D, Scudder SA, et al. Intermittent erlotinib in combination with pemetrexed: phase I schedules designed to achieve pharmacodynamic separation. J Thorac Oncol. 2009; 4: 862–868. PubMed: https://pubmed.ncbi.nlm.nih.gov/19494788/
  42. Riely GJ, Rizvi NA, Kris MG, Milton DT, Solit DB, et al. Randomized phase II study of pulse erlotinib before or after carboplatin and paclitaxel in current or former smokers with advanced non-small-cell lung cancer. J Clin Oncol. 2009; 27: 264–270. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2645610/
  43. Janne PA, Wang X, Socinski MA, Crawford J, Stinchcombe TE, Gu L et al. Randomized phase II trial of erlotinib alone or with carboplatin and paclitaxel in patients who were never or light former smokers with advanced lung adenocarcinoma: CALGB 30406 trial. J Clin Oncol. 2012; 30: 2063–2069. PubMed: https://pubmed.ncbi.nlm.nih.gov/22547605/
  44. Mok TSK, Wu YL, Yu CJ, Zhou C, Chen YM, et al. Randomized, placebo-controlled, phase II study of sequential erlotinib and chemotherapy as first-line treatment for advanced non-small-cell lung cancer. J Clin Oncol. 2009; 27: 5080–5087. PubMed: https://pubmed.ncbi.nlm.nih.gov/19738125/
  45. Wu YL, Lee JS, Thongprasert S, Yu CJ, Zhang L, et al. Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial. Lancet Oncol. 2013; 14: 777–786. PubMed: https://pubmed.ncbi.nlm.nih.gov/23782814/
  46. Griesinger F, Roeper J, Netchaeva M, Lueers AC, Falk M, et al. Intercalated EGFR TKI and chemotherapy induction therapy in EGFR mt+ NSCLC stage IIIA and IIIB: report of 5 cases. J Clin Oncol. 2016; 34(15_suppl): e20059-e20059.
  47. Overbeck TR, Griesinger F. Two cases of psoriasis responding to erlotinib: time to revisiting inhibition of epidermal growth factor receptor in psoriasis therapy? Dermatology (Basel). 2012; 225: 179–182. PubMed: https://pubmed.ncbi.nlm.nih.gov/23095682/
  48. Tsao MS, Sakurada A, Cutz JC, Zhu CQ, Kamel-Reid S, et al. Erlotinib in Lung Cancer — Molecular and Clinical Predictors of Outcome. New Engl J Med. 2005; 353: 133–144. PubMed: https://pubmed.ncbi.nlm.nih.gov/16014883/
  49. Quan X, Gao H, Wang Z, Li J, Zhao W, et al. Epidermal growth factor receptor somatic mutation analysis in 354 Chinese patients with non-small cell lung cancer. Oncol Lett. 2018; 15: 2131–2138. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5776883/
  50. Zhang SM, Zhu QG, Ding XX, Lin S, Zhao J, et al. Prognostic value of EGFR and KRAS in resected non-small cell lung cancer: a systematic review and meta-analysis. Cancer Manag Res. 2018; 10: 3393–3404. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6138965/
  51. Jeremić B, Casas F, Dubinsky P, Gomez-Caamano A, Čihorić N, et al. Treatment-Related Predictive and Prognostic Factors in Trimodality Approach in Stage IIIA/N2 Non-Small Cell Lung Cancer. Frontiers Oncol. 2018; 8: 30. PubMed: https://pubmed.ncbi.nlm.nih.gov/29527511/
  52. Gandhi L, Rodriguez-Abreu D, Gadgeel S, Esteban E, Felip E, et al. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med. 2018; 378: 2078–2092. PubMed: https://pubmed.ncbi.nlm.nih.gov/29658856/
  53. Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, et al. Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score of 50% or Greater. J Clin Oncol. 2019; 37: 537–546. PubMed: https://pubmed.ncbi.nlm.nih.gov/30620668/
  54. Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016; 375: 1823–1833. PubMed: https://pubmed.ncbi.nlm.nih.gov/27718847/
  55. Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, et al. Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. N Engl J Med. 2018; 378: 2288–2301. PubMed: https://pubmed.ncbi.nlm.nih.gov/29863955/

Figures:

Figure 1

Figure 1

Figure 1

Figure 2

Similar Articles

  • A decade of targeted therapy for non-small cell lung cancer
    Khalid Abu Ajaj* Khalid Abu Ajaj*. A decade of targeted therapy for non-small cell lung cancer. . 2017 doi: 10.29328/journal.jprr.1001005; 1: 023-027
  • Induction therapy with Erlotinib (E) and Gemcitabine/Platinum (GP) in stage III NSCLC
    Tobias R Overbeck*, Stefan HP Wenleder*, Bernhard C Danner, Wolfgang Körber, Karin Toepelt, Bernhard Hemmerlein, Christina Perske, Markus Falk, Markus Tiemann, Claudia Tomala, Elke Stitz and Frank Griesinger Tobias R Overbeck*,Stefan HP Wenleder*,Bernhard C Danner,Wolfgang Körber, Karin Toepelt,Bernhard Hemmerlein, Christina Perske,Markus Falk,Markus Tiemann,Claudia Tomala,Elke Stitz,Frank Griesinger. Induction therapy with Erlotinib (E) and Gemcitabine/Platinum (GP) in stage III NSCLC. . 2021 doi: 10.29328/journal.jprr.1001018; 5: 001-018
  • Non-smoking woman with adenocarcinoma of the lung, IV stage with ROS1 mutation and acquired thrombophilia
    Immanuels Taivans*, Natalja Senterjakova, Viktors Kozirovskis, Gunta Strazda, Jurijs Nazarovs and Valentina Gordjusina Immanuels Taivans*,Natalja Senterjakova,Viktors Kozirovskis,Gunta Strazda,Jurijs Nazarovs,Valentina Gordjusina. Non-smoking woman with adenocarcinoma of the lung, IV stage with ROS1 mutation and acquired thrombophilia. . 2021 doi: 10.29328/journal.jprr.1001027; 5: 064-072

Recently Viewed

Read More

Most Viewed

Read More