Immunotherapy in NSCLC: A Promising and Revolutionary Weapon
Lung cancer is the leader malignancy worldwide accounting 1.5 millions of deaths every year. In the United States the 5 year-overall survival is less than 20% for all the newly diagnosed patients. Cisplatin-based cytotoxic chemotherapy for unresectable or metastatic NSCLC patients in the first line of treatment, and docetaxel in the second line, have achieved positive results but with limited benefit in overall survival. Targeted therapies for EGFR and ALK mutant patients have showed better results when compared with chemotherapy, nevertheless most of patients will fail and need to be treated with chemotherapy if they still have a good performance status.
Immunotherapy recently has become the most revolutionary treatment in solid tumors patients. First results in unresectable and metastatic melanoma patients treated with an anti CTLA-4 monoclonal antibody showed an unexpected 3-year overall survival of at least 25%.
Lung cancer cells have multiple immunosuppressive mechanisms that allow to escape of the immune system and survive, however blocking CTLA-4 pathway with antibodies as monotherapy treatment have not achieved same results than in melanoma patients. PD-1 expression has been demonstrated in different tumor types, suggesting than PD-1 / PD-L1 pathway is a common mechanism used by tumors to avoid immune surveillance and favoring tumor growth. Anti PD-1 and anti PD-L1 antibodies have showed activity in non-small cell lung cancer patients with significant benefit in overall survival, long lasting responses and good safety profile, including naïve and pretreated patients regardless of the histological subtype. Even more, PD-1 negative expression patients achieve similar results in overall survival when compared with patients treated with chemotherapy. In the other side high PD-1 expression patients that undergo immunotherapy treatment achieve better results in terms of survival with lesser toxicity. Combining different immunotherapy treatments, combination of immunotherapy with chemotherapy or with targeted treatment are under research with some promising PRELIMINARY results in non-small cell lung cancer patients.
This chapter attempts to summarize the development of immunotherapy treatment in non-small cell lung cancer patients and explain the results that have leaded immunotherapy as a new standard of treatment in selected NSCLC patients.
KeywordsImmunotherapy PDL1 PD1 NSCLC Immune checkpoints
Thanks to Dr. Rodolfo Mauceri for his contribution for the images for this chapter.
Authors declare not commercial funding, not honoraria for this manuscript and not participation direct or indirectly by pharmaceutical industry.
Authors declare personal disclosures that could be considered of interest regarding the content of the chapter.
Christian Rolfo: Novartis speaker bureau, Mylan scientific advisor, Sanfo research grant, Precision Medicine: Steering committee.
Christian Caglevic: Principal investigator for clinical trials in NSCLC with immunotherapy drugs (MSD, AZ) and subinvestigator (BMS). Speaker (BMS and MSD), Advisory board (MSD–AZ), Consultant (BMS–MSD), Courses and transportation financial (BMS)
María Carmela Santarpia: not disclosures.
Antonio Araujo: not disclosures.
Elisa Giovannetti: not disclosures.
Carolina Díaz Gallardo: not disclosures.
Patrick Pauwels: not disclosures.
Mauricio Mahave: not disclosures.
- 4.NSCLC Meta-Analyses Collaborative Group. Chemotherapy in addition to supportive care improves survival in advanced non–small-cell lung cancer: a systematic review and meta-analysis of individual patient data from 16 randomized controlled trials. J Clin Oncol. 26:4617–25.Google Scholar
- 8.Rolfo C, Caglevic C, Mahave M, Bustamante E, Castañon E, Gil BI, Marquez-Medina D. Chapter 14: Chemotherapy beyond the second line of treatment in non-small cell lung cancer: new drug development. In: Marquez-Medina D, editor. Fighting lung cancer with conventional therapies. New York: Nova Science Publishers; 2015. p. 229–40.Google Scholar
- 18.Abbas A, Lichtman A, Pillai S. Immunity to tumors. In: Abbas AK, Lichtman AH, Pillai S, editors. Celular and molecular immunology. Philadelphia, PA: Elsevier; 2015. p. 383–97.Google Scholar
- 33.Zatloukal P, Heo DS, Park K, et al. Randomized phase II clinical trial comparing tremelimumab (CP-675,206) with best supportive care (BSC) following first-line platinum-based therapy in patients (pts) with advanced non-small cell lung cancer (NSCLC). J Clin Oncol (Meeting Abstracts). 2009;27(15S):8071.Google Scholar
- 45.Horn L, Rizvi N, Mazieres J et al. Longer-term follow-up of a phase 2 study (CheckMate 063) of nivolumab in patients with advanced refractory squamous (SQ) non-small cell lung cancer (NSCLC). J Thor Oncol. 2015;10(9 suppl 2), abstract 02.03.Google Scholar
- 48.Borghaei H, Brahmer J., Horn L. et al. Nivolumab vs docetaxel in patients with advanced NSCLC: CheckMate 017/057 2-y update and exploratory cytokine profile analyses. J Clin Oncol. 2016;34(suppl; abstr 9025).Google Scholar
- 50.Antonia S, Brahmer J, Gettinger S, et al. Nivolumab (anti-PD-1; BMS-936558, ONO-4538) in combination with platinum-based doublet chemotherapy in advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2014;32:5s(suppl; abstr 8113).Google Scholar
- 51.Gettinger S, Shepherd F, Antonia S, et al. First-line nivolumab (anti-PD-1; BMS-936558, ONO-4538) monotherapy in advanced NSCLC: safety, efficacy, and correlation of outcomes with PD-L1 status. J Clin Oncol. 2014;32:5s(suppl; abstr 8024).Google Scholar
- 52.Gettinger SN. Presented at European Society for Medical Oncology (ESMO), September 25–29, 2015, Vienna, Austria.Google Scholar
- 53.Antonia S, Gettinger S, Quan Man Chow L, et al. Nivolumab (anti-PD-1; BMS-936558, ONO-4538) and ipilimumab in first-line NSCLC: interim phase I results. J Clin Oncol. 2014;32:5(suppl; abstr 8023).Google Scholar
- 54.Rizvi NA, Gettinger SN, Goldman JW, et al.: Safety and efficacy of first-line nivolumab and ipilimumab in non-small cell lung cancer. 16th World conference on lung cancer. Abstract ORAL02.05. Presented September 7, 2015.Google Scholar
- 55.Hellmann M., Gettinger S., Goldman J., et al. CheckMate 012: “Safety and efficacy of first-line nivolumab and ipilimumab in advanced NSCLC”. J Clin Oncol. 2016; 34(suppl; abstr 3001).Google Scholar
- 56.Najjar Y, Kirkwood J. Pembrolizumab: pharmacology and therapeutics. Am J Hematol Oncol. 2014;10(5):17–9.Google Scholar
- 58.Hui R., Gandhi L., Carcereny Costa E, et al. Long-term OS for patients with advanced NSCLC enrolled in the KEYNOTE-001 study of pembrolizumab. J Clin Oncol. 2016;34 (suppl; abstr 9026)Google Scholar
- 60.Baas P, Garon E, Herbst R., et al. Relationship between level of PD-L1 expression and outcomes in the KEYNOTE-010 study of pembrolizumab vs docetaxel for previously treated, PD-L1–Positive NSCLC. J Clin Oncol. 2016;34(suppl; abstr 9015).Google Scholar
- 61.Garon E., Herbst R, Kim DW, et al. Pembrolizumab vs docetaxel for previously treated advanced NSCLC with a PD-L1 tumor proportion score (TPS) 1%–49%: results from KEYNOTE-010. J Clin Oncol. 2016;34(suppl; abstr 9024).Google Scholar
- 62.Herbst R, Baas P, Perez-Gracia JL et al. Archival vs new tumor samples for assessing PD-L1 expression in the KEYNOTE-010 study of pembrolizumab vs docetaxel for previously treated advanced NSCLC. J Clin Oncol. 2016;34(suppl; abstr 3030).Google Scholar
- 67.Brahmer J, Rizvi N, Lutzky J, et al. Clinical activity and biomarkers of MEDI4736, an anti-PD-L1 antibody, in patients with NSCLC. J Clin Oncol. 2014;32:5(suppl; abstr 8021).Google Scholar
- 68.Rizvi N, Brahmer J, Ou SH, et al. Safety and clinical activity of MEDI4736, an anti-programmed cell death-ligand 1 (PD-L1) antibody, in patients with non-small cell lung cancer (NSCLC). J Clin Oncol. 2015;33(15 Suppl):8032.Google Scholar
- 69.Antonia S., Kim SW, Spira A., et al. Safety and clinical activity of durvalumab (MEDI4736), an anti-PD-L1 antibody, in treatment-naïve patients with advanced non–small-cell lung cancer. J Clin Oncol. 2016;34(suppl; abstr 9029).Google Scholar
- 72.Spigel D, Gettinger S., Horn L., et al. Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol. 2013;31(suppl; abstr 8008).Google Scholar
- 74.Schmid P., Hegde P., Zou W., et al. Association of PD-L2 expression in human tumors with atezolizumab activity. J Clin Oncol. 2016;34(suppl; abstr 11506).Google Scholar
- 75.Liu S., Powderly J., Camidge R. et al. Safety and efficacy of MPDL3280A (anti-PDL1) in combination with platinum-based doublet chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2015;33(suppl; abstr 8030).Google Scholar
- 76.Besse B, Johnson M, Jänne PA, et al. Phase II, single-arm trial (BIRCH) of atezolizumab as first-line or subsequent therapy for locally advanced or metastatic PD-L1-selected non-small cell lung cancer (NSCLC). Presented at 2015 European Cancer Congress, September 25–29, Vienna, Austria. Abstract 16LBA.Google Scholar
- 78.Smith D.,Vansteenkiste J., Fehrenbacher L., et al. Updated survival and biomarker analyses of a randomized phase II study of atezolizumab vs docetaxel in 2 L/3 L NSCLC (POPLAR). J Clin Oncol. 2016;34(suppl; abstr 9028).Google Scholar
- 79.Hamanishi J, Mandai M, Konishi I. Immune checkpoint inhibition in ovarian cancer. Int Immunol. 2016;7. pii:dxw020.Google Scholar
- 80.Kelly K, Patel M., Infante J. et al. Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with metastatic or locally advanced solid tumors: assessment of safety and tolerability in a phase I, open-label expansion study. J Clin Oncol. 2015;33(suppl; abstr 3044).Google Scholar
- 81.Gulley J, Spigel D, Kelly K, et al. Avelumab (MSB0010718C), an anti-PD-L1 antibody, in advanced NSCLC patients: a phase 1b, open-label expansion trial in patients progressing after platinum-based chemotherapy. J Clin Oncol (Meeting Abstracts). 2015;33(15_suppl):8034.Google Scholar
- 82.Verschraegen C., Chen F., Spigel D., et al. Avelumab (MSB0010718C; anti-PD-L1) as a first-line treatment for patients with advanced NSCLC from the JAVELIN Solid Tumor phase 1b trial: safety, clinical activity, and PD-L1 expression. J Clin Oncol. 2016;34(suppl; abstr 9036).Google Scholar
- 85.Globocan 2012: “Estimated Cancer Incidence, Mortality and Prevalence Worlwide 2012.” http://globocan.iarc.fr/Pages/fact_sheets_population.aspx
- 86.NIH, National Cancer Institute: surveillance, epidemiology and end results. http://seer.cancer.gov/statfacts/html/lungb.html
- 88.Carbognin L, Pilotto S, Milella M, et al. Differential activity of nivolumab, pembrolizumab and MPDL3280A according to the tumor expression of programmed death-ligand-1 (PD-L1): sensitivity analysis of trials in melanoma, lung and genitourinary cancers. PLoS One. 10(6):e0130142. doi: 10.1371/journal.pone.0130142.