Innovation

Optimization of neo-epitopes is based on the double detection of HLA-A2 (Major Histocompatibility Complex molecule or MHC) and TCR receptors. The two families of epitopes are then combined (those strongly bound to HLA-A2 and those strongly bound to TCR receptors) for an increased cytotoxic T response and for an activation of immune response.

Main references to Tedopi® and recent treatment options in lung cancer

  1. Barve M, Bender J, Senzer N, Cunningham C, Greco FA, McCune D, Steis R, Khong H, Richards D, Stephenson J, et al. ;Induction of immune responses and clinical efficacy in a phase II trial of IDM-2101, a 10-epitope cytotoxic T-lymphocyte vaccine, in metastatic non-small-cell lung cancer; J Clin Oncol. 2008;26(27):4418‑25. doi: 10.1200/JCO.2008.16.6462.
  2. Beebe M, Qin M, Moi M, Wu S, Heiati H, Walker L, Newman M, Fikes J, Ishioka GY. Formulation and characterization of a ten-peptide single-vial vaccine, EP-2101, designed to induce cytotoxic T-lymphocyte responses for cancer immunotherapy ; Hum Vaccin. 2008;4(3):210‑8.
  3. Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Arén Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR. ; Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer ; N Engl J Med. 2015;373(2):123-35. doi: 10.1056/NEJMoa1504627.
  4. Brown S.D., Rene L. Warren, Ewan A. Gibb, Spencer D. Martin, John J. Spinelli, Brad H. Nelson, and Robert A. Holt, Genome Res. 2014. 24: 743-750 © 2014.; Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival.
  5. Bulut I, Meral M, Kaynar H, Pirim I, Bilici M, Gorguner M.
    Analysis of HLA class I and II alleles regarding to lymph node and distant metastasis in patients with non-small cell lung cancer. Lung Cancer. 2009;66(2):231‑6.
  6. Ciuleanu T, Stelmakh L, Cicenas S, Miliauskas S, Grigorescu AC, Hillenbach C, Johannsdottir HK, Klughammer B, Gonzalez EE.
    Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomised multicentre, open-label, phase 3 study.
    Lancet Oncol. 2012;13(3):300‑8. doi: 10.1016/S1470-2045(11)70385-0.
  7. Ford CH, Newman CE, Mackintosh P ; HLA frequency and prognosis in lung cancer ; Br J Cancer, 81;43(5):610‑4.
  8. Garassino MC, Martelli O, Broggini M, Farina G, Veronese S, Rulli E, Bianchi F, Bettini A, Longo F, Moscetti L, Tomirotti M, Marabese M, Ganzinelli M, Lauricella C, Labianca R, Floriani I, Giaccone G, Torri V, Scanni A, Marsoni S; TAILOR trialists ; Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial ; Lancet Oncol. 2013;14(10):981‑8. doi: 10.1016/S1470-2045(13)70310-3.
  9. Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L, Carcereny E, Ahn MJ, Felip E, Lee JS, Hellmann MD, Hamid O, Goldman JW, Soria JC, Dolled-Filhart M, Rutledge RZ, Zhang J, Lunceford JK, Rangwala R, Lubiniecki GM, Roach C, Emancipator K, Gandhi L; KEYNOTE-001 Investigator; ; N Engl J Med. 2015;372(21):2018-28. doi: 10.1056/NEJMoa1501824.
  10. Grenga I. et al., Journal for ImmunoTherapy of Cancer 2014
  11. Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, Gatzemeier U, Tsao TC, Pless M, Muller T, Lim HL, Desch C, Szondy K, Gervais R, Shaharyar, Manegold C, Paul S, Paoletti P, Einhorn L, Bunn PA Jr.
    Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004;22(9):1589‑97.
  12. Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z,Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975-2012, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2012/, based on November 2014 SEER data submission, posted to the SEER web site, April 2015
  13. Kleponis J. et al, Fueling the engine and releasing the break: combinational therapy of cancer vaccines and immune checkpoint inhibitors – Cancer Biol Med. 2015
  14. Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, Sebastian M, Neal J, Lu H, Cuillerot JM, Reck M., Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study.
    J Clin Oncol 2012; 30(17): 2046-54. doi: 10.1200/JCO.2011.38.4032.
  15. McGranahn M et al., Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade, Science 2016
  16. Masucci GV, Andersson E, Villabona L, Helgadottir H, Bergfeldt K, Cavallo F, et al. Survival of the fittest or best adapted: HLA-dependent tumor development. J Nucleic Acids Investig [Internet]. 1 mars 2010 [Accessed 23 sept 2013];1(1). Available at: http://www.pagepress.org/journals/index.php/jnai/article/view/1654.
  17. Minn A J et al., Combination Cancer Therapies with Immune Checkpoint Blockade: Convergence on Interferon Signaling- Cell 2016
  18. Nagata Y, Hanagiri T, Mizukami M, Kuroda K, Shigematsu Y, Baba T, Ichiki Y, Yasuda M, So T, Takenoyama M, Sugio K, Nagashima A, Yasumoto K ; linical significance of HLA class I alleles on postoperative prognosis of lung cancer patients in Japan. Lung Cancer. 2009;65(1):91‑7. doi: 10.1016/j.lungcan.2008.10.012.
  19. Nemunaitis J, Cunningham, C ,Bender, J, Ishioka, G, Maples, P, Pappen, B, Stephenson, J, Morse, M, Mills, B, Greco, A, McCune, D, Steis, R, Nugent, F, Khong, HT, Richards, D. Phase II trial of a 10-epitope CTL vaccine, IDM-2101, in metastatic NSCLC patients: Induction of immune responses and clinical efficacy.
    International Society for Biological Therapy of Cancer 2007, p 891-2.
  20. Nemunaitis J, Nemunaitis M, Senzer N, Snitz P, Bedell C, Kumar P, Pappen B, Maples PB, Shawler D, Fakhrai H.
    Phase II trial of Belagenpumatucel-L, a TGF-beta2 antisense gene modified allogeneic tumor vaccine in advanced non small cell lung cancer (NSCLC) patients. Cancer Gene Ther. 2009;16(8):620-4. doi: 10.1038/cgt.2009.15.
  21. Nemunaitis J. et al, T-cytotoxic specific immunotherapy in NSCLC with brain metastases. P2.01-003 – Abstract 1202 16th world conference on lung cancer, September 2015
  22. Paz-Ares L, Horn L, Borghaei H, Spigel DR, Steins M, Ready N, Quan Man Chow L, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhaeufl M, Rodriguez O, Burgio MA, Fayette J, Gettinger SN, Harbison C, Dorange C, Graf Finckenstein F, Brahmer JR.
    Phase III, randomized trial (CheckMate 057) of nivolumab (NIVO) versus docetaxel (DOC) in advanced non-squamous cell (non-SQ) non-small cell lung cancer (NSCLC). J Clin Oncol 33; 2015 (suppl; abstr LBA109).
  23. Reck M, Popat S, Reinmuth N, De Ruysscher D, Kerr KM, Peters S; ESMO Guidelines Working Group.
    Metastatic non-small-cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25 Suppl 3:iii27-39. doi: 10.1093/annonc/mdu199.
  24. Rizvi N, Brahmer J, Ou SH et al. ; Safety and clinical activityof MEDI4736, an anti-programmed cell death-ligand (PD-L1) antibody in patients with non-small-cell lung cancer ; J Clin Oncol 2015; 33 (suppl; abstr 8032)
  25. Rizvi NA, Garon E, Leighl N et al. ; Optimizing PD-L1 as biomarker of response with pembrolizumab as first-line therapy for PD-L1 positive metastatic non-small cell lung cancer: updated data from KEYNOTE-001.
    J Clin Oncol 2015; 33 (suppl; abstr 8026)
  26. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, Martins R, van Kooten M, Dediu M, Findlay B, Tu D, Johnston D, Bezjak A, Clark G, Santabárbara P, Seymour L; National Cancer Institute of Canada Clinical Trials Group ; Erlotinib in Previously Treated Non–Small-Cell Lung Cancer ; N Engl J Med. 2005;353(2):123‑32.
  27. So T, Takenoyama M, Sugaya M, Yasuda M, Eifuku R, Yoshimatsu T, Osaki T, Yasumoto K ; Unfavorable prognosis of patients with non-small cell lung carcinoma associated with HLA-A2. Lung Cancer ; 2001;32(1):39‑46.
  28. Spira AI, Park K, Mazières J et al. ; Efficacy, safety and predictive biomarkers results from a randomized phase II study comparing MPDL3280A vs docetaxel in 2/3L NSCLC (POLAR) ; J Clin Oncol 2015; 33 (suppl; abstr 8010)
  29. Strauss J et al., Considerations for the combination of anticancer vaccines and immune checkpoint inhibitors- Expert Opin Biol Ther 2016
  30. Yadav M. et al, Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing. Nature vol 515, Nov 2014

Tedopi Phase 3

Atalante 1, an international registration Phase 3 trial currently ongoing

The Atalante 1 trial is being conducted in a total of 70 expert investigational sites in Europe and in the United States, and will include 500 patients. The study initiated in early 2016 and is expected to be completed in 2018, provided that the recruitment of patients, their observed survival and the safety of the product meet the strict criteria set for this study.
This study is aiming to evaluate the benefits of Tedopi® as compared to current standard chemotherapies (docetaxel or pemetrexed, both approved second line therapies). Tedopi® is administered as a second-line (after failure of platinium based therapy) or third-line (after failure of immune checkpoint inhibitors) treatment in HLA-A2 positive patients; HLA-A2 is a key receptor for the cytotoxic T-immune response in those patients diagnosed with stage IIIB (locally advanced) or IV (metastatic) NSCLC. The primary endpoint of Atalante1 is overall survival. Phase 2 results with Tedopi® have shown highly promising efficacy and an increase in survival duration alongside a good safety profile.

On June 23, 2017, OSE Immunotherapeutics announced that following the recommendation by IDMC (independent experts) on this phase 3 clinical study, the Company is temporarily pausing patient accrual while continuing treatment for patients already enrolled in order to further assess the study’s current patient profile in relation to the potential benefit of Tedopi® with more mature data (view the press release).

Atalante 1 is being conducted internationally by a steering committee co-chaired by two clinical experts specializing in lung cancer treatments ; in Europe, by Dr. Benjamin Besse, Head of the Thoracic Pathology Committee at the Institut Gustave Roussy (Villejuif), and ; in the United States by Giuseppe Giaconne, Professor of Oncology, Medicine and Pharmacology at the Georgetown Lombardi Comprehensive Cancer Center in Washington. Of the 500 patients to be included in the clinical trial, approximately 80% will be recruited by European clinical centers, and the remaining 20% by U.S. centers.

Tedopi®

Recommended as a second- or third line therapy, after at least one first line failure
Launch of the Atalante 1 study
Study initiated in January 2016
Results
Results expected in 2018 (provisional timetable)
Design of the study
– 500 patients in Europe and the U.S.

– Comparison of Tedopi® to current therapeutic standards, docetaxel or pemetrexed (benchmark chemotherapeutic agents of second line therapies)

Population (inclusion criterias)
– Patients with lung cancer NSCLC, at invasive stage IIIb or metastatic stage IV, after at least one first line failure

– Patients expressing the HLA-A2 positive receptor (45% of the population), responding to Tedopi®

Primary endpoint
Overall survival
Secondary endpoints
– Progression-free survival of the disease (PFS)
– Quality of life (QOL)
– Overall response rate (ORR)
– Tolerance
Principal Investigators
Benjamin Besse, IGR Paris
Giuseppe Giaccone,
NIH Washington