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TG4010 immunotherapy plus chemotherapy as first-line treatment of advanced non small cell lung cancer (NSCLC): Phase IIb results of the TIME trial
  1. John Nemunaitis1,
  2. Zsolt Papai2,
  3. Hervé Léna3,
  4. Gyorgy Losonczy4,
  5. Frederic Forget5,
  6. Christos Chouaid6,
  7. Alexandra Szczesna7,
  8. Radj Gervais8,
  9. Christian H Ottensmeier9,
  10. Joseph Beck10,
  11. Andrzej Kazarnowicz11,
  12. Virginie Westeel12,
  13. Didier Debieuvre13,
  14. Anne Madroszyk14,
  15. Enriqueta Felip15,
  16. Jean Marc Limacher16 and
  17. Elisabeth Quoix17
  1. Aff1 grid.416487.80000000404554449Mary Crowley Medical Research Center Dallas TX USA
  2. Aff2 Fejer Megyei Szent Gyorgy Korhaz Szekesfehervar Hungary
  3. Aff3 grid.414271.5Hôpital Pontchaillou Rennes France
  4. Aff4 grid.11804.3c0000000109429821Semmelweis Egyetem AOK Budapest Hungary
  5. Aff5 Centre Hospitalier de l'Ardenne Libramont Belgium
  6. Aff6 grid.414145.10000000417652136Centre Hospitalier Intercommunal de Créteil Créteil France
  7. Aff7 Mazowieckie Centrum Leczenia Chorob Pluc i Gruzlicy Otwock Poland
  8. Aff8 grid.418189.d0000000121751768Centre François Baclesse Caen France
  9. Aff9 grid.430506.4Southampton University Hospitals NHS Trust Southampton UK
  10. Aff10 grid.492660.f0000 0004 0633 1919Highlands Oncology Group Fayetteville AZ USA
  11. Aff11 SP Zespol Gruzlicy i Chorob Pluc w Olsztynie Olsztyn Poland
  12. Aff12 grid.411158.80000000406389213CHU de Besancon Hopital Jean Minjoz Besançon France
  13. Aff13 grid.414085.c000000009480048XCH Mulhouse Hopital Emile Muller Moenchsberg Mulhouse France
  14. Aff14 grid.418443.e0000000405984440Institut Paoli Calmettes Marseille France
  15. Aff15 grid.411083.f0000000106758654Vall d'Hebron University Hospital Barcelona Spain
  16. Aff16 grid.420228.e0000 0004 0638 2273Transgene S.A. Illkirch France
  17. Aff17 grid.413866.e0000000089286711Nouvel Hôpital Civil Strasbourg France

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Meeting abstracts


TG4010 is an immunotherapy using an attenuated and modified poxvirus (MVA) coding for MUC1 and interleukin-2 to induce a cellular immune response against MUC1 expressing tumors. Previous Phase 2 trials have demonstrated the efficacy and safety of TG4010 in combination with chemotherapy. In addition, level of Triple Positive Activated Lymphocytes (TrPAL; CD16+, CD56+, CD69+) was identified as a potential biomarker predictive of efficacy


TIME is a double blind, placebo-controlled Phase IIb/III study. The Phase IIb part compared first-line chemotherapy combined with TG4010 or placebo and further assessed the predictive value of baseline level of TrPAL. Eligibility criteria included previously untreated stage IV NSCLC, MUC1+ tumor by immunohistochemistry, PS ≤1. TG4010 (108 pfu) or placebo was given SC weekly for 6 weeks (w), then every 3w up to progression, in combination with chemotherapy. Primary endpoint was progression-free survival (PFS) and secondary endpoints were response rate (ORR), duration of response, survival (OS), safety and subgroup analyses according to histology and level of TrPAL. (NCT01383148).


222 pts were randomized 1:1. In pts with normal TrPAL the study met its primary endpoint with a probability >95% that the PFS HR is < 1 in pts treated with TG4010. Preplanned subgroup analyses were performed using an optimal cut-off value for the level of TrPAL defining 2 subpopulations (low and high TrPAL). In 147 patients with low TrPAL, PFS was significantly increased in TG4010 arm (HR=0.66 [CI95% 0.46-0.94] p= 0.010) as well as OS (HR=0.67 [CI95%0.46-0.98) p=0.018) while there was no benefit in pts with high TrPAL. Activity was even more important in patients with low TrPAL and non-squamous tumor (n=127) with PFS HR =0.59 (CI95% 0.40-0.87; p=0.003), and OS HR=0.59 (CI95% 0.39-0.91; p=0.007). In this subgroup, ORR was 39.3% vs 30.3% and duration of response 43.1 vs 18.1weeks in TG4010 and placebo arms, respectively. TG4010 related adverse events were mainly low-grade injection site reactions. The impact of PDL1 expression by immunohistochemistry in the tumor of patients treated with TG4010 supports the activity of TG4010 whether the tumor is positive or negative for PDL1 expression.


These results provide further evidence of the efficacy of TG4010 in combination with chemotherapy in NSCLC and of the potential of TrPAL as a predictive biomarker. Future development of TG4010 is being planned, both in combination with chemotherapy (Phase 3 part of the TIME trial) and in combination with immune checkpoint inhibitors.

Trial registration identifier NCT01383148.