9.1 mo., HR 0.86, 95%CI 0.75 -0.98, p=0.023), PFS (4.5 mo. Vs. 3 mo., HR 0.76, 95%CI 0.68 -0.86, p<0.0001) and overall response rate (ORR: 23% vs. 14%, p <0.001), without detrimental effect on quality of life. Ramucirumab has been approved in this indication by FDA but not by EMA (as of April 2015). Immunotherapeutic approach has been tested in the treatment of NSCLC. Several Immune checkpoint inhibitors (ICIs) exist (such as CTLA -4 and programmed death 1 (PD -1) receptor) which dampen the T -cell immune response to antigens expressed by tumor cells. Checkpoint OSE2101 Protocol OSE2101C301 Confidential Version n°6.0 Page 28 of 101 02 February 2022 inhibition with Ipilimumab, a monoclonal antibody against CTLA -4, has been tested in NSCLC and reported a significant improvement in immune -related PFS compared to pl acebo when administered concomitantly with chemotherapy ( 47). The PD -1 receptor is another checkpoint molecule expressed on activated T cells and e ngaged by ligands PD -L1 and PD -L2, which are expressed by tumor cells and infiltrating immune cells. Tumor PD -L1 expression is prevalent in NSCLC, and the interaction of PD -1 with the PD -L1 and PD -L2 ligands inhibits T -cell activation and promotes tumor i mmune escape. In 2015 , two randomized Phase III trials have reported the efficacy of nivolumab, a fully human IgG4 monoclonal antibody antiPD -1, in advanced NSCLC patients who had disease progression during or after first -line chemotherapy . In squamous NSC LC subtype, 272 patients were randomized to nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks). Nivolumab reported a significant improvement in OS over docetaxel (9.2 months vs. 6 months, p<0.001), with 1 -y OS of 42% versus 24%, respectively. The response rates were also significantly improved with nivolumab compared with docetaxel, 20% vs. 9%, respectively (p=0.008) ( 10). Nivolumab has been approved by FDA and EMA for 2nd line treatment of stage IV squamous cell NSCLC following results of this trial. In the second Phase III trial, 582 non -squamous patients were randomized to nivolumab or docetaxel at the same schedule. Nivol umab significantly improved OS (12.2 months vs. 9.4 months, p= 0.0015), 1-yOS (51% vs. 39%) and median duration of response (17.1 months vs. 5.6 months) compared to docetaxel, respectively ( 60). In both trials the toxicity profile was in favor of nivolumab. Of note, in squamous subtype, the expression PD -L1 was neither prognostic nor predictive of benefit with nivolumab. However, in non -squamous histo logy, PD -L1 expression was a predictive marker of efficacy of nivolumab. The full results of this trial ( 8) led to approval of Nivolumab by FDA in non -squamous NSCL C as well. These results reinforce immunotherapy as a new strategy in the treatment of NSCLC patients. Other ICIs have been tested in NSCLC. Pembrolizumab, an anti -PD1 inhibitor, has been tested in a phase I study in advanced NSCLC patients. Pembrolizumab reported an objective response rate of 19.4% with a median duration of response of 12.5 months, with an acceptab le toxicity profile. In those patients with high expression of PD -L1 (expression in at least 50% of tumor cells) the response rate was 45.2% with a median PFS of 6.3 months, suggesting that the expression of PD -L1 correlated with improved the efficacy of p embrolizumab ( 26). The updated results of this trial in 101 treatment -naïve PD -L1+ NSCLC patients reported an ORR of 24% and a median PFS of 6 month s with no significant between -dose differences, with the greatest efficacy observed in patients with PD -L1 staging in ≥ 50% of tumor cells ( 70). Pr eliminary results of pembrolizumab in a Phase II trial in 10 advanced NSCLC patients with untreated asymptomatic brain metastasis has reported a 44% and 34% of brain and systemic response rate, respectively ( 31). The results of the Keynote 010 trial led to approval of pembrolizumab in patients with NSCLC with PD -L1 expression on at least 1% of tumor cells as both dose s tested improved OS over docetaxe l with a favorable benefit risk ratio ( 36). Two anti -PD-L1 antibodies, atezolizumab (MPDL3280A) and durvalumab (MEDI4736), have been tested in NSCLC. Updated resu lts of atezolizumab in a phase I trial with 88 advanced NSCLC patients, reported an ORR of 21%, with a median duration of response of 67 weeks and 1-year OS of 82%. PD -L1 expression in the tumor microenvironment appeared to be a OSE2101 Protocol OSE2101C301 Confidential Version n°6.0 Page 29 of 101 02 February 2022 predictive biomarker for M PDL3280 clinical efficacy ( 38). In a single arm Phase II study in 205 PD-L1 selected patients with NSCLC, atezolizumab have reported clinical efficacy in both chemo -naïve and previously treated patients (ORR 29% and 17%, respectively) and some evidence of clinical efficacy in previously treated patients with as ymptomatic brain metastases (75). In a randomized Phase II trial (POLAR study) with 287 previously treated NSCLC patients, atezolizumab has been co mpared to docetaxel. Atezolizumab has reported a trend toward OS improvement (11.4 months vs. 9.5 months, HR 0.77; 95 CI 0.55 -1,06, p=0.11) with an improved overall survival benefit observed with increasing PD -L1 expression ( 76). The complete results of the POPLAR study were published later by Fehrenbacher et al ( 19). Eventually the OAK Phase III study in 2nd or 3rd line therapy of advanced NSCLC showed improved median OS (13.8 vs 9.6 months) with atezolizumab compared to docetaxel ( 68). In 198 NSCLC patients, MEDI4736 administered at 10 mg/kg IV every 2 weeks until unacceptable toxicity, disease progression, or for up to 12 months, has reported an ORR of 16% (27% in PD -L1+ and 5% in PD -L1-), and DCR at 12 weeks of 42%. The ORR was higher in squamous (21%) than non -squamous (13%) patients. The duration of response ranged from 0.1 to 54.4 weeks. Preliminary OS data suggests that PD -L1+ patients appear to have improved OS compared with patients with PD -L1- tumors (NA vs. 8.