Bristol Myers Squibb (NYSE: BMY) today announced that the European Commission (EC) has approved Opdivo (nivolumab) in combination with platinum-based chemotherapy for the neoadjuvant treatment of resectable non-small cell lung cancer (NSCLC) at high risk of recurrence in adult patients with tumor cell PD-L1 expression ≥1%....The EC’s decision is based on results from the Phase 3 CheckMate -816 trial, in which three cycles of Opdivo with chemotherapy demonstrated a statistically significant and clinically meaningful improvement in event-free survival (EFS) and pathologic complete response (pCR) compared to chemotherapy alone when administered before surgery.

Bristol Myers Squibb (NYSE: BMY) today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended approval of Opdivo (nivolumab) in combination with platinum-based chemotherapy for the neoadjuvant treatment of resectable non-small cell lung cancer (NSCLC) at a high risk of recurrence in adult patients with tumor cell PD-L1 expression ≥1%....The positive opinion is based on results from the CheckMate -816 trial...

In both cohorts, programmed death ligand 1 expression ≥ 1% and ECOG PS 0-1 were associated with longer OS (P < .05);…

...PD-L1 positivity (HR 0.75; 95%CI 0.60-0.93; P= < .0001) were associated with prolonged survival...real-world overall survival at 2-years was consistent with pivotal nivolumab trials overall and in subgroups.

...-toxicity profile of the combination, the down-staging rate, complete resection rate, time to progression and overall survival, surgical outcome and surgical complications.- Explore the expression of other biomarkers, such as PD-L1, in tumor tissue: at screening and after surgery (resected tumor sample), free DNA and circulating tumor cells in liquid biopsy, describe whether PD-L1 expression is a predictive biomarker for ORR- Describe Progression Free Survival (PFS) in PD-L1+ (>=1%) population- Report imaging response vs pathological response rate El perfil de toxicidad de la combinación, la tasa de estadificación descendente, la tasa de resección completa, el tiempo hasta la progresión y la supervivencia global, el resultado quirúrgico y las complicaciones quirúrgicas.- Explorar la expresión de otros biomarcadores, como PD-L1, en el tejido tumoral: en el cribado y después de la cirugía (muestra de tumor resecada), el ADN libre y las células tumorales circulantes en biopsia líquida, describen si la expresión de PD-L1 es un biomarcador predictivo para ORR- Describa la supervivencia libre de progresión (PFS) en la población PD-L1 + (> = 1%)- Informe de la respuesta de imagen vs tasa de respuesta patológica...

...PD-L1 expression levels - PD-L1 expression levels; PD-L1 expression levels - PD-L1 expression levels; tumor mutation burden - tumor mutation burden; Serum cytokine levels - Serum cytokine levels; Immunotherapy efficacy - Immunotherapy efficacy...

...PFS - PFS; LC - LC; DBF - DBF; OS - OS; relationship of PD-L1 expression and the clinical outcome - relationship of PD-L1 expression and the clinical outcome; QOL - QOL; Cognitive Function - Cognitive Function; Safety - Safety...

...Overall survival (OS)`Progression-free survival (PFS)`Time to next therapy (TTNT)`Best overall response rate (BORR)`Distribution of participant demographics characteristics: Age`Distribution of participant demographics characteristics: Sex`Distribution of clinical characteristics: Smoking status`Distribution of clinical characteristics: ECOG at initial diagnosis and at nivolumab initiation`Distribution of clinical characteristics: Histology`Distribution of clinical characteristics: TNM classification`Distribution of clinical characteristics: Location of metastases`Distribution of clinical characteristics: EGFR mutation`Distribution of clinical characteristics: ALK translocation`Distribution of clinical characteristics: HER2 mutation`Distribution of clinical characteristics: BRAF mutation`Distribution of clinical characteristics: KRAS mutation`Distribution of clinical characteristics: ROS1 mutation`Distribution of clinical characteristics: MET mutation`Distribution of clinical characteristics: PD-L1 expression`Distribution of clinical characteristics: PD-L1 expression on tumor or stromal cells`Incidence of Adverse Drug Reactions`Incidence of Seriousness criteria`Incidence of Intensity/ Grade`Incidence of AE duration`Incidence of Action taken regarding the BMS treatment`Incidence of Incidence rate...

...Progression Free Survival`Overall Survival`Tolerance`Responses rate according to tissue PD-L1 expression`Quality of life measured by LCSS questionnaire`Duration of response`impact on HIV control and immunological, other associated chronic infection susceptible of reactivation and potential occurrence of autoimmunity...

...Objective Response Rate (ORR)`Time To Objective Response (TTOR)`Duration of Objective Response (DOOR)`Progression-Free Survival (PFS)`Percentage of Participants Experiencing Disease-Related Symptom Improvement by Week 12`Overall Survival (OS) by PD-L1 Expression at Baseline`Objective Response Rate (ORR) by PD-L1 Expression at Baseline...

...Maximum response rate of distant non-irradiated disease`Progression-free survival`Correlation between tumor PD-L1 expression and clinical outcomes`Patient quality of life`Neurocognitive function, as measured by the HVLT-R`Neurocognitive function, as measured by TMT`Neurocognitive function, as measured by COWA`Acute and late toxicity of SRS + Nivolumab`Imaging indicators of response...

...Impact on lung function`OS rates in PD-L1 expressers (≥ 1%) and non-expressers (< 1%)`DFS rates in PD-L1 expressers (≥ 1%) and non-expressers (< 1%)`OS rates (squamous and non-squamous)`DFS rates (squamous and non-squamous)`Measuring immune cell responses with treatment...

...The outcome measures of 18F-PD-L1 PET/CT related to the date of the first documented tumor progression as determined by modified RECIST, or death due to any cause`The outcome measures of 18F-PD-L1 PET/CT related to the date of death due to any cause`Correlation between PD-L1 expression measured by 18F-PD-L1 PET/CT and PD-L1 expression measured by IHC...

...Objective Response Rate (ORR) in All Randomized Participants`Time To Response (TTR) in Months for All Confirmed Responders`Duration of Objective Response (DOR) in Months for All Confirmed Responders`Progression Free Survival Rate (PFSR)`Progression-Free Survival (PFS) Time in Months for All Randomized Participants`Percentage of Participants Experiencing Disease-related Symptom Improvement by Week 12`Overall Survival (OS) Time in Months by Baseline PD-L1 Expression for All Randomized Participants`Objective Response Rate (ORR) by Baseline PD-L1 Expression for All Randomized Participants`Progression Free Survival (PFS) Time in Months by Baseline PD-L1 Expression for All Randomized Participants...

...Track 1 = participants naive for prior immuno-oncology (IO) therapy and PD-L1 positive Track 2 = participants naive for prior immuno-oncology (IO) therapy and PD-L1 negative Track 3 = participants with prior anti-PD-1/PD-L1 therapy Track 4 = participants naive for prior anti-PD-1/PD-L1 therapy (established upon enrollment closure of tracks 1,2 and 3) Track 5 = participants with prior anti-PD-1/PD-L1 therapy (established upon enrollment closure of tracks 1,2 and 3). ...

...The positive rate of PD-L1 expression in tumor tissues was detected by immunohistochemistry`PD-L1 expression levels`PD-1 expression levels`Detection of the average number of mutations per megabyte in tumor tissues by NGS`tumor mutation burden`Detect the expression level of cytokines in serum`Serum cytokine levels`Objective Response Rate (ORR) by irRC and RECIST 1.1`Number of participants with treatment-related adverse events as assessed by CTCAE v4.0...

...Overall survival`Progression Free Survival as determined by RECIST 1.1`Mutation load as determined by FoundationOne testing`Incidence of adverse events (AEs) graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03`PD-L1 expression as determined by immunohistochemistry...

...These may include biomarkers which are often studied amongst patients with non-small cell lung cancer such as PD-L1 expression, EGFR and KRAS mutational status but also novel biomarkers relating to effects of radiation on the immune response. ...

...Secondary Endpoints- Frequency of treatment related adverse events of all grades and grade ≥ 3 as per CTCAE v. 4- The proportion of patients receiving at least 1, 2, 3, 4, 5 and 6 doses within 16 weeks of commencing nivolumab after SBRT - Local, loco-regional and distant rates of relapse at 3, 6, 12 and 24 months- Overall survival rate (OS) of the 31 patients at 6, 12 and 24 months- Disease Free Survival (DFS) rate of the 31 patients at 6, 12 and 24 months- Estimation of the health related quality of life (HRQoL) score at each time point of analysis Exploratory Endpoints- Assessment of rates of toxicity within percentage of predicted FEV1 bands- Assessment of rates of toxicity within percentage of predicted DLCO bands- OS and DFS rates in PD-L1 expressers (≥ 1%) and non-expressers (< 1%)- OS and DFS rates in squamous and non-squamous subgroups Analysis of research blood and biopsy samples...

...Progression-Free Survival in Participants With PD-L1 Expression >= 5%...

All patients were treated with a regimen of platinum-based chemotherapy combined with immunotherapy of nivolumab every three weeks and ipilimumab every 6 weeks....Patients whose programmed death ligand-1 (PD-L1) tumor expression level was ≥1% showed a higher median OS than those with PD-L1 expression of less than 1%.

Pts with previously treated, immunotherapy-naive advanced NSCLC received 2.4 mg C-E IM every 2 weeks(w) for 4 doses (loading phase) in combination with N 240mg IV every 2 w, then continued monthly maintenance C-E combined with N 240mg IV every 2 w....Pts with PD-L1 expression ≥1% had higher 3-yr OS [38% (90% CI 12, 63)] and 3-year PFS [38% (90% CI 12, 63)] compared to pts with no PD-L1 expression (3-yr OS 23% [90% CI 8, 44] and 3-yr PFS 8% [90% CI 1, 25]).

Two doses of nivolumab (3 mg/kg) were administered for 4 weeks before surgery to 21 patients with Stage I–IIIA NSCLC....The presence of MPR and pre-treatment tumor PD-L1 positivity (TPS ≥1%) each trended toward favorable RFS; HR, 0.61 [95% confidence interval (CI), 0.15–2.44] and HR, 0.36 (95% CI, 0.07–1.85), respectively.

In the experimental arm, PDL1 expression (≥1%) significantly identified patients with improve PFS (HR: 0.26; 95%CI: 0.08-0.77; P = 0.015). Pathological complete response (pCR) rate was 36.2% in the experimental arm versus 6.8% in the control arm (P = 0.007). None of the patients showing a pCR has progressed or deceased (P LogRank <0.001 and P LogRank= 0.013 for PFS and OS, respectively)....The efficacy of nivolumab in combination with platinum-based chemotherapy in patients with resectable stage IIIA NSCLC is supported by survival data. The benefit is especially observed in patients with tumors with positive PD-L1 expression and in those patients achieving pCR.

...patients of squamous histology and non-squamous histology patients with PD-L1 expression ≥1%...For squamous-NSCLC...Median OS was 8.4 months (95% CI, 7.2‑9.7 months) compared with a median OS of 9.2 months (95% CI: 7.3-12.6 months) in CM017 (Figure 1). The median DOT in SACT was 3.5 months.For non-squamous...Median OS was 9.2 months (CIs not available) compared with 12.21 months (95% CI: 9.7-15.1 months) in CM057 (Figure 2). Median DOT was 4.1 months

...patients with advanced or recurrent NSCLC who received nivolumab every 2 weeks as second or third-line treatment...66% had PD-L1 1% or more expression...disease control rate (DCR) and the objective response rate (ORR) at week 25 were 41.2% (95% CI, 34.9%–47.6%) and 18.5% (95% CI, 13.8–24.0), respectively. Median progression-free survival (PFS) was 3.9 months (95% CI, 3.3–5.5) and overall survival (OS) was 13.0 months (95% CI, 11.4–16.5).

In a patient-level analysis, data were extracted from available trials of durvalumab...Moderate correlations were observed between ΔORR and OS HR: ITT, -0.63; PD-L1-enriched, -0.53. At the patient level, a positive association was observed between PFS and OS in non-small-cell lung cancer (Kendall's Tau=0.793; 95% confidence interval, 0.789-0.797), head-and-neck squamous-cell carcinoma (0.794; 0.789-0.798), and bladder cancer (0.872; 0.869-0.875).

Progression free survival was significantly longer in the patients with 7% or more of PD-L1 positivity rates (n = 8) than in those with less than 7% (n = 8) (p < 0.01) at week 8, suggesting the predictive significance of early evaluation of PD-L1 expression on CTCs after nivolumab treatment.

The median PFS was significantly higher in RAD51Bme+ patients (p = 0.0216; Figure 3A). Furthermore, patients with RAD51Bme+ disclosed a lower risk of disease progression (HR 0.37; 95% CI: 0.15–0.88; p = 0.025) compared with RAD51Bme-….PD-L1+ and RAD51Bme+ are promising biomarkers to predict response to PD-1 blockade rather than overall prognostic factors in NSCLC’s patients.

Pts received by nivolumab (87.2%), pembrolizumab (7.7%) or atezolizumab (5.1%)….PD-L1 status was assessed in 18 tumours (46.1%). In PDL1+ pts, ORR was 53.3% (8/15) and DCR was 66.7% (10/15).

Overall, the three antibodies provide a significant differential effect in terms of activity according to PD-L1 expression on tumor cells. The predictive value of PD-L1 on tumor cells seems to be more robust for anti-PD-1 antibody (nivolumab and pembrolizumab), and in the context of advanced melanoma and NSCLC.

Our case report demonstrated a full response to first-line Nivolumab in a patient with PD-L1-positive NSCLC having visceral and brain metastases.