Ono Pharmaceutical Co., Ltd...announced that Ono Pharma Taiwan Co., Ltd. (“OPTW”), a Taiwanese subsidiary of ONO, received the approval of Opdivo® (nivolumab)...from the Taiwan Food and Drug Administration (TFDA) in Taiwan for additional indication of the first-line treatment of advanced or recurrent non-small cell lung cancer with no EGFR or ALK genomic tumor aberrations, in the following combination therapies:...Combination therapy with Opdivo and Yervoy* (tumors express PD-L1 ≧1%)...

Ono Pharmaceutical Co., Ltd...announced that Ono Pharma Korea Co., Ltd. (“OPKR”), a Korean subsidiary of ONO, received approval of Opdivo® (generic name: nivolumab) intravenous Infusion...Combination therapy with Opdivo and Yervoy* (tumors express PD-L1 ≧1%)

Ono Pharmaceutical Co., Ltd. (Osaka, Japan; President, Representative Director, Gyo Sagara; “ONO”) and Bristol-Myers Squibb K.K. (Shinjuku, Tokyo; President, Jean-Christophe Barland; “BMSKK”) today announced that the companies have received approval in Japan for the following combination therapies of Opdivo® (generic name: nivolumab) intravenous Infusion (“Opdivo”), a human anti-programmed death-1 (PD-1) monoclonal antibody, and Yervoy® (generic name: ipilimumab) Injection (“Yervoy”), a human monoclonal antibody against cytotoxic T-lymphocyteassociated antigen 4 (CTLA-4) for the first-line treatment of unresectable, advanced or recurrent nonsmall cell lung cancer, for a partial change in approved items of the manufacturing and marketing approval in Japan. These approvals are based on the results from...CheckMate -227...CheckMate -9LA study...

OPDIVO is a programmed death receptor-1 (PD-1) blocking antibody indicated for the treatment of...adult patients with metastatic non-small cell lung cancer expressing PD-L1 (≥1%) as determined by an FDA approved test, with no EGFR or ALK genomic tumor aberrations, as first-line treatment in combination with ipilimumab.

PD-L1 expression positive (≥1%-49%)…Adenocarcinoma, large cell, NSCLC NOS…other recommended...Nivolumab + ipilimumab + pemetrexed + (carboplatin or cisplatin)

PD-L1 expression positive (≥1%-49%)…Adenocarcinoma, large cell, NSCLC NOS…useful in certain circumstances...Nivolumab + ipilimumab

Patients with tumor PD-L1 ≥1% were randomized to nivolumab plus ipilimumab, nivolumab, or chemotherapy….In patients with baseline brain metastases, 5-year systemic and intracranial PFS rates were higher with nivolumab plus ipilimumab (12% and 16%, respectively) than chemotherapy (0% and 6%). Fewer patients with baseline brain metastases developed new brain lesions with nivolumab plus ipilimumab (4%) versus chemotherapy (20%). No new safety signals were observed....With all patients off immunotherapy for ≥3 years, nivolumab plus ipilimumab continued to provide long-term, durable survival benefit in patients with or without brain metastases. Intracranial efficacy outcomes favored nivolumab plus ipilimumab versus chemotherapy.

...OS remained longer with nivolumab plus ipilimumab versus chemotherapy in patients with PD-L1 ≥1% (HR 0.76; 95% CI: 0.65-0.90) and PD-L1 <1% (0.64; 0.51-0.81); 4-year OS rate with nivolumab plus ipilimumab versus chemotherapy was 29% versus 18% (PD-L1 ≥1%); 24% versus 10% (PD-L1 <1%)....At >4 years' minimum follow-up, with all patients off immunotherapy treatment for ≥2 years, first-line nivolumab plus ipilimumab continued to demonstrate durable long-term efficacy in patients with advanced NSCLC.

...1150 patients were enrolled and 719 (62·5%) randomly assigned to nivolumab plus ipilimumab...Randomisation was stratified by tumour histology, sex, and PD-L1 expression.….overall survival in all randomly assigned patients was significantly longer in the experimental group than in the control group (median 14·1 months [95% CI 13·2–16·2] vs 10·7 months [9·5–12·4]; hazard ratio [HR] 0·69 [96·71% CI 0·55–0·87]; p=0·00065).

NIVO 360 mg Q3W + IPI 1 mg/kg Q6W + chemo (2 cycles) (n = 361) or chemo (4 cycles) alone (n = 358), stratified by PD-L1 (< 1% vs ≥1%)… OS was significantly prolonged with NIVO + IPI + chemo vs chemo (HR 0.69, 96.71% CI: 0.55–0.87; P = 0.0006); statistically significant improvements in PFS and ORR were seen.

Overall ICI in combination improved survival across PD-L1 expression level subgroups compared with chemotherapy (platinum doublets +/- bevacizumab). Indirect comparisons of ICIs in combination therapy for first-line treatment in advanced non-squamous NSCLC showed little evidence of differences between pembrolizumab or atezolizumab in combination with chemotherapy and nivolumab/ipilimumab. 

In an exploratory analysis of patients whose tumors expressed PD-L1 <1%, Opdivo plus Yervoy demonstrated three-year OS rates of 34%, compared to 15% for chemotherapy alone (HR: 0.64; 95% CI: 0.51 to 0.81)….The addition of Yervoy to Opdivo also continued to show benefit compared to Opdivo monotherapy in patients whose tumors expressed PD-L1 ≥1% and compared to Opdivo plus chemotherapy in those with PD-L1 <1% with a minimum of three years of follow-up.

With longer follow-up (minimum 12.7 mo), NIVO + IPI + chemo vs chemo continued to provide longer OS; median 15.6 vs 10.9 mo (HR 0.66, 95% CI: 0.55–0.80); 1-y OS rates were 63 vs 47%. Clinical benefit was consistent across all efficacy measures in key subgroups including by PD-L1 and histology.

At 3 y, 18% of pts with PD-L1 ≥ 1% treated with NIVO + IPI remained progression-free vs 12% with NIVO and 4% with chemo; 38% of confirmed responders remained in response in the NIVO + IPI arm at 3 y vs 32% in the NIVO arm and 4% in the chemo arm. In pts with PD-L1 < 1%, OS HR for NIVO + IPI vs chemo was 0.64 (95% CI, 0.51–0.81); 3-y OS rates were 34% (NIVO + IPI), 20% (NIVO + chemo), and 15% (chemo); 13%, 8%, and 2% of pts remained progression-free; and 34%, 15%, and 0% of confirmed responders remained in response, respectively.

First-line treatment with nivolumab plus ipilimumab resulted in a longer duration of overall survival than did chemotherapy in patients with NSCLC, independent of the PD-L1 expression level.

...Subjects must have programmed death-ligand 1 (PD -L1) immunohistochemical (IHC) testing, with results, performed by the central lab during the Screening period...

...Participants must have PD-L1 IHC testing with results performed by a central laboratory during the screening period. Objective Response Rate (ORR) by BICR by PD-LI Tumor Cell Expression...PD-L1 expression was defined as the percent of tumor cells with membrane staining in a minimum of 100 evaluable tumor cells per validated Dako PD-L1 IHC 28-8 pharmDx test. PD-L1 expression was classified as PD-L1 ≥1% (≥1% tumor cells with membrane staining in a minimum of a hundred evaluable tumor cells), PD-L1 < 1% and PD-L1 not quantifiable (without quantifiable PD-L1 expression), PD-L1 expression ≥ 50%, PD-L1 expression 1 to 49%. PFS by BICR by PD-L1 Tumor Cell Expression...OS by PD-L1 Tumor Cell Expression...

...Objective response rate (ORR)...In all treated PD-L1 positive (≥ 1%)...ORR...In all treated PD-L1 negative (< 1%)...

In the dual group, patients with PD-L1 TPS 0-20% had significantly longer PFS (10.5 months (5.0-NA) vs. 4.1 months (0.23-NA), p=0.017) and OS (NA months (18.6-NA) vs. 9.0 months (0.23-NA), p=0.0014) than those with PD-L1 TPS 21-49%....The results suggest that nivolumab and ipilimumab-based therapy may be a better treatment option, especially for patients with negative and lower PD-L1 TPS (<20%).

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%.

NON-SUPPORTIVE EVIDENCE: Adult patients (pts) with stage IV / recurrent NSCLC, ECOG performance status ≤ 1, and no known sensitizing EGFR/ALK alterations were stratified by PD-L1 (< 1% vs ≥ 1%)…2-year OS rates were 38% vs 26%. Median PFS with NIVO + IPI + chemo vs chemo was 6.7 months vs 5.3 months (HR, 0.67 [95% CI, 0.56–0.79])...ORR was 38% with NIVO + IPI + chemo vs 25% with chemo. Similar clinical benefit with NIVO + IPI + chemo vs chemo was observed in all randomized pts and across the majority of subgroups, including by PD-L1 expression level...

NON SUPPORTIVE EVIDENCE: Pts with PD-L1 ≥ 1% continued to show durable benefit with NIVO + IPI vs chemo (HR, 0.76 [95% CI, 0.65–0.90]); 4-year OS rates were 29% (NIVO + IPI), 21% (NIVO), and 18% (chemo). At 4 years, 14% (NIVO + IPI), 10% (NIVO), and 4% (chemo) remained progression free....In pts with PD-L1 < 1%, OS HR for NIVO + IPI vs chemo was 0.64 (95% CI, 0.51–0.81); 4-year OS rates were 24% (NIVO + IPI), 13% (NIVO + chemo) and 10% (chemo)....With 4 years’ minimum follow-up, 1L NIVO + IPI continued to provide durable, long-term OS benefit vs chemo in pts with advanced NSCLC regardless of PD-L1 expression or histology.

CheckMate 227 Part 1 (NCT02477826) enrolled pts who were chemo-naive with stage IV / recurrent NSCLC….After a minimum follow-up of 37.7 months (database lock, 28 Feb 2020), response rates (PD-L1 ≥ 1% and < 1%) were 33.4% with NIVO + IPI vs 28.0% with chemo....In 1L advanced NSCLC, pts treated with NIVO + IPI had a higher chance of achieving deeper responses than those treated with chemo.

A total of 121 Asian pts were randomized to NIVO + IPI and 124 to chemo; baseline characteristics were generally balanced between arms…Median progression-free survival (PFS) was 11.0 mo with NIVO + IPI vs 6.7 mo with chemo (HR, 0.64 [95% CI, 0.43–0.95])...Among all randomized Asian pts (PD-L1 ≥ 1% + < 1%), improved efficacy with NIVO + IPI vs chemo was also observed...

For patients with tumor PD-L1 level of ≥1%, pooled meta-analyses showed that both N-I and PEM improved overall survival (OS) relative to chemotherapy (N-I: hazard ratio [HR] 0.82, 95% CI 0.69-0.97; PEM: HR 0.81, 95% CI 0.71-0.93); whereas only N-I significantly improved progression-free survival (PFS) (N-I: HR 0.79, 95% CI 0.65-0.96; PEM: HR 1.07, 95% CI 0.94-1.21)....N-I and PEM provide comparable OS benefit for PD-L1-positive NSCLC. N-I further improves PFS relative to PEM but at meaningful cost of toxicities.

Of treated patients with tumor available for testing, 252 patients (88%) of 288 were evaluable for PD-L1 expression and 98 patients (82%) of 120 for TMB. ORR was 30% overall and 41% and 15% in patients with 1% or greater and less than 1% tumor PD-L1 expression, respectively.