Date: 2016-06-04
Type of
information: Presentation of results at a congress
phase: 1b
Announcement: presentation of results at the American Society of Clinical Oncology (ASCO) annual meeting, in Chicago
Company: BMS (USA - NY)
Product: Opdivo® (nivolumab)+Yervoy® (ipilimumab)
Action
mechanism:
- monoclonal antibody/immune checkpoint inhibitor . Nivolumab is an investigational, fully-human PD-1 immune checkpoint inhibitor that binds to the checkpoint receptor PD-1 (programmed death-1) expressed on activated T-cells. PD-1, a receptor expressed on the surface of lymphocytes, plays a role in a regulatory pathway that suppresses activated lymphocytes in the body. Available evidence suggests that cancer cells exploit this pathway to escape from immune responses. Opdivo® is thought to provide benefit by blocking PD-1-mediated negative regulation of lymphocytes (i.e., the interaction of PD-1 with its ligands PD-L1 and PD-L2), thereby enhancing the ability of the immune system to recognize cancer cells as foreign and eliminate them. Opdivo® is the world’s first approved drug targeting PD-1. This monoclonal antibody has been generated under a research collaboration entered into in May 2005 between Ono and Medarex. When Medarex was acquired by BMS in 2009, it also granted BMS its rights to develop and commercialize the anti-human PD-1 monoclonal antibody in North America. Through the collaboration agreement entered into in September 2011 between Ono and BMS, Ono granted BMS exclusive rights to develop and commercialize Opdivo® in the rest of the world, except in Japan, Korea and Taiwan where Ono has retained all rights to develop and commercialize the compound.
- Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a negative regulator of T-cell activation. Ipilimumab binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation. The mechanism of action of ipilimumab’s effect in patients with melanoma is indirect, possibly through T-cell mediated anti-tumor immune responses.
Disease: non-small cell lung cancer
Therapeutic
area: Cancer - Oncology
Country: Canada, USA
Trial
details:
- This phase 1 study is evaluating the safety and tolerability of Nivolumab (BMS-936558) when combined with three platinum-based doublet chemotherapy regimens (cisplatin/gemcitabine; cisplatin/pemetrexed; and carboplatin/paclitaxel) in subjects with NSCLC. - The study is evaluating the safety and tolerability of nivolumab as maintenance therapy in combination with bevacizumab/Avastin that will be given after at least 4 cycles of platinum doublet chemotherapy. - The study is evaluating the safety and tolerability of nivolumab in combination with erlotinib among epidermal growth factor receptor (EGFR) mutation positive non-squamous NSCLC subjects and as monotherapy in subjects with NSCLC. - The study is evaluating the safety and tolerability of nivolumab in combination with ipilimumab in subjects with squamous and non-squamous NSCLC.In the study, patients were tested for PD-L1 expression and 68% of patients in the Q12W cohort and 77% of patients in the Q6W cohort expressed PD-L1. Exploratory endpoints included overall survival (OS) and efficacy by PD-L1 expression. (NCT01454102)
Latest
news:
- • On June 4, 2016, BMS announced updated results from CheckMate -012, a multi-arm, Phase 1b trial evaluating Opdivo® and Yervoy®, in patients with chemotherapy-naïve advanced non-small cell lung cancer (NSCLC). In this study, Opdivo® was administered as monotherapy or as part of a combination with other agents, including Yervoy®, at different doses and schedules. Data from the Opdivo® monotherapy arm and other cohorts were previously reported. These updated results include findings from a pooled analysis of two Opdivo® and Yervoy® combination regimen cohorts, [3 mg/kg of Opdivo® every two weeks plus 1 mg/kg of Yervoy® either every six (Q6W) or 12 weeks (Q12W) (n=77)] which showed the magnitude of response rate from the combination regimen was enhanced with increased PD-L1 expression. In these combination regimen cohorts, the confirmed objective response rate (ORR) in patients with ?1% PD-L1 expression was 57% and the confirmed ORR was up to 92% (n=12/13) in patients with ?50% PD-L1 expression. In patients with <1% PD-L1 expression, the confirmed ORR was 15%. The ORR was 47% and 39% for the Q12W and Q6W, respectively in the overall population which included all patients regardless of PD-L1 expression level.
- In the study, the rate of treatment related Grade 3/4 adverse events (AEs) was 37%, 33%, and 19% for the Q12W, Q6W and Opdivo monotherapy cohorts, respectively. The rate of treatment-related Grade 3/4 AEs leading to discontinuation was 5%, 8%, and 10% of patients in the Q12W, Q6W and Opdivo monotherapy arms, respectively. There were no treatment-related deaths. Results from CheckMate -012 continue to support the dosing schedule selected – 3 mg/kg of Opdivo® every two weeks plus 1 mg/kg of Yervoy® every six weeks – for evaluation in further studies, including the Phase 3 trial, CheckMate -227, comparing Opdivo, the Opdivo® and Yervoy® combination regimen or Opdivo® and platinum-based doublet chemotherapy versus platinum-based doublet chemotherapy in chemotherapy-naïve Stage IV or recurrent NSCLC.
- The efficacy and safety results of the three dosing schedules in CheckMate -012 reported at ASCO are below.
|
|
Nivo 3 Q2W
+ Ipi 1 Q12W
(n = 38)
|
|
Nivo 3 Q2W
+ Ipi 1 Q6W
(n = 39)
|
|
Nivo 3 Q2W
(n = 52) |
| Confirmed ORR, %
(95% CI)
|
|
47
(31, 64) |
|
39
(23, 55) |
|
23*
(13, 37) |
| Median duration of response,
mo (95% CI) |
|
NR (11.3, NR) |
|
NR (8.4, NR) |
|
NR (5.7, NR) |
| Median length of follow-up,
mo (range) |
|
12.9 (0.9–18.0) |
|
11.8 (1.1–18.2) |
|
14.3 (0.2–30.1) |
- *not randomized
- CheckMate -012 also evaluated the efficacy by PD-L1 expression, an exploratory endpoint, of Opdivo as monotherapy (previously reported) and in combination withYervoy across the Q6W and Q12W dosing schedules. The chart below describes the efficacy results based on PD-L1 expression levels presented at ASCO.
|
|
Nivo 3 Q2W
+ Ipi 1 Q12W
(n = 38)
|
|
Nivo 3 Q2W
+ Ipi 1 Q6W
(n = 39)
|
|
Nivo 3 Q2W
(n = 52) |
| ORR, % (n/N)
<1% PD-L1
?1% PD-L1
?50% PD-L1
|
|
30 (3/10)
57 (12/21)
100 (6/6)
|
|
0 (0/7)
57 (13/23)
86 (6/7)
|
|
14 (2/14)
28 (9/32)
50 (6/12)
|
| Median PFS (95% CI), mo
<1% PD-L1
?1% PD-L1
?50% PD-L1
|
|
4.7 (0.9, NR)
8.1 (5.6, NR)
13.6 (6.4, NR)
|
|
2.4 (1.7, 2.9)
10.6 (3.6, NR)
NR (7.8, NR)
|
|
6.6 (2.0, 11.2)
3.5 (2.2, 6.6)
8.4 (2.2, NR)
|
| 1-year OS rate (95% CI), %
<1% PD-L1
?1% PD-L1
?50% PD-L1
|
|
NC
90 (66, 97)
NC
|
|
NC
83 (60, 93)
100 (100, 100)
|
|
69 (50, 82)
79 (47, 93)
83 (48, 96)
|
- The rate of total adverse events in the Q12W (82%) and Q6W (72%) arms were comparable to monotherapy (71%). In the study, Grade 3/4 adverse events (AEs) were 37%, 33%, and 19% for the Q12W, Q6W and Opdivo monotherapy arms, respectively. Treatment-related Grade 3/4 AEs lead to discontinuation in 5% and 8% of patients in the Q12W and Q6W cohorts, respectively and were similar to Opdivomonotherapy. There were no treatment-related deaths. The treatment-related select AEs in patients administered the optimized dosing schedule (3 mg/kg of Opdivo every two weeks plus 1 mg/kg of Yervoy every six weeks) were skin related (36%), gastrointestinal (23%), endocrine (20%), and pulmonary (6%) and there were ?5% treatment-related Grade 3/4 AEs per category.
- • On September 7, 2015, BMS announced updated results from the Opdivo (nivolumab)+Yervoy (ipilimumab) arms in CheckMate -012, a multi-arm Phase 1b trial evaluating Opdivo® in patients with chemotherapy-naïve advanced non-small cell lung cancer (NSCLC). These updated results include findings from the administration of four new dosing schedules of Opdivo+Yervoy (n=148), which resulted in confirmed objective response rates (ORR) ranging from 13% to 39% depending on the administered regimen. Median duration of response was not reached in any of these arms with a median follow-up of 6.2 months to 16.6 months, and median progression-free survival (PFS) ranged from 4.9 months to 10.6 months.
- The types of treatment-related serious adverse events (SAEs) reported in these cohorts for CheckMate -012 were consistent with other previously-reported Opdivo+Yervoy cohorts of this trial. The new dosing schedules in this study resulted in less toxicity than previously-reported dosing schedules, and were characterized by low frequency of treatment-related adverse events (AEs) leading to discontinuation (3% to 10%) and no treatment-related deaths. These data have been presented at the 16th World Conference on Lung Cancer (WCLC).
- CheckMate -012 is a multi-arm Phase 1b trial evaluating the safety and tolerability of Opdivo in patients with chemotherapy-naïve advanced NSCLC, as either a monotherapy or in combination with other agents, including Yervoy, at different doses and schedules. The results presented at WCLC include 148 squamous (SQ) and non-SQ patients who received Opdivo+Yervoy at one of the following new dosing schedules. Across the studied regimens and doses, Opdivo+Yervoy showed confirmed ORR ranging from 13% to 39% while median PFS ranged from 4.9 months to 10.6 months.
- Efficacy and safety results from the new dosing schedules of Opdivo+Yervoy evaluated in CheckMate -012 are below.
|
N1 + I1* Q3W
(N = 31) |
|
N1 Q2W + I1* Q6W
(N = 40) |
|
N3 Q2W + I1**
Q12W
(N = 38) |
N3 Q2W + I1**
Q6W
(N = 39) |
| Confirmed ORR, %
(95% CI) |
13 (4, 30) |
|
25 (13, 41) |
|
39 (24, 57) |
31 (17, 48)) |
| Partial Response |
13 |
|
25 |
|
39 |
31 |
| Unconfirmed
Partial Response |
3 |
|
3 |
|
5 |
8 |
| Unconfimed +
Confirmed |
16 |
|
28 |
|
44 |
39 |
| PFS rate at 24
weeks, % (95% CI) |
55 (36, 71) |
|
NC |
|
63 (44, 76) |
NC |
| Median PFS,
months (95% CI) |
10.6 (2.1, 16.3) |
|
4.9 (2.8) |
|
8.0 (4.2) |
8.3 (2.6) |
| Grade 3-4
Treatment-related
AEs, % |
29 |
|
35 |
|
29 |
28 |
| Grade 3-4
treatment-related
AEs leading to
discontinuation, % |
10 |
|
8 |
|
3 |
10 |
| * Nivolumab 1mg/kg+ ipilimumab 1mg/kg; ** Nivolumab 3mg/kg+ ipilimumab 1mg/kg |
- CheckMate -012 also evaluated the efficacy of Opdivo+Yervoy by PD-L1 expression. Of 148 patients enrolled, 71% had tumor samples evaluable for PD-L1 expression. Clinical activity was observed in both PD-L1 expressors and non-expressors, with greater activity in PD-L1 expressors, representing approximately 70% of the studied population. See table below for efficacy results per PD-L1 expression.
|
|
|
|
|
|
|
N1 + I1* Q3W
(N = 31) |
|
N1 Q2W + I1* Q6W
(N = 40) |
|
N3 Q2W + I1**
Q12W
(N = 38) |
|
N3 Q2W + I1**
Q6W
(N = 39) |
| ?1% PD-L1 expression |
| ORR, % (n/N) |
|
|
8
(1/12) |
|
24
(5/21) |
|
48
(10/21) |
|
48
(11/23) |
| mPFS, wks (95% CI) |
|
|
11.5
(7.1, ) |
|
21.1 (11.4, ) |
|
34.6 (15.9, 35.3) |
|
NR (15.4, ) |
| PFS rate at 24 wks,
% (95% CI) |
|
|
42 (15, 67) |
|
40 (18, 61) |
|
74 (48, 88) |
|
65 (42, 81) |
| <1% PD-L1 expression |
| ORR, % (n/N) |
|
|
15 (2/13) |
|
14 (1/7) |
|
22 (2/9) |
|
0 (0/7) |
|
mPFS, wks
(95% CI)
|
|
|
34.0 (8.9, ) |
|
NR (10.1, ) |
|
23.1 (4.0, ) |
|
10.3 (7.4, 12.7) |
| PFS rate at 24 wks,
% (95% CI) |
|
|
57 (25, 80) |
|
NC |
|
39 (9, 69) |
|
0 |
| * Nivolumab 1mg/kg+ ipilimumab 1mg/kg; ** Nivolumab 3mg/kg+ ipilimumab 1mg/kg |
- The safety profile of Opdivo+Yervoy in this trial was consistent with previously-reported studies. There were low frequency of treatment-related grade 3-4 AEs leading to discontinuation (3%–10%) and no treatment-related deaths. Discontinuation rates were comparable to the Opdivo monotherapy arm of this study.
- Data from these dosing schedules, along with previously reported data from CheckMate -012, informed the ongoing Phase 3 trial comparing Opdivo orOpdivo+Yervoy versus platinum doublet chemotherapy in chemotherapy-naïve patients with advanced NSCLC (CheckMate -227).
Is
general: Yes
