Bristol-Myers Squibb Announces Phase 1 Results from First Trial Combining Immune Checkpoint Inhibitors, Investigational Agent Nivolumab and Yervoy® (ipilimumab), in Patients with Advanced Melanoma

Princeton, New Jersey (ots/PRNewswire) -

Intended only for European media based outside of the UK

- 53% response rate observed in patients receiving 1 mg/kg nivolumab plus 3
mg/kg Yervoy concurrently (n= 9 of 17), the dose used in the Phase 3 trial; of these
responders all experienced at least 80% tumor shrinkage within 12 weeks
- Grade 3-4 treatment-related adverse events occurred in 53% of patients on the
concurrent-regimen and 18% of patients on the sequenced-regimen
- Data published today in New England Journal of Medicine
- Estimated survival data from this Phase 1 trial presented at 49th annual
meeting of the American Society of Clinical Oncology
- Phase 3 trial of nivolumab in combination with Yervoy in advanced melanoma
underway

Bristol-Myers Squibb today announced results from Study 004, a
dose-ranging Phase 1 trial (n=86) evaluating the safety and
anti-tumor activity of its investigational PD-1 receptor blocker,
nivolumab, combined either concurrently (n=53) or sequentially (n=33)
with Yervoy(R) (ipilimumab) in patients with advanced melanoma. In
patients who received the dose used in the Phase 3 trial (1 mg/kg
nivolumab + 3 mg/kg Yervoy) in the concurrent regimen, 53% (n= 9 of
17) had confirmed objective responses (OR) by mWHO criteria. In all
nine of these responders, tumors shrank by at least 80% by the time
of the first scheduled clinical treatment assessment (12 weeks),
including three complete responses (CRs). In response-evaluable
patients across all concurrent cohorts, 40% (n= 21 of 52) had an OR.
Sixteen patients (31%) had tumor shrinkage of at least 80% by the
time of the first clinical trial assessment, including five CRs.
Responses were ongoing among 19 of 21 responders, with responses
lasting from between 6.1+ to 72.1+ weeks at the time of data
analysis. Clinical activity was observed in both the concurrent and
sequenced regimens. Median overall survival has not been reached
after approximately 13 months of median follow up in the concurrent
cohorts. The estimated one-year survival rate across all concurrent
cohorts was 82% (95% CI 69.0 - 94.4%).

Grade 3-4 treatment-related adverse events occurred in 53% of
patients on the concurrent-regimen and 18% of patients on the
sequenced-regimen. No treatment-related deaths were reported.

The data on nivolumab in combination with Yervoy were published
today in the New England Journal of Medicine (NEJM). The estimated
survival data were presented at the 49th Annual Meeting of the
American Society of Clinical Oncology (Abstract # 9012).

"This is the first clinical trial to evaluate the safety and
efficacy of combining two immune-checkpoint inhibitors, which are
agents that target the pathways tumor cells use to evade recognition
and destruction by the immune system," said Dr. Jedd D. Wolchok,
Ludwig Center for Cancer Immunotherapy at Memorial Sloan-Kettering
Cancer Center, presenter of the results and lead author on the New
England Journal of Medicine paper. "The responses observed with the
concurrent combination of nivolumab and ipilimumab in this Phase 1
trial of patients with advanced melanoma are very encouraging and
support further research in randomized trials to evaluate the concept
of combining agents that target different, but complementary, immune
checkpoint pathways."

"An unmet medical need remains for many types of advanced cancer
and Bristol-Myers Squibb is committed to leading advances in a new
field of research, immuno-oncology, which is a rapidly evolving,
innovative treatment modality centered on harnessing the natural
capabilities of a patient's own immune system to fight cancer," said
Brian Daniels, senior vice president, Global Development and Medical
Affairs, Bristol-Myers Squibb. "Results from this Phase 1 study
provide important insights about the potential of combinations in
immuno-oncology and deepen our understanding of how cancer cells
evade the immune system."

Bristol-Myers Squibb is developing a robust pipeline of compounds
that directly modulate the immune system across a broad range of
cancers. This includes the development program for nivolumab, which
now consists of seven potentially registrational trials in three
tumor types: non-small cell lung cancer (NSCLC), advanced renal cell
carcinoma and advanced melanoma, including one in combination with
Yervoy. The Phase 3 development program for Yervoy is also ongoing
and includes Phase 3 trials in adjuvant melanoma, NSCLC and
metastatic castrate-resistant prostate cancer.

Study 004 Results

Clinical activity was observed in both the concurrent and
sequenced regimens. In the concurrent-regimen cohort, confirmed OR by
mWHO criteria was observed in nine of 17 (53%) patients treated at a
dose of 1 mg/kg nivolumab + 3 mg/kg Yervoy, the dose used in the
Phase 3 trial. All nine responders achieved 80% or greater tumor
reduction by the time of the first scheduled clinical trial
assessment (12 weeks), including three CRs. In response-evaluable
patients across all concurrent cohorts, OR was observed in 21 of 52
(40%) of patients. Sixteen patients (31%) had tumor shrinkage of at
least 80% by the time of the first clinical trial assessment (12
weeks). Four patients experienced an OR by immune-related response
criteria and two patients had unconfirmed responses. These six
patients were not included in the calculation of objective response
rates. Responses were ongoing among 19 of 21 responders, with
responses lasting from between 6.1+ to 72.1+ weeks at the time of
data analysis. The median overall survival has not been reached after
approximately 13 months of median follow up in the combined
concurrent cohorts. The estimated one-year survival rate across all
concurrent cohorts was 82% (95% CI 69.0 - 94.4%).

In the sequenced-regimen cohorts, six of 30 patients achieved OR
(20%) including one CR. Four (13%) patients achieved 80% or greater
tumor reduction at 8 weeks. Three patients had immune-related
responses and three patients had unconfirmed responses. These six
patients were not included in the calculation of objective response
rates. These findings showed that patients who did not respond to
prior Yervoy responded to subsequent nivolumab.

AEs were more frequent in patients treated with the concurrent
combination compared to each single agent. No treatment-related
deaths were reported. In the concurrent-regimen, treatment-related
AEs occurred in 93% of patients with the most common being rash
(55%), pruritus (47%), fatigue (38%), and diarrhea (34%). Grade 3-4
treatment-related AEs were observed in 53% of patients, the most
common being elevations in lipase (13%), aspartate aminotransferase
(13%) and alanine aminotransferase (11%). Three patients had Grade
1-2 pneumonitis (6%) and one patient had Grade 3 pneumonitis (2%). In
the sequenced regimen, treatment-related AEs occurred in 73% of
patients with the most common being pruritus (18%) and lipase
elevation (12%). Grade 3-4 treatment-related AEs were observed in 18%
of patients with lipase elevation (6%) as the most common. One
patient had Grade 1-2 pneumonitis (3%).

About Study 004

Study 004 is a dose-ranging Phase 1 study (n=86) evaluating the
safety, antitumor activity and pharmacokinetics of nivolumab in
concurrent and sequenced combination with Yervoy in patients with
advanced melanoma.

The study consists of two treatment regimens, both of which are
administered as intravenous infusions. In the concurrent regimen
(n=53), eligible patients received nivolumab and Yervoy every 3 weeks
for 4 doses, followed by nivolumab alone every 3 weeks for 4 doses.
Combined treatment was subsequently continued every 12 weeks for up
to 8 doses. Cohorts of a maximum of seventeen patients per dose level
(0.3 mg/kg nivolumab + 3 mg/kg Yervoy; 1 mg/kg nivolumab + 3 mg/kg
Yervoy; 3 mg/kg nivolumab + 1 mg/kg Yervoy; 3 mg/kg nivolumab + 3
mg/kg Yervoy) were enrolled. In the sequenced regimen (n=33),
patients previously treated with Yervoy received nivolumab alone
every 2 weeks. Cohorts of six patients per dose level (1, 3 mg/kg)
were enrolled. After completion of therapy, patients without
confirmed disease progression were followed for 2.5 years. Patients
with initial disease control and subsequent disease progression could
be retreated with the original regimen. Initial disease control was
defined as complete response, partial response, or stable disease for
greater than or equal to24 weeks. All cohorts were enrolled in
sequence from each other.

Two Distinct Immune Checkpoint Inhibitors

Nivolumab and Yervoy are both immune checkpoint inhibitors, but
they are monoclonal antibodies that target different receptors for
distinct T-cell checkpoint pathways.

Nivolumab is an investigational, fully-human IgG4 anti-PD-1
receptor blocking monoclonal antibody that binds to the checkpoint
receptor PD-1 (programmed death-1) expressed on activated T cells.
Nivolumab inhibits the binding of PD-1 with its tumor-expressed
ligands, programmed death-ligand 1 (PD-L1/B7-H1) and PD-L2 (B7-DC).
Blocking of the interaction of the PD-1 receptor with its ligands may
allow T-cells to elicit an anti-tumor immune response.

Yervoy, which is a recombinant, human monoclonal antibody, blocks
the cytotoxic T- lymphocyte antigen-4 (CTLA-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 through T-cell mediated anti-tumor immune
responses. On 25 March 2011, the US Food and Drug Administration
(FDA) approved ipilimumab 3 mg/kg monotherapy for patients with
unresectable or metastatic melanoma. In July 2011, the EU approved
ipilimumab 3 mg/kg for the treatment of adult patients with
previously-treated unresectable or metastatic melanoma. Yervoy is now
approved in 41 countries.

For full Prescribing Information, please refer to the SMPC.[1]

About the Bristol-Myers Squibb and Ono Pharmaceutical Partnership

Through a collaboration agreement with Ono Pharmaceutical in 2011,
Bristol-Myers Squibb expanded its territorial rights to develop and
commercialize nivolumab (BMS-936558/ONO-4538) globally except in
Japan, Korea and Taiwan where Ono has retained all rights to the
compound.

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose
mission is to discover, develop and deliver innovative medicines that
help patients prevail over serious diseases.

Bristol-Myers Squibb Forward-Looking Statement

This press release contains "forward-looking statements" as that
term is defined in the Private Securities Litigation Reform Act of
1995 regarding product development. Such forward-looking statements
are basedon current expectations and involve inherent risks and
uncertainties, including factors that could delay, divert or change
any of them, and could cause actual outcomes and results to differ
materially from current expectations. No forward-looking statement
can be guaranteed. Among other risks, there can be no guarantee that
the late-stage clinical trials described in this release will support
regulatory filings, that nivolumab will receive regulatory approval,
that the combination use of nivolumab and Yervoy will receive
regulatory approval, or that, if approved, they will become
commercially successful. Forward-looking statements in this press
release should be evaluated together with the many uncertainties that
affect Bristol-Myers Squibb's business, particularly those identified
in the cautionary factors discussion in Bristol-Myers Squibb's Annual
Report on Form 10-K for the year ended December 31, 2012, in our
Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K.
Bristol-Myers Squibb undertakes no obligation to publicly update any
forward-looking statement, whether as a result of new information,
future events or otherwise.

Reference

1) Yervoy Summary of Product Characteristics. July 2011. Available at:
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002213/human_med_001465.jsp&mid=WC0b01ac058001d124
Last accessed June 2013.

Contacts:
Media: Elzbieta Zawislak, +48-608-55-55-89 elzbieta.zawislak@bms.com
Investors: Ranya Dajani, +1-609-252-5330, ranya.dajani@bms.com ; Ryan Asay,
+1-609-252-5020, ryan.asay@bms.com

ots Originaltext: Bristol-Myers Squibb GmbH & Co.KG aA
Im Internet recherchierbar: http://www.presseportal.de