WILMINGTON, Del. -- (Business Wire)
AstraZeneca (NYSE:AZN) and MedImmune, AstraZeneca’s global biologics
research and development arm, today presented encouraging results from
their novel combination-focused immuno-oncology portfolio at the
American Society of Clinical Oncology (ASCO) Annual Meeting 2015.
Overall, data indicated clinical activity with manageable safety
profiles for the anti-programmed cell death ligand 1 (PD-L1) monoclonal
antibody MEDI4736, both as monotherapy and in combination with other
immuno-oncology and small molecule therapies across different tumor
types and tumor biology.
MEDI4736 and tremelimumab combination shows clinical activity and
tolerability in both PD-L1 positive and PD-L1 negative advanced
non-small cell lung cancer (NSCLC) patients; dose confirmed for future
studies
Results from the combination study of MEDI4736 and tremelimumab, a
cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) monoclonal
antibody, in the treatment of advanced NSCLC, demonstrated clinical
activity in heavily-pretreated patients with a manageable safety
profile, establishing appropriate doses to move forward into Phase III
combination trials.
MEDI4736 and tremelimumab target two different tumor escape pathways;
engaging the immune system to fight the cancer’s immune-evading tactics
and maintaining tumor specific T-cell responses.
Data from the Phase Ib open label, dose escalation study of patients
with advanced NSCLC, showed that the combination of the PD-L1 and CTLA-4
blockade helped to increase response rates in both PD-L1 biomarker
positive and negative patients. 63 patients with 16 weeks or more of
follow up were evaluable for clinical activity, 102 patients were
evaluated for safety. Notably, the data demonstrated specific clinical
activity and tolerability in PDL-1 negative patients, who make up
approximately 70% of NSCLC patients and who are less likely to respond
to monotherapy. In the PD-L1 negative patient subset, overall response
rate (ORR) was 27% (9/33) and disease control rate (DCR) – defined as
complete response (CR), partial response (PR) or stable disease (SD) for
16 weeks or more - was 48% (16/33). Overall, nearly half of patients in
the study achieved a partial response or stable disease, with ORR of 27%
(17/63) and DCR of 41% (26/63). (Antonia et al, abstract #3014)
Overall adverse events (AEs) were manageable and generally reversible
using standard treatment guidelines. The most frequently reported
treatment related grade 3/4 AEs across all dose cohorts were colitis,
diarrhea, elevated lipase and elevated liver function tests. 20/102
patients discontinued the study due to drug-related AEs in this
heavily-pretreated disease setting.
The combination data presented at ASCO builds on preliminary results
from 18 patients presented at the European Society of Medical Oncology
Congress in September 2014.
“The maturing data presented today on the combination of MEDI4736 and
tremelimumab are truly exciting - we are starting to see the potential
of combination therapy become a reality,” said Dr. Ed Bradley, Senior
Vice President and Head of the Oncology Innovative Medicines unit,
MedImmune. “We are particularly encouraged by the data indicating that
these complementary agents can be combined to increase T-cell activity
and improve the clinical activity among the broader patient population
of non-small cell lung cancer patients whose tumors are PD-L1 negative
and are therefore in need of better treatments.”
A range of doses were identified that provided clinical benefit with
acceptable tolerability, with a specific dose and schedule of MEDI4736
20mg every four weeks (12 total doses) and tremelimumab 1mg/kg every
four weeks (four total doses) selected for future Phase III combination
trials in NSCLC. This decision was supported by data from the trial,
which evaluated key indicators of best outcomes for patients (clinical
efficacy, tolerability and biologic activity) to ensure that each
molecule contributes optimally in the combination. Data indicated that
the selected dose of tremelimumab is well tolerated and enhances
clinical activity as efficaciously as the other doses studied.
Bahija Jallal, Executive Vice President, MedImmune, said: “We are
encouraged by the immunotherapy data being presented here at ASCO 2015,
but this is just the tip of the iceberg as we continue to follow the
science and build on the diversity of our portfolio with smart
combinations. We believe the most powerful combinations will likely
target multiple mechanisms in the immune system where cancer wages its
battles – T-cell activation, antigen presentation and innate immunity,
and the tumor microenvironment. AstraZeneca and MedImmune are uniquely
positioned to lead in this area, through our biologics and small
molecule portfolio and through targeted collaborations, which allow us
to explore novel combinations across this cycle of anti-tumor immunity.”
The study design for the ongoing Phase III ARCTIC trial, designed to
evaluate the efficacy and safety of the combination of MEDI4736 and
tremelimumab in NSCLC patients with PD-L1-negative tumours, as well as
MEDI4736 versus standard of care in NSCLC patients with PD-L1-positive
tumours, was also presented at ASCO.(Planchard et al,
abstract #TPS8104) A Phase II study of MEDI4736 and tremelimumab as
monotherapies and in combination in patients with recurrent squamous
cell carcinoma of the head and neck (SCCHN) was also recently started.
Data reinforce the potential of MEDI4736 as a cornerstone for
combinations with other immunotherapies and small molecule treatments in
multiple tumor types
Other data at ASCO underpinned the potential for MEDI4736 in combination
with other immuno-oncology and small molecules in melanoma and lung
cancer:
-
Preliminary results from the first ever Phase I triple combination
study of MEDI4736 with BRAF (dabrafenib) and/or MEK (trametinib)1
inhibitors in patients with advanced melanoma showed clinical activity
with acceptable tolerability, with all three agents at full doses. In
patients with advanced BRAF-mutation positive melanoma, confirmed
partial responses were seen in 69% of patients (18/26) receiving
MEDI4736 plus dabrafenib and trametinib. The disease control rate (CR,
PR or SD) was 100% and 89% of responding patients (16/18) had ongoing
responses after a median follow-up duration of 7.1 months. Overall,
AEs were consistent with the known safety profiles of the combination
components, and no exacerbation of immune-related AEs was apparent.
(Ribas et al, Abstract #3003; Oral Abstract Session: Developmental
Therapeutics – Immunotherapy, Monday, June 1, 2:15 pm)
-
Dose escalation data from a Phase I study of MEDI4736 in combination
with gefitinib, AstraZeneca’s epidermal growth factor receptor
(EGFR) mutation positive tyrosine kinase inhibitor (TKI) in advanced
NSCLC showed that treatment was generally well tolerated, with early
treatment activity in heavily pre-treated patients. (Creelan et al,
abstract #3047)
-
Preliminary results from TATTON, a multi-arm Phase Ib trial of AZD9291
combined with MEDI4736, AZD6094 or selumetinib in EGFR-mutant lung
cancer patients who have progressed following therapy with an
EGFR-TKI, indicated that MEDI4736 and AZD9291 were tolerated at their
Phase III doses in the combination arm. (Oxnard et al, Poster #2509)
MEDI4736 monotherapy: data indicate durable responses in multiple
tumor types
Increasingly mature data from an ongoing Phase I/II, multicenter,
open-label study of MEDI4736 in patients with solid tumors will continue
to demonstrate durable anti-tumor activity and a manageable safety
profile. Analysis of data from 200 response evaluable patients with
NSCLC treated with MEDI4736 and with 12 weeks or more of follow-up
showed ORR of 16% (27% in PD-L1 positive patients), and DCR (CR, PR or
SD for 12 weeks or more) of 42% (48% in PD-L1 positive). ORR was higher
in patients with squamous (21%) than non-squamous (13%) disease.
Responses were durable with 66% (21/32) ongoing. Drug-related AEs at
grade 3 or higher were reported in 8% of patients. (Rizvi et al, Poster
#340).
Additional results were also presented on MEDI4736 monotherapy in
patients with SCCHN. Of 62 response evaluable patients with 24 weeks or
more of follow up, ORR was 11% (18% in PD-L1 positive patients), and DCR
(CR, PR or SD for 24 weeks or more) was 15% (18% in PD-L1 positive
patients). Responses are ongoing in 71% (5/7) of responding patients.
Drug related AEs at grade 3 or higher were reported in 10% of patients.
(Segal et al, Poster #337)
Positive progress with companion diagnostic test to help identify
patients who are more likely to respond to MEDI4736, reinforcing
personalized healthcare approach
A PD-L1 companion diagnostic test that is being developed jointly by
Ventana Medical Systems and MedImmune has demonstrated robust,
reproducible results as a biomarker to predict response to MEDI4736.
Three separate pathologist reviews of 81 patients with NSCLC and 100
patients with SCCHN from MEDI4736 clinical trials showed an overall
accuracy of 97% and 91% in the NSCLC and SCCHN samples respectively. The
consistency of the results across the pathologist reviews shows that the
selected scoring algorithm is precise, reproducible and practical in the
clinical setting. In the MEDI4736 monotherapy trials, both NSCLC and
SCCHN patients identified as PD-L1 positive by the scoring algorithm had
a higher response to MEDI4736 than those identified as PD-L1 negative.
(Rebelatto et al, abstract #8033)
– ENDS –
NOTES TO EDITORS
1 Novartis medicines for treatment of patients with
metastatic melanoma.
About AstraZeneca in Oncology
Oncology is a therapeutic area in which AstraZeneca has deep-rooted
heritage. It will be potentially transformational for the Company’s
future, becoming the sixth growth platform. Our vision is to help
patients by redefining the cancer treatment paradigm and one-day
eliminate cancer as cause of death. By 2020, we are aiming to bring six
new cancer medicines to patients.
Our broad pipeline of next-generation investigational medicines is
focused on four main disease areas - ovarian, lung, breast, and
hematological cancers. These are being targeted through four key
platforms – immuno-oncology, the genetic drivers of cancer and
resistance, DNA damage repair and antibody drug conjugates.
About MedImmune
MedImmune is the worldwide biologics research and development arm of
AstraZeneca. MedImmune is pioneering innovative research and exploring
novel pathways across key therapeutic areas, including respiratory,
inflammation and autoimmunity; cardiovascular and metabolic disease;
oncology; neuroscience; and infection and vaccines. The MedImmune
headquarters is located in Gaithersburg, Md., one of AstraZeneca’s three
global R&D centers. For more information, please visit www.medimmune.com.
About AstraZeneca
AstraZeneca is a global, innovation-driven biopharmaceutical business
that focuses on the discovery, development and commercialization of
prescription medicines, primarily for the treatment of cardiovascular,
metabolic, respiratory, inflammation, autoimmune, oncology, infection
and neuroscience diseases. AstraZeneca operates in over 100 countries
and its innovative medicines are used by millions of patients worldwide.
For more information please visit www.astrazeneca-us.com.
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