- Combination of TG4001 and avelumab demonstrates anti-tumor
activity (23.5% overall response rate (ORR)) in patients with
previously treated recurrent and/or metastatic HPV-related
cancers.
- In patients without liver metastases, an ORR of 34.8% and a
median progression-free survival (PFS) of 5.6 months were
achieved.
Regulatory News:
Transgene (Paris:TNG) (Euronext Paris: TNG), a
biotech company that designs and develops virus-based
immunotherapeutics against cancer, today announced the detailed
results from the Phase 1b/2 trial combining TG4001, a
HPV16-targeted therapeutic vaccine, with avelumab (BAVENCIO®), a
human anti-PD-L1 antibody, in HPV16-positive recurrent and/or
metastatic malignancies.
Following the unauthorized download of all abstracts on the SITC
website, Transgene is communicating the content of the
late-breaking poster abstract that will be presented at the SITC
35th Anniversary Annual Meeting (SITC 2020), to be held virtually
November 9-14, 2020.
The purpose of this exploratory Phase 1b/2 trial was to evaluate
the safety and efficacy of the combination of TG4001 and an immune
checkpoint inhibitor in a heterogeneous group of patients with
aggressive, recurrent and/or metastatic HPV16-positive cancers.
Key findings of the trial:
-
The combination of TG4001 and
avelumab demonstrates anti-tumor activity (23.5% ORR) in
patients with previously treated recurrent and/or metastatic
HPV-related cancers.
-
Presence of liver metastases
has a profound impact on outcome in terms of ORR and PFS. In
patients without liver metastases, an ORR of 34.8% and a median PFS
of 5.6 months were achieved.
-
The treatment induced
HPV-specific T-cell responses and was associated with increased
levels of immune cell infiltration in the tumors and expression of
genes associated with activation of the immune system.
-
These results warrant further
confirmation in a larger controlled randomized study.
An overall response rate of 23.5% was observed in the 34
evaluable patients. 8 patients achieved confirmed response,
including 1 complete response and 7 partial responses (according to
RECIST 1.1). Responses were observed in all primary tumor types and
across all lines of prior therapy. These results compare favorably
to current standards of care and single-agent immune checkpoint
inhibitors [1-7].
In patients without liver metastases (n=23), the response
rate is 34.8% and median progression free survival (PFS) reaches
5.6 months versus 0% and a PFS of 1.4 month in patients with
liver metastases (n=11). The presence of liver metastases is
generally associated with very poor prognosis [9] even when
patients are treated with an anti-PD-1/PD-L1 [10-12].
“The results we have announced today demonstrate the potential
of the combination of TG4001 with an immune checkpoint inhibitor in
this particularly severe disease setting. We observed very
encouraging responses rates, as high as 34.8 % in patients who did
not have liver metastases. In addition, the observed median PFS
shows that the regimen can induce a sustained and durable response,
which is also shown consistently by the induction of a specific
immune response. Based on these promising findings, Transgene
intends to continue the clinical development of TG4001 in a larger,
controlled confirmatory study as we look to provide a better
treatment option for this patient population,” added Dr. Maud
Brandely, MD, PhD, Chief Medical Officer of Transgene.
Commenting on this novel immunotherapy regimen, Prof.
Christophe Le Tourneau, MD, Head of the Department of Drug
Development and Innovation (D3i) at the Curie Institute, and
Principal Investigator of the trial, added: “We have seen very
encouraging efficacy results in this hard-to-treat patient
population, as well as a satisfying safety profile. I believe this
combination regimen has the opportunity to provide real hope for
patients with HPV-16 related cancers.”
The trial is conducted in collaboration with Merck KGaA,
Darmstadt, Germany, and Pfizer.
Philippe Archinard, Chairman and CEO of Transgene, and Dr.
Maud Brandely, MD, PhD, Chief Medical Officer of Transgene, will
provide some further background to the data after the publication
of the e-poster during a conference call and webcast scheduled on
November 12, at 6:00 pm CET.
Number and title of the late-breaking
poster abstract: (793) TG4001 (Tipapkinogene sovacivec)
and avelumab for recurrent/metastatic (R/M) Human Papilloma Virus
(HPV)-16+ cancers: clinical efficacy and immunogenicity.
Authors: Christophe Le
Tourneau, Philippe Cassier, Frédéric Rolland, Sébastien Salas,
Jean-Marc Limacher, Olivier Capitain, Olivier Lantz, Ana Lalanne,
Christina Ekwegbara, Annette Tavernaro, Hakim Makhloufi, Kaïdre
Bendjama, Jean-Pierre Delord.
Session & Q&As: The
e-poster will be displayed in the Virtual Poster Hall from November
11 to November 14, 2020, 9:00 a.m.-5:00 p.m. ET (3:00-11:00 p.m.
CET). The first author will be available for questions on November
11 from 5:15–5:45 p.m. ET (11:15-11:45 p.m. CET) and November 13
from 4:40-5:10 p.m. ET (10:40-11:10 p.m. CET).
Body of the abstract:
Background
Specific immune cell responses against
oncogenic antigens are major determinants to achieve long-term
disease control for HPV-related malignancies. We developed TG4001,
a viral based vaccine against the HPV E6 and E7 antigens. Following
the demonstration of its safety in Phase 1b, we aimed to evaluate
the antitumor activity and immune priming effects of TG4001 in
combination with the PD-L1 inhibitor avelumab in HPV-related
malignancies in phase II (NCT03260023).
Methods
Patients (pts) with previously treated R/M
HPV-16+ cancers received TG4001 at 5x107 pfu SC weekly for 6 weeks,
every 2 weeks up to M6, and every 12 weeks thereafter in
combination with avelumab IV at 10mg/kg every 2 weeks. PBMC and
tissue samples were collected longitudinally prior to and during
the treatment period. Specific T cell response was assessed using
ex-vivo IFNg-ELISPOT, and changes in the tumor microenvironment by
phenotyping of immune infiltrate and transcriptomic analyses of
immune related genes.
Results
34 pts with anal (15), oropharyngeal (8),
cervical (6) or vulvar/vaginal (5) cancer, were enrolled. Median
age was 61 years; the majority (88%) had received at least 1 prior
line of chemotherapy (CT) with 32% having received ≥ 2 lines. 8 pts
achieved confirmed response according to RECIST 1.1 (1 CR, 7 PR,
ORR 23.5%). Responses were observed in all primary tumor types and
across all lines of prior therapy. Liver metastases had a profound
impact on outcome: ORR was 34.8% and PFS 5.6 months in pts without
liver metastases (n=23) versus 0% and PFS of 1.4 months in pts with
liver metastases (n=11). Consistent with Phase 1b data, the
combination had a favorable safety profile.
11 pts were evaluable for T-cell response
at day (D) 43. 7/11 patients had vaccine-induced reactive T cells
against E6, E7 or both. In particular, in the patient with CR,
lesions disappearance was accompanied by the development of a
strong T-cell response against E6 and E7. This response developed
as early as D43 and sustained at 6 months after initiation of
therapy, consistent with the durable disease-control. Increased
infiltrates, expression of immune related genes and higher PD-L1
protein expression were observed across all patients suggesting a
remodeling of the tumor microenvironment consistent with a switch
toward a “hot tumor” phenotype.
Conclusions
Our study suggests that immunotherapeutic
combination of TG4001 and avelumab shows valuable tumor activity in
pts with previously treated advanced HPV-16+ cancers. These results
warrant validation in a larger cohort of patients.
Trial Registration
NCT03260023
About the trial
This multi-center, open-label Phase 1b/2 trial is assessing the
safety and efficacy of this immunotherapy combination regimen
(TG4001 + avelumab) in patients with HPV16-positive cancers who
have disease progression after at least one line of systemic
treatment (NCT03260023). Prof. Christophe Le Tourneau, M.D., PhD,
Head of the Department of Drug Development and Innovation (D3i) at
the Curie Institute, and a world expert in drug development and
head and neck cancers, is the Principal Investigator of the study.
The trial is being conducted in collaboration with Merck KGaA,
Darmstadt, Germany, a leading science and technology company, which
in the US and Canada operates its biopharmaceutical business as EMD
Serono, and Pfizer Inc. (NYSE: PFE).
34 patients received TG4001 at the dose of 5x107 pfu, SC, weekly
for 6 weeks, every 2 weeks up to six months, and every 12 weeks
thereafter, in combination with avelumab at 10 mg/kg, IV every two
weeks, until disease progression.
The primary endpoint of the Phase 2 part is the overall response
rate (ORR, using RECIST 1.1).
Secondary endpoints include progression-free survival, overall
survival, disease control rate and other immunological
parameters.
More information on the trial is available on
clinicaltrials.gov.
***
About TG4001
TG4001 is an investigational therapeutic vaccine based on a
non-propagative, highly attenuated Vaccinia vector (MVA), which is
engineered to express HPV16 antigens (E6 & E7) and an adjuvant
(IL-2). TG4001 is designed to have a two-pronged antiviral
approach: to alert the immune system specifically to cells
presenting the HPV16 E6 and E7 antigens, that can be found in
HPV16-related tumors, and to further stimulate the
infection-clearing activity of the immune system through
interleukin 2 (IL-2). TG4001 has been administered to more than 300
individuals, demonstrating good safety, significant HPV clearance
rate and promising efficacy results [8; 24]. Its mechanism of
action and good safety profile make TG4001 an excellent candidate
for combinations with other therapies in HPV-mediated solid
tumors.
About HPV-Positive Cancers
HPV-positive cancers comprise a variety of malignancies,
including head and neck cancers and anogenital cancers [13].
Squamous cell carcinoma of the head and neck (SCCHN) is a
heterogeneous group of cancers that can affect sites including the
oral cavity, pharynx, and larynx [14]. The incidence of
HPV16-related SCCHN has significantly increased in recent years
[14]. HPV16 infection is associated with more than 85% of
oropharynx squamous cell carcinomas [14], i.e. approximately 10,000
patients at metastatic stage and receiving a second line of
treatment [15]. Other HPV16-positive cancers include cervical [16],
vaginal [17], vulvar [18], anal [19] and penile [20] cancers, i.e.
approximately 15,000 cancers at metastatic stage and eligible for a
second line of treatment [21].
Current treatments include chemoradiotherapy, immune checkpoint
inhibitors, or surgical resection with radiotherapy. However,
better options are needed for advanced and metastatic HPV+ cancers.
It is thought that this immunotherapy combined with other
immunotherapeutic agents such as immune checkpoint inhibitors could
provide a promising potential treatment option that would address
this strong medical need [23,24]. With immune checkpoint
inhibitors, median overall survival remains inferior to 11 months
[1-7] and median progression-free survival is between 2 and 4
months [1-7]. In this heterogenous group of malignancies, overall
response rates are around 10–15% [1-7].
Avelumab Approved Indications
Avelumab (BAVENCIO®) is indicated in the US for the maintenance
treatment of patients with locally advanced or metastatic
urothelial carcinoma (UC) that has not progressed with first-line
platinum-containing chemotherapy. BAVENCIO is also indicated for
the treatment of patients with locally advanced or metastatic UC
who have disease progression during or following
platinum-containing chemotherapy, or have disease progression
within 12 months of neoadjuvant or adjuvant treatment with
platinum-containing chemotherapy.
Avelumab in combination with axitinib is approved in the US for
the first-line treatment of patients with advanced renal cell
carcinoma (RCC).
In the US, the FDA granted accelerated approval for BAVENCIO for
the treatment of adults and pediatric patients 12 years and older
with metastatic Merkel cell carcinoma (MCC). This indication is
approved under accelerated approval based on tumor response rate
and duration of response. Continued approval may be contingent upon
verification and description of clinical benefit in confirmatory
trials.
Avelumab Important Safety Information from the US
FDA-Approved Label
The warnings and precautions for avelumab (BAVENCIO®) include
immune-mediated adverse reactions (such as pneumonitis and
hepatitis [including fatal cases], colitis, endocrinopathies,
nephritis, and other immune-mediated adverse reactions as a single
agent or in combination with axitinib [which can be severe and have
included fatal cases]), infusion-related reactions, hepatotoxicity
in combination with axitinib, major adverse cardiovascular events
(MACE) in combination with axitinib [which can be severe and have
included fatal cases], and embryo-fetal toxicity.
Common adverse reactions (reported in at least 20% of patients)
in patients treated with BAVENCIO® monotherapy include fatigue,
musculoskeletal pain, diarrhea, nausea, infusion-related reaction
peripheral edema, decreased appetite, urinary tract infection and
rash. Common adverse reactions (reported in at least 20% of
patients) in patients receiving BAVENCIO® in combination with
axitinib include diarrhea, fatigue, hypertension, musculoskeletal
pain, nausea, mucositis, palmar-plantar erythrodysesthesia,
dysphonia, decreased appetite, hypothyroidism, rash,
hepatotoxicity, cough, dyspnea, abdominal pain and headache. Grade
3-4 hematology laboratory value abnormalities reported in at least
10% of patients with Merkel cell carcinoma treated with BAVENCIO®
monotherapy include lymphopenia; in patients receiving BAVENCIO® in
combination with axitinib, grade 3-4 clinical chemistry
abnormalities include blood triglyceride increased and lipase
increased.
For full US Prescribing Information and Medication Guide for
BAVENCIO®, please see http://www.BAVENCIO.com.
References
[1]
Cohen et al. Pembrolizumab versus
methotrexate, docetaxel, or cetuximab for recurrent or metastatic
head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised,
open-label, phase 3 study. Lancet. 2019;393:156–67
[2]
Ferris et al. Nivolumab for Recurrent
Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med.
2016;375:1856-1867
[3]
Guigay et al. Avelumab (anti–PD-L1) in
patients with platinum refractory/ ineligible recurrent or
metastatic squamous cell carcinoma of the head and neck (R/M
SCCHN): results from a phase 1b cohort, 2020 ESMO Annual Meeting,
19-21 September 2020, Poster presentation
[4]
Morris et al. Nivolumab for Previously
Treated Unresectable Metastatic Anal Cancer (NCI9673): A
Multicentre, Single-Arm, Phase 2 Study. Lancet Oncol.
2017;18(4):446-453
[5]
Marabelle et al. Pembrolizumab for
previously treated advanced anal squamous cell carcinoma: Pooled
results from the KEYNOTE-028 and KEYNOTE-158 studies. J Clin Oncol
38: 2020 (suppl; abstr 4020)
[6]
Lonardi et al. Randomized phase II trial
of avelumab alone or with cetuximab for unresectable, locally
advanced or metastatic squamous cell anal carcinoma progressed to
at least one line of treatment: The CARACAS study. J Clin Oncol.
38:2020 (suppl; abstr 4051)
[7]
Chung et al. Efficacy and Safety of
Pembrolizumab in Previously Treated Advanced Cervical Cancer:
Results From the Phase II KEYNOTE-158 Study. J Clin Oncol.
2019;10;37(17):1470-1478
[8]
Le Tourneau et al. “Phase Ib/II trial of
TG4001 (Tipapkinogene sovacivec), a therapeutic HPV-vaccine, and
Avelumab in patients with recurrent/metastatic HPV16 positive
cancers” 2019 ESMO Annual Meeting, 30 September 2019, Poster
presentation
[9]
Bilen et al. Sites of metastasis and
association with clinical outcome in advanced stage cancer patients
treated with immunotherapy. BMC Cancer. 2019;19: 857
[10]
Tumeh et al. Liver Metastasis and
Treatment Outcome with Anti-PD-1 Monoclonal Antibody in Patients
with Melanoma and NSCLC. Cancer Immunol Res 2017; 5: 417 -424
[11]
Sridhar et al. Prognostic Significance of
Liver Metastasis in Durvalumab-Treated Lung Cancer Patients. Clin
Lung Cancer 2019; e601 – e608
[12]
Reck et al. Atezolizumab plus
bevacizumab and chemotherapy in non-small-cell lung cancer
(IMpower150): key subgroup analyses of patients with EGFR mutations
or baseline liver metastases in a randomised, open label phase 3
trial. Lancet Respir Med 2019; 7: 387 - 401
[13]
ICO/IARC – HPV Information Center>
Prevention at a glance – accessed July 2020
[14]
Kreimer et al., Human Papillomavirus Types
in Head and Neck Squamous Cell Carcinomas Worldwide: A Systematic
Review. Cancer Epidemiol Biomarkers Prev. 2005;14(2):467-75
[15]
HPV-positive oropharynx cancer: Company
estimates based on: Globocan/IARC 2018 Cancer Fact Sheets:
oropharynx (C09-10) – accessed July 2020; ICO/IARC – HPV
Information Center 2018 Statistics – accessed July 2020; Kreimer et
al., Human Papillomavirus Types in Head and Neck Squamous Cell
Carcinomas Worldwide: A Systematic Review. Cancer Epidemiol
Biomarkers Prev. 2005;14(2):467-75
[16]
HPV-positive cervical cancer:
Globocan/IARC 2018 Cancer Fact Sheets: cervix uteri (C53) –
accessed July 2020; ICO/IARC – HPV Information Center 2018
Statistics – accessed July 2020
[17]
HPV-positive vaginal cancer: Globocan/IARC
2018 Cancer Fact Sheets: vagina (C52) – accessed July 2020;
ICO/IARC – HPV Information Center 2018 Statistics – accessed July
2020; Kreimer et al., Human Papillomavirus Types in Head and Neck
Squamous Cell Carcinomas Worldwide: A Systematic Review. Cancer
Epidemiol Biomarkers Prev. 2005;14(2):467-75
[18]
HPV-positive vulvar cancer: Globocan/IARC
2018 Cancer Fact Sheets: vulva (C51) – accessed July 2020; ICO/IARC
– HPV Information Center 2018 Statistics – accessed July 2020; CDC
United States Cancer Statistics: Data Visualizations – accessed
July 2020; SEER Cancer stat facts: vulvar cancer – accessed July
2020
[19]
HPV-positive anal cancer: Globocan/IARC
2018 Cancer Fact Sheets: anus (C21) – accessed July 2020; ICO/IARC
– HPV Information Center 2018 Statistics – accessed July 2020;
CDC>Cancer Home>HPV and Cancer>Statistics>Rates by Race
and Ethnicity>HPV-Associated Anal Cancer Rates by Race and
Ethnicity– accessed July 2020; American Cancer Society: Anal Cancer
– accessed July 2020
[20]
HPV-positive penile cancer: Globocan/IARC
2018 Cancer Fact Sheets: penis (C60) – accessed July 2020; ICO/IARC
– HPV Information Center 2018 Statistics – accessed July 2020;
CDC>Cancer Home>HPV and Cancer>Statistics>Rates by Race
and Ethnicity>HPV-Associated Cancers Rates by Race and Ethnicity
– accessed July 2020; Kreimer et al., Human Papillomavirus Types in
Head and Neck Squamous Cell Carcinomas Worldwide: A Systematic
Review. Cancer Epidemiol Biomarkers Prev. 2005;14(2):467-75
[21]
Company estimates based on notes 16, 17,
18, 19, 20
[22]
Melero et al. Evolving synergistic
combinations of targeted immunotherapies to combat cancer. Nat Rev
Cancer. 2015;15(8): 457-472.
[23]
Van der Burg et al. Vaccines for
established cancer: overcoming the challenges posed by immune
evasion Nat Rev Cancer. 2016;16(4):219-233
[24]
Harper et al. The Efficacy and Safety of
Tipapkinogen Sovacivec Therapeutic HPV Vaccine in Cervical
Intraepithelial Neoplasia Grades 2 and 3: Randomized Controlled
Phase II Trial With 2.5 Years of Follow-Up. Gynecologic Oncology.
2019; 153(3):521-529
About Transgene
Transgene (Euronext: TNG) is a publicly traded French
biotechnology company focused on designing and developing targeted
immunotherapies for the treatment of cancer. Transgene’s programs
utilize viral vector technology with the goal of indirectly or
directly killing cancer cells.
The Company’s clinical-stage programs consist of two therapeutic
vaccines (TG4001 for the treatment of HPV-positive cancers, and
TG4050, the first individualized therapeutic vaccine based on the
myvac® platform) as well as two oncolytic viruses (TG6002 for the
treatment of solid tumors, and BT-001, the first oncolytic virus
based on the Invir.IO™ platform).
With Transgene’s myvac® platform, therapeutic vaccination enters
the field of precision medicine with a novel immunotherapy that is
fully tailored to each individual. The myvac® approach allows the
generation of a virus-based immunotherapy that encodes
patient-specific mutations identified and selected by Artificial
Intelligence capabilities provided by its partner NEC.
With its proprietary platform Invir.IO™, Transgene is building
on its viral vector engineering expertise to design a new
generation of multifunctional oncolytic viruses. Transgene has an
ongoing Invir.IO™ collaboration with AstraZeneca.
Additional information about Transgene is available at:
www.transgene.fr.
Follow us on Twitter: @TransgeneSA
Disclaimer
This press release contains forward-looking statements, which
are subject to numerous risks and uncertainties, which could cause
actual results to differ materially from those anticipated. The
occurrence of any of these risks could have a significant negative
outcome for the Company’s activities, perspectives, financial
situation, results, regulatory authorities’ agreement with
development phases, and development. The Company’s ability to
commercialize its products depends on but is not limited to the
following factors: positive pre-clinical data may not be predictive
of human clinical results, the success of clinical studies, the
ability to obtain financing and/or partnerships for product
manufacturing, development and commercialization, and marketing
approval by government regulatory authorities. For a discussion of
risks and uncertainties which could cause the Company’s actual
results, financial condition, performance or achievements to differ
from those contained in the forward-looking statements, please
refer to the Risk Factors (“Facteurs de Risque”) section of the
Universal Registration Document, available on the AMF website
(http://www.amf-france.org) or on Transgene’s website
(www.transgene.fr). Forward-looking statements speak only as of the
date on which they are made and Transgene undertakes no obligation
to update these forward-looking statements, even if new information
becomes available in the future.
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Transgene: Lucie Larguier Director Corporate
Communications & IR +33 (0)3 88 27 91 04
investorrelations@transgene.fr
Media: Citigate Dewe Rogerson David Dible/Sylvie
Berrebi + 44 (0)20 7638 9571
transgene@citigatedewerogerson.com
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