New Data for BAVENCIO(R) (avelumab) for Advanced Cancers to Be Presented at ESMO 2019

Merck

New Data for BAVENCIO(R) (avelumab) for Advanced Cancers to Be Presented at ESMO 2019

PR80777

DARMSTADT, Germany, and NEW YORK, Sept. 27, 2019 /PRNewswire=KYODO JBN/ --

Analyses from the Phase III JAVELIN Renal 101 study support efficacy of

BAVENCIO plus axitinib across multiple subgroups of patients with advanced

renal cell carcinoma (RCC)

Abstracts highlight data on BAVENCIO as a monotherapy and in combination in

multiple advanced cancers

Not intended for US, Canada and UK-based media

Merck and Pfizer Inc. (NYSE: PFE) today announced the presentation of multiple

analyses from the JAVELIN clinical development program assessing BAVENCIO (r)

(avelumab) alone or as part of combination regimens for the treatment of

advanced cancers, including renal cell carcinoma (RCC), metastatic Merkel cell

carcinoma (mMCC) and some other solid tumors at the European Society for

Medical Oncology (ESMO) Congress 2019 in Barcelona, Spain.

"These data at ESMO underscore the clinical activity of treatment with BAVENCIO

across multiple tumor types and patient populations," said Chris Boshoff, M.D.,

Ph.D., Chief Development Officer, Oncology, Pfizer Global Product Development.

"Furthermore, these presentations demonstrate our commitment to identifying the

patients most likely to benefit from this immunotherapy as a single agent, or

in combination approaches."

"The immunotherapy era has led to vast progress in the treatment of cancer, yet

we know that many patients with advanced or aggressive cancers still need

additional treatment options," said Luciano Rossetti, M.D., Executive Vice President,

Head of Global Research & Development at the Biopharma business of Merck.

"We are committed to continued research of BAVENCIO as we seek to

further advance treatment options for patients with certain cancers."

Data to be presented at ESMO include three subgroup analyses of the Phase III

JAVELIN Renal 101 study (NCT02684006), a randomized, multicenter, open-label

study of BAVENCIO in combination with axitinib in 886 patients with untreated

advanced RCC from patients across all International Metastatic RCC Database

Consortium (IMDC) risk groups. This study, results of which were published in

The New England Journal of Medicine in February 2019, demonstrated that

BAVENCIO in combination with axitinib significantly improved progression-free

survival (PFS) compared with sunitinib in patients with advanced RCC, with a

generally acceptable safety tolerability profile, including serious adverse events.[1]

Results from new analyses of JAVELIN Renal 101 being presented at ESMO, which

assessed the effect of BAVENCIO in combination with axitinib in subgroups

including patients who did not undergo cytoreductive nephrectomy, patients with

sarcomatoid histology, and Japanese patients, are consistent with findings from

the overall JAVELIN Renal 101 study population and provide a better

understanding of the combination in a broad range of patients with advanced

RCC. In May 2019, the U.S. Food and Drug Administration (FDA) approved BAVENCIO

in combination with axitinib for the first-line treatment of patients with

advanced RCC.[2] The Committee for Medicinal Products for Human Use (CHMP) of

the European Medicines Agency (EMA) adopted a positive opinion recommending

approval of BAVENCIO in combination with axitinib for the first-line treatment

of adult patients with advanced RCC in September 2019.  

Presentation #908PD: Phase III JAVELIN Renal 101 Study Subgroup Analysis of

Patients with Advanced RCC who did not Undergo Upfront Cytoreductive Nephrectomy

-Sunday, September 29, 15:20 – 15:20: Pamplona Auditorium (Hall 2)

A post-hoc analysis of JAVELIN Renal 101 evaluated patients with advanced RCC

who did not undergo prior surgery to remove as much of the visible tumors on

the kidneys as possible (cytoreductive nephrectomy), which comprised 20.2% of

participants in the study. The findings showed that patients with advanced RCC

treated with BAVENCIO in combination with axitinib who did not undergo an

upfront cytoreductive nephrectomy experienced greater shrinkage of the primary

renal tumor versus sunitinib (≥30% shrinkage for best percent change in

renal target lesions from baseline in 34.5% versus 9.7%, respectively).[3]

The majority of patients with advanced RCC undergo nephrectomy before starting

systemic treatment,[4] and those who do undergo nephrectomy may experience

complications or delays in treatment.[5] These results are the first of their

kind to report the efficacy of an immunotherapy plus a tyrosine kinase inhibitor

in patients with advanced RCC when there is still a primary tumor present.[3]

Presentation #910PD: Phase III JAVELIN Renal 101 Study Subgroup Analysis of

Patients with Advanced RCC with Sarcomatoid Histology

- Sunday, September 29, 15:20 – 15:20: Pamplona Auditorium (Hall 2)

A post-hoc analysis of JAVELIN Renal 101 in patients with advanced RCC with

sarcomatoid histology, an aggressive subtype of RCC[6] that carries the worst

prognosis for patients with renal tumors,[7],[8] included 12.2% of participants

in the trial. The results presented at ESMO showed that BAVENCIO plus axitinib

improved PFS and objective response rate (ORR) versus sunitinib in patients

with advanced RCC with sarcomatoid histology (median PFS: 7.0 months versus 4.0

months, HR 0.57 [95% CI, 0.325-1.003]; median ORR: 46.8% versus 21.3%).

These findings provide insight into the biology of sarcomatoid histology and

treatment with this immunotherapy in this subgroup of patients.[9]

Presentation #956P: Phase III JAVELIN Renal 101 Study Subgroup Analysis of

Japanese Patients with Advanced RCC

  

- Monday, September 30, 12:20 - 12:20: Poster Area (Hall 4)

An analysis assessing the efficacy and safety of Japanese patients with

advanced RCC (n=67) in JAVELIN Renal 101 study showed that BAVENCIO in

combination with axitinib improved median PFS compared to sunitinib in Japanese

patients with advanced RCC regardless of PD-L1 expression (16.6 months versus

11.2 months, respectively; HR, 0.66; [95% CI, 0.30-1.46]). Common

treatment-emergent adverse events (grade greater than or equal to 3) in each arm included

hand-foot syndrome (9% versus 9%), hypertension (30% versus 18%), and platelet

count decreased (0% versus 32%).[10] A supplemental application for BAVENCIO in

combination with axitinib in unresectable or metastatic RCC was submitted in

Japan in January 2019.

Additional presentations at ESMO show the potential impact of BAVENCIO as a

monotherapy and as a component of novel combinations:

- An analysis of health-related quality of life (HRQoL) from the Phase II

JAVELIN Merkel 200 study, in which patients with mMCC, an aggressive form of

skin cancer with poor outcomes,[11] treated with BAVENCIO reported stable or

improved HRQoL across various time points (presentation #1320P).[12]

- Interim results from the Phase Ib JAVELIN IL-12 study evaluating BAVENCIO in

combination with M9241, Merck's investigational IL-12 fusion protein containing

an anti-DNA antibody, in patients with solid tumors, which informed the

recommended dosing for Phase II of this study (presentation #1224P).[13]

- Post-hoc analyses from the JAVELIN Solid Tumor Phase I trial (presentation

#1493P)14 and Phase III JAVELIN Lung 200 study (presentation #1492P)15 that

further elucidate the effects of BAVENCIO in patients with advanced non-small

cell lung cancer.

About BAVENCIO(R) (avelumab)

BAVENCIO is a human anti-programmed death ligand-1 (PD-L1) antibody. BAVENCIO

has been shown in preclinical models to engage both the adaptive and innate

immune functions. By blocking the interaction of PD-L1 with PD-1 receptors,

BAVENCIO has been shown to release the suppression of the T cell-mediated

antitumor immune response in preclinical models.[16]-[18] BAVENCIO has also

been shown to induce NK cell-mediated direct tumor cell lysis via

antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro.[18]-[20] In

November 2014, Merck and Pfizer announced a strategic alliance to co-develop

and co-commercialize BAVENCIO.

BAVENCIO Approved Indications

In September 2017, the European Commission granted conditional marketing

authorization for BAVENCIO (R) (avelumab) as a monotherapy for the treatment of

adult patients with metastatic Merkel cell carcinoma (MCC). BAVENCIO is

currently approved for patients with MCC in 50 countries globally, with the

majority of these approvals in a broad indication that is not limited to a

specific line of treatment.

In the US, BAVENCIO in combination with axitinib is indicated for the

first-line treatment of patients with advanced renal cell carcinoma (RCC).

Additionally, the US FDA granted accelerated approval for BAVENCIO for the

treatment of (i) adults and pediatric patients 12 years and older with

metastatic Merkel cell carcinoma (mMCC) and (ii) patients with locally advanced

or metastatic urothelial carcinoma (mUC) 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. These indications are approved under accelerated approval based

on tumor response rate and duration of response. Continued approval for these

indications 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 (r)) include

immune-mediated adverse reactions (such as pneumonitis and hepatitis, colitis,

endocrinopathies, nephritis and renal dysfunction and other adverse reactions),

infusion-related reactions, hepatotoxicity, major adverse cardiovascular events

(MACE), and embryo-fetal toxicity.

The most common adverse reactions (all grades, greater than or equal to 20%) in patients with

metastatic Merkel cell carcinoma (MCC) were fatigue (50%), musculoskeletal pain

(32%), diarrhea (23%), nausea (22%), infusion-related reaction (22%), rash

(22%), decreased appetite (20%), and peripheral edema (20%).

Selected treatment-emergent laboratory abnormalities (all grades, greater than or equal to 20%)

in patients with metastatic MCC were lymphopenia (49%), anemia (35%), increased

aspartate aminotransferase (34%), thrombocytopenia (27%), and increased alanine

aminotransferase (20%).

The most common adverse reactions (all grades, greater than or equal to 20%) in patients with

locally advanced or metastatic urothelial carcinoma (UC) were fatigue (41%),

infusion-related reaction (30%), musculoskeletal pain (25%), nausea (24%),

decreased appetite/hypophagia (21%), and urinary tract infection (21%).

Selected laboratory abnormalities (Grades 3-4, greater than or equal to 3%) in patients with

locally advanced or metastatic UC were hyponatremia (16%), increased

gamma-glutamyltransferase (12%), lymphopenia (11%), hyperglycemia (9%),

increased alkaline phosphatase (7%), anemia (6%), increased lipase (6%),

hyperkalemia (3%), and increased aspartate aminotransferase (3%).

Fatal adverse reactions in patients occurred in 1.8% of patients with advanced

renal cell carcinoma (RCC) receiving BAVENCIO in combination with axitinib.

These included sudden cardiac death (1.2%), stroke (0.2%), myocarditis (0.2%),

and necrotizing pancreatitis (0.2%).

The most common adverse reactions (all grades, greater than or equal to 20%) in patients with

advanced RCC receiving BAVENCIO in combination with axitinib (vs sunitinib)

were diarrhea (62% vs 48%), fatigue (53% vs 54%), hypertension (50% vs 36%),

musculoskeletal pain (40% vs 33%), nausea (34% vs 39%), mucositis (34% vs 35%),

palmar-plantar erythrodysesthesia (33% vs 34%), dysphonia (31% vs 3.2%),

decreased appetite (26% vs 29%), hypothyroidism (25% vs 14%), rash (25% vs

16%), hepatotoxicity (24% vs 18%), cough (23% vs 19%), dyspnea (23% vs 16%),

abdominal pain (22% vs 19%), and headache (21% vs 16%).

Selected laboratory abnormalities (all grades, greater than or equal to 20%) worsening from

baseline in patients with advanced RCC receiving BAVENCIO in combination with

axitinib (vs sunitinib) were blood triglycerides increased (71% vs 48%), blood

creatinine increased (62% vs 68%), blood cholesterol increased (57% vs 22%),

alanine aminotransferase increased (ALT) (50% vs 46%), aspartate

aminotransferase increased (AST) (47% vs 57%), blood sodium decreased (38% vs

37%), lipase increased (37% vs 25%), blood potassium increased (35% vs 28%),

platelet count decreased (27% vs 80%), blood bilirubin increased (21% vs 23%),

and hemoglobin decreased (21% vs 65%).

Axitinib Important Safety Information from the US FDA-Approved Label

In the study of advanced RCC after failure of one prior systemic therapy, the

warnings and precautions for axitinib include hypertension, including

hypertensive crisis, arterial and venous thrombotic events, hemorrhagic events,

cardiac failure, gastrointestinal perforation and fistula, hypothyroidism,

wound healing complications, reversible posterior leukoencephalopathy syndrome

(RPLS), proteinuria, liver enzyme elevation, hepatic impairment and fetal harm

during pregnancy.

Common adverse events (reported in at least 20% of patients) in patients

receiving axitinib were diarrhea, hypertension, fatigue, decreased appetite,

nausea, dysphonia, hand-foot syndrome, weight decreased, vomiting, asthenia and

constipation.

About Merck-Pfizer Alliance

Immuno-oncology is a top priority for Merck and Pfizer. The global strategic

alliance between Merck and Pfizer enables the companies to benefit from each

other's strengths and capabilities and further explore the therapeutic

potential of BAVENCIO, an anti-PD-L1 antibody initially discovered and

developed by Merck. The immuno-oncology alliance is jointly developing and

commercializing BAVENCIO. The alliance is focused on developing high-priority

international clinical programs to investigate BAVENCIO as a monotherapy as

well as combination regimens, and is striving to find new ways to treat cancer.

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Pfizer Disclosure Notice

The information contained in this release is as of September 27, 2019.

Pfizer assumes no obligation to update forward-looking statements contained in this

release as the result of new information or future events or developments.

This release contains forward-looking information about BAVENCIO (avelumab),

including a new indication approved in the U.S. for BAVENCIO in combination

with axitinib for the treatment of patients with advanced renal cell carcinoma,

the alliance between Merck and Pfizer involving BAVENCIO and clinical

development plans, including their potential benefits, that involves

substantial risks and uncertainties that could cause actual results to differ

materially from those expressed or implied by such statements. Risks and

uncertainties include, among other things, uncertainties regarding the

commercial success of BAVENCIO and axitinib; the uncertainties inherent in

research and development, including the ability to meet anticipated clinical

endpoints, commencement and/or completion dates for our clinical trials,

regulatory submission dates, regulatory approval dates and/or launch dates, as

well as the possibility of unfavorable new clinical data and further analyses

of existing clinical data and uncertainties regarding whether the other primary

endpoint of JAVELIN Renal 101 will be met; risks associated with interim data;

the risk that clinical trial data are subject to differing interpretations and

assessments by regulatory authorities; whether regulatory authorities will be

satisfied with the design of and results from our clinical studies; whether and

when any drug applications may be filed for BAVENCIO in combination with

axitinib in any other jurisdictions or in any jurisdictions for any other

potential indications for BAVENCIO or combination therapies; whether and when

the pending applications in the European Union and Japan for BAVENCIO in

combination with axitinib may be approved and whether and when regulatory

authorities in any jurisdictions where any other applications are pending or

may be submitted for BAVENCIO or combination therapies, including BAVENCIO in

combination with axitinib may approve any such applications, which will depend

on myriad factors, including making a determination as to whether the product's

benefits outweigh its known risks and determination of the product's efficacy,

and, if approved, whether they will be commercially successful; decisions by

regulatory authorities impacting labeling, manufacturing processes, safety

and/or other matters that could affect the availability or commercial potential

of BAVENCIO or combination therapies, including BAVENCIO in combination with

axitinib; and competitive developments.

A further description of risks and uncertainties can be found in Pfizer's

Annual Report on Form 10-K for the fiscal year ended December 31, 2018, and in

its subsequent reports on Form 10-Q, including in the sections thereof

captioned "Risk Factors" and "Forward-Looking Information and Factors That May

Affect Future Results", as well as in its subsequent reports on Form 8-K, all

of which are filed with the U.S. Securities and Exchange Commission and

available at www.sec.gov and www.pfizer.com.

References

1. Motzer R, et al. Avelumab plus axitinib versus sunitinib for advanced

renal-cell carcinoma. N Engl J Med 2019; 380:1103-1115

2. BAVENCIO Prescribing Information. Rockland, MA: EMD Serono Inc.; 2019.

3. Albiges L, et al. Primary renal tumour shrinkage in patients (pts) who did

not undergo upfront cytoreductive nephrectomy (uCN): subgroup analysis from the

phase 3 JAVELIN Renal 101 trial of first-line avelumab + axitinib (A + Ax) vs sunitinib (S)

for advanced renal cell carcinoma (aRCC). Annals of Oncology. 2019. TBD.

4. Culp S. Cytoreductive nephrectomy and its role in the present-day period of

targeted therapy. Ther Adv Urol. 2015;7(5):275-285.

5. Silberstein J, et al. Systemic classification and prediction of

complications after nephrectomy in patients with metastatic renal cell

carcinoma (RCC). BJU Int. 2012;110(9):1276-1282.

6. Pichler, Renate et al. "Renal Cell Carcinoma with Sarcomatoid Features:

Finally New Therapeutic Hope?" Cancers. 2019;11(3):422.

7. Al-Juhaishi, T et al. "Survival outcomes in sarcomatoid renal cell

carcinoma." Journal of Clinical Oncology. 2018;36:15_suppl

8. American Cancer Society. Survival Rates for Kidney Cancer

https://amp.cancer.org/cancer/kidney-cancer/detection-diagnosis-staging/survival-rates.html.

Accessed September 2019.

9. Choueiri T, et al. Efficacy and biomarker analysis of patients (pts) with

advanced renal cell carcinoma (aRCC) with sarcomatoid histology (sRCC):

subgroup analysis from the phase 3 JAVELIN Renal 101 trial of first-line

avelumab plus axitinib (A+ Ax) vs sunitinib (S). Annals of Oncology. 2019. TBD.

10. Uemura M, et al. Randomized phase 3 trial of avelumab + axitinib vs

sunitinib as first-line treatment for advanced renal cell carcinoma: JAVELIN

Renal 101 Japanese subgroup analysis. Annals of Oncology. 2019. TBD.

11. Becker, J.C., Merkel cell carcinoma, Annals of Oncology. 2010: 21, 7_suppl:vii81–vii85

12. D'Angelo S, et al. Health-related quality of life in patients with

metastatic Merkel cell carcinoma receiving second-line or later avelumab

treatment: 36-month follow up data. Annals of Oncology. 2019. TBD.

13. Strauss J, et al. Phase 1b, open-label, dose-escalation study of M9241 (NHS-IL12) plus

avelumab in patients (pts) with advanced solid tumors. Annals of Oncology. 2019. TBD.

14. Hrinczenko B, et al. Long-term avelumab treatment in patients with advanced

non-small cell lung cancer (NSCLC): post hoc analyses from JAVELIN Solid Tumor.

Annals of Oncology. 2019. TBD.

15. Barlesi F, et al. Assessing the impact of subsequent checkpoint inhibitor

(CPI) treatment on overall survival: post hoc analyses from the phase 3 JAVELIN

Lung 200 study of avelumab vs docetaxel in platinum-treated locally

advanced/metastatic non-small cell lung cancer (NSCLC). Annals of Oncology. 2019. TBD.

16. Dolan DE, Gupta S. PD-1 pathway inhibitors: changing the landscape of

cancer immunotherapy. Cancer Control. 2014;21(3):231-237.

17. Dahan R, Sega E, Engelhardt J, et al. FcyRs modulate the anti-tumor

activity of antibodies targeting the PD-1/PD-L1 axis. Cancer Cell.

2015;28(3):285-295.

18. Boyerinas B, Jochems C, Fantini M, et al. Antibody-dependent cellular

cytotoxicity activity of a novel anti-PD-L1 antibody avelumab (MSB0010718C) on

human tumor cells. Cancer Immunol Res. 2015;3(10):1148-1157.

19. Kohrt HE, Houot R, Marabelle A, et al. Combination strategies to enhance

antitumor ADCC. Immunotherapy. 2012;4(5):511-527.

20. Hamilton G, Rath B. Avelumab: combining immune checkpoint inhibition and

antibody-dependent cytotoxicity. Expert Opin Biol Ther. 2017;17(4):515-523.

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Source: Merck

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