Arvinas, Inc. (Nasdaq: ARVN) and Pfizer Inc. (NYSE: PFE) today
announced clinical data for vepdegestrant (ARV-471), a novel oral
PROteolysis TArgeting Chimera (PROTAC®) estrogen receptor (ER)
degrader, in combination with palbociclib (IBRANCE®). Interim
results from the Phase 1b combination cohort demonstrate
encouraging clinical activity in heavily pre-treated patients with
a median of four lines of therapy across disease settings with
locally advanced or metastatic ER positive/human epidermal growth
factor 2 (HER2) negative (ER+/HER2-) breast cancer. These data will
be presented in a spotlight presentation at the 2023 San Antonio
Breast Cancer Symposium (SABCS).
“We are thrilled to see this level of clinical activity in such
a heavily pre-treated patient population,” said John Houston,
Ph.D., chairperson, chief executive officer, and president at
Arvinas. “Vepdegestrant is the only PROTAC® ER degrader in
late-stage clinical development. The results from this trial
evaluating vepdegestrant in combination with palbociclib help
advance our goals of benefitting patients with ER+/HER2- breast
cancer. It is encouraging to see preliminary signals of activity in
both wild-type and ESR1 mutant tumors, with manageable tolerability
and low rates of discontinuation.”
Vepdegestrant is a PROTAC® ER degrader designed to directly
harness one of the cell’s natural protein disposal processes to
specifically target and degrade the estrogen receptor.
Vepdegestrant is being co-developed by Arvinas and Pfizer and is
currently being evaluated as a monotherapy in the second-line
setting in the ongoing Phase 3 VERITAC-2 trial and in the
first-line setting in combination with palbociclib in the ongoing
study lead-in cohort of the Phase 3 VERITAC-3 trial.
“Our goal is to develop a novel, tolerable next-generation
estrogen-targeting agent that can help patients with ER+/HER2-
breast cancer address disease progression,” said Adam Schayowitz,
Ph.D., vice president, development head, breast cancer, colorectal
cancer and melanoma, Pfizer. “Collectively, the data presented this
year at SABCS for vepdegestrant, especially in combination with
palbociclib, show the potential of this investigational innovative
therapeutic option. Our ongoing collaboration with Arvinas
exemplifies our shared commitment to bringing new therapies to
patients with ER+/HER2- breast cancer, who may feel uncertain and
vulnerable in the face of recurrent advanced disease.”
Pending additional data and agreement with regulatory
authorities, Arvinas and Pfizer plan to broaden development of
vepdegestrant to include new combinations with cyclin-dependent
kinase (CDK) inhibitors in both the first- and second-line
settings. The companies plan to initiate a new second-line Phase 3
trial of vepdegestrant in combination with palbociclib and
potentially other CDK4/6 inhibitors, and a new first-line Phase 3
trial of vepdegestrant plus Pfizer’s novel CDK4 inhibitor
(PF-07220060).
Vepdegestrant + Palbociclib Phase 1b Study In a
spotlight presentation, interim data from the Phase 1b cohort of
the first-in-human (FIH) ARV-471-mBC-101 study evaluating
vepdegestrant in combination with palbociclib (NCT04072952)
assessed the safety, tolerability and anti-tumor activity of the
combination among 46 patients with heavily pre-treated locally
advanced or metastatic ER+/HER2- breast cancer. At the time of data
cutoff (June 6, 2023), patients had received a median of four prior
therapies across all lines (median of three in the metastatic
setting); 87% were previously treated with a cyclin-dependent
kinase 4 and 6 (CDK4/6) inhibitor; 80% were previously treated with
fulvestrant; and 76% were previously treated with chemotherapy,
including 46% in the metastatic setting.
Patients were treated once daily with oral doses of
vepdegestrant at 180 mg (n=2), the recommended Phase 3 dose (RP3D)
of 200 mg (n=21), 400 mg (n=3) or 500 mg (n=20), plus 125 mg of
palbociclib given orally once daily for 21 days, followed by seven
days off treatment in 28-day cycles.
Vepdegestrant in combination with palbociclib demonstrated:
- A clinical benefit rate (CBR,
defined as the rate of confirmed complete response, partial
response, or stable disease ≥ 24 weeks) of 63% (95% CI: 47.5–76.8),
or 29/46 patients; at the RP3D of 200 mg (n=21), the CBR was 67%
(95% CI: 43.0 – 85.4), or 14/21 patients
- CBR in patients with mutant ESR1:
72% (95% CI: 52.8-87.3), or 21/29 patients; at the RP3D of 200 mg
(n=14), the CBR was 79% (95% CI: 49.2 – 95.3), or 11/14
patients
- CBR in patients with wild-type ESR1:
53% (95% CI: 26.6-78.7), or 8/15 patients; at the RP3D of 200 mg
(n=7), the CBR was 43% (95% CI: 9.9 – 81.6), or 3/7 patients
- An objective response rate (ORR) in
evaluable patients with measurable disease at baseline (n=31) of
42% (95% CI: 24.5–60.9), or 13/31 patients; at the RP3D of 200 mg
(n=15), the ORR was 53% (95% CI: 26.6 – 78.7)
- ORR in patients with mutant ESR1:
47% (95% CI: 23.0-72.2), or 8/17 patients
- ORR at the RP3D of 200 mg (n=10):
60% (95% CI: 26.2 – 87.8)
- ORR in patients with wild-type ESR1:
42% (95% CI: 15.2-72.3), or 5/12 patients
- ORR at the RP3D of 200 mg (n=5): 40%
(95% CI: 26.6 – 78.7)
- Median progression free survival
(PFS) of 11.1 months (95% CI: 8.2 – NE); 22 of 46 patients across
all doses had progression events by time of data cutoff
- PFS in patients with mutant ESR1:
11.0 months (95% CI: 8.2-NE), 13 of 29 patients had progression
events by data cutoff
- PFS in patients with wild-type ESR1:
11.1 months (95% CI: 2.8-NE), 8 of 15 patients had progression
events by data cutoff
In an assay of circulating tumor DNA (ctDNA), patients with ESR1
mutations (n=22 evaluable for ctDNA analysis after 1 cycle of
treatment) demonstrated a -96.8% mean decrease (range: -75.6% to
-100%) in ESR1 mutant allele fraction after 1 cycle of
treatment.
The safety profile of vepdegestrant plus palbociclib was
manageable with palbociclib dose reductions and/or interruptions
per protocol which are consistent with those described in the
prescribing label. The primary toxicity associated with the
vepdegestrant plus palbociclib combination was neutropenia. Grade 4
neutropenia occurred in 8 of 21 patients (38%) treated at the RP3D
of vepdegestrant (200 mg) plus palbociclib 125 mg. Grade 3/4
neutropenia occurred in 89% of all patients. There was a higher
occurrence of Grade 4 neutropenia, although discontinuation rates
of palbociclib and rates of infection were in line with historical
palbociclib data.
No cases of febrile neutropenia were reported in any of the 46
patients treated with the combination. Three of 46 patients
discontinued palbociclib due to neutropenia including one out of 21
treated with the RP3D of vepdegestrant (200 mg) plus palbociclib
125 mg.
The majority of Grade 4 neutropenia events occurred in the first
cycle of treatment and occurrences of Grade 3/4 neutropenia
decreased with palbociclib dose reductions as described in the
prescribing label. The safety profile was otherwise consistent with
the profile of palbociclib and what has been observed in other
clinical trials for vepdegestrant.
An increase in palbociclib exposure (46% - 58%) was observed
compared to historical pharmacokinetic (PK) data, with similar
increases observed with vepdegestrant 200 mg and 500 mg QD.
“While many patients I treat with ER+/HER2- breast cancer
respond well to current therapies, disease progression is still an
unfortunate reality and there is a significant need for additional
therapies to help us treat ER+/HER2- breast cancer that has spread
to other parts of the body, or metastasized,” said Erika Hamilton,
M.D., director of Breast Cancer Research at Sarah Cannon Research
Institute in Nashville, Tennessee, and a lead investigator in the
vepdegestrant clinical program and presenting author on the data
presentation at SABCS. “Vepdegestrant represents a potential new
approach to degrading ER, a pathway known to drive breast cancer
progression, and I am encouraged by the early data seen in the
Phase 1b cohort of this study. Importantly, patients were able to
utilize standard dose reductions to manage neutropenia and remain
on treatment.”
Additional Abstracts Presented at SABCS
Together, Arvinas and Pfizer will share five additional
abstracts at SABCS, including a vepdegestrant monotherapy VERITAC
Phase 2 dose expansion update, a pharmacokinetic/pharmacodynamic
(PK/PD) model evaluating the optimal dosing of palbociclib in
combination with vepdegestrant, and three additional Trial in
Progress abstracts.
The VERITAC Phase 2 monotherapy dose expansion of the
ARV-471-mBC-101 study analyzed the safety, efficacy, and
tolerability of vepdegestrant amongst 35 heavily pre-treated
patients with locally advanced or metastatic ER+/HER2- breast
cancer. This update includes 12 months of additional follow-up
data, and the tolerability and efficacy profile remained largely
consistent with previous data disclosures.
In the PK/PD model simulation, a 100 mg dose of palbociclib in
combination with vepdegestrant produced similar incidence of Grade
4 neutropenia and comparable average palbociclib exposure compared
to historical reference.
Titles for the five additional abstracts are listed here.
Investor Call & Webcast Details
A conference call and webcast will be held with executives from
Arvinas and Pfizer to discuss the data presented at SABCS. Details
for this call will be provided in a separate press release shared
on www.arvinas.com. Participants are invited to listen by going to
the Events and Presentation section under the Investors page on the
Arvinas website at www.arvinas.com. A replay of the webcast will be
archived on the Arvinas website following the presentation.
About vepdegestrant (ARV-471)Vepdegestrant is
an investigational, orally bioavailable PROTAC protein degrader
designed to specifically target and degrade the estrogen receptor
(ER) for the treatment of patients with ER positive (ER+)/human
epidermal growth factor receptor 2 (HER2) negative (ER+/HER2-)
breast cancer.
In preclinical studies, vepdegestrant demonstrated up to 97% ER
degradation in tumor cells, induced robust tumor shrinkage when
dosed as a single agent in multiple ER-driven xenograft models, and
showed increased anti-tumor activity when compared to a standard of
care agent, fulvestrant, both as a single agent and in combination
with a CDK4/6 inhibitor. In July 2021, Arvinas announced a global
collaboration with Pfizer for the co-development and
co-commercialization of vepdegestrant; Arvinas and Pfizer will
equally share worldwide development costs, commercialization
expenses, and profits. Ongoing and planned clinical trials will
continue to monitor and evaluate the safety and anti-tumor activity
of vepdegestrant.
About ArvinasArvinas is a clinical-stage
biotechnology company dedicated to improving the lives of patients
suffering from debilitating and life-threatening diseases through
the discovery, development, and commercialization of therapies that
degrade disease-causing proteins. Arvinas uses its proprietary
PROTAC Discovery Engine platform to engineer proteolysis targeting
chimeras, or PROTAC targeted protein degraders, that are designed
to harness the body’s own natural protein disposal system to
selectively and efficiently degrade and remove disease-causing
proteins. In addition to its robust preclinical pipeline of PROTAC
protein degraders against validated and “undruggable” targets, the
company has three investigational clinical-stage programs: ARV-766
and bavdegalutamide for the treatment of men with metastatic
castration-resistant prostate cancer; and vepdegestrant (ARV-471)
for the treatment of patients with locally advanced or metastatic
ER+/HER2- breast cancer. Arvinas, as part of its overall business
strategy, selectively assesses opportunities for potential
collaboration, license, marketing and royalty arrangements, and
similar transactions, to advance and accelerate the development and
enhance the commercial potential of its product candidates. For
more information, visit www.arvinas.com.
Arvinas Forward-Looking StatementsThis press
release contains forward-looking statements within the meaning of
The Private Securities Litigation Reform Act of 1995 that involve
substantial risks and uncertainties, including statements regarding
the potential advantages and therapeutic benefits of vepdegestrant
(ARV-471), as well as other statements with respect to
vepdegestrant, including the presentation and/or publication of
data from vepdegestrant trials. All statements, other than
statements of historical facts, contained in this press release are
forward-looking statements. The words “believe,” “expect,” “may,”
“plan,” “potential,” “will,” “continue,” and similar expressions
are intended to identify forward-looking statements, although not
all forward-looking statements contain these identifying words.
We may not actually achieve the plans, intentions or
expectations disclosed in our forward-looking statements, and you
should not place undue reliance on our forward-looking statements.
Actual results or events could differ materially from the plans,
intentions and expectations disclosed in the forward-looking
statements we make as a result of various risks and uncertainties,
including but not limited to: our and Pfizer, Inc.’s (“Pfizer”)
performance of our respective obligations with respect to our
collaboration with Pfizer; whether we and Pfizer will be able to
successfully conduct and complete clinical development for
vepdegestrant and obtain marketing approval for and commercialize
vepdegestrant on our current timelines or at all; whether our cash
and cash equivalent resources will be sufficient to fund our
foreseeable and unforeseeable operating expenses and capital
expenditure requirements; and other important factors discussed in
the “Risk Factors” section of our Annual Report on Form 10-K for
the year ended December 31, 2022, and subsequent other reports on
file with the Securities and Exchange Commission. The
forward-looking statements contained in this press release reflect
our current views with respect to future events, and we assume no
obligation to update any forward-looking statements except as
required by applicable law. These forward-looking statements should
not be relied upon as representing our views as of any date after
the date of this release.
About IBRANCE® (palbociclib) 125 mg tablets and
capsulesIBRANCE is an oral inhibitor of CDKs 4 and
6,1 which are key regulators of the cell cycle that trigger
cellular progression.2,3 In the U.S., IBRANCE is a prescription
medicine indicated for the treatment of adults with HR+,
HER2- advanced or metastatic breast cancer in combination with
an aromatase inhibitor as the first hormonal based therapy; or with
fulvestrant in people with disease progression following hormonal
therapy.
The full U.S. Prescribing Information for the IBRANCE tablets
and the IBRANCE capsules can be
found here and here.
IMPORTANT
IBRANCE®(palbociclib) SAFETY
INFORMATION FROM THE U.S. PRESCRIBING INFORMATION
Neutropenia was the most frequently
reported adverse reaction in PALOMA-2 (80%) and PALOMA-3 (83%). In
PALOMA-2, Grade 3 (56%) or 4 (10%) decreased neutrophil counts were
reported in patients receiving IBRANCE plus letrozole. In PALOMA-3,
Grade 3 (55%) or Grade 4 (11%) decreased neutrophil counts were
reported in patients receiving IBRANCE plus fulvestrant. Febrile
neutropenia has been reported in 1.8% of patients exposed to
IBRANCE across PALOMA-2 and PALOMA-3. One death due to neutropenic
sepsis was observed in PALOMA-3. Inform patients to promptly report
any fever. Monitor complete blood count prior to starting IBRANCE,
at the beginning of each cycle, on Day 15 of first 2 cycles and as
clinically indicated. Dose interruption, dose reduction, or delay
in starting treatment cycles is recommended for patients who
develop Grade 3 or 4 neutropenia.
Severe, life-threatening, or fatal interstitial
lung disease (ILD) and/or pneumonitis can occur in
patients treated with CDK4/6 inhibitors, including IBRANCE when
taken in combination with endocrine therapy. Across clinical trials
(PALOMA-1, PALOMA-2, PALOMA-3), 1.0% of IBRANCE-treated patients
had ILD/pneumonitis of any grade, 0.1% had Grade 3 or 4, and no
fatal cases were reported. Additional cases of ILD/pneumonitis have
been observed in the post-marketing setting, with fatalities
reported. Monitor patients for pulmonary symptoms indicative of
ILD/pneumonitis (e.g. hypoxia, cough, dyspnea). In patients who
have new or worsening respiratory symptoms and are suspected to
have developed pneumonitis, interrupt IBRANCE immediately and
evaluate the patient. Permanently discontinue IBRANCE in patients
with severe ILD or pneumonitis.
Based on the mechanism of action, IBRANCE can
cause fetal harm. Advise females of
reproductive potential to use effective contraception during
IBRANCE treatment and for at least 3 weeks after the last dose.
IBRANCE may impair fertility in
males and has the potential to cause genotoxicity.
Advise male patients to consider sperm preservation before taking
IBRANCE. Advise male patients with female partners of reproductive
potential to use effective contraception during IBRANCE treatment
and for 3 months after the last dose. Advise females to inform
their healthcare provider of a known or suspected pregnancy. Advise
women not to breastfeed during IBRANCE
treatment and for 3 weeks after the last dose because of the
potential for serious adverse reactions in nursing infants.
The most common adverse
reactions(≥10%) of any grade reported
in PALOMA-2 for IBRANCE plus letrozole
vs placebo plus letrozole were neutropenia (80% vs 6%), infections
(60% vs 42%), leukopenia (39% vs 2%), fatigue (37% vs 28%), nausea
(35% vs 26%), alopecia (33% vs 16%), stomatitis (30% vs 14%),
diarrhea (26% vs 19%), anemia (24% vs 9%), rash (18% vs 12%),
asthenia (17% vs 12%), thrombocytopenia (16% vs 1%), vomiting (16%
vs 17%), decreased appetite (15% vs 9%), dry skin (12% vs 6%),
pyrexia (12% vs 9%), and dysgeusia (10% vs 5%).
The most frequently reported Grade ≥3 adverse
reactions
(≥5%) in PALOMA-2 for
IBRANCE plus letrozole vs placebo plus letrozole were neutropenia
(66% vs 2%), leukopenia (25% vs 0%), infections (7% vs 3%), and
anemia (5% vs 2%).
Lab abnormalities of any grade occurring
in PALOMA-2 for IBRANCE plus letrozole
vs placebo plus letrozole were decreased WBC (97% vs 25%),
decreased neutrophils (95% vs 20%), anemia (78% vs 42%), decreased
platelets (63% vs 14%), increased aspartate aminotransferase (52%
vs 34%), and increased alanine aminotransferase (43% vs 30%).
The most common adverse reactions
(≥10%) of any grade reported
in PALOMA-3 for IBRANCE plus fulvestrant
vs placebo plus fulvestrant were neutropenia (83% vs 4%),
leukopenia (53% vs 5%), infections (47% vs 31%), fatigue (41% vs
29%), nausea (34% vs 28%), anemia (30% vs 13%), stomatitis (28% vs
13%), diarrhea (24% vs 19%), thrombocytopenia (23% vs 0%), vomiting
(19% vs 15%), alopecia (18% vs 6%), rash (17% vs 6%), decreased
appetite (16% vs 8%), and pyrexia (13% vs 5%).
The most frequently reported Grade ≥3 adverse
reactions
(≥5%) in PALOMA-3 for
IBRANCE plus fulvestrant vs placebo plus fulvestrant were
neutropenia (66% vs 1%) and leukopenia (31% vs 2%).
Lab abnormalities of any grade occurring
in PALOMA-3 for IBRANCE plus fulvestrant
vs placebo plus fulvestrant were decreased WBC (99% vs 26%),
decreased neutrophils (96% vs 14%), anemia (78% vs 40%), decreased
platelets (62% vs 10%), increased aspartate aminotransferase (43%
vs 48%), and increased alanine aminotransferase (36% vs 34%).
Avoid concurrent use of strong CYP3A
inhibitors. If patients must be administered a strong
CYP3A inhibitor, reduce the IBRANCE dose to 75 mg. If the strong
inhibitor is discontinued, increase the IBRANCE dose (after 3-5
half-lives of the inhibitor) to the dose used prior to the
initiation of the strong CYP3A inhibitor. Grapefruit or grapefruit
juice may increase plasma concentrations of IBRANCE and should be
avoided. Avoid concomitant use of strong CYP3A
inducers. The dose of sensitive CYP3A
substrates with a narrow therapeutic index may need
to be reduced as IBRANCE may increase their exposure.
For patients with severe hepatic
impairment (Child-Pugh class C), the recommended dose
of IBRANCE is 75 mg. The pharmacokinetics of
IBRANCE have not been studied in
patients requiring hemodialysis.
About Pfizer OncologyAt Pfizer Oncology, we are
committed to advancing medicines wherever we believe we can make a
meaningful difference in the lives of people living with cancer.
Today, we have an industry-leading portfolio of 24 approved
innovative cancer medicines and biosimilars across more than 30
indications, including breast, genitourinary, colorectal, blood and
lung cancers, as well as melanoma.
About Pfizer: Breakthroughs That Change Patients’
LivesAt Pfizer, we apply science and our global resources
to bring therapies to people that extend and significantly improve
their lives. We strive to set the standard for quality, safety and
value in the discovery, development and manufacture of health care
products, including innovative medicines and vaccines. Every day,
Pfizer colleagues work across developed and emerging markets to
advance wellness, prevention, treatments and cures that challenge
the most feared diseases of our time. Consistent with our
responsibility as one of the world's premier innovative
biopharmaceutical companies, we collaborate with health care
providers, governments and local communities to support and expand
access to reliable, affordable health care around the world. For
more than 170 years, we have worked to make a difference for all
who rely on us. We routinely post information that may be important
to investors on our website at www.Pfizer.com. In addition, to
learn more, please visit us on www.Pfizer.com and follow us on
Twitter at @Pfizer and @Pfizer News, LinkedIn, YouTube and like us
on Facebook at Facebook.com/Pfizer.
Pfizer Disclosure Notice:The information
contained in this release is as of December 5, 2023. 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
vepdegestrant (ARV-471), IBRANCE® (palbociclib) and a global
collaboration between Pfizer and Arvinas to develop and
commercialize vepdegestrant, including their potential benefits and
plans for clinical trials, 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, the uncertainties
inherent in research and development, including the ability to meet
anticipated clinical endpoints, commencement and/or completion
dates for 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; 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
the clinical studies; whether and when any applications may be
filed for vepdegestrant, IBRANCE or any potential combinations for
any potential indications in any jurisdictions; whether and when
regulatory authorities may approve any potential applications that
may be filed for vepdegestrant, IBRANCE or any potential
combinations in any jurisdictions, 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 vepdegestrant,
IBRANCE or any potential combinations 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 vepdegestrant,
IBRANCE or any potential combinations; whether the collaboration
between Pfizer and Arvinas will be successful; uncertainties
regarding the impact of COVID-19 on Pfizer’s business, operations
and financial results; 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, 2022, 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.
Arvinas Contacts
Investor Contact:Jeff Boyle, Arvinas Investor
Relations347-247-5089Jeff.Boyle@arvinas.com
Media Contact:Kirsten Owens, Arvinas
Communications203-584-0307Kirsten.Owens@arvinas.com
Pfizer Contacts
Investor Contact:+1 (212)
733-4848IR@pfizer.com
Media Contact:+1 (212)
733-1226PfizerMediaRelations@pfizer.com
1 IBRANCE® (palbociclib) Prescribing Information. New
York. NY: Pfizer Inc: 2022.2 Weinberg, RA. pRb and Control of the
Cell Cycle Clock. In: Weinberg RA, ed. The Biology of
Cancer. 2nd ed. New York, NY: Garland Science; 2014:275-329.3
Sotillo E, Grana X. Escape from Cellular Quiescence. In: Enders GH,
ed. Cell Cycle Deregulation in Cancer. New York, NY: Humana Press;
2010:3-22.
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