Vepdegestrant
ARV-471
The product of a global collaboration between Arvinas Inc and Pfizer Inc, vepdegestrant has the potential to become the first PROteolysis Targeting Chimera (PROTAC®) protein degrader to reach the market. Vepdegestrant is designed to target and degrade the estrogen receptor (ER) protein, and early studies have shown that PROTAC-induced protein degradation is more complete than with oral selective estrogen receptor degraders (SERDs). This promises a potential strategy to overcome endocrine resistance in breast cancer, which could be groundbreaking for this patient population. Label expansions being explored include combination with IBRANCE® (palbociclib; Pfizer Inc).
About Vepdegestrant
- Arvinas Inc
- Pfizer Inc
- ER PROTAC degrader
- Oral administration to treat adults with estrogen receptor (ER)-positive/HER2-negative locally advanced or metastatic breast cancer
- ~90K new cases of previously untreated (first-line) metastatic HR-positive/HER2-negative breast cancer in the G7 markets in 2024
- ~115K new cases of previously treated (second- and third-line) HR-positive/HER2-negative breast cancer in the G7 markets in 2024
Why is it a drug to watch?
Vepdegestrant is being developed as potential monotherapy and part of combination therapy for ER-positive/HER2-negative metastatic breast cancer. Vepdegestrant is the first PROTAC therapy to reach phase 3 development in breast cancer where it has shown promising efficacy in the phase 2 VERITAC trial.
Results have been reported from the following trials:
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Phase 1b of the VERITAC trial (part C): patients treated with at least one prior line of endocrine therapy and no more than 2 lines of chemotherapy in the metastatic setting:
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Vepdegestrant in combination with IBRANCE
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ITT population (N=46; ESR1-mutant and wild-type patients)
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87% had received prior treatment with a CDK4/6 inhibitor (78% had received IBRANCE)
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80% had received prior fulvestrant
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46% had received chemotherapy in the metastatic setting
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ORR: 42% (47% in the ESR1-mutant subgroup, N=29)
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Median PFS: 11.2 months (13.7 months in the ESR1-mutant subgroup)
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Subgroup of patients with no prior CDK4/6 inhibitor treatment:
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Median PFS: 19.3 months (2 of 6 events)
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Phase 2 cohort expansion of the VERITAC trial (part B): patients treated with at least one prior line of endocrine therapy and CDK4/6 inhibitors in the metastatic setting:
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Vepdegestrant monotherapy
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ITT population (N=71; ESR1-mutant and wild-type patients with a median number of 3 prior regimens in the metastatic setting)
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78.9% had received prior treatment with fulvestrant
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45.1% had received prior chemotherapy in the metastatic setting
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CBR: 38% (51.2% in the ESR1-mutant subgroup)
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Median PFS: 3.7 months (5.7 months in the ESR1-mutant subgroup)
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Subgroup of patients (N=8) with no prior fulvestrant or chemotherapy in the metastatic setting
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CBR: 62.5%
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Median PFS: 19 months (4 of 8 events)
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ORR: 29%
The following phase 3 trials are ongoing:
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VERITAC-2: patients with metastatic ER-positive/HER2-negative breast cancer who have received prior treatment with CDK4/6 inhibitors and endocrine therapy in the metastatic setting with no more than one additional line of endocrine therapy (second- and third-line metastatic setting)
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Vepdegestrant monotherapy vs fulvestrant
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Dual primary endpoints: PFS in the ITT population and in the ESR1-mutant subgroup
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Expected topline data: February 2025
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VERITAC-3: endocrine-sensitive patients who have not received prior treatment for their metastatic setting nor adjuvant CDK4/6 inhibitors (first-line metastatic setting):
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Vepdegestrant in combination with IBRANCE vs letrozole in combination with IBRANCE
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Primary endpoint: PFS in the ITT population
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Two additional pivotal trials are planned (pending further data and regulatory agreement):
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Vepdegestrant in combination with atirmociclib in the first-line setting
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Vepdegestrant in combination with IBRANCE or potentially other CDK4/6 inhibitors in the second- and third-line setting
Several phase 1/1b and phase 2 studies (TACTIVE-K/N/U/E) are also investigating the preliminary efficacy and safety for vepdegestrant in combination with other targeted agents as well as its efficacy in the neoadjuvant setting.
Review and approval status
July 2023
- Innovation passport designation via the Innovative Licensing Access Pathway (ILAP): U.K. MHRA
February 2024
- Fast track designation: U.S. FDA
Actual and expected launch:
- 2025: European Union, Japan, United States
- 2027: Mainland China
Patents estimated to expire beginning in 2022
Drug Timeline & Success Rates
Source: Cortellis Competitive Intelligence, Drug Timeline & Success Rates Prediction current as of October 31, 2024
How will vepdegestrant impact the market for breast cancer?
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Breast cancer is one of the largest therapy markets in oncology in terms of current dollar value, owing to the large number of diagnosed incident cases, high drug treatment rates and typically long treatment durations.
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In 2033, sales are expected to be dominated by two drug classes that will amass sales of approximately $27bn and capture nearly two-thirds of the total market share: HER2-targeted agents and CDK4/6 inhibitors. HR-positive/HER2-negative sales are anticipated to increase from $13.8bn in 2023 to $23.2bn in 2033.
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Within the class of ER-targeting agents, next-generation drugs are expected to collectively garner $3.1bn in sales in 23033, largely driven by the market entry of vepdegestrant and the oral SERD camizestrant (AstraZeneca). Others that will likely be approved over the next few years include the oral SERD imlunestrant (Eli Lilly and Co), oral selective estrogen receptor modulator (SERM) lasofoxifene (Sermonix Pharmaceuticals Inc) and the complete ER antagonist (CERAN) palazestrant (Olema Pharmaceuticals Inc).
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Vepdegestrant is expected to gain its first market approval as a monotherapy for the treatment of patients with endocrine-sensitive metastatic HR-positive/HER2-negative breast cancer who have received at least one prior line of endocrine therapy in the metastatic setting and have had exposure to a CDK4/6 inhibitor (i.e., second- and later-line setting). We expect that the agent will gain a broad label (for ESR1-mutant and non-mutant) and compete for patient share with other emerging ER-targeting drugs forecast to enter the same setting.
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In the first-line metastatic HR-positive/HER2-negative setting, we expect approval of vepdegestrant in combination with IBRANCE (Pfizer Inc) in a non-biomarker-restricted population; this regimen will compete with approved CDK4/6-inhibitor based regimens that have standard endocrine therapy (e.g., letrozole) as a backbone.
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Label expansions of vepdegestrant in combination with other targeted therapies for first-line metastatic HR-positive/HER2-negative disease, a larger and thus more lucrative setting, could boost its sales and improve its market share in this segment
What gaps in treatment does vepdegestrant fill?
Following treatment in the metastatic HR-positive/HER2-negative breast cancer setting, a high proportion of patients (~30-40%) develop disease recurrence owing to the acquisition of ESR1 mutations. The oral SERD ORSERDU® (elacestrant; Menarini Group) is the only therapy in the market with proven efficacy in this subgroup of patients. Vepdegestrant degrades both ESR1-mutant and ESR1-wildtype, and we expect it to become part of the treatment armamentarium in the post-CDK4/6-inhibitor setting, where currently available therapies (especially for patients without mutations that can be targeted) show limited efficacy outcomes. Additionally, its development in combination with CDK4/6 inhibitors in the first-line setting could provide better inhibition of ER-driven tumor survival and proliferation than standard endocrine therapies (e.g., aromatase inhibitors), thereby delaying disease progression.
What hurdles might it need to overcome to reach blockbuster status?
Regulatory approval and launch of multiple ER-targeting agents in the second- and later-line settings could introduce intense competition and therefore constrain uptake of vepdegestrant. Blockbuster status also hinges on successful label expansions for use in the treatment of first-line metastatic disease where it is currently being investigated in combination with IBRANCE (Pfizer Inc).
