Combination Enfortumab Vedotin + Pembrolizumab Granted Breakthrough Therapy in Bladder Cancer – OncoZine
By daniellenierenberg
The U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to enfortumab vedotin-ejfv (Padcev; Astellas Pharma and Seattle Genetics) in combination with Mercks (known as MSD outside the United States and Canada) anti-PD-1 therapy pembrolizumab (Keytruda) for the treatment of patients with unresectable locally advanced or metastatic urothelial cancer who are unable to receive cisplatin-based chemotherapy in the first-line setting.
It is estimated that approximately 81,000 people in the U.S. will be diagnosed with bladder cancer in 2020. [1] Urothelial cancer accounts for 90% of all bladder cancers and can also be found in the renal pelvis, ureter, and urethra. [2] Globally, approximately 549,000 people were diagnosed with bladder cancer in 2018, and there were approximately 200,000 deaths worldwide. [3]
The recommended first-line treatment for patients with advanced urothelial cancer is cisplatin-based chemotherapy. For patients who are unable to receive cisplatin, such as people with kidney impairment, a carboplatin-based regimen is recommended. However, fewer than half of patients respond to carboplatin-based regimens and outcomes are typically poorer compared to cisplatin-based regimens. [4]
Conditionally approvedEnfortumab vedotin-ejfv, a first-in-class antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer, was conditionally approved by the FDA in December 2019 based on the Accelerated Approval Program. [5][6]
Antibody-drug Conjugates or ADCs are highly targeted biopharmaceutical drugs that combine monoclonal antibodies specific to surface antigens present on particular tumor cells with highly potent anti-cancer agents linked via a chemical linker.
With seven approved drugs on the market, ADCs have become a powerful class of therapeutic agents in oncology and hematology.
Continued approval for enfortumab vedotin-ejfv in combination with pembrolizumab for the treatment of patients with advanced or metastatic urothelial cancer may be contingent upon verification and description of clinical benefit in confirmatory trials. [5]
The drug is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and a platinum-containing chemotherapy before (neoadjuvant) or after (adjuvant) surgery or in a locally advanced or metastatic setting.
Nonclinical data suggest the anticancer activity of enfortumab vedotin is due to its binding to Nectin-4 expressing cells followed by the internalization and release of the anti-tumor agent monomethyl auristatin E (MMAE) into the cell, which result in the cell not reproducing (cell cycle arrest) and in programmed cell death (apoptosis). [5]
Breakthrough therapyThe Breakthrough Therapy process is designed to expedite the development and review of drugs that are intended to treat a serious or life-threatening condition. The designation is based upon preliminary clinical evidence indicating that the drug may demonstrate substantial improvement over available therapies on one or more clinically significant endpoints. In the case of enfortumab vedotin, the designation was based on the initial results from Phase Ib/II EV-103 Clinical Trial.
The FDAs Breakthrough Therapy designation reflects the encouraging preliminary evidence for the combination of enfortumab vedotin and pembrolizumab in previously untreated advanced urothelial cancer to benefit patients who are in need of effective treatment options, said Andrew Krivoshik, M.D., Ph.D., Senior Vice President, and Oncology Therapeutic Area Head, Astellas.
We look forward to continuing our work with the FDA as we progress our clinical development program as quickly as possible.
This is an important step in our investigation of enfortumab vedotin in combination with pembrolizumab as first-line therapy for patients with advanced urothelial cancer who are unable to receive cisplatin-based chemotherapy, said Roger Dansey, M.D., Chief Medical Officer, Seattle Genetics.
Based on encouraging early clinical activity, we recently initiated a phase III trial of this platinum-free combination and look forward to potentially addressing an unmet need for patients.
Clinical trialThe Breakthrough Therapy designation was granted based on results from the dose-escalation cohort and expansion cohort A of the Phase Ib/II trial, EV-103 (NCT03288545), evaluating patients with locally advanced or metastatic urothelial cancer who are unable to receive cisplatin-based chemotherapy-treated in the first-line setting with enfortumab vedotin-ejfv in combination with pembrolizumab.
The initial results from the trial were presented at the European Society of Medical Oncology (ESMO) 2019 Congress, and updated findings at the 2020 Genitourinary Cancers Symposium.
EV-103 is an ongoing, multi-cohort, open-label, multicenter phase Ib/II trial of PADCEV alone or in combination, evaluating the safety, tolerability, and efficacy in muscle-invasive, locally advanced and first- and second-line metastatic urothelial cancer.
Adverse eventsSerious adverse reactions occurred in 46% of patients treated with enfortumab vedotin-ejfv. The most common serious adverse reactions (3%) were urinary tract infection (6%), cellulitis (5%), febrile neutropenia (4%), diarrhea (4%), sepsis (3%), acute kidney injury (3%), dyspnea (3%), and rash (3%). Fatal adverse reactions occurred in 3.2% of patients, including acute respiratory failure, aspiration pneumonia, cardiac disorder, and sepsis (each 0.8%).
Discontinuing treatmentAdverse reactions leading to discontinuation occurred in 16% of patients; the most common adverse reaction leading to discontinuation was peripheral neuropathy (6%). Adverse reactions leading to dose interruption occurred in 64% of patients; the most common adverse reactions leading to dose interruption were peripheral neuropathy (18%), rash (9%) and fatigue (6%). Adverse reactions leading to dose reduction occurred in 34% of patients; the most common adverse reactions leading to dose reduction were peripheral neuropathy (12%), rash (6%) and fatigue (4%).
The most common adverse reactions (20%) were fatigue (56%), peripheral neuropathy (56%), decreased appetite (52%), rash (52%), alopecia (50%), nausea (45%), dysgeusia (42%), diarrhea (42%), dry eye (40%), pruritus (26%) and dry skin (26%). The most common Grade 3 adverse reactions (5%) were rash (13%), diarrhea (6%) and fatigue (6%).
Specific recommendations
HyperglycemiaHyperglycemia occurred in patients treated with enfortumab vedotin-ejfv, including death and diabetic ketoacidosis (DKA), in patients with and without pre-existing diabetes mellitus. The incidence of Grade 3-4 hyperglycemia increased consistently in patients with higher body mass index and in patients with higher baseline A1C. In one clinical trial, 8% of patients developed Grade 3-4 hyperglycemia. Patients with baseline hemoglobin A1C 8% were excluded.
Physicians are recommended to closely monitor blood glucose levels in patients with, or at risk for, diabetes mellitus or hyperglycemia and, if blood glucose is elevated (>250 mg/dL), withhold the drug.
Peripheral neuropathyPeripheral neuropathy (PN), predominantly sensory, occurred in 49% of the 310 patients treated with enfortumab vedotin-ejf in clinical trials. Two percent (2%) of patients experienced Grade 3 reactions. In one clinical trial, peripheral neuropathy occurred in patients treated with enfortumab vedotin-ejf with or without preexisting peripheral neuropathy.
The median time to onset of Grade 2 was 3.8 months (range: 0.6 to 9.2). Neuropathy led to treatment discontinuation in 6% of patients. At the time of their last evaluation, 19% had complete resolution, and 26% had partial improvement.
Physicians should:
Occular disordersOcular disorders occurred in 46% of the 310 patients treated with enfortumab vedotin-ejf. The majority of these events involved the cornea and included keratitis, blurred vision, limbal stem cell deficiency and other events associated with dry eyes. Dry eye symptoms occurred in 36% of patients, and blurred vision occurred in 14% of patients, during treatment with enfortumab vedotin-ejf.
The median time to onset to symptomatic ocular disorder was 1.9 months (range: 0.3 to 6.2).
Physicians should monitor patients for ocular disorders and consider:
Skin reactionsSkin reactions occurred in 54% of the 310 patients treated with enfortumab vedotin-ejf in clinical trials. Twenty-six percent (26%) of patients had a maculopapular rash and 30% had pruritus. Grade 3-4 skin reactions occurred in 10% of patients and included symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), bullous dermatitis, exfoliative dermatitis, and palmar-plantar erythrodysesthesia. In one clinical trial, the median time to onset of severe skin reactions was 0.8 months (range: 0.2 to 5.3).
Of the patients who experienced rash, 65% had complete resolution and 22% had partial improvement.
Physicians should monitor patients for skin reactions, and consider:
Infusion site extravasationSkin and soft tissue reactions secondary to extravasation have been observed after the administration of enfortumab vedotin-ejf. Of the 310 patients, 1.3% of patients experienced skin and soft tissue reactions. Reactions may be delayed.
Erythema, swelling, increased temperature, and pain worsened until 2-7 days after extravasation and resolved within 1-4 weeks of peak. One percent (1%) of patients developed extravasation reactions with secondary cellulitis, bullae, or exfoliation.
Physicians should ensure adequate venous access prior to starting enfortumab vedotin-ejf and monitor for possible extravasation during administration. If extravasation occurs, stop the infusion and monitor for adverse reactions.
Embryo-fetal toxicityEnfortumab vedotin-ejf can cause fetal harm when administered to a pregnant woman.
Physicians should advise patients of the potential risk to the fetus and advise female patients of reproductive potential to use effective contraception during enfortumab vedotin-ejf treatment and for 2 months after the last dose. At the same time, they should advise male patients with female partners of reproductive potential to use effective contraception during treatment with enfortumab vedotin-ejf and for 4 months after the last dose.
Clinical trialA Study of Enfortumab Vedotin Alone or With Other Therapies for Treatment of Urothelial Cancer (EV-103) NCT03288545
References[1] American Cancer Society. Cancer Facts & Figures 2020. Online. Last accessed on January 23, 2020.[2] American Society of Clinical Oncology. Bladder cancer: introduction (10-2017). Online. Last accessed on January 23, 2020.[3] International Agency for Research on Cancer. Cancer Tomorrow: Bladder. Online. Last accessed on January 23, 2020.[4] National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Bladder Cancer. Version 4; July 10, 2019. Online. Last accessed on January 23, 2020.[5] Enfortumab vedotin-ejfv (Padcev; Astellas Pharma [package insert]. Northbrook, IL)[6] Challita-Eid P, Satpayev D, Yang P, et al. Enfortumab Vedotin Antibody-Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models. Cancer Res 2016;76(10):3003-13.
A version of this article was first published in ADC Review | Journal of Antibody-drug Conjugates.
Read more here:
Combination Enfortumab Vedotin + Pembrolizumab Granted Breakthrough Therapy in Bladder Cancer - OncoZine
- 001 Elaine Fuchs discusses research on skin and adult stem cells [Last Updated On: June 25th, 2011] [Originally Added On: June 25th, 2011]
- 002 Skin Stem Cells: Their Biology [Last Updated On: June 25th, 2011] [Originally Added On: June 25th, 2011]
- 003 Come Back Kid [Last Updated On: June 26th, 2011] [Originally Added On: June 26th, 2011]
- 004 Emerge Labs New Anti Aging Swiss Apple Stem Cell Skin Care [Last Updated On: June 26th, 2011] [Originally Added On: June 26th, 2011]
- 005 PhytoCell.mp4 [Last Updated On: June 26th, 2011] [Originally Added On: June 26th, 2011]
- 006 Elaine Fuchs Part 2: Tapping the Potential of Adult Stem Cells, and Summary [Last Updated On: June 28th, 2011] [Originally Added On: June 28th, 2011]
- 007 Elaine Fuchs Part 1: Introduction to Stem Cells [Last Updated On: July 1st, 2011] [Originally Added On: July 1st, 2011]
- 008 Stem Cell Facial At Metamorphosis Day Spa Using Emerge Labs Skin Care [Last Updated On: July 1st, 2011] [Originally Added On: July 1st, 2011]
- 009 A Major Breakthrough in Skin Care and Nutrition [Last Updated On: July 7th, 2011] [Originally Added On: July 7th, 2011]
- 010 The Skin Gun stem cell research [Last Updated On: July 7th, 2011] [Originally Added On: July 7th, 2011]
- 011 The Skin Gun [Last Updated On: July 7th, 2011] [Originally Added On: July 7th, 2011]
- 012 E'shee HBA Global Expo 2011, NYC. Skin Care Anti-Aging Symposium [Last Updated On: July 8th, 2011] [Originally Added On: July 8th, 2011]
- 013 World's 1st Nutricosmetic with Stem Cell Nutrients [Last Updated On: July 15th, 2011] [Originally Added On: July 15th, 2011]
- 014 Stem cells acquired from human skin [Last Updated On: August 22nd, 2011] [Originally Added On: August 22nd, 2011]
- 015 DermaStem Renewal Serum - Stem Cells for Your Skin from STEMTech - New Paradigm in Beauty! [Last Updated On: August 30th, 2011] [Originally Added On: August 30th, 2011]
- 016 Stem Cells Made From Human Skin [Last Updated On: September 4th, 2011] [Originally Added On: September 4th, 2011]
- 017 ReLuma-stemcells- skin rejuvenation [Last Updated On: September 5th, 2011] [Originally Added On: September 5th, 2011]
- 018 Jeunesse Global Business Opportunity with Stem Cell Skin Care Developed by Dr Nathan Newman [Last Updated On: September 5th, 2011] [Originally Added On: September 5th, 2011]
- 019 Dr Nathan Newman- Formulator of Stem Cell Skin Care Line LUMINESCE [Last Updated On: September 6th, 2011] [Originally Added On: September 6th, 2011]
- 020 Luminesce Stem Cell Skin Care - Leaders in Jeunesse [Last Updated On: September 7th, 2011] [Originally Added On: September 7th, 2011]
- 021 Stem Cell Therapy - BioLogic Anti-Aging Skin Cream [Last Updated On: September 7th, 2011] [Originally Added On: September 7th, 2011]
- 022 Isolation and Culture of Adult Epithelial Stem Cells from Human Skin [Last Updated On: September 8th, 2011] [Originally Added On: September 8th, 2011]
- 023 Stem Cell Skin Care- What is the role of stem cells in Luminesce Featuring Dr Nathan Newman [Last Updated On: September 9th, 2011] [Originally Added On: September 9th, 2011]
- 024 Genetic Skin Disease (EB): Spotlight on Stem Cell Research - Patient Advocate [Last Updated On: September 11th, 2011] [Originally Added On: September 11th, 2011]
- 025 Genetic Skin Disease (EB): Optimizing Embryonic Stem Cell Differentiation Protocols [Last Updated On: September 12th, 2011] [Originally Added On: September 12th, 2011]
- 026 Genetic Skin Disease (EB): Spotlight on Stem Cell Research - Introduction [Last Updated On: September 13th, 2011] [Originally Added On: September 13th, 2011]
- 027 The Skin Gun (Stem Cell research to replace burnt off skin. Done in 3 days!) [Last Updated On: September 15th, 2011] [Originally Added On: September 15th, 2011]
- 028 Best natural skin care serum using stem cell technology [Last Updated On: September 22nd, 2011] [Originally Added On: September 22nd, 2011]
- 029 Stem Cells: Fulfilling the Promise - 2011 CIRM Grantee Meeting [Last Updated On: September 24th, 2011] [Originally Added On: September 24th, 2011]
- 030 Jeunesse Global Opportunity- Stem Cell Skin Care [Last Updated On: September 25th, 2011] [Originally Added On: September 25th, 2011]
- 031 Research on skin cancer: ERC funds studies on stem cells [Last Updated On: September 26th, 2011] [Originally Added On: September 26th, 2011]
- 032 Stem Cell Therapy Skin Repair and Anti-Wrinkle Cream [Last Updated On: September 29th, 2011] [Originally Added On: September 29th, 2011]
- 033 Skin engineering [Last Updated On: September 30th, 2011] [Originally Added On: September 30th, 2011]
- 034 Stem Cell Face Treatment - What People Are Saying | Beverly Hills | Los Angeles [Last Updated On: October 1st, 2011] [Originally Added On: October 1st, 2011]
- 035 How To Use Your Stem Cells For Facial Skin Rejuvenation [Last Updated On: October 5th, 2011] [Originally Added On: October 5th, 2011]
- 036 AMAZING - Stem Cell Skin Cream And Liquid Face Lift Revealed [Last Updated On: October 5th, 2011] [Originally Added On: October 5th, 2011]
- 037 Dr Nathan Newman MD Stem Cell Face lift on Channel 7 KABC.flv [Last Updated On: October 5th, 2011] [Originally Added On: October 5th, 2011]
- 038 Genetic Skin Disease (EB): Spotlight on Stem Cell Research - Welcome [Last Updated On: October 5th, 2011] [Originally Added On: October 5th, 2011]
- 039 Dr.Thomas Barnes' PRP Hair Growth and Skin Rejuvenation [Last Updated On: October 5th, 2011] [Originally Added On: October 5th, 2011]
- 040 For Damaged Skin - Rejuvenate Your Own Stem Cells [Last Updated On: October 5th, 2011] [Originally Added On: October 5th, 2011]
- 041 real food real life - Stemulance stem cell face products [Last Updated On: October 5th, 2011] [Originally Added On: October 5th, 2011]
- 042 Dr Amiya Prasad discusses ACell for Hair Regrowth and Skin Rejuvenation with EYES IN Magazine [Last Updated On: October 5th, 2011] [Originally Added On: October 5th, 2011]
- 043 Stem Cell Face Lift - English (Part 5) [Last Updated On: October 6th, 2011] [Originally Added On: October 6th, 2011]
- 044 Cell Reprogramming Transformed [Last Updated On: October 6th, 2011] [Originally Added On: October 6th, 2011]
- 045 Care for Your Skin with Lifeline Skin Care [Last Updated On: October 6th, 2011] [Originally Added On: October 6th, 2011]
- 046 Dr Nathan Newman Repairs Laugh Lines With Stem Cell Face Lift [Last Updated On: October 6th, 2011] [Originally Added On: October 6th, 2011]
- 047 Ellis Martin Report with International Stem Cell Corp [Last Updated On: October 6th, 2011] [Originally Added On: October 6th, 2011]
- 048 Stem Cell Banking: The Perspective of an iPS Donor Family [Last Updated On: October 6th, 2011] [Originally Added On: October 6th, 2011]
- 049 Dr Nathan Newman Stem Cell Face Lift on Entertainment Tonight [Last Updated On: October 8th, 2011] [Originally Added On: October 8th, 2011]
- 050 Elaine Fuchs Part 1: Introduction to Stem Cells English Subtitle [Last Updated On: October 12th, 2011] [Originally Added On: October 12th, 2011]
- 051 Signals Stem Cell Skin Care Anti Aging Skin Care - Video [Last Updated On: October 14th, 2011] [Originally Added On: October 14th, 2011]
- 052 Stem Cell Skin Care - Born Different.mp4 - Video [Last Updated On: October 18th, 2011] [Originally Added On: October 18th, 2011]
- 053 APPLE STEMCELL by SEMCELL - Video [Last Updated On: October 21st, 2011] [Originally Added On: October 21st, 2011]
- 054 Jeunesse Luminesce Stem Cell Skin care Before and After Pictures - Video [Last Updated On: October 23rd, 2011] [Originally Added On: October 23rd, 2011]
- 055 Stem Cell Therapy -- Reduce Wrinkles,Promote Younger, Healthier Looking Skin - Video [Last Updated On: October 25th, 2011] [Originally Added On: October 25th, 2011]
- 056 Scientists Create Liver from Reprogrammed Human Skin Cells No Stem Cells Needed - Video [Last Updated On: October 25th, 2011] [Originally Added On: October 25th, 2011]
- 057 Vitiligo and Stem Cells: Narrowband UVB Phototherapy in Nonsegmental Vitiligo - Video [Last Updated On: October 25th, 2011] [Originally Added On: October 25th, 2011]
- 058 Dr Nathan Newman MD Stem Cell Face lift on Entertainment Tonight - NewHopeForAging.com - Video [Last Updated On: October 25th, 2011] [Originally Added On: October 25th, 2011]
- 059 Skin Healing And Anti-Aging - Rejuvenate Aging Skin Cells - Video [Last Updated On: October 25th, 2011] [Originally Added On: October 25th, 2011]
- 060 Stem Cell Face Lift - Video [Last Updated On: October 27th, 2011] [Originally Added On: October 27th, 2011]
- 061 Stem Cell Therapy Face Cream - Video [Last Updated On: October 27th, 2011] [Originally Added On: October 27th, 2011]
- 062 Growing skin in lab with stem cells Video Reuters - Video [Last Updated On: October 27th, 2011] [Originally Added On: October 27th, 2011]
- 063 Stem Cells and Their Lineages in Skin - Video [Last Updated On: October 27th, 2011] [Originally Added On: October 27th, 2011]
- 064 Stem Cells Rock - Video [Last Updated On: October 27th, 2011] [Originally Added On: October 27th, 2011]
- 065 Stem Cell Therapy: Healing Force of the future - Video [Last Updated On: October 29th, 2011] [Originally Added On: October 29th, 2011]
- 066 Alex Cosmeceuticals - Phyto Stem Cell Technology - Video [Last Updated On: October 29th, 2011] [Originally Added On: October 29th, 2011]
- 067 Reprogramming skin cells into embryonic stem cells - Video [Last Updated On: October 29th, 2011] [Originally Added On: October 29th, 2011]
- 068 Ellis Martin Report with International Stem Cell Corp - YouTube2.flv - Video [Last Updated On: October 30th, 2011] [Originally Added On: October 30th, 2011]
- 069 Dr Lyras Plastic Surgery - Skin Needling 3 - Tv 2011 - Video [Last Updated On: November 5th, 2011] [Originally Added On: November 5th, 2011]
- 070 Donna Queen-Lifeline Skin Care at the CACS - Video [Last Updated On: November 8th, 2011] [Originally Added On: November 8th, 2011]
- 071 Turning Science Into Action with Heather Livingston - Part 1 www.miraclecell.info - Video [Last Updated On: November 12th, 2011] [Originally Added On: November 12th, 2011]
- 072 US scientists unveil new cloning method for embryonic stem cells - Video [Last Updated On: November 12th, 2011] [Originally Added On: November 12th, 2011]
- 073 A Stem Cell Story - Video [Last Updated On: November 12th, 2011] [Originally Added On: November 12th, 2011]
- 074 Perspectives of a Stem Cell Donor Family - Video [Last Updated On: November 13th, 2011] [Originally Added On: November 13th, 2011]
- 075 Adult Stem Cell Success Stories - Amy Daniels - Video [Last Updated On: November 15th, 2011] [Originally Added On: November 15th, 2011]
- 076 StemCellTV - From National Geographic - The Skin Gun - Healing Burns with Stem Cells - Video [Last Updated On: November 16th, 2011] [Originally Added On: November 16th, 2011]
- 077 Stem Cell Skin Care Jeunesse- Dr Newman FAQ - Video [Last Updated On: November 18th, 2011] [Originally Added On: November 18th, 2011]
- 078 Dr Nathan Newman and Jeunesse Stem Cell Skin Care - Video [Last Updated On: November 26th, 2011] [Originally Added On: November 26th, 2011]
- 079 Apple Stem Cell-Skin aging solution - Video [Last Updated On: November 29th, 2011] [Originally Added On: November 29th, 2011]
- 080 Luminesce rejuvenation serum cellular rejuvenation stem cell skin Products - Video [Last Updated On: November 29th, 2011] [Originally Added On: November 29th, 2011]
