Homepage – Forum › Forums › Research, Clinical Trials, and New Treatments › PADCEV and Immunotherapy combo is a game changer for advanced bladder cancer
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Joe.
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April 29, 2024 at 6:02 pm #47609
Joe
ParticipantThis is the statement posted at FDA site with the heading FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer
On December 15, 2023, the Food and Drug Administration (FDA) approved enfortumab vedotin-ejfv (Padcev, Astellas Pharma) in combination with pembrolizumab (Keytruda, Merck) for patients with locally advanced or metastatic urothelial cancer (la/mUC). FDA previously granted accelerated approval to this combination for patients with la/mUC who are ineligible for cisplatin-containing chemotherapy. The excellent result of the clinical trial EV-302 which compared the combo treatment with cisplatin based chemotherapy as the first line treatment for la/mUC. In the EV-302 phase 3 study of 886 untreated patients, the combo produced a median overall survival (OS) rate of 31.5 months compared to 16.1 months for chemo. The combo produced similar success in progression-free survival (PFS), reducing the risk of disease progression or death by 55%. Patients on the combo regimen lived a median of 12.5 months without progression, versus 6.3 months for the chemo arm. *1
In the BCC Webinar on clinical trials, Dr. Peter Black mentioned that the presentation of the result of Phase 3 clinical trial of the combination PADCEV (enfortuymab vedotin-ejfv) and Keytruda (Pembrolizumab had received a standing ovation from participants during the European Society for Medical Oncology (ESMO) in October, 2023.
It has been known cisplatin works well for bladder cancers, so up to now, cisplatin based chemotherapy such as the combination two different chemotherapy drugs, i.e. Gemcitabine and Cisplatin has been the first line treatment for la/mUC. However it is known that cancers tend to develop resistance to chemotherapy over time. But, after platinum-based chemotherapy, there is no internationally accepted standard of care. Single-agent paclitaxel and docetaxel are commonly used worldwide. *2
In 2017, two immunotherapy drugs, Pembrolizumab (Keytruda) by Merck and Atezolizumab (Tecentriq) by Roche were approved as the 2nd line treatment for la/mUC when the first line chemotherapy failed. Keytruda is PD-1 immune checkpoint inhibitor and Tecentriq is PD-L1 in immune check point inhibitor. Both drugs had shown similar efficacies and side effects. The clinical trial which led to the approval of Keytruda showed the median overall survival was 10.3 months in the Keytruda group as compared with 7.4 moths in the chemotherapy group. The estimated progression-free survival rate at 12 months was 16.8% in the pembrolizumab group and 6.2% in the chemotherapy group. Though Keytruda resulted in modest improvement over chemotherapy, Keytruda improved significant durability once the treatment worked.
PADCEV belongs to a group of drugs called Antibody-Drug Conjugate (ADC). ADC uses synthesized human antibody as drug delivery vehicle which carries a load of cytotoxin, which has anti-tumor activities. PADCEV targets NECTIN-4 protein which are often highly expressed on cell membrane of bladder cancers. Once PADCEV binds to NECTIN-4 of cancer cell, it releases Monomethyl auristatin E (MMAE) is a very potent antimitotic agent that inhibits cell division by blocking the formation of microtubules which is almost the final step of the cell division cycle, leading to the death of the cell. In December, 2019 FDA approved PADCEV as the third line treatment for la/mUC when the 2nd line treatment immunotherapy failed. I believe PADCEV became available for patients in Canada in 2022. *3
Then it has become a bit complicated. After, PADCEV was approved by FDA in December, 2019. In June 2020, FDA approved another immunotherapy Drug (PD-L1 inhibitor) Avelumab (Bavencio) as maintenance treatment for la/mUC immediately after the first line cisplatin based chemotherapy for those patient which did not progress during the chemotherapy treatment. The clinical trial of Avelumab (Bavencio) improved over all survival at 1 year to 71.3% compared to 58.4% in the group who just received best supportive care alone. Health Canada approved Avelumab (Bavencio) in January 2021 for bladder cancer. I think Avelumab (Bavencio) became available for patients in Canada after March, 2021. *4
Because the PADCEV and Keytruda combo treatment as the first line treatment for la/mUC doubled over all survival and progression free survival with durability over traditional cisplatin based chemotherapy, the combo is expected to be the standard 1st line treatment for la/mUC. The combo treatment may make the role of Avelumab irrelevant. Both PADCEV and Keytruda are already approved drug in Canada. So, the approval process for the combo treatment may take less time. Lets hope so. A challenge is the price of the combo treatment. A US industry paper is saying that PADCEV + Keytruda combo treatment can initially cost Medicare per patient $435K annually, compared to platinum based chemotherapy only $3.5K , and chemotherapy with Avelumab maintenance $96K. *5
Zitter Insights polled 35 commercial payers covering 116.7 million lives, 26 Medicare payers covering 42.3 million lives, 50 oncologists and 52 practice managers about their management of and prescribing for bladder cancer. Payers said that an annualized net price for Padcev + Keytruda between $189,000 and $204,000 would be appropriately priced, while a price more than $281,000 would be too expensive, leading to their not covering or highly restricting the regimen. *6
A 2020 study shows that the cost of the same cancer drug costs about 2.31 times in the US compared European countries. For example, Keytruda costs $14,167 monthly in the US whereas it costs $9,150 in UK, $7600 in Germany and $8,300 in France. I expect it is costing Canada similar to European countries. I hope Padcev + Keytruda combo treatment will become accessible to Canadian patients soon.
I will list the links to related studies and documents in the following post.
April 30, 2024 at 5:16 pm #47612Joe
ParticipantThe links to relevant information. I tried to use the link but the the whole text disappeared. The link must be copied and pasted in any search engine. Sorry for inconvenience. Maybe the keymaster can edit and see the link function works.
FDA announcement
“tinyurl.com/24uktd4y”
New England Journal of Medicine (NEJM) 2024 2 mins video
“www.youtube.com/watch?v=9XZseJ7csOY”
Dr, Peter Black explains significance of the combo treatment . BCC Webinar December, 2023 Clinical Trials Demystified
“www.youtube.com/watch?v=q5NNk15a2SQ&t=933s” Start at 15:00
Urotoday journal – Detail results from EV-302 clinical trial
“tinyurl.com/yc2vaw92”
Immune checkpoint inhibitor 5 mint video – Harvard Medical School
“www.youtube.com/watch?v=B8Q_m7hnvRQ”
The efficacy and side effects of Keytruda – PD-1 inhibitor May 2017 NEJM
“www.nejm.org/doi/full/10.1056/NEJMoa1613683”
1 min video on Mechanism of Action of PADCEV
“www.youtube.com/watch?v=S2QgLNRQtCs”
The result of the clinical trial of PADCEV alone as 3rd line treatment Feb, 2021 NEJM
“www.nejm.org/doi/full/10.1056/NEJMoa2035807”
Definition of Locally advanced bladder cancers Translational Andrology and Urology – 2016 Read the first section in Abstract
“www.ncbi.nlm.nih.gov/pmc/articles/PMC5071186/”
Pricing of the combo treatment – American Society of Clinical Oncology Journal Oct, 2023
“ascopubs.org/doi/10.1200/OP.2023.19.11_suppl.11”
Pricing of the combo treatment – Prime Therapeutics
“www.primetherapeutics.com/news/fda-approves-game-changing-regimen-for-urothelial-cancer-but-will-cost-pose-issue/”
May 5, 2024 at 1:31 pm #47620Joe
ParticipantIt seems that PADCEV and Keytruda combination treatment for locally advanced and metastatic urothelial carcinoma is already in the hand of CADTH for Reimbursement Review. CADTH is asking patient/clinician input from April 9, 2024 till June 3, 2024. CADTH is limiting input from patients group rather than individual. So, if any patient or caregiver is interested giving input, I think technically you should be able to give your input through BCC. Note that CADTH is now called Canada’s Drug Agency. CADTH stands for Canadian Agency for Drugs and Technology in Health. “www.cadth.ca/about-us”.
“www.cadth.ca/enfortumab-vedotin-0”
Below is the steps for CADTH Reimbursement application process, which is taken from CADTH site.
- Pre-submission Phase
- Application Phase
- Stakeholder Input
- Patient Group Input
- Clinician Group Input
- Drug program Input
- Review Phase
- Initiation of the Review
- CADTH Review Reports
- Recommendation Phase
- Expert Committees
- The pan-Canadian Oncology Drug Review (pCODR) Expert Review committee (pERC) is used for drugs that are reviewed though CADTH’s pCODR process. The expert committees may recommend that a drug be reimbursed; that a drug be reimbursed with conditions; or that a drug not be reimbursed. The expert committee meeting schedule is available on the CADTH website.
- Draft Recommendation
- Final Recommendation
- Expert Committees
- Implementation Phase
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May 9, 2024 at 3:10 pm #47631LP
ParticipantJoe, thank you for this information. For your point ” So, if any patient or caregiver is interested giving input, I think technically you should be able to give your input through BCC” how can we give our input to BCC? Please advise. Thank you and to all the BCC volunteers for this great forum
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This reply was modified 9 months, 1 week ago by
LP. Reason: missing word
May 10, 2024 at 2:22 pm #47634theresab
ModeratorHi LP,
You can sign up to provide your input here:We currently are in need of patients to provide input if they have received PADCEV in the past.
Thanks!
July 28, 2024 at 4:55 pm #47834alestirl
ParticipantHi everyone. Has anyone had experience with seeking special approval of this combo to have it funded as a first-line treatment after radical cystectomy? Or experience going through the respective pharmaceutical companies’ compassionate funding programs for it? My dad has stage 4 bladder cancer and has had a radical cystectomy. His cancer is quite aggressive. He is meant to start chemo in a couple of weeks and I’m trying desperately to see if this EV & Pembro combo therapy could be an option for him instead, given the research results. Any assistance would be immensely appreciated. Thank you.
PS – We are in BC, so would be seeking funding through the BC Medical Services Plan.
July 29, 2024 at 11:42 am #47835Joe
ParticipantHi Alestiri,
Not for PADCEV (EV) and Keytruda (Pembrolizumab) combo treatment, but I had heard of a patient who exhausted the treatment, at that time it was chemotherapy, for advanced bladder cancer, managed to access a bladder cancer treatment which was approved by FDA but not accessible in BC. It was the patient’s oncologist who had arranged the treatment for the patient. So, I think the oncologist of your father is the right channel. Please google “Health Canada’s special access programs”. It leads to the Health Canada’s site on Special Access Programs. which the oncologist can fill out the form. I expect that the oncologist is knowledgeable the process.
I have noticed that Health Canada’s special access programs has a few requirements that the request must be for treating a patient with a serious or life-threatening condition where conventional treatments: have failed, are unsuitable for, are not available in Canada. Because chemotherapy which is accessible first line treatment (conventional) for locally advanced and metastatic bladder cancer after RC, which seems to have been arranged by the oncologist, I am not sure the special access program could apply. The oncologist should be able to answer the question too.
FYI, the conventional & accessible treatment for patients in BC after chemotherapy is immunotherapy either by Avelumab if the chemotherapy is working or Keytruda if the chemotherapy does not work well. If immunotherapy does not work, PADCEV is approved drug for this situation. Anyway, the oncologist is the right person about the treatment path and its effectiveness for what if scenario if the combo treatment is not accessible.
In terms of financing the combo treatment, I do no think BC Health Care System reimburse the combo treatment yet. It has not gone through the necessary processes, including the economic evaluation of the combo treatment by Canada Drug Agency, price negotiation by the pan-Canadian Pharmaceutical Alliance on be half of all government drug plans, then after that province must to decide to reimburse the treatment. It will be awhile. So, essentially, the drug companies, in this case, Astellas for PADCEV and MERCK for Keytruda must agree to provide the drug free or at specially discounted price. I looked up the contact information of the manufacturer of PADCEV – Astellas and Keytruda – Merck. They may be able to give you more information on the subject.
Astellas Pharma Canada , Markham, Ontario. Phone 905-470-7990 or 1-800-575-1382 Customer Service 1-800-668-8641
Merck Canada Inc. Quebec, H9H 4M7 Phone 514-428-7920 or 1-800-361-7031 Customer Service 1-800-463-7251 email montreal.orderdesk@merck.com
August 5, 2024 at 11:59 am #47842alestirl
ParticipantJoe: Thank you so much for all of this very helpful information! I have contacted a drug access navigator at the BC Cancer Agency to look into it more. I sincerely appreciate all of this information and the time you took to provide it. Thank you again!
August 21, 2024 at 2:21 pm #47872marilouc
ModeratorHi BCC Community,
We are looking for someone who has been treated with the combination of Enfortumab Vedotin (Padcev/EV) plus Pembrolizumab (Keytruda) to share their experience.
If you have experience with this new treatment, please email me at marilouc@bladdercancercanada.org.
- Marilou (marilouc@bladdercancercanada.org)
November 5, 2024 at 2:03 pm #48001Joe
ParticipantIn October 2024, Canadian Agency for Drugs and Technologies in Health (CADTH) – issued Reimbursement Recommendation with Conditions (Draft) for the Padev + Keytruda combo treatment. The details of the recommendation is available from Canada’s Drug Agency site.
“www.cda-amc.ca/sites/default/files/DRR/2024/PC0353-Padcev_DRAFT_REC.pdf”
I think the next step is the price negotiation. According to the report, based upon submitted price by suppliers, the combo treatment costs $24,547 per 28 days, or roughly $300,000 per year. A price deduction of 78% for both drugs would be required to meet the Canada’s price expectation.
It is noted that in September 3, 2024, European Commission approved the combo treatment. On October 8, 2024 UK approved the combo treatment. Their approvals do not mean that the combo treatment is accessible to patients right away. Each European Union (EU) country must conduct its own health technology assessment (HTA) similar to CADTH to decide if the drug will be covered by public health insurance. Germany may take the treatment available within 6 months.
In UK, National Institute for Health and Care Excellence (NICE) has started the appraisal the clinical and cost effectiveness of Keytruda with PADCEV within its marketing authorisation for treating untreated locally advanced or metastatic urothelial cancer. The expected reporting by NICE is 04 June 2025.
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