Historically, metastatic bladder cancer was treated with platinum based chemotherapy such as Cisplatin + Gemcitabine as the first line treatment. Then around 2015 PD-1 immune checkpoint immunotherapy was developed first for Melanoma with great success in extending patients survival. In 2016 or 2017, the same immunotherapy was applied to bladder cancer with not as great but with success in extending locally advanced and metastatic bladder cancer. The first immunotherapy approved for metastatic bladder cancer was Pembrolizumab (Keytruda) by Merck also Atezolizumab (Tecentriq) by Roche. Keytruda is PD-1 immune checkpoint inhibitor and Tecentriq is PD-L1 immune checkpoint inhibitor. In general, efficacy and side effects are similar between PD-1 inhibitor or PD-L1 inhibitor. Both drugs were approved as second line treatment for metastatic bladder cancer when platinum based chemotherapy did not work well. FYI, In November, 2022, Roche announced voluntary withdrawal of Tecentriq for metastatic bladder cancer as the 2nd line treatment from FDA drug list. PADCEV which is targeted chemotherapy based upon Antibody Drug Conjugate technology targeting cells with Nectin-4 protein expressed on cell membrane. Bladder cancer is known to highly express NECTIN-4. PADCEV which was co-developed by Astellas, a Japanese Pharmaceutical company and Seagen, now bought by Pfizer. PADCEV was approved in December, 2019 as the 3rd line treatment for metastatic bladder cancers when the 2nd line immunotherapy did not work well.
It is a bit complicated, but in June, 2020, Avelumab (Bavencio) PD-L1 inhibitor by Merck KGaA (different from Merck in the US) Germany and Pfizer was approved as maintenance immunotherapy treatment right after the fist line chemotherapy treatment is completed rather than waiting for the firs line chemotherapy stops working. Then, in August 2021, Nivolumab (Opdivo) by BMS was approved as adjuvant immunotherapy right after radical cystectomy for patients of high risk for metastasis. Both Avelumab and Nivolumab improved (increased survival rate).
All above mentioned may have become less relevant with the combination treatment of PADCEV + Pembrolizumab (Keytruda) which was approved by FDA on December 15, 2023. The combo was approved as the first line treatment of locally advanced or metastatic bladder cancer. The clinical trialEV-302/KN-A39 (NCT04223856), an open-label, randomized trial of 886 patients with la/mUC and no prior systemic therapy for advanced disease. Patients were randomized 1:1 to receive either enfortumab vedotin-ejfv with pembrolizumab or platinum-based chemotherapy (gemcitabine with either cisplatin or carboplatin). Randomization was stratified by cisplatin eligibility, PD-L1 expression, and presence of liver metastases.
The combo doubled over all survival compared to platinum based chemotherapy as the first line treatment for locally advanced or metastatic bladder cancer. Apparently, the result of the combo clinical trial was so good that it received a standing ovation from the audience - oncologist, urologist and others at the 2023 European Society of Medical Oncology (ESMO) Annual Congress held in Madrid, Spain. You can review two charts - progression free survival and over all survival between patients who received the combo vs platinum based chemotherapy. It says the risk of progression or death was reduced by 55% with the combo treatment. It is noted that the result did not make much difference either for patients with cisplatin eligible for ineligible or regardless of patients' PD-L1 expression level. it means PADCEV + Keytruda combo is likely to become the first line treatment for locally advance or metastatic bladder cancer patients replacing platinum based chemotherapy, i.e. Gemcitabine +Cisplatin or Carboplatin. Ii may make Pembrolizumab (Keytruda) as the 2nd line and Avelumab (Bavencio) as maintenance treatment after 1st line chemotherapy irrelevant.
A challenge is the price of the combo treatment. The industry paper is saying that PADCEV + Keytruda combo treatment can cost Medicare per patient $435K annually, compared to platinum based chemotherapy only $3.5K , and chemotherapy with Avelumab maintenance $96K. We will see how the actual price of PADCEV +Keytruda combo will end up.
The link to Urotoday on result of EV-302 (PADCEV + Keytruda) clinical trial which led to the approval of the combo treatment
tinyurl.com/49ddpvfj
The link to expected price
ascopubs.org/doi/10.1200/OP.2023.19.11_suppl.11 
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