Enfortumab Vedotin for Urothelial Carcinoma

• 24 Sep 2020 10:15:00 AM
• |Onco Urology

Dear All,

Man’s Desire to live a few days longer is well known and it plays a pivotal role in Drug Development. The financial Toxicity associated with such treatments is often ignored and in a country like India, it is a real concern.

Urothelial Ca has emerged from its ‘Orphaned State’ to one of the most researched cancer among GU Cancers and the numerous avenues now being opened appears far more than P Ca. It is true that treatment of Urothelial Ca is much higher than most of the GU Cancers.

At one time we had only Cisplatin based therapies for MIBC but today we have diverse drugs for MIBC, be it for primary Tt (Adjuvant or Neoadjuvant) or as 2^nd or even 3^rd line therapies due to failure or unresponsiveness of other therapies.

Immune Checkpoint Inhibitors (ICIs) are considered as effective treatment for MIBC (both PD-1 and PD-L1) and started with its use as 2^nd line treatment for failed first line with Cisplatin based treatments. But it soon found its niche in Cisplatin Ineligible Scenario. Some researchers observed the usefulness of ICIs in the primary setting and began using it as Neoadjuvant for Trimodality Bladder Sparing Regimes.

But it was soon found that even ICIs could be unresponsive in many and treatments with ICIs were only resulting in financial drain.

This has made Researchers to explore many other avenues and have come out with antibody-drug conjugate enfortumab vedotin-ejfv (Padcev^TM). Antibody-drug conjugates (ADCs) deliver potent cytotoxic agents using highly selective monoclonal antibodies. Targeting the near-universal expression of Nectin-4 on UC cells is a viable therapeutic strategy.

On December 18, 2019, the antibody-drug conjugate enfortumab vedotin-ejfv (Padcev^TM) was granted accelerated approval for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitor and platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced, or metastatic setting.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784850/pdf/JCO.19.01140.pdf  and Another article in PDF format

EV demonstrated an overall response rate of 44%, and a median duration of response of 7.6 months. Estimated overall survival was 11.7 months with a median estimated progression-free survival of 5.6 months.

The dosage schedule recommended is Enfortumab Vedotin-ejfv at 1.25 mg/kg on days 1, 8, and 15 of 28-day cycles until disease progression or unacceptable toxicity.

EV, a first-in-class anti-Nectin-4 ADC, provides impressive response rates with manageable toxicities, making it a promising treatment option for patients with multiply relapsed or refractory UC.

The US Food and Drug Administration-approved EV demonstrate antitumor activity in heavily pre-treated patients with UC but harbours important adverse effects and financial concerns.

Though mentioned as Manageable Toxicity, studies have found, Serious adverse events occurred in 46% of patients, with the most common being urinary tract infection, cellulitis, febrile neutropenia, diarrhea, sepsis, acute kidney injury, dyspnea, and rash. Adverse events led to dose interruption in 64%, most commonly due to peripheral neuropathy, rash, and fatigue, and to dose reduction in 34%, most commonly due to peripheral neuropathy, rash, and fatigue. Adverse events led to treatment discontinuation in 16% of patients, most commonly due to peripheral neuropathy. Fatal adverse events occurred in 3.2% of patients, including acute respiratory failure, aspiration pneumonia, cardiac disorder, and sepsis.

Further development of EV continues in a phase III trial examining EV plus Pembrolizumab with or without platinum compared with conventional platinum-based chemotherapy.

There is a likelihood that many more drugs will emerge and change our pattern of treatments but how much will become the way we treat in India should be explored. We have a tendency to ape the West and declare what is offered in the West should be palatable for us in India.

With warm Regards,

Venu

Comments(3)

• 

  Venugopal P

  25 Sep 2020 10:31:46 AM

  Dear All,

  In continuation of the previous write up, there are several new molecules being developed for Advanced/metastatic U Ca and I am posting two studies addressing two other agents.

  Though these may not be in use in our country for a while, it is also possible that we will begin hearing about these from our pundits sooner than later.

  I have provided the information regarding these products as an attachment for your reading. I do not know how much of these are going to be beneficial for us but it is better to know the happenings around us than being ignorant.

  With warm Regards

  Venu

   

  View Document

• 

  Venugopal P

  13 Nov 2020 09:04:46 AM

  Dear All,

  In continuation of the previous two write ups and Articles, I am providing another set of articles addressing Emerging and emerged New Treatment options for MIBC. Of late Immune Check Point Inhibitors (ICIs) are being projected as Major advancement for MIBC but it has its own limitations. Ideally, ICIs are administered only after knowing PD-L1 expression positivity. Each drug appears to have its own expression.

  Two newer Molecules have been discussed in the Documents provided. But to understand more regarding the various molecules that have arrived or arriving are necessary for us to have some knowledge as what the future may offer for these unfortunates with MIBC.

  I am proving you 4 reading materials which I have gathered from many available to enable us to understand the various progresses made in Chemotherapeutics as well as ICIs and beyond.

  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6295780/pdf/10.1177_1756287218814100.pdf

  http://tcr.amegroups.com/article/view/13775/html (PDF available)

  https://journals.sagepub.com/doi/pdf/10.1177/1078155220971026

  https://www.nejm.org/doi/pdf/10.1056/NEJMoa1817323?articleTools=true

  Understanding these newer options will take all of us forward and will be of benefit the trainees in our group for furtherance of their knowledge.

  With warm regards,

  Venu

   

• 

  Venugopal P

  13 Nov 2020 09:16:23 AM

  As the first Link provided may not open, I am providing alternate link for the same article

  https://journals.sagepub.com/doi/pdf/10.1177/1756287218814100

  Venu