Enfortumab Vedotin for Urothelial Carcinoma
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 2nd or even 3rd 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 2nd 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 (PadcevTM). 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 (PadcevTM) 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,
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