If you're interested in reading more about BDCs and the development of zelenectide:
- Article on chemical structure: pubs.acs.org/doi/10.1021/...
- Trials in progress manuscript on phase II/III in UC: ascopubs.org/doi/10.1200/...

What to expect next for this BDC, zelenectide pevedotin?

Phase III study in locally advanced/metastatic urothelial carcinoma & Ph II in #breastcancer & #NSCLC are underway. Urothelial study may be hard to interpret since control arms aren't getting EV/pembro.

clinicaltrials.gov/study/NCT062...

How did this play out in real life?

In this #JCO study, expected very short half-life (~1 hr) of the full compound, and MMAE half life between 37-50 hours with no accumulation between cycles.

- 33% neuropathy vs 67% w EV/pembro
- 22% skin tox vs 52% rash w EV

ascopubs.org/doi/10.1200/...

So what's the major difference? Size.

Because they are small and have relatively rapid renal clearance, in early preclinical studies BDCs had a “fast in, fast out” pharmacokinetics that were supposed to result in less systemic exposure to toxic payload and greater tumor penetration.

Both drugs have a cleavable linker that allows the MMAE payload (💣) to be cleaved off in the tumor microenvironment.

BDCs build on the concept of ADCs. They have a bicyclic (hence the name) domain that can bind to a given cell surface protein-- in this case, Nectin 4, which is amplified in many solid tumors and the target of enfortumab vedotin (EV).

If you're interested in reading more about BDCs and the development of zelenectide:
- Article on chemical structure: pubs.acs.org/doi/10.1021/...
- Trials in progress manuscript on phase II/III in UC: ascopubs.org/doi/10.1200/...

What to expect next for this BDC, zelenectide pevedotin?

Phase III study in locally advanced/metastatic urothelial carcinoma & Ph II in #breastcancer & #NSCLC are underway. Urothelial study may be hard to interpret since control arms aren't getting EV/pembro.

clinicaltrials.gov/study/NCT062...

How did this play out in real life?

In this #JCO study, expected very short half-life (~1 hr) of the full compound, and MMAE half life between 37-50 hours with no accumulation between cycles.

- 33% neuropathy vs 67% w EV/pembro
- 22% skin tox vs 52% rash w EV

ascopubs.org/doi/10.1200/...

So what's the major difference? Size.

Because they are small and have relatively rapid renal clearance, in early preclinical studies BDCs had a “fast in, fast out” pharmacokinetics that were supposed to result in less systemic exposure to toxic payload and greater tumor penetration.

Both drugs have a cleavable linker that allows the MMAE payload (💣) to be cleaved off in the tumor microenvironment.

BDCs build on the concept of ADCs. They have a bicyclic (hence the name) domain that can bind to a given cell surface protein-- in this case, Nectin 4, which is amplified in many solid tumors and the target of enfortumab vedotin (EV).

Makes sense for areas where there's a lot of RWE and prior trial data about efficacy of the de-escalated version (as in the examples included - de-esc ICI, SONIA)-- worry about risks of this approach where there is less data on efficacy with de-escalated regimens.

- Our voices will never be louder or more abundant than all that information. Our goal is to build relationships that allow people to trust us in doing the best for us.

- In the world where I can type a diagnosis into an LLM and get targeted marketing across several social media platforms, an oncologist's job isn't just to transmit information. It's helping people curate what info they're processing from the rest of the world about their cancer.

- Instead, trust has to come from our relationships, not titles.

- In the modern era, being a doctor doesn't automatically earn trust (and often the opposite, induces some healthy skepticism)

* @majorajay.bsky.social and multidisciplinary/international colleagues!