Another antibody-Drug Conjugate for melanoma

For a little background and explanation here's a blurb from a prior post...

ADC and the NCT01522664, Phase I trial, Genentech/Roche, ADC, Antibody Drug Conjugate DEDN6526A

"An ADC (antibody drug conjugate) is like a Trojan Horse!!!  It takes a bad ass cytotoxin, like auristatin (that's the one being used here), an anti-mitotic agent that derives its action by preventing tubulin polymerization and therefore stops cell division, attaches it via a special molecule to a monoclonal antibody that targets antigens preferentially expressed on the surface of the targeted cancer cells..in this case, Endothelin B.  This method allows patients to survive being treated with really toxic agents without suffering the terrible side effects that would certainly ensue should those cytotoxins be injected directly.  By taking them under cover, only the bad cells we want to target are damaged."

The full post gives more data about this particular ADC, their history in general, and the one discussed in the article below:  new-treatment-for-melanoma-adc's

A dear one of mine participated in the trial noted in that post and while the therapy did diminish some of his tumor burden and gave him about a year in which to find a new treatment before growth of tumors resumed....it was not a panacea.  The "bad ass cytotoxin" leached more into his system than one would hope a REAL Trojan Horse would allow.  He did suffer a good deal of fatigue, hair loss, and significant neuropathies that, while improving now, are still somewhat troubling.  At any rate, here is a study of an older ADC...previously used most in HER-2 breast cancer...that targets the surface protein gpNMB instead of Endothelin B, but does use the same bad boy cytotoxin - auristatin E...being utilized as treatment for melanoma patients.

Phase I/II study of the antibody-drug conjugate Glembatumumab Vedotin in patients with advanced Melanoma.  Ott, Hamid, Pavlick, Sznol, et al.  J Clin Oncol. 2014 September 29.

"The antibody-drug conjugate glembatumumab vedotin links a fully human immunoglobulin G2 monoclonal antibody against the melanoma-related glycoprotein NMB to the potent cytotoxin monomethyl auristatin E."  117 patients were given glembatumumab vedotin every 3 weeks (in a dose escalation and phase II expansion with three different dosing levels).  Grade 3/4 toxicities that occurred in 2 or more patients were:  rash, neutropenia, fatigue, neuropathy, arthralgia, myalgia, and diarrhea.  3 treatment related deaths occurred at doses exceeding what was determined to be the maximum tolerated dose (MTD) due to pneumococcal sepsis, toxic epidermal necrolysis and renal failure.  In the schedule I, phase II expansion cohort (n=34):  5 patients (15%) had a partial response, 8 (24%) had stable disease for more than 6 months.  The objective response rate was 2 of 6 for the schedule 2 MTD and 3 of 12 for the schedule 3 group.  Rash was correlated to greater overall response and improved progression-free survival.  "CONCLUSION:  Glembatumumab vedotin is active in melanoma. The MTD (1.88mg/kg once every 3 weeks) was associated with a promising overall response rate and was generally well tolerated.  More frequent dosing was potentially associated with a greater overall response rate but increased toxicity."

I still very much like the idea of antibody drug conjugates.  But, the "bad ass cytotoxin" is not as linked as we would like it to be.  I fear we have a long way to go!  Merci mille fois!!!.... to J and all the other ratties who teach the rest of us so much.  Much love - c