ASCO 2017: Antibody-drug conjugate (ADC) - Glembatumumab Vedotin in advanced melanoma

I have researched and written about ADC's (glembatumumab vedotin in particular) before.  Here are a couple of posts: Antibody-Drug Conjugate for melanoma

In 2013 I wrote:
"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."

"ADC's have been in the works since the 80's. Over that time laboratory researchers have found many more possible antibodies to use (and studied which tumors express them the most) and a variety of gradually improving techniques to "link" the chemotherapeutic agent to the antibody. Improved "linkers" seem to have made it easier to use a variety of antibodies as well as cytotoxic agents while keeping the whole little trifecta intact until it reaches its destination.  Patent information seems to indicate that researchers feel they may even be able to target infectious organisms in the future.  Two ADC's have been marketed for lymphoma and leukemia.  And, just a couple of weeks ago, Celldex got FDA approval for CDX-011 (glembatumumab vedotin) as a treatment for Her-2 breast cancer.  Interestingly, initially, this drug which uses "auristatin conjugated to a monoclonal antibody that recognizes GPNMB, expressed at higher levels in melanoma and breast tumors"  was tested in patients with melanoma as well as breast cancer.  Sievers and Senter, in a Seattle Genentech report state, "In a phase I/II trial in patients with unresectable late-stage melanoma, CDX-011 showed overall response rates ranging from 14% to 19% depending on dosing frequency and GPNMB expression levels."  However, at this point, it seems that this particular ADC is no longer being utilized in melanoma trials."

Now there is this...looking at CDX011-05 ~ 

A phase II study of glembatumumab vedotin (GV), an antibody-drug conjugate (ADC) targeting gpNMB, in advanced melanoma.

ASCO 2017. J Clin Oncol 35, 2017. Ott, Pavlick, Johnson,...Infante, Luke, ...Hamid.

Background: gpNMB is an internalizable transmembrane glycoprotein expressed in melanoma and multiple other tumor types. The ADC GV (CDX-011) delivers the potent cytotoxin MMAE to gpNMB+ cells. GV has shown promising activity in advanced melanoma and breast cancer. Methods: This Phase II study (CDX011-05) assessed the efficacy and safety of GV monotherapy (1.9 mg/kg q3w) for patients (pts) with advanced melanoma progressive after less than/= to 1 chemotherapy, greater than/= to 1 checkpoint inhibitor (CPI) and if BRAF^V600mutated, greater than/= to 1 BRAF/MEK inhibitor. Central IHC determined gpNMB expression in archival and/or pre-treatment tumor. Primary endpoint was objective response rate (ORR) (RECIST 1.1) with greater than/ = to 6 responders out of 52 evaluable pts as threshold for antitumor activity. Additional endpoints: progression free survival (PFS), overall survival (OS), duration of response (DOR), safety, PK/PD and correlation of tumor gpNMB expression with efficacy. Results: 62 pts enrolled (all evaluable) had median age of 67 years; 55% male; 21% BRAF^V600mutated; 63% with greater than/= to 3 lines prior therapy; 100% had prior CPI; 100% Stage IV; 89% M1c. One confirmed complete response (CR) and 6 confirmed partial responses (PR, including 1 unconfirmed CR) were seen (confirmed ORR = 11%); 33 pts had stable disease including 3 unconfirmed PR. Median DOR = 6.0 (range: 4.1, 14+) months (mos), median PFS = 4.3 mos and median OS = 9.8 mos; 26 pts continue to be followed for survival. All pts with available tissue (60/60) had gpNMB+ tumors; 47/60 had 100% gpNMB+ epithelial cells; no clear correlation with outcome was seen in this population with consistent high expression. Toxicities included alopecia, neuropathy, rash, fatigue and neutropenia. Treatment-related rash in cycle 1 was associated with improved ORR (rash = 22%; no rash = 7%), PFS and OS. Conclusions: GV has promising activity (primary endpoint of ORR was met) with a manageable safety profile in heavily pre-treated melanoma pts. Additional cohorts evaluating GV with either varlilumab, an activating anti-CD27 monoclonal antibody, or PD-1 inhibitors are open to accrual to provide further insights into the synergy of ADC and immunotherapy. Clinical trial information: NCT02302339

Hmmm....  Here we go:  First off, it is not clear to me why they are now calling the drug "CDX011-05".  A new name implies that it is different in some way...but the difference (if there is one) is not clarified here.  At any rate ~ in this Phase II study, 62 patients, all with stage IV melanoma, 21% with BRAF V600 mutation, 63% having undergone 3 or more prior treatment regimens, were enrolled.  There was one complete response and 6 partial responses for a total ORR of 11%.  33 patients had stable disease. Toxicities were what we have come to expect with this ADC:  alopecia, neuropathy, rash, fatigue, and neutropenia.  One interesting note was that those who developed a rash in the first cycle had an improved response.  Also interesting is the fact that the studies I addressed in the 2013 post with "CDX011" touted ORR of 14 and 19%.

Not sure about the future of this therapy.  They really need to work on making the "link" stronger so that there is less leakage of the chemo that leads to much of the side effects.  Perhaps that is what they tried to do in the CDX011-05 version...don't know.  Also not sure about a decreased ORR in this study compared to the previous.  However, I will be forever grateful to this therapy for keeping one of my dearest ones around for a year more, giving him time to find a therapy that worked better for him in the end.

This one's for my dear J and F!!!! love, c

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

New treatment for melanoma!!!! - ADC's - Antibody-Drug Conjugate

New scoop!!!! New trial!!!!   So...what the heck is an ADC????

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.

ADC's have been in the works since the 80's. Over that time laboratory researchers have found many more possible antibodies to use (and studied which tumors express them the most) and a variety of gradually improving techniques to "link" the chemotherapeutic agent to the antibody. Improved "linkers" seem to have made it easier to use a variety of antibodies as well as cytotoxic agents while keeping the whole little trifecta intact until it reaches its destination.  Patent information seems to indicate that researchers feel they may even be able to target infectious organisms in the future.  Two ADC's have been marketed for lymphoma and leukemia.  And, just a couple of weeks ago, Celldex got FDA approval for CDX-011 (glembatumumab vedotin) as a treatment for Her-2 breast cancer.  Interestingly, initially, this drug which uses "auristatin conjugated to a monoclonal antibody that recognizes GPNMB, expressed at higher levels in melanoma and breast tumors"  was tested in patients with melanoma as well as breast cancer.  Sievers and Senter, in a Seattle Genentech report state, "In a phase I/II trial in patients with unresectable late-stage melanoma, CDX-011 showed overall response rates ranging from 14% to 19% depending on dosing frequency and GPNMB expression levels."  However, at this point, it seems that this particular ADC is no longer being utilized in melanoma trials.

Back to the ADC at hand...Genentech's GR-7636:  This drug targets Endothelin receptor ETB, which is apparently expressed on most melanoma tumors (as well as skin cells in general....and is even in the pathway for their embryonic development....which explains why one of the side effects can be skin irritation and rashes).  So much so...that at first folks tried the drug bosentan, a dual endothelin A/B receptor antagonist which is similar to anti-PD1 in that it uses an antibody to modify a specific cell receptor, but UNLIKE anti-PD1, the receptor is on the melanoma cell itself, and the hope was that by antagonizing it [blocking it] the cell would die....while anti-PD1 hopes to activate white cells and bring the immune system to attack the tumor cell.  Anyhow, they tried bosentan alone and combined with dacarbazine but had disappointing results.

One other note on Endothelin B and its expression in melanoma cells:  In the Asundi paper:  They assayed the amount of cell expression of the receptor and found it to have a range of expression from 1500 to 33000 per cell line. In their mouse model, they showed efficacy of their ADC for both the low and high end of cell expression.

So.....it seems that researchers have found a very melanoma specific, cell surface receptor, which provides a target using antibodies bonded to a highly potent cell toxin which is rapidly taken in from the cell surface and converted to the active agent inside the cell.  Theoretically, this will allow targeted delivery of extremely cytotoxic agents and in the mouse model produced rapid (i.e. one week) death of melanoma cells with no recurrence for three months.  Luckily, a dear one of mine, is embarking on this rattie adventure at Sarah Cannon in Nashville.  There, though they are only reporting on 15-20 patients currently enrolled, they say that they have determined the most effective dose and schedule, side effects have been minimal, responses are clear (or not) by 6 weeks, and are attaining about a 30% response rate. Due to the explanation above, prior ipi or anti-PD1 is NOT an obstacle since this regimen works in an entirely different fashion.  Recruitment is apparently 1 patient per every 3 week cycle, per trial site.

Wishing you the best in your rattie adventure, J.  Hang tough, all of you. - c


Bibliography:

An antibody-drug conjugate targeting the endothelin B receptor for the treatment of melanoma.
Asundi, et al.  Clinical Cancer Research. 2011 Mar 1;17(5):965-75  Genentech, Inc, San Fran, CA

Antibody-drug conjugates in cancer therapy.  Sievers and Senter. Anne. Rev. Med. 2013. 64:15-29.  First published October 3, 2012.  Seattle Genetics, Bothell, Washington.

Antibody-drug conjugates.  Zolot, Basu, Million.  Nature Reviews. April 2013, Vol 12.

Maturing antibody-drug conjugate pipeline hits 30.  Mullard. Nature Reviews. May 2013, Vol 12.