Friday, June 16, 2017

ASCO 2017: Antibody-drug conjugate (ADC) - Glembatumab 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 BRAFV600mutated, 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% BRAFV600mutated; 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

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