Thursday, March 27, 2014

Anti-PDL1 for melanoma: A Phase 1 trial of MEDI4736 in Combination With Dabrafenib and Trametinib or With Trametinib Alone

A Phase 1 Open-label Study of Safety and Tolerability of MEDI4736 in Combination With Dabrafenib and Trametinib or With Trametinib Alone 
NCT02027961


The study above is now recruiting.  You can see all the details on ClinicalTrials.gov by entering the NCT#.  Some folks on the forums are asking questions about it so I thought I could  try to answer a few points here.

Dabrafenib (Tafinlar) is a BRAF inhibitor that achieves a 70-80% response rate in melanoma patients with the BRAF v600E mutation.  Its down sides include the fact that the response can come with some nasty side effects and it can cease working for many melanoma patients in 6-9 months, though there are some out there who have done great for years. (You know you're the man Dick K!!!)  Trametinib (Mekinist) is a downstream inhibitor in the same pathway as the BRAF inhibitors.  The good news is that it seems to work in patients with NRAS mutations as well as those having the BRAF v600E mutation.  Recently the combo of these drugs was approved and is helping patients get rid of their tumors with fewer side effects and with less chance of melanoma learning how to work around the drugs.  (I have posts on Jan 13, 2013 and more recently on Feb 13, 2014 with more information on these drugs.)


MEDI4736 is an anti-PDL1 drug produced by MedImmune.  Anti-PDL1 is an antibody that blocks a switch on a melanoma cell that turns off your immune system.  Anti-PD1 drugs, are antibodies that block the switch on the white cells so that they can attack melanoma.

As someone who (along with most of the folks in my BMS anti-PD1 (Nivo) study at Moffitt) has had my tumor tested for the expression of PD-L1 on its surface...I have a very specific interest in the intel coming out about the anti-PDL1 drugs.   Back in 2012, The New England Journal of Medicine noted that in patients from a Nivo study, with a variety of tumor types, 25 of the 42 patients tested had tumors that were positive for PD-L1.  "Of these 25 patients, 9 had an objective response.  NONE of the 17 patients with PD-L1 NEGATIVE tumors had an objective response."  NOW...with that said....since then I have been told by the folks at Moffitt that that data was really important AND also told that it didn't mean so much after all.  We have still NOT been told what our personal tumors tested out to be...nor have I seen a report on that data.
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To back up a step here is a basic info report on a different anti-PDL1 product:  Promising drug prevents cancer cells from shutting down immune system  
31 May 2013 19:19:03 yale.edu
"An investigational drug that targets the immune system’s ability to fight cancer is showing promising results in Yale Cancer Center (YCC) patients with a variety of advanced or metastatic forms of the disease. Updated data from this Phase 1 clinical trial are being formally presented at the 2013 annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago. Yale Cancer Center is one of the lead trial sites. The abstract was made public by ASCO in advance of the meeting.
The drug, known as MPDL3280A and manufactured by Roche Genentech, is designed to prevent a cancer cell’s mutated and overexpressed PD-L1 gene protein from putting the immune system to sleep. The overexpressed PD-L1 protein turns off the immune system’s T-cells by binding to its PD-1 and B7.1 proteins. In doing so, it disguises itself and evades detection and destruction by the body’s immune response.
This new drug is the latest advance in the burgeoning field of immunotherapy, which aims to boost the body’s immune system to fight the foreign pathogens of cancer. By blocking the cancer tumor’s PD-L1 protein, MPDL3280A frees the immune system to do its job. This PD-L1 targeted antibody was specially engineered to increase safety and efficacy over earlier immunotherapy agents.
Yale oncologists report that the efficacy of MPDL3280A was evaluated in 140 patients with locally advanced or metastatic solid tumors who had exhausted other means of therapy. Tumor shrinkage was observed in patients with non-small cell lung cancer, melanoma, kidney cancer, colorectal cancer, and gastric cancer. Yale oncologists say ongoing, durable responses were observed in nearly all patients who responded to the drug. Overall, 29 out of 140 patients (21 percent) experienced significant tumor shrinkage, and the highest number of responses were in patients with lung cancer and melanoma.
MPDL3280A was generally well tolerated, they say, with few immune-related adverse events. Some patients were continuing to respond more than a year after starting treatment.
“We have been very impressed by the response in seriously ill patients whose cancer had metastasized. So far, almost none of those who showed tumor shrinkage have gotten worse, which is extraordinary,” said lead author Roy Herbst, M.D., professor of medicine and chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital at Yale-New Haven. “Immunotherapy treatment is providing new hope for cancer patients,” he added."
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Currently there is a Phase 2 study ongoing, using anti-PDL1 with avastin in renal cell carcinoma.  There is also a Phase 3 study in progess using anti-PDL1 in patients with non-small cell lung cancer.  Neither of these studies have published outcomes thus far...to my knowledge.
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From ASCO, 2013:  A study of MPDL3280A (engineered anti-PDL1):  Activity, safety, and characterization of immune response in pre- and on-treatment tumors in metastatic melanoma patients.  Sosman, Hamid, Lawrense, Flaherty, Hodi, et al.
"Melanoma tumor cells may utilize PD-L1 overexpression to escape immune surveillance...In Phase 1 study, metastatic melanoma patients received MPDL3280A IV every 3 weeks for up to 1 year and had tumor assessments every 6 weeks.  As of Feb 2013, 44...patients dosed at 0.1-20mg/kg were evaluated...61% received >/= 1 prior systemic regimen and 36% received prior immunotherapy.  14% of patients experienced grade 3/4 treatment related adverse events, including [elevated liver enzymes].  No grade 3-5 pneumonitis or colitis was reported. 38...patients...dosed at 1-20mg/kg prior to August 2012 were evaluable...An objective response rate of 32% (11/34) was observed in patients with cutaneous, mucosal or unknown primary histology (0/4 ocular patients responded).  Resection of remaining mass in a responding patient after 1 year of therapy showed no evidence of viable tumor.  Responses were durable, with 10/11 ongoing (responding patients on study for 3-10.5 months).  Analysis of archival tumor samples showed that PD-L1 positive patients had a higher rate of disease control versus PD-L1 negative patients [87% vs 20%]."
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Clearly, as there is no data out on the combo this clinical trial is examining (to my knowledge) I don't have any intel to add that addresses that specifically.  But, for those of you with interest in the trial and its components....perhaps this background information will be helpful.
Wishing you all my best - c

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