mayi12345
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Hi all,
My dad has NSCLC EGFR exon 19 del with cMET amplification. Currently considering trial on combination therapy PD-L1 + Avastin (VEGF2 inhibitor). I would like to know is there a reason behind the clinical design?
I recently read research paper about inverse relations between expression of PD-L1 and VEGFs in pre-clinical trial. And VEGF relates to apoptosis (if i remember correctly, it relates to CD80, another binder with PD-L1 [please forgive me if i am wrong, i just started to learn medicine when my dad got sick ;p]).
But since Avastin and the alike (e.g. Axitinib) has moderate-severe side effect, i would like to re-consider if this trial is the best for my dad.
Thank you for your help!
Forums
Reply # - September 16, 2014, 07:53 AM
Hi and welcome to Grace. I'm
Hi and welcome to Grace. I'm sorry about your dad's diagnosis but I'm sure we'll be able to help you understand some of the details better.
There are more trials in the works with PD-1 and PD-L1 that are combined with other drugs including one arm combining avastin because researchers are hopeful that combining these new immuno-therapies with other drugs will heighten each other's efficacy and give long durable responses to those with lung and other solid tumor cancers. There's no data on safety yet as the trial is still in the safety (phase 1) phase. There are no guaranties but trialist are careful who they pick to test new drugs and drug combinations to insure as few adverse events as possible. Avastin has been used for quite a few years for those with non squamous nsclc with few problems.
Information on the trial I think you're asking about is here, http://clinicaltrials.gov/ct2/show/NCT01633970?term=pd-L1+avastin&rank=1
I'm sorry we can't say 'don't worry' but as you can probably imagine that's too much a legal risk to tell someone not to worry not to mention we just don't have all the info. Again researchers are clearly a very cautious and knowledgeable group of people and are very careful what and who they treat and keep a very close watch on their patients/fellow heros in the advancement of cancer treatment.
All best,
Janine
Reply # - September 16, 2014, 06:40 PM
I think the main reason for
I think the main reason for the design is that these immune checkpoint inhibitors are being combined with every other treatment in oncology to treat a vast array of cancers in every clinical setting. I think that these agents are very helpful for a minority of patients, but they are not profoundly beneficial for the majority of patients. I would be particularly wary about displacing a well-established treatment very widely recognized as very helpful (such as an EGFR inhibitor for EGFR mutation-positive NSCLC) with an immune checkpoint inhibitor based on irrational exuberance.
In short, I think the threshold for displacing a proven valuable therapy should be higher than the threshold for trying a treatment when there are not extremely compelling alternatives. I would love to offer an immune checkpoint inhibitor trial for most or all of my patients, but I wouldn't prioritize it over a treatment with a proven track record.
Good luck.
-Dr. West
Reply # - September 16, 2014, 06:55 PM
Thank you Janine and Dr. West
Thank you Janine and Dr. West. My dad has already developed drug resistance to Tarceva and the combination of Iressa + INC280 did not work well for him (mets in the liver and keep progressing). And hence considering the trial.
From limited data, PD-L1 shows responses as high as 80% on NSCLC patients with high PD-L1 expression (3+). For that reason, it is worth trying for my dad who does not have better option.
Reply # - September 16, 2014, 07:04 PM
If he has exhausted the good
If he has exhausted the good EGFR-based options already, that's different.
Also, as I said above, I'd love for my patients to get a shot at an immune checkpoint inhibitor. And though we haven't clarified the value of PD-L1 expression completely, there is a consistent favorable association of high PD-L1 expression with a good response to immune checkpoint inhibitors.
Even if the value of the combination of Avastin with an immune checkpoint inhibitor is questionable, I think it's a compelling option to pursue, especially for someone who has already received many other options.
-Dr. West
Reply # - September 16, 2014, 07:22 PM
Thank you Dr. West. I am
Thank you Dr. West. I am currently reading article about vascular normalization theory. apparently Avastin will help homogenize solid tumor and reduce hypoxia, while at the same time, it can also reduce the vessel permeability and reduce intake of large molecules. Maybe there will be a prime time to use Avastin, such as the vessel pore is not too small to permeate antibody (e.g. PD-L1) and vessel is normalized and anti-cancer therapy can be delivered systematically?
Do you know of any research regarding to mechanisms behind anti-VEGF resistance?
Thanks again!
Reply # - September 16, 2014, 08:58 PM
I would say that everything
I would say that everything you're reading about is more speculative than supported by actual clinical evidence. I think it's understandable to want to research everything, but I don't think it's very helpful when what you're learning isn't certain enough to base decisions on. I would really caution against drawing conclusions from work that is more theory than fact and has no actual clinical evidence to support it.
-Dr. West