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Denise Brock

Lung Cancer Video Library – PDL1 as a Biomarker for Second Line

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GRACE Cancer Video Library - Lung

 

H. Jack West, MD
President & CEO, GRACE

 

We are pleased to have GRACE’s Jack West, MD, Medical Director, Thoracic Oncology Program, Swedish Cancer Institute in Seattle, Washington, and President and CEO of GRACE bring 2017 updates to our Lung Cancer Video Library.  

In this latest video, Dr. West discusses exciting new advances in NSCLC –  PDL1 as a Biomarker for Second Line.

 


 

 

 

 

 

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Denise Brock

Lung Cancer Video Library – PDL1 As A Biomarker For First Line

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GRACE Cancer Video Library - Lung

 

H. Jack West, MD
President & CEO, GRACE

 

We are pleased to have GRACE’s Jack West, MD, Medical Director, Thoracic Oncology Program, Swedish Cancer Institute in Seattle, Washington, and President and CEO of GRACE bring 2017 updates to our Lung Cancer Video Library.  

In this latest video, Dr. West discusses exciting new advances in NSCLC –  PDL1 as a Biomarker for First Line.  

 


 

 

 

 

 

How Did You Like This Video?

Please feel free to offer comments and raise questions in our Discussion Forums.


 We would like to thank the following companies for their support of this program

 

                

 

 

                        

 

 
 

 

 


  


GRACE Video

Immunotherapy for First Line Therapy of Advanced NSCLC

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GRACE Cancer Video Library - Lung

GCVL_LU-FE09_Immunotherapy_First_Line_Therapy_Advanced_NSCLC

 

Dr. Eddie Garon considers the data on immunotherapies for first line treatment of advanced NSCLC and whether we are likely to use these agents instead of or in combination with standard chemotherapy soon.

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So, initially, development of the PD-1 and PD-L1 inhibitors were in patients who were previously treated, as that is a very difficult clinical scenario. Now, we do know, in the front line setting, that there is data that would indicate that many patients do quite well with chemotherapy, certainly not all, and the toxicities are certainly there, but chemotherapy can be quite effective in patients with non-small cell lung cancer. So, the question when you have a drug that is as effective, or a class of drugs that are as effective, as the PD-1 and PD-L1 inhibitors in previously treated non-small cell lung cancer, is: can those results be moved forward — can patients receive this as their initial therapy, rather than traditional chemotherapy approaches?

This is a place where, in my estimation, evaluation of the biomarker is going to be particularly important. So, there is data that would indicate patients who have higher degrees of staining for PD-L1 are more likely to respond to these immune checkpoint inhibitors. Of course, there is other biomarker work that is underway as well, some of which has been published, and some of which continues to go on, that may also be very helpful in identifying the appropriate set of patients. But, when one is looking at front line checkpoint inhibitors, one has to realize that, if you can identify a group of patients that are unlikely to have a response to a checkpoint inhibitor, that group of patients, probably, would be better off receiving standard chemotherapy in the front line setting, which we know can be quite effective, and, therefore, most of the studies that are looking at front line therapy are selecting patients who have, for instance, high level expression of PD-L1, and that has been, certainly, a major focus — people have taken different approaches. There are some studies that are specifically identifying patients, and only randomizing patients who have a high degree of staining to chemotherapy or a checkpoint inhibitor in the front line setting. Others are enrolling patients more broadly, but limiting their analysis to the patients who have a high degree of staining.

What I will say is, as somebody who has, for instance, studies in the front line setting that would give everyone a checkpoint inhibitor, as well as studies in the front line settings that would give only selected patients a checkpoint inhibitor, I have been very reluctant, at this point, with the data we have available, to enroll patients on a front line checkpoint inhibitor without knowing their PD-L1 status, because my concern is that, although you can say, well, those patients could always get chemotherapy later, we know that some patients with non-small cell lung cancer don’t get to their second treatment, and, in fact, that is not an uncommon scenario. We know, as well, that it does take some time for these checkpoint inhibitors to be effective in many of the patients in whom they are effective.

So, I have some concerns — for instance, if a patient has low level staining, although we don’t have all of the data yet, my suspicion is that, for instance, a patient with absent PD-L1 staining would probably be better off getting standard chemotherapy in the front line setting, and I think that it’s an important thing for patients to know, and of course the clinical data will sort of lead us there, but it is not clear that this is the absolute best therapy for everyone at every time. I think that there is a group of patients for whom that is likely to be the case — the group of patients in the KeyNote 001 study, which was looking at Keytruda, where they had not previously been treated — the survival in that group was so impressive, in fact, that we couldn’t even report on the bottom limit of the 95% confidence interval for survival, because patients just were staying on, they weren’t dying, of the people who had high level staining. That being said, the people who had absent staining — they didn’t do as well, and that’s a group of people, where my suspicion is, would do better with chemotherapy. We will see when the clinical data comes out.


GRACE Video

Do Clinical Characteristics Alter Your Enthusiasm for Immune Checkpoint inhibitors?

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WCLC_2015_Clinical_Characteristics_Alter_Enthusiasm_Immune_Checkpoint_inhibitors

 

Drs. Leora Horn, Ben Solomon, & Jack West assess whether clinical factors such as being a never-smoker or having a driver mutation (EGFR, ALK, etc.) reliably predict minimal benefit from immunotherapy agents.

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Dr. West:  We’re starting to see some early results suggesting that never-smokers and patient with driver mutations, like EGFR, or an ALK rearrangement, or ROS1, are particularly unlikely to have very good responses to these agents, the immune checkpoint inhibitors. Even if PD-L1 testing isn’t required, do these clinical characteristics matter to you, in terms of whether you’re less likely to recommend an immune checkpoint inhibitor as an early therapy in patients with no smoking history, or a driver mutation, are you thinking that this is really not likely to work, or are patients or clinicians so eager to use them that it’s really the first opportunity, no matter what the patient characteristics are?

Dr. Solomon: Yes, so I think the data so far haven’t been that exciting in patients, certainly with EGFR mutations, and probably also patients with ALK rearrangements, and why that is, I think, remains to be sorted out. Like you were suggesting, maybe it has to do with the mutational load, within tumors. So, I think — we want patients to receive the most effective treatments early on, and certainly, I don’t think there’s a role outside of clinical trial of using these inhibitors before therapy with an ALK or an EGFR inhibitor. I think there are some really interesting studies that look at using concurrent EGFR or ALK inhibitors with a PD-1 inhibitor, and I think it will be really interesting to see whether that increases response rates in these populations.

Dr. West:  What are your thoughts about the role for immune checkpoint inhibitors in never-smokers, and patients with driver mutations?

Dr. Horn:  I completely agree with what Ben said, you know, and many of those patients have been excluded from the first line trials, if you’re EGFR or ALK positive, because there are such great options for those patients. There was a little hint of — maybe we’re going to see some responses with the community study that was presented with nivolumab, where they showed around a 10-11% response rate in those patient populations — very small numbers, so maybe there are a group of patients that will respond, but I agree that the combination therapies look really, really interesting. The difference is that EGFR inhibitors — they’re incredibly effective, but at some point, they’re failing the patients, whereas, if a PD or PD-L1 inhibitor is working, they really have these long, durable responses that are often measured beyond just one year of therapy.


GRACE Video

Should PD-L1 be Used as a Biomarker for Immunotherapy in Lung Cancer?

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GRACE Cancer Video Library - Lung

GCVL_LU-FE04_PD-L1_Immunotherapy_Biomarker_Lung_Cancer

 

Dr. Eddie Garon, UCLA, reviews the controversial question of whether PD-L1 expression is a reliable enough biomarker to be used to select patients to receive or not receive immune checkpoint inhibitor therapy in lung cancer.

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So, the role of PD-L1 as a biomarker may be among the most controversial areas in the checkpoint inhibitor story. So, in melanoma, they have seen tremendous results with the checkpoint inhibitors, and early on in the development, the melanoma physicians were very dismissive of the role of a biomarker, in general, because they were seeing such good responses. Nonetheless, many of the studies in non-small cell lung cancer have specifically sought out the biomarker and there have been many different biomarkers that have been assessed, but the one that has been assessed most strongly in a clinical setting is the expression of PD-L1.

Again, PD-1 inhibitors are blocking the interaction between PD-1 and PD-L1, so it seems reasonable, perhaps, that the degree of expression of PD-L1 would correlate with the response to drug. And, in a very large study, in which we required all patients to have a biopsy around the time of therapy, looking at Keytruda, we saw that there were tremendous differences with respect to response rate, progression-free survival, as well as overall survival, with patients who had a high degree of staining for PD-L1, doing significantly better than patients who had a low degree of staining. When that data was published, there was some concern because there certainly were patients who had low level of PD-L1 staining, or even absent PD-L1 staining, who did have responses to the drug, and the thought was, how could you leave people behind? How could you not give patients the PD-1 or PD-L1 inhibitors, for instance, if you are in a situation where there are some patients who have no staining, who still respond — and that’s a very fair criticism. However, when you look at the data from the CheckMate 057 study, what you see is that there, again, now, in this case, they actually weren’t treating everyone with Opdivo, they were randomizing patients to receive either Opdivo or Taxotere, and they did identify one cutoff where, if you look, there was tremendous benefit in patients who had high level staining, but in patients who had lower level staining, those patients did equally well, whether they were on Taxotere or Opdivo; and the data from the POPLAR study with atezolizumab, where they look at it slightly different — they look at not only tumor cells, but they also look at the PD-L1 expression on infiltrating immune cells. In that study, again, they identified patients who had higher degrees of staining who did particularly better, and at least numerically, when you look, there was a group that they were able to identify where it looked like they did a little bit better if they got Taxotere.

So, this is still an area that is under active investigation, it is quite controversial, and the additional thing that’s important for patients to know is that it’s going to be a very hard situation, because, the way drug development currently is, one essentially gets credit, additional credit, for developing a biomarker along with the drug. And, so, for instance, in Keytruda, even though they had just a phase 1 study, that phase 1 study which showed clear correlation with a biomarker, may hasten that drug being available for patients. But, the challenge in that is that each company has their own diagnostic test, and it can be confusing because the tests are not identical. As I mentioned, atezolizumab evaluates both tumor cells and immune infiltrating cells, while the other tests really evaluate tumor cells alone, and similarly, the sensitivity and specificity of the antibody can differ — now that, I know, gets very technical, but I think what a patient could take from it is that 30% staining for PD-L1, for instance, with one antibody, doesn’t mean that you would have 30% staining for PD-L1 with another antibody. And, so, to some extant, each company has looked at their own antibody with their own drug, and I think this is going to be something that is confusing to patients as these things roll out. And, there are many efforts underway of sort of harmonize this, and hopefully we will be able to get to a point where it is easier for patients and clinicians to interpret the data.


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