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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

What is the Optimal Duration of Immunotherapy?

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GCVL_LU-FE08_Immunotherapy_Optimal_Duration

 

UCLA Med Center’s Dr. Eddie Garon discusses the open question of the optimal duration of ongoing treatment with immunotherapy for lung cancer.

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The duration of therapy that’s appropriate for immunotherapy is very hard to know. There are not good studies, to date — there are some theoretical reasons that you could go either way, that being, you could say that you’re going to need to treat these patients forever, versus that you would need to treat patients for a period of time. Different clinical trials have had different durations of therapy — there are some trials that have treated until the time of progression, there are some trials that have treated patients for one year, some trials that have treated patients for two years. We certainly know that there are some people who, for a variety of reasons, need to come off drug for a period of time, who will continue to do well after going off drug for even long periods of time; whether that means that these patients can stop the drug, we don’t know. Also, many of the toxicities tend to be seen early, but there are patients that can have toxicities that are seen late, so it’s not that there is no harm in continuing to treat a patient who is doing well — there may be harm, they may derive no additional benefit but some risk of additional toxicity.

The answer is: we don’t know yet. There are studies that are under way that are trying to evaluate this question, but in reality, those studies are very, very hard to conduct, they take a long time to get results, and you have to enroll a huge number of people upfront, knowing that only a percentage of those patients are going to still be on drug a year later, and it does end up being a very difficult question to answer. I think, in many respects, these questions are going to be answered in our clinics. There will also probably be payers that have some input into this. In my clinic, I tend to have a lot of people who, you know, sort of — that’s where we reached out for clinical trials of immune checkpoint inhibitors, and those people are terrified of stopping their drug; they understand that it may be the wrong thing to continue it after years, but they still want to continue it. On the other hand, patients who are seen in a practice that is not the same as mine, where they’re maybe not quite as motivated, they’re not the people who have flown in for a checkpoint inhibitor every few weeks, that group of people may get sick of coming in for the drug, and they may choose to stop it, and that may be where our data comes from — although, as I say, there are studies that are ongoing, the CheckMate 153 study looking at Opdivo will look to address that question, but again, studies like that take a long time to answer their question, if they can answer it at all.


GRACE Video

Time to Response to Immunotherapy and the Concept of Pseudoprogression

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GRACE Cancer Video Library - Lung

GCVL_LU-FE07_Immunotherapy_Response_Time_Pseudoprogression_Concept

 

Dr. Eddie Garon reviews the pattern of response to immunotherapy in lung cancer, along with the concept of “pseudoprogression”.

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So, we have seen, certainly, some variability in the time to response; we have seen some people who will even have palpable lesions that will shrink, you know, within days — although that is rare. In general, what we find is that, generally, somewhere around 6 to 8 weeks is when we see patients who are having response to drug. It tends to be quite rapid — when you look at the clinical data, you can see that probably most of the patients who have what we call a clinical response to these drugs, that response occurs probably at the first imaging analysis, usually somewhere about two months after starting. Although there has always been this sense that it will take a long period of time for someone to respond to an immune therapy, and that is true, for instance, compared to a standard chemotherapy, where the effects are often seen within a couple of weeks, here it tends to be delayed from that, but it doesn’t tend to be delayed for months and months.

One other important issue to address is this issue of pseudoprogression, and this is something that people in the immunotherapy field have talked about for a long time, that if you have an effective immunotherapy, that you may have immune cells that infiltrate into the tumor and, as a result, rather than getting smaller, that the tumor would actually get larger. That could certainly happen over a short period of time, but what I would say, to date, is it’s not something we’ve seen a lot in lung cancer. Our colleagues in melanoma certainly report this as being a significant issue — patients who will have initial growth of their tumor on imaging, and then, afterwards, will have shrinking. We certainly do have several intriguing anecdotes, sort of individual patients that people will describe who have had, sort of, increases in their tumor volume, but then get better, but I would say that it is actually quite uncommon in lung cancer.

What we do see with some frequency is someone who will develop a new lesion. So, for instance, maybe they’ll have three areas that you’re following, all of them will get a little bit better, but then you will find one area that is a new area, that’s, you know, a centimeter and a half, that shows up on scans. By our typical way of evaluating radiographs, we would consider that to be progression. In my clinic, and as part of clinical trials, we’ve incorporated sort of different evaluations, that have, in some cases, allowed patents in that setting to continue on therapy. And, what I would say is, in somebody who is feeling good, who has an ambiguous response, one like what I mentioned, where several areas got better, but one area is new, or one area grew while other areas got better, but is clinically doing well — it may be worth continuing that patient on drug. But, when I see patients in second opinion and things like that, I will say that I much more frequently tell them that it is time to stop the immune checkpoint inhibitor, than to continue and hope for pseudoprogression. That, I would say, is very rare to see; we treated 98 patients at UCLA on the KEYNOTE-001 study, and I can’t think of a single patient that had, what we would call, sort of a flare response, where everything on the scan got worse, and then subsequently got better. So, I can’t give you an exact percentage, but what I would say is that it is rare. The thing that’s going to be more important is trying to interpret some of these ambiguous radiographic responses, which can be seen, but if everything is getting worse on the scan, what I’ve told people is, almost certainly, it means that the drug is not working.


GRACE Video

Immunotherapy Combinations: Is this the Future for Treating Lung Cancer?

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GRACE Cancer Video Library - Lung

GCVL_LU-FE06_Immunotherapy_Combinations_Future_Treating_Lung_Cancer

 

As we learn more about immunotherapy for lung cancer, combinations with multiple immunotherapy agents are being explored. Medical oncologist Dr. Eddie Garon considers whether combinations are likely to emerge as the leading immunotherapy approach.

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So, as a research community, I feel like we’ve come a long way. It used to be, even not so long ago, that you would have a new drug, and that the first thing you would do is try to figure out how to add it to all of the established regimens that we were using. Now, that is not the initial development of the checkpoint inhibitors — the initial development has been looking at the single agent, and looking at checkpoint inhibitors as an alternative to chemotherapy. That being said, in this development, we’re sort of now moving back to that, where we’re seeing an effort to incorporate the immune checkpoint inhibitors, along with other approaches — things like chemotherapies, targeted therapies, and those are clinical trials that are under way.

Now, there is certainly some biologic rationale for this, in that, one thought is that if you are able to destroy cancer cells, that you basically would, it’s sometimes described as free-up an antigen, or free-up targets, for the immune system, and that therefore, it would be a more effective approach. There certainly are a host of studies underway, looking at adding checkpoint inhibitors to standard chemotherapy, and to most of the targeted therapies that have been developed — that is something that you are certainly seeing.

So, one of the areas that people have been interested in looking at is actually combining PD-1 or PD-L1 inhibitors with other immune checkpoints, and the ones that has been most extensively evaluated have been inhibitors of CTLA-4, and some of the reason for this is actually practical — there is a CTLA-4 inhibitor, Yervoy, that is clinically available because it’s used to treat metastatic melanoma, so any drug company can run a study with Yervoy. Yervoy is an expensive drug, and so it’s an expensive study to run, but it can be done. Also, Bristol-Myers Squibb who makes Opdivo also makes Yervoy, and MedImmune is a drug company now owned by AstraZeneca, that is developing both an inhibitor of PD-L1, as well as CTLA-4.

There has been some intriguing data looking at that combination specifically, and there have been some indications that, perhaps in patients who have low level of staining for PD-L1, that you can effectively treat those patients with the combination of agents. I’m a little cautious on those studies, in that the toxicity is clearly higher when you combine a CTLA-4 inhibitor with a PD-1 and PD-L1 inhibitor, and although the numbers to date look quite good, I’m concerned that that may be in a more robust group of patients, as not everyone who I would feel good about putting on a single agent PD-1 or PD-L1 inhibitor study, would I also feel good about putting on one of these combination studies. So, I am very eager to see if some of the promising data that has been seen to date with this combination of a PD-1 or PD-L1 inhibitor with a CTLA-4 inhibitor can be shown on a broad scale, in a larger group of patients.

In addition, our understanding of immunology has certainly increased over time, and there are other immune checkpoints, as well as vaccines, and other immune-based approaches that people are starting to look at in the setting of clinical trials. I think there are a host of exciting clinical trials out there — it will be interesting to see the outcome, I’m sometimes concerned that maybe the clinical trials are getting ahead of where the science are, and that some of these can be associated with harm, but on the other hand, it will be interesting to see what the results are, and it is an exciting time in immunotherapy, certainly.


GRACE Video

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

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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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