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Dr West

OAK trial with Tecentriq (atezolizumab) is positive: How a “me too” result may change the landscape in advanced NSCLC

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With positive trials of two immune checkpoint inhibitors, Opdivo (nivolumab) and Keytruda (pembrolizumab), in second line NSCLC and compared with Taxotere (docetaxel), it should come as a surprise to nobody that another checkpoint inhibitor, Tecentriq (atezolizumab) has also proven superior to Taxotere in the OAK trial of previously treated NSCLC patients, as reported in a press release today.  Perhaps the biggest surprise is that this result actually has the potential to shake up the field even with Tecentriq as a late third entrant into the race.

The trial in question is called OAK, which is a very straightforward head to head phase III trial of Tecentriq, a PD-L1 inhibitor, vs. standard Taxotere in 1225 patients who had received one or two lines of prior chemotherapy and were not restricted by level of PD-L1 expression.

OAK trial image

This trial is very similar to trials with the PD-1 inhibitor Opdivo in patients with previously treated squamous NSCLC (Checkmate 017) and another with Opdivo in previously treated non-squamous NSCLC (Checkmate 057), without restriction by PD-L1 status. Both of those trials demonstrated a significant improvement in overall survival compared with Taxotere, leading to the approval of Opdivo in previously treated patients with advanced NSCLC, regardless of PD-L1 status.  In addition, the Keynote-010 trial of the PD-L1 inhibitor Keytruda vs. Taxotere also demonstrated a very similar survival benefit but was restricted to patients with PD-L1 expression.  At this time, the approval of Keytruda is only specifically for patients who test positive for PD-L1 with a threshold level of >50% expression, based on an earlier trial with Keytruda that demonstrated clearly greatest benefit in the much smaller minority of patients with high level PD-L1 expression using a 50% cutoff (about 28% of patients).

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GRACE Video

Are There Clinically Significant Distinctions Between PD-1 and PD-L1?

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GRACE Cancer Video Library - Lung

GCVL_LU-FE02_Clinically_Significant_Differences_PD-1_PD-L1

 

Dr. Jack West, Swedish Cancer Institute, compares the mechanism of action, efficacy and toxicity of PD-1 and PD-L1 inhibitors.

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Among the most exciting developments in lung cancer over the last few years has been the introduction of immune checkpoint inhibitors — agents that are given by vein that help to stimulate the immune system, really by turning off one of the braking mechanisms. There are two main treatment approaches that are used, they’re called PD-L1 inhibitors and PD-1 inhibitors. These PD-1 and PD-L1 are receptors that attach to each other, and when they work together they lead to a braking mechanism for the immune system. These antibodies can block either the PD-1 or the PD-L1 side of that and turn off that braking mechanism, much like taking off the emergency brake on a car and leading it to roll ahead.

PD-1 is on the T cells of the immune system, PD-L1 is on the tumor cells, so there are different agents and they block different sides of this interaction. The question is: does it matter which one you get or are they all pretty much the same? There are two agents as of now that are FDA approved in advanced lung cancer and those are Opdivo, known as nivolumab, and Keytruda, known as pembrolizumab, although there are other agents that are likely to become FDA approved in the future.

These two agents, Opdivo and pembrolizumab, are both PD-1 inhibitors. Others such as atezolizumab and others are known as PD-L1 inhibitors. Does it matter which one you get — do the results differ? Well we don’t absolutely know because we have not yet seen the results or even done a trial that directly compares how patients do when they get one over another, but the results are remarkably similar regardless of which agent is tested in the same setting. Specifically they all seem to produce response rates of about 15% to 20% in the broad population, and if we look at patients who have significant PD-L1 expression, the protein that is associated with the more inhibitory effect, we see better results with any of these.

It remains to be seen whether you can treat a patient with a PD-1 inhibitor like Keytruda, like Opdivo, and then get a good result once they show progression because you’ve given them a PD-L1 inhibitor, but for all intents and purposes, the results in terms of efficacy and also side effect profiles are remarkably similar and most specialists feel they are really essentially interchangeable until we see evidence showing otherwise.


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

What is the Optimal Duration of Immunotherapy?

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GRACE Cancer Video Library - Lung

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.


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