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Dr West

Death by “Pseudo-progression”: Knowing When to Cut Your Losses with Immunotherapy

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Among the many novel concepts in managing immunotherapy is the potential for “pseudo-progression”. This unusual phenomenon is when a patient’s scans of the areas of cancer actually appear worse on early imaging, potentially even with new lesions, after starting immunotherapy, but a patient’s scans later show shrinkage of the cancer.  These patients typically feel well, often with improvement in their cancer-related symptoms (fatigue, appetite, etc.) that don’t seem to be concordant with their worse-appearing scans.

Why might this happen? Some biopsies of lesions that have grown or appeared as new in such patients help explain that the growth is from infiltration of immune cells around tumor cells, preceding the time when those tumor cells are attacked and eradicated by the immune system.  In cases where new nodules appear that then resolve with later scans, it is felt that this situation represents immune cells infiltrating a “micro-nodule” of cancer that wasn’t visible until it was surrounded by immune cells that then enlarged it enough to become newly detectable on scans.

Pseudoprogression West JAMA Oncol 2015

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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

Immunotherapy Combinations

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GRACEcast-526_Lung_West_Immunotherapy_Combinations

 

Dr. Jack West, Swedish Cancer Institute, discusses current trials seeking to determine the efficacy of combining immunotherapy agents in lung cancer.

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The class of agents known as immune checkpoint inhibitors have really invigorated our study of lung cancer, and many other cancers over the last few years. Agents like Opdivo, also known as nivolumab, and Keytruda, known as pembrolizumab, are now commercially available, FDA approved as a second line therapy for patients who have progressed on first line standard chemotherapy. We are now actively asking the question of whether we might be able to move these immunotherapies into the first line setting and also asking whether we might do well by giving a combination of immune therapies, rather then just one treatment at a time.

So these agents, immune checkpoint inhibitors, are largely categorized into PD-1 or PD-L1 inhibitors, and those are just targeting two separate sides of an interaction between two receptors. The PD-L1 is on the tumor cells, PD-1 is on the immune T cells, and so blocking either side of this can lead to a beneficial effect because this effect leads to a braking mechanism on the immune system — you take away that braking system and you turn off the brakes and lead things to move forward, and that’s what we often see.

There are other agents that can also lead to braking mechanisms and that have been studied in other cancers. An agent such as Yervoy, which is known as ipilimumab is a CTLA-4 inhibitor and this is an agent that’s been approved in melanoma. In fact, the combination of Opdivo (nivolumab) and Yervoy (ipilimumab), as two different ways of blocking the immune system, have been shown to be beneficial as a combination in melanoma compared with either one on its own. Because of that, we’re looking at combinations of immunotherapies compared with single immunotherapy approaches, or standard chemotherapies.

One interesting study being done right now is called CheckMate 227 and it is looking at first line treatment of patients with advanced lung cancer that is either squamous or non-squamous histology. It does not require any level of PD-L1 expression on the tumors, the protein associated with tendency toward better efficacy of immunotherapies, partly with the thought that the combination of two immunotherapies may make even the cancers that don’t express PD-L1 respond well. This trial is looking at first line therapy with either standard chemotherapy of cisplatin or carboplatin with Alimta for non-squamous cancers, or Gemzar (gemcitabine) for squamous cancers, compared with either Opdivo alone or a combination of Opdivo and Yervoy — Opdivo being a PD-1 inhibitor, Yervoy being a CTLA-4 inhibitor — and asking the question of whether immunotherapy is as good, better, or worse than standard chemotherapy as a first line treatment, and whether the combination of two immunotherapies is better than first line therapy. 

I should mention that there are other trials looking at very similar versions of this question using different combinations of immunotherapies. There are many companies looking at several different immunotherapies in development and they are overall really very comparable and all quite exciting.

You can learn more about this specific trial from the link on the screen,

CheckMate 227 Clinical Trial

but I would encourage you, if you talk to your doctor and they recommend a trial with an immunotherapy in the first line setting, potentially comparing it to chemotherapy, to carefully consider it — it does not have to be this specific trial to be of interest.

We’re going to learn more about this in the coming years and we’re going to figure out the best way to integrate immunotherapies with our standard treatment approaches today.


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.


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