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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

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

Clinical Trials of Immune Checkpoint Inhibitors as First Line Therapy for Advanced NSCLC

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LCAM 2015

 

Dr. Jack West summarizes the rationale for testing immune checkpoint inhibitors as a first line treatment for patients with advanced NSCLC and highlights details of two trials testing this question.

November is Lung Cancer Awareness Month. What are you grateful for?

Watch, read, and then share your own stories of empowerment in our online forum. Your story may inspire others.

Get more information about the IMpower-110 Trial and CheckMate-227 Trial.

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GRACE Video

Is It Feasible and Clearly Beneficial to Combine Immunotherapy Approaches?

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Drs. Leora Horn, Ben Solomon, & Jack West review the potential rationale and possible limitations of combining different immuntherapy strategies with one another.

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Dr. West:  I would say, one of the other really hot concepts at World Lung and various other meetings, is combinations with immunotherapy. And that can be two different immunotherapy agents, perhaps a drug like Yervoy (ipilimumab), which is a CTLA-4 inhibitor, that really targets a different part of the immune system, in combination with these immune checkpoint inhibitors, like PD-L1, PD-1 — or, as we have alluded a bit to, chemotherapy in combination with immunotherapy or targeted therapy. How excited are you by some of the combinations, starting with, say, the different immune therapies combined together — is this incrementally far better than any one of these drugs, and is it financially possible to do this in the world we live in?

Dr. Solomon: So, I think in melanoma, the combination data looks super exciting. I think the combination of ipilimumab and nivolumab looks really impressive, particularly in PD-L1 negative patients, and it has to be a said, even that data are relatively early data. We know that it improves progression-free survival, where we’re yet to find out whether this changes overall survival. In lung cancer, I think Leora probably has been involved in some of the studies, but I’m not sure that we’re at that stage with the data — we’re relatively early, and the early studies were hampered by a lot of toxicity in the patients, and I think at this meeting we saw some slightly different schedules that might have improved the toxicity. Leora?

Dr. West:  Of course, we do need to be mindful that melanoma patients are often quite a bit younger and healthier than your average lung cancer patient. So, what is your thought on this matter?

Dr. Horn:  I agree that the data is very early — the MedImmune with tremelimumab combinations, and the nivolumab and ipilimumab combinations, but the toxicity, I do think, is going to be a big issue for lung cancer patients. They are older, they’re just not as hardy, and the toxicities are not inconsequential when they do happen.

Dr. West:  Yeah, I think that it’s appealing to think that, maybe, combinations will work in a broader range of patients, in whom a single agent may not be enough, and that, hopefully in a few years, we will be able to predict, reliably, which patients are best served by a single drug, versus a combination, if we can find combinations that are tolerable.


Dr West

PD-L1 Expression for Immunotherapy Agents in Lung Cancer? Vital or “Don’t Ask, Don’t Tell”?

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In the span of a week, we’ve just had new FDA approvals of Keytruda (pembrolizumab) for previously treated advanced non-small cell lung cancer (NSCLC) patients with tumors that express PD-L1, followed by a broadened approval for Opdivo (nivolumab) for previously treated patients with advanced non-squamous NSCLC, without a requirement for PD-L1 expression testing. This second approval for Opdivo complements the prior lung cancer approval for Opdivo, for patients with advanced squamous NSCLC, without restriction by PD-L1 expression.

So now what? Do we test for PD-L1 and use that to decide between Keytruda and Opdivo? Do we use PD-L1 testing to determine when to give an immune checkpoint inhibitor, or even if we should give it at all? Or do we just decide that if we can give one checkpoint inhibitor without restriction by PD-L1 expression, it’s not worth the time, cost, or effort of doing a test to make things more restrictive?

This is a controversial question, and my own views have been evolving as I carefully consider the treatment landscape. I’ll present why I think we SHOULD be doing PD-L1 expression testing, why it doesn’t necessarily matter which of these treatments you give, and how I see this debate shifting as new data emerge and our treatment approaches are likely to change in the next few years.

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