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Should Immune Checkpoint Inhibitors and Other Therapies Be Combined Concurrently or Sequentially?

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Drs. Leora Horn, Ben Solomon, & Jack West consider the merits of administering immune checkpoint inhibitors concurrently with standard first line chemotherapy or targeted therapy vs. sequential treatment.

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Dr. West:  With regard to combinations of immunotherapy with conventional treatments, such as chemotherapy for patients without a driver mutation, or patients with a driver mutation who would otherwise get a targeted therapy, how optimistic are you about concurrent treatment, versus sequential? Do you think there’s a good reason to favor a concurrent approach, versus thinking that you would do just as well or better by just sequencing these independently, Leora?

Dr. Horn:  So, I’m not a big fan of the concurrent with chemotherapy trials. You know, there has been data presented a couple times showing that patients maybe have a greater response, but I actually question whether some patients even needed to get chemotherapy to begin with, and a lot of the trials, I worry, are comparing chemotherapy with or without immunotherapy, but there’s no arm that’s immunotherapy alone and, so, are you just getting the responses that you would have seen with immunotherapy if you had just used that up front? And there are a little bit more toxicities, when you’re looking at these combination trials.

Dr. West:  What are your thoughts, Ben?

Dr. Solomon:  Yeah, look, I think it’s still early, I think we had some encouraging data, although, just with respect to response rate, about the combinations of platinum doublets with PD-L1 inhibitors. I think Ross Camidge presented a study where, in a very small number of patients, the response rate with the combination seemed to be about 60%, which we would think would be higher than expected with chemotherapy, and I thought that was encouraging. Whether the sequence made any difference, I think, remains to be seen, and in that particular study, toxicities didn’t seem to be a big issue, but I think they’re early days, and I think patients may well respond to immunotherapy alone — and I think a question will be sorting out which patients can be treated with immunotherapy alone, and which patients won’t respond and do need combinations, either with other immunotherapy agents, or with chemotherapy.

Dr. West:  Right, one of the concepts is that perhaps the cell kill from chemotherapy, or a targeted therapy can lead to greater immunosensitivity — kind of prime the system, and lead to more robust immune responses, it’s something that hasn’t been tested really. I would say that, as we had started to discuss, it’s a pretty broad approach to clinical trials with immunotherapy, which is basically alone or in combination with everything, and every setting, of every cancer, and if there’s any upside of that, it’s that these will all be tested in the light of day, we’ll see what the data show. Right now, we’re pretty devoid of data and just speculating, but in a couple of years we’ll actually have data to compare and make some intelligent recommendations.


GRACE Video

Are Immune Checkpoint Inhibitors Sufficiently Tolerable to Recommend Them for Older or More Frail Patients?

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Drs. Ben Solomon, Leora Horn, & Jack West consider whether immunotherapy might prove to be more problematic when given to a broader population of older and frail patients with advanced lung cancer.

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Dr. West:  What about issues of the tolerability of these immune checkpoint inhibitors? What are your impressions of — are they really trivial toxicity, compared with conventional chemotherapy, are there issues with patients who would really not be great candidates for chemotherapy being treated with immune therapies, potentially with challenging consequences if they have any toxicities… Have you seen that, or are you hearing about that in patients being admitted with complications who you think might not have been great candidates?

Dr. Horn:  So, it doesn’t seem that the elder patients, or the poor performance status patients, are having worse toxicities. In fact, I do — in my experience, it’s easier than chemotherapy. You know, people leave and sometimes they come back, “are you sure you gave me something a few weeks ago?” If patients don’t have toxicities, these drugs are far superior to chemotherapy. They don’t leave people feeling tired or down for four to five days after treatment, but in those patients that develop pneumonitis or colitis, are the two really big toxicities that seem to have a big impact on quality of life, you know, if people’s thyroids stop working, it’s easily fixed, but those can really have in impact on how people do. The nice thing is, it’s less frequent than neuropathy from chemotherapy or febrile neutropenia, or some of the other things that we see as a result of chemotherapy.

Dr. West:  Your thoughts?

Dr. Solomon:  Yeah, I completely agree, and certainly the PD-1 and PD-L1 inhibitors are really well tolerated. They do have some different toxicities which Leora mentioned, that patients need to be aware of, in particular, pneumonitis, and I think those are important symptoms to bring to the attention of doctors, and they need to be investigated, and patients put on steroids if there is evidence of that — but certainly, compared with some of the other immunotherapies, such as ipilimumab, those toxicities are much less frequent, and the drugs, even in older, frailer patients, are tolerated really well.

Dr. West:  It’s important just to underscore that early identification of a toxicity and addressing that, whether by stopping the drug or initiating steroids, in some patients, is critical. So, I think the biggest challenge would be if patients don’t mention it, and doctors are oversubscribed and are not attending to it. But, hopefully, as everyone gets more experienced with them, we’ll know what to be looking for and asking about.

Dr. Solomon:  Exactly.


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.


GRACE Video

Are there Clinically Significant Differences Among Immune Checkpoint Inhibitors Treating Lung Cancer?

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Drs. Leora Horn, Ben Solomon, & Jack West consider whether the data suggest that the better tested PD1 and PD-L1 inhibitors have differences in activity or tolerability or are essentially interchangeable.

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Dr. West:  Here at the World Conference on Lung Cancer, like ASCO, immunotherapy was a really hot topic — not a lot of new data here, but still a lot of on going controversies, and one of them, in fact, a featured question at a symposium that I hosted on current debates, is whether these agents are clearly clinically distinct, or largely interchangeable. Do you have a sense of that based on the data, your own impressions, right now?

Dr. Horn:  So, the response rates seem similar — it’s hard to gauge between agents because they seem to have different cut points, different assays. I think that there are going to be some differences between a PD-1 and the PD-L1 agents, and some of the clinical experience that I’ve had at our institution is that, PD-1 patients, for the most part, who have come off therapy, I’ve had less patients who have progressed at a later point, and I’ve actually treated one patient who came off a PD-L1 inhibitor, after progression, with retreatment with a PD-1 inhibitor, who then responded. So, I think that there is interesting science that we need to sort out between the way these different drugs act, but it may turn out that there are some subtle differences in the efficacy between the PD-L1 versus the PD-1 inhibitors.

Dr. West:  I think these are the kinds of questions we’re wrestling with — for instance, as we get other drugs on the market, will it make sense to treat with a PD-L1 inhibitor after a PD-1 inhibitor, or vice versa, or is there a huge amount of cross-resistance, toxicity differences — pneumonitis really a significant issue with PD-1 but maybe not an issue with PD-L1. What are your thoughts Ben?

Dr. Solomon:  Yeah, I think it’s still early days in terms of resolving those questions. I think most of the data, like Leora was describing, are anecdotal now. At a clinical level, response rates and toxicity are broadly similar across the classes. I think there may be some subtle differences that are emerging — I mean there are different targets, PD-1 is a receptor which is on the surface of lymphocytes, whereas PD-L1 is a ligand, which is expressed on the surface of tumor cells, and the ligand can interact with different receptors, and the receptor can be activated by different ligands. So, it wouldn’t surprise me, over time, whether some differences emerge.


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