Cancer Network: There are already a few immunotherapy-immunotherapy combinations approved for melanoma, and also two targeted therapy combinations. What have we learned so far about the development of these types of combinations that could help us develop additional combination regimens for melanoma and other tumor types?
Dr. Wargo: I think what we’ve learned is that even though monotherapy regimens using immunotherapy or a targeted therapy can work for some patients, it’s really only in a minority of patients that this works well. The majority of patients will need a combination therapy approach.
Now, certainly, we have seen different combination regimens, [such as] immunotherapy-immunotherapy regimens such as ipilimumab plus nivolumab approved for melanoma—and potentially this combination will be approved for other cancers. The issue with these regimens is that we see significant toxicity, so I think there is still room for progression. Can we test immunotherapy-immunotherapy combinations that are potentially just as efficacious but less toxic? I think there are some being tested now, [and the results of these studies] may help answer that question.
In addition, can we actually use targeted therapy in combination with immunotherapy to improve responses? The rationale for this goes back several years. Specifically for melanoma, targeted therapy was really first approved and shown to be very effective in treating patients with stage IV melanoma. But we learned early on that patients do progress on therapy, and that the duration of response is relatively short-lived. Now, in the early days of immunotherapy for melanoma, we know that with treatment with the initial immune checkpoint inhibitor that was approved, an anti–CTLA-4 [cytotoxic T-lymphocyte–associated antigen 4] antibody, we saw that a minority of patients actually responded but the patients that did respond had durable responses.
Early on, there was clinical interest in combining targeted and immunotherapy agents, hoping that we would get to a higher response that we see with targeted therapy and the prolonged response seen with immunotherapy. Now, with the advent of anti-PD1 [programmed death 1] and anti-PDL1 [programmed death ligand 1] immunotherapy for melanoma, we are certainly seeing higher response rates, but the majority of patients still do not respond, or the responses are not durable. So, there is always room for these different mechanisms of action combinations.
On top of all of this, we also know that there is a strong scientific rationale for combining targeted therapy with immunotherapy. Namely, we know that these oncogenic mutations can actually cause immune evasion in tumors and that by blocking these oncogenic mutations, you can make these tumors more immunogenic. We showed this in melanoma several years ago. Now there are ongoing studies in patients, combining targeted therapies with immunotherapy, namely with immune checkpoint antibodies—and this approach is showing great progress.
Cancer Network: Are there specific immunotherapy-targeted therapy combinations being tested, and what are we beginning to understand about combining these types of therapies?
Dr. Wargo: Definitely. Some of the first targeted therapy- immunotherapy combinations involved BRAF-targeted oral therapy in combination with cytokine immunotherapy such as interleukin-2. I can tell you that this combination wasn’t very effective for a number of reasons.
One reason is that [the interleukin-2] trial was started in the setting of all of these checkpoint inhibitor antibodies that were being tested, so as soon as the trial started, these newer agents were just starting to be tested in clinical trials. [As a result], the interleukin-2 trial just was not getting a lot of traction.
In addition, we know that interleukin-2 itself can actually increase the frequency of regulatory T cells, which actually inhibit the immune response you want against the tumor. We saw evidence of this in a trial that we ran out of the Massachusetts General Hospital in which there was some hint of efficacy, but we also saw that there were more regulatory T cells in the patient’s tumor microenvironment after patients were treated with interleukin-2. Now, that is some of the early work, and some of this work included combining anti-CTLA4 antibodies with BRAF-targeted agents.
The early trials combining these two agents were somewhat disturbing in that there was significant hepatotoxicity. Because of this, these trials were stopped early on, but now with the use of other immune checkpoint inhibitors in combination with targeted agents, we are seeing less toxicity and higher efficacy. Some of these agents that are being tested in clinical trials are dabrafenib (an oral BRAF inhibitor) and trametinib (an oral MEK inhibitor), combined with PDR1, which is an antibody that targets the PD-1 checkpoint molecule.
Many other trials are also underway, so this is not only being tested in melanoma but in other solid tumors, as well as in hematologic malignancies. There are hints of efficacy but it will take some time to get the full readout; [this is] because we know that when using targeted agents, there can be a very high response rate, but what we are looking for in these trials is durability of response rates.
Cancer Network: In general, to figure out what immunotherapy-immunotherapy combinations make sense to test, are these first being tested in the lab to [better understand] how the immune system responds before taking these into the clinic?
Dr. Wargo: For the immunotherapy-immunotherapy combinations, we still have a good deal to learn. I think there are some very strong lessons that we can learn from preclinical models. However, preclinical models are not always perfect, and we don’t necessarily see the same toxicity in preclinical models compared to what we see in patients, so we need to think outside the box regarding how best to test these different combinations.
One particularly appealing strategy is using these agents in a neo-adjuvant setting before a tumor is actually resected. So if a patient comes in with a potentially resectable metastases, we are running some novel clinical trials looking at immunotherapy-immunotherapy combinations to test, not only [to determine] how effective these are, but [to learn] what are their effects on the tumor microenvironment. [Using this approach], we can better understand if they are working, why are they working, and if they are not, what we can do to make these therapies work better in this setting.
Cancer Network: From a research perspective, are there additional questions that you and other researchers are addressing that will help us to come up with better immunotherapy-targeted therapy combination strategies?
Dr. Wargo: I think what we are grappling with now is that there are just so many combination trials that are being run and a lot of these are not [pharmaceutical company–sponsored trials], but investigator-initiated trials.
In 2017, there were close to 500 new trials that combined a checkpoint blockade molecule, and they were testing these drugs in combination with all kinds of different strategies. One of the biggest issues here is that, as it stands, these approaches have been somewhat fragmented and disorganized. The approach is researchers doing lots of small trials and not necessarily with consistent collection of biospecimens or even looking at the same clinical endpoints. The thing that we need to do as an oncology community now is to come together to design studies that actually test these combinations as a more global strategy and in a coordinated and more concerted fashion.
I think the neoadjuvant studies provide a real opportunity, and we are working with others globally to form a neoadjvuant consortium for melanoma. The goal would be to work with other investigators to extend that beyond melanoma to other cancer types. Efforts like this, as well as efforts through the Friends of Cancer Research…can really make a big difference.