Combination Therapies: What Works Best for Immuno-Oncology?

Benjamin P. Levy, MD: The immunotherapy paradigm, as it stands today in June 2016, is as a single agent. But, I think a lot of us feel that the future of these drugs is in combination strategies rooted in scientific rationale. And, most of the data that are leaking out of ASCO and other meetings are looking at combinations. There’s a lot of potential synergy. One option is to give these drugs in combination with a CTLA4 antibody, another checkpoint drug, and the data are missed on how effective that is. We saw data yesterday, at least, that this combination works very well in a small number of patients that were PD-L1 positive. It also may work in a treatment refractory setting in a combination setting. I’m not sure how much off-label use there is of that right now. There are some toxicity signals that preclude, I think, routine use of looking at these drugs together, but it may be a new standard at some point.

The other strategy that’s being looked at is combining immunotherapy with chemotherapy—taking patients who are treatment naïve, getting chemotherapy, and giving them also an immunotherapy. And the data there also looks quite promising. There’s biological rationale. Chemotherapy may make the tumor more immunogenic. Giving immunotherapy with chemotherapy may be something that, down the road, may pan out in clinical trial.

But, I think there are so many trials going on, we won’t be able to sort this out for another year or two, to understand what the optimal regimen is. I do think that immunotherapy would probably be used off-label as a first-line single agent. I think I’m seeing this in the community. I have a stage 4 squamous cell patient who’s coming to my office, as a second opinion, who got immunotherapy first-line. That’s not what it’s approved for, but they’re getting it, and insurance companies are paying for it. And if you look at the data, at least the data that I’ve been privy to, there is a 25% uptake in the first line. So, I think the most unusual off-label use of these drugs currently is as a single-agent first-line therapy. I don’t think the data are there for this approach. Combination strategies are tough to give off-label because of the toxicity signals; not only the chemotherapy, but with CTLA4 antibodies.

There’s a lot of work being done with immunotherapy both with targeted therapies and radiation therapy. I’ll tackle the targeted therapy question first. There is some scientific rationale to look at immunotherapy with tyrosine kinase inhibitors either against EGFR or ALK. However, there’s been early safety signals that there may be an increased risk of pneumonitis. And so, there is efficacy there, but whether this will pan out and move forward is unclear. The pneumonitis signal is there in a fair number of patients. TKIs alone cause pneumonitis. Immunotherapy alone, there’s a 5% rate of pneumonitis. Combining them together may not be the best option. I’m leading a phase I trial that’s going to try to look at this again in a very careful way, in which the enrollment is staggered so we can look at it very slowly and very carefully, about immunotherapy with targeted therapies. Immunotherapy’s not only being looked at in combination with first and second generation TKIs, but it’s also being looked at in combination with T790M-directed therapies for EGFR-resistant patients. And I think there’s a lot of work that needs to be done in safety.

In terms of radiation, certainly there are thoughts that this can be used in a rational way with radiation. There’s an abscopal effect with these immunotherapies. If you radiate a spot and immunotherapy is given, another spot that you didn’t radiate may shrink quite dramatically. There are ongoing trials looking at immunotherapy either by radiating sites outside the lung, or, looking at it after radiation of the lung. I think there are also some interesting safety signals by giving immunotherapy with radiation to the lung that may enhance or elicit more of a pneumonitis picture.

The way I see this being done with radiation is palliative radiation to another site of disease outside the lung; giving immunotherapy, and seeing if it can synergize. Radiation may upregulate antigens on the tumor, and that may make this more likely to respond to immunotherapeutic approaches. And then, also looking at immunotherapy after chemoradiation. For stage 3 patients who are unresectable, who get chemoradiation, there’s a trial that’s already completed looking at immunotherapy for up to a year—not during it, but after it—to see if there’s an extension in survival.