ASTRO 2015

Systemic immunotherapy and radiotherapy combination shows promise in advanced skin cancer

Dr Susan Hiniker - Stanford University, Stanford, USA

Anti-CTLA4 immunotherapy is the first in its class inhibitor of an immune checkpoint which is approved for use in the treatment of malignant melanoma and can produce durable responses in a subset of patients but still many patients don’t respond to therapy. Radiation is known to affect the local tumour environment in such a way as to promote immune responses; there are a number of mechanisms. Early preclinical laboratory work has shown that combining radiation and immunotherapy can produce better results than seen with either therapy alone, with responses seen outside the treatment field. A number of institutions, including Stanford, have published case reports of patients who have had an excellent, in some cases complete, response to this therapy where one metastatic lesion is irradiated with combination systemic ipilimumab and the patient achieves a response outside of the treatment field. So we wanted to look at that in a larger fashion in a prospective phase II trial enrolling patients.

Could you outline what you did in the phase II study?

We enrolled 22 patients on a prospective phase II clinical trial. All patients had metastatic melanoma stage 4, one to two sites of disease were irradiated and there was at least one measurable site of disease that was not irradiated to assess for response which had to be at least 1.5cm. Patients were treated with four cycles of ipilimumab, we used 3mg/kg, and radiation was delivered within five days after the first dose of ipilimumab. After the four cycles of ipilimumab, two to four weeks following the fourth cycle, they were imaged with CT or PET scan to assess their initial response to therapy and then were imaged every three months thereafter. As this was a phase II study our primary endpoint was actually safety so we were looking at whether there is any additional toxicity from the combination of these two therapies and we didn’t find additional toxicity beyond what would be expected.

Ipilimumab can cause significant adverse events. Could these signs be made worse when combined with radiation therapy?

We did see, certainly, toxicity. We saw approximately a 14% rate of grade 3-4 toxicity which is really on a par with what’s been reported for ipilimumab monotherapy, generally in the order of close to 20%, but that being said, we don’t believe that radiation itself caused any additional toxicity. That being said, as you mentioned, ipilimumab itself carries significant toxicity. One of our patients had a perforated colon and so, because of that, we have interests and many others have interests in using inhibitors of the PD1 access which are more efficacious and better tolerated as part of a combination therapy approach.

What have been the results of the study so far?

The results were very interesting. We found approximately a 20% partial or complete response rate, this was measured as the best response that patients had at any time of therapy. We had three patients who had a systemic complete response to therapy, no evidence of disease at all following treatment. Those are ongoing so the patients continue to have a complete response. We had three patients who had a partial response as best response, meaning that there is some shrinkage of their disease outside the field but not enough to be a complete response. That was for about a median of 40 weeks. Then we have five other patients who had stable disease as best response for a median of about 39 weeks. So overall, in terms of patients who had complete, partial or stable disease, all of which are meaningful in this population, we found 50% had that. The other 50% of patients had progressive disease on their first time point after treatment as their best response and didn’t respond to therapy. So we found a higher overall response rate than seen with ipilimumab alone, which is generally in the order of closer to 15-20%, and we also found, interestingly, more patients who had a complete response. So the 14% of patients who have had this durable complete response was higher than has been seen with ipilimumab alone, which is generally in the order of approximately 2-3% although it has been reported differently in different studies.

How would combined treatment be given, as a one-off dose or repeated administration?

Generally the way this ipilimumab is given is as a one-time course of therapy thing although patients can be re-treated and sometimes will respond again in the future. The exciting areas right now are really in the PD1 access and so there’s a prospective multi-centre phase II trial that should be opening soon involving Memorial-Sloan Kettering and Stanford and other institutions that will look at the combination of PD1 inhibitors plus radiation and possibly another arm looking at PD1 inhibitors plus ipilimumab plus radiation, although that’s still under consideration.

Will there be a study comparing ipilimumab versus radiation therapy versus the combination?

That’s a possibility. I think right now everyone is so excited about the PD1 inhibitors and they’re safer that it’s hard to want to give someone ipilimumab alone as the first line at this point. Many patients didn’t have toxicity but the ones who did it could be severe, so that makes sense but we’re not certain yet.

You mentioned a subset of carefully selected patients may benefit, have you looked at biomarkers yet?

We performed a biomarker exploration on a subset of patients, so the last ten patients or so we performed immune assay response studies in the peripheral blood. Using that we found indications that patients with higher levels of IL2, both pre-treatment and at two time points during treatment, as well as higher levels of CD8 T central memory cells again at all three points, pre-treatment and two points during treatment, had better responses than patients who did not. Again, this is only in a subset of patients but it was still a significant finding with p less than 0.05. So I think that we will find markers, we’re not there yet and it would need to be confirmed in a longer, larger study.

What about using immunotherapy earlier in the disease course?

It’s too early for that. People have wondered, that’s a good question, people have wondered whether these immune therapies should be used as adjuvant treatment in people without metastatic disease but maybe high risk disease. They’re not currently approved for use in that setting and, particularly with drugs like ipilimumab with high rates of toxicity, we’re not certain yet whether the risks of that toxicity would outweigh the potential benefit.

From a practical perspective what do these results mean for clinical practice?

One main message that these results mean is that if there’s a patient who is receiving ipilimumab and a physician is considering giving them radiation during that course of treatment, our results indicate that this is safe and that there is not need for concern, at least in our population of patients, of excess toxicity which is always something we think about as radiation oncologists when a patient is receiving especially one of these newer systemic agents – will there be a potential for synergistic toxicity. So that’s a main message. But another message I would say is that, from a secondary objective of the response rates, this combination approach does appear to be promising, that a subset of patients, the three who had these ongoing complete responses and another patient who this trial was predicated on or directly preceded by. Right before the trial opened we treated our first patient who was our case report, metastatic disease with combination therapy, and he’s had a complete response and is over four years out with no evidence of disease. So for a subset of carefully selected patients, and the problem is we don’t totally know how to select them yet, this can be extremely promising.

Do you have a take home message?

Of the times in history to have metastatic melanoma this is a fairly good one. There are a lot of new systemic therapies which are very exciting, new combination therapies which are very exciting and scientists working on harnessing the immune system to create really ongoing durable responses to therapy. So there’s a lot of reason for hope.