This trial that we set up in advanced penile cancer patients was initiated because advanced penile cancer patients have a very poor survival, especially the stage 4 patients which also includes local regional disease still. We have previously conducted two trials at our centre, one investigating neoadjuvant chemotherapy which is the current standard in the guidelines. What we noticed was good responses but also a high rate of toxicity and early relapses. So that’s why we set up another trial investigating chemoradiotherapy which is also used in anal cancer. We used actually the same treatment schedule that’s used in anal cancer in our centre and we saw better responses and less toxicity but we also included the better patients. So especially for the patients with advanced disease with distant metastasis there was still not really an option for treatment because there are not a lot of treatment options for this group of patients. That’s why we set up the PERICLES study investigating immunotherapy with or without radiotherapy in advanced penile cancer patients.
The PERICLES study is a single centre phase II study which actually has two treatment arms and is not randomised. We included 32 patients with advanced penile cancer and they either had distant metastasis or local regionally advanced. They had a performance status of 0 or 1 and any previous treatment was allowed except for anti-PD-1 or PD-L1 treatments. Then all the patients received atezolizumab every three weeks for one year and the patients in arm A also received local regional radiotherapy according to the same treatment schedule as used in the chemoradiation trial.
The decision for arm A with radiotherapy or arm B with only atezolizumab was made based on the clinical presentation of the patients. If they could receive radiotherapy, they did not have any overlapping previous radiotherapy fields, and we expected a benefit of radiotherapy, they received local regional radiotherapy, otherwise they were included in arm B and only received atezolizumab. We followed them using CT thorax abdomens every 12 weeks to evaluate response. Then we set the primary objective, actually quite ambitiously, at a one year progression free survival of 35% or more. Secondary objectives were overall survival, response rate and toxicity.
Toxicity within the trial was actually well manageable. There were grade 3/4 adverse events in only 10%, related to immunotherapy. Related to radiotherapy this was higher, this was 65% but this was mainly caused by clinically insignificant lymphocyte count decrease in 50% of the patients. If we look at the clinical efficacy we noticed that the best overall response rate in arm A was actually 44% but it’s difficult to make a distinction between a response to atezolizumab and a response to radiotherapy. That’s why we also look at arm B which only received atezolizumab and had a best overall response rate of 17% which is quite substantial actually. So both arms had complete responders and durable responders which was actually not before investigated in penile cancer in such a trial specifically for penile cancer.
Unfortunately we did not reach the one year progression free survival and not our primary objective.
At the same time when looking at arm A and arm B and comparing them for progression free survival, we did not see a difference there. So that might be that the radiotherapy is not beneficial, at least we did not see a synergistic effect of radiotherapy on the progression free survival. Maybe this was because the radiotherapy scheme was suboptimal for immune modulation.
We have already looked at two different biomarkers, one was the PD-L1 status which is scored positive if 50% of tumour cells were positive. We saw that the patients who were PD-L1 positive had a slightly better progression free survival and overall survival. But we cannot make any hard conclusion on this because the data are still too immature and it’s quite a small group of patients. But we also saw the same trend of a slightly better progression free survival and overall survival for high risk human papilloma virus patients of which we had 14 in this trial.
Since we did see anti-tumour activity of atezolizumab in advanced penile cancer patients with complete and durable responders, we still are very interested in immunotherapy, despite that we did not reach our primary endpoint. But we’re currently evaluating pre- and on-treatment biopsies which we collected to see if there are other biomarkers for response and if we could maybe find different combination therapies or get a sense for which combination therapies might overcome resistance and then we plan to set up another trial to investigate this further and to see which treatment with immunotherapy would be the best for penile cancer patients.
These results should be interpreted that there is activity of atezolizumab for advanced penile cancer. We actually have a best overall response rate of 17% which is, with single checkpoint blockade, reasonable. The toxicity is manageable for these patients and we have some direction for biomarkers with high risk HPV positive or PD-L1 positive but we still need more data and we should definitely do more trials for immunotherapy. People can expect that this might become a new treatment for penile cancer in the future.