Use of the immune checkpoint inhibitor atezolizumab with or without radiotherapy showed antitumor activity in stage IV penile cancer in the phase II PERICLES trial, although the study failed to meet the primary endpoint of 1-year progression-free survival of at least 35%. The hints of activity were strong enough for the study authors to recommend further investigation and the identification of biomarkers for patient selection. The study was presented at the 2022 ASCO Genitourinary Cancers Symposium.1
“We observed antitumor activity of atezolizumab in advanced penile cancer, a disease with limited treatment options. Although there is still much work to be done to identify patients who will respond, we are enthusiastic about the potential of immunotherapy in penile cancer,” stated lead study author Hielke-Martijn de Vries, MD, a urology resident and PhD candidate at the Netherlands Cancer Institute in Amsterdam.
Hielke-Martijn de Vries, MD
Advanced penile cancer is a rare disease, with a very poor prognosis—a 2-year survival rate of 21% from the time of diagnosis. Additionally, patients with stage IV tumors experience high morbidity due to progressive locoregional disease.
Previous studies of the tumor microenvironment have identified the presence of high-risk human papillomavirus (HPV) in 25% to 50% of patients with penile cancers and PD-L1 expression in 40% to 60% of tumors. Atezolizumab targets PD-L1, and PERICLES was designed by the principal investigator, Michiel van der Heijden, MD, a medical oncologist at Netherlands Cancer Institute in Amsterdam, to evaluate the drug with or without radiotherapy in advanced penile cancer.
Dr. de Vries told listeners that two smaller studies in advanced penile cancer had been conducted at the Netherlands Cancer Institute. One study evaluated neoadjuvant chemotherapy with docetaxel, cisplatin, and fluorouracil, which led to high toxicity, early relapses, and 23% of patients discontinuing treatment.2 A separate trial of chemoradiation led to less toxicity and better progression-free survival compared with chemotherapy alone, but this study also included patients with earlier stages of disease,3 and it is not an option for patients with distant metastasis.
The single-center, randomized PERICLES trial enrolled 32 patients (median age = 67) with stage IV squamous cell carcinoma of the penis and a World Health Organization performance status of 0 or 1. Baseline characteristics were similar in the groups that did or did not receive radiotherapy. PD-L1 expression was present in 44%. Previous treatment with anti–PD-1/PD-L1 inhibitors was not allowed. In fact, 25% had received no prior treatment at all, but 34% had prior radiotherapy, 22% had prior chemoradiation, 6% had prior chemotherapy, and 69% had prior surgery. About 59% had distant metastases.
All patients were treated with atezolizumab at 1,200 mg every 3 weeks for a maximum of 1 year. Cohort A included 20 patients who also received locoregional radiotherapy (33 fractions of 1.5–1.8 Gy). Cohort B included 12 patients treated with atezolizumab alone. There was no randomization; groups were chosen based on clinical presentation and expected benefit of radiotherapy.
Median follow-up was 22 months. Among 30 evaluable patients, the 1-year progression-free survival rate was similar in both study arms—12.5%—which was much lower than the prespecified rate of at least 35%. Median progression-free survival was 2.5 months.
Response to treatment was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, with scans of the abdomen and thorax every 12 weeks. The overall response rate was 33%, with three complete responses and seven partial responses. Eight of the responses were in the atezolizumab-plus-radiotherapy arm. The two complete responses were in patients whose cancers were PD-L1–positive and HPV-positive. In the atezolizumab-alone arm, there was one partial response and one complete response. By RECIST criteria, the overall response rate was 44% with the combination therapy and 17% with atezolizumab alone.
For more about the PERICLES trial, see an interview with Hielke-Martijn de Vries, MD, on The ASCO Post Newsreels at ascopost.com/videos.
Survival data were immature; the 1-year overall survival rate was 43.4%, and the median overall survival was 11.5 months. Survival appeared to be slightly longer in patients who were PD-L1–positive, Dr. de Vries noted.
A total of 20 patients (63%) experienced an immunotherapy-related adverse event; 3 of 32 (9.4%) had grade 3 or 4 adverse events. Of the patients who received radiotherapy, 90% experienced an adverse event of any kind, and 65% had a grade 3 or 4 adverse event, most of which were caused by a clinically insignificant lymphocyte count decrease.
DISCLOSURE: This study was sponsored by Hoffmann–La Roche. Dr. de Vries reported no conflicts of interest.
1. de Vries HM, et al: Clinical results of PERICLES. 2022 ASCO Genitourinary Cancers Symposium. Abstract 3. Presented February 19, 2022.
2. Djajadiningrat RS, et al: Neoadjuvant taxane-based combination chemotherapy in patients with advanced penile cancer. Clin Genitourin Cancer 13:44-49, 2015.
3. Ottenhof SR, et al: Chemoradiation in the treatment of loco-regionally advanced penile cancer. Eur Urol Suppl 18(1):e655, 2019.
Hao G. Nguyen, MD, PhD
Invited discussant Hao G. Nguyen, MD, PhD, of the University of California, San Francisco, said: “New treatments are needed for advanced penile cancer. PERICLES is the first randomized trial for patients with stage IV penile cancer treated without chemotherapy. Although ...