Atezolizumab fails to meet PFS endpoint in advanced squamous cell carcinoma of the penis

The phase II PERICLES trial investigated whether immunotherapy would be effective against advanced squamous cell carcinoma of the penis based on preclinical data suggesting patients had high rates of infiltrating immune cells and high PD-L1 expression. However, after a median follow-up of 22 months, atezolizumab with or without radiotherapy did not demonstrate progression-free survival efficacy in patients with advanced squamous cell carcinoma of the penis.

Patients with advanced squamous cell carcinoma of the penis have a poor prognosis (two-year overall survival from moment of diagnosis of 21%) and high morbidity, due to progressive locoregional disease. Pre-clinical studies show high rates of infiltrating immune cells and high PD-L1 expression, suggesting that immunotherapy may be beneficial for these patients. In the PERICLES study, Dr. de Vries et al. assessed the activity of atezolizumab in patients with advanced squamous cell carcinoma of the penis, with or without radiotherapy to control locoregional lymph node disease.

Study design

PERICLES is a single-centre, non-randomised phase II study with two treatment arms. In total, 32 patients with advanced penile cancer were included. These patients had either distant metastases or locoregionally advanced penile cancer. Patients had a WHO performance status of 0-1 and any previous treatment was allowed, except for anti-PD-(L)1. All patients received atezolizumab 1,200 mg every three weeks for a maximum of one year. Patients expected to benefit from RT for locoregional disease control (arm A) additionally received 33 fractions of 1.5 Gy (locoregional affected lymph node regions and penile region) and 1.8 Gy (macroscopic tumor + margin) irradiation. Response was evaluated with 12-weekly CT scans of the abdomen and thorax using RECIST1.1. Primary objective was a one-year progression-free survival of at least 35%, to exclude 15%.

Results

From October 2018 until August 2021 the trial enrolled 20 patients in arm A (radiotherapy + atezolizumab) and 12 patients in arm B (atezolizumab only). All 32 included patients had stage IV disease. When comparing the baseline characteristics of patients in arm A and B, there were no major differences. Eight patients (25%) received no prior treatment and the percentage of distant metastases was high at 59%. An immunotherapy or radiotherapy-related grade 3-4 adverse event (AE) was observed in 3/32 (9.4%) and 13/20 (65.0%) patients, respectively. However, these radiotherapy related TRAEs were caused by a clinically insignificant decreased lymphocyte count in 50% of the patients, rendering the treatment well tolerated.

Two patients did not have measurable disease and could not be included in the efficacy analysis. After a median follow-up of 22 months, the best overall response rate in arm A was 44%, as compared to 17% in arm B. Although there were complete and durable responders in both treatment arms, the one-year PFS was only 12.5% (95% confidence interval: 5.0-31.3%), which did not meet the primary objective. Furthermore, there was no difference between the two treatment arms. Overall survival (OS) data are still immature and further follow-up is needed. Biomarker analyses revealed that both PFS and OS in patients with PD-L1 status ≥50% was slightly better, although data are still immature. The same is true for patients in the high-risk human papillomavirus (HPV) positive population. Interestingly, there were two patients in arm B who responded well to treatment who were both PD-L1 ≥50% positive and high-risk HPV positive.

Conclusion

Antitumour activity of atezolizumab was observed in advanced penile cancer, including complete and durable responses. The primary endpoint of one-year PFS will however not be reached and there is no evidence to suggest a synergistic effect of radiotherapy. Further follow-up is needed to asses high-risk HPV and PD-L1 as biomarkers.

Reference

De Vries HM, et al. Clinical results of PERICLES: A phase II trial investigating atezolizumab +/- radiotherapy for advanced squamous cell carcinoma of the penis. Presented at ASCO GU 2022; Abstract 3.