Clinical results of PERICLES: A phase II trial investigating atezolizumab +/- radiotherapy for advanced squamous cell carcinoma of the penis.

Abstract

3 Background: Patients (Pts) with advanced squamous cell carcinoma of the penis (aPeCa) have a poor prognosis (21% 2-year overall survival from moment of diagnosis) 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, we assess the activity of atezolizumab (atezo) in aPeCa pts, with or without radiotherapy (RT) to control locoregional lymph node disease. Methods: A single-centre phase 2 study with two treatment arms (non-randomized) was conducted in 32 histologically confirmed aPeCa pts with a WHO performance status of 0-1 (NCT03686332). Any previous treatment except for immunotherapy was allowed. Study treatment consisted of atezo 1200 mg every 3 weeks (all pts). Pts expected to benefit from RT for locoregional disease control (cohort 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. Toxicity was scored by NCI-CTCAE V4. The primary endpoint was 1-year progression free survival (PFS) for the full cohort. Results: From Oct 2018 to Aug 2021, 20 pts were included in cohort A (RT + atezo) and 12 pts in cohort B (only atezo). Median follow-up was 22 months (interquartile range (IQR) 4.3-14). Median age was 67 years (IQR 60-72) and all patients had stage IV aPeCa. Pts received no prior treatment (25%), or prior RT (34%), chemoradiation (22%), chemotherapy (6%) or surgery (69%). An immunotherapy or radiotherapy-related grade 3-4 AE was observed in 3/32 (9.4%) and 1/20 (5.0%) patients, respectively. There were no grade 5 treatment-related AEs. One-year PFS was 12% (95% confidence interval (CI) 4.0-33), which did not meet the primary objective. The response rate of RECIST1.1 evaluable pts was 30% (see table). In two patients with pulmonary metastases, a complete response was observed. Initial responses with early progression were seen in 5 pts. Median overall survival (OS) was 12 months (95% CI 5.4-19). Conclusions: Anti-tumor activity of atezo was observed in aPeCa, including complete and durable responses. The trial failed to meet its primary objective (PFS). Our results suggest that a subset of aPeCa pts has incomplete immunological activity and/or early resistance to atezo. Analysis of tumor tissue collected in this trial (including on-treatment biopsies) could suggest new therapeutic strategies to overcome resistance and improve clinical outcome to immunotherapy in aPeCa. Clinical trial information: NCT03686332. [Table: see text]

Comprehensive genomic profiling of penile squamous cell carcinoma and the impact of human papillomavirus status on immune‐checkpoint inhibitor‐related biomarkers

“…In the PERICLES phase 2 trial of atezolizumab ± radiotherapy to locoregional lymph nodes in advanced pSCC, 1‐year progression‐free survival (PFS) was only 12%. Interestingly, complete responses were observed in two patients with pulmonary metastasis, which again emphasizes a potential role for ICIs in subsets of patients 40 . A retrospective study on ICI outcomes in pSCC reported a clinical benefit of 14.3% along with a median overall survival and PFS of 8.2 and 1.9 months, respectively, consistent with poor responses that used an unselected ICI approach 41 .…”

“…Interestingly, complete responses were observed in two patients with pulmonary metastasis, which again emphasizes a potential role for ICIs in subsets of patients. 40 A retrospective study on ICI outcomes in pSCC reported a clinical benefit of 14.3% along with a median overall survival and PFS of 8.2 and 1.9 months, respectively, consistent with poor responses that used an unselected ICI approach. 41 In a case series from a phase 2 basket trial, Hahn et al…”

First‐line programmed death receptor‐1 (PD‐1) inhibitor and epidermal growth factor receptor (EGFR) blockade, combined with platinum‐based chemotherapy, for stage IV penile cancer

“…To our knowledge, only a weak response to chemotherapy plus EGFR blockade has been observed [20], and immune checkpoint inhibitors alone or combined with radiotherapy for advanced PSCC did not show satisfactory efficacy in the initial results of the PERICLES study [21]. Preclinical evidence showed that EGFR‐driven lung tumours presented with high PD‐L1 expression and an inhibitory tumour microenvironment, suggesting that the combination of EGFR blockade and PD‐1 inhibitors may be a promising strategy in tumour control and delaying drug resistance [22].…”

Emerging Therapies in Penile Cancer

“…Recently presented results of PERICLES phase II trial (NCT03686332), which included 32 patients with advanced penile cancer treated with atezolizumab, an anti-PD-L1 monoclonal antibody, alone or associated with local radiotherapy, showed a 30% oobjective response rate among 10 evaluable patients for response by RECIST 1.1 (including two complete responses), but the trial did not reach the expected PFS, its primary endpoint. Immunotherapy-related grade 3 or 4 adverse events occurred in 9.4% of patients ( 30 ). Avelumab, another anti-PD-L1 antibody already approved for the treatment of advanced urothelial cancer, is also under investigation in penile cancer as maintenance (NCT03774901) or second-line therapy (NCT03391479) after chemotherapy.…”