Atezolizumab With or Without Radiotherapy for Advanced Squamous Cell Carcinoma of the Penis (The PERICLES Study): A Phase II Trial

Abstract

PURPOSE Patients with advanced penile squamous cell carcinoma have a poor prognosis (21% 2-year overall survival [OS] from diagnosis). We assessed the activity of atezolizumab (anti–PD-L1) in patients with advanced penile cancer, with or without radiotherapy (RT). PATIENTS AND METHODS A single-center, nonrandomized phase II study with two treatment arms was conducted in 32 patients with histologically confirmed advanced penile cancer. All patients received atezolizumab (1,200 mg) once every 3 weeks. Twenty patients, who were expected to benefit from RT for locoregional disease control, received additional irradiation. The primary end point was 1-year progression-free survival (PFS) for the complete cohort and was reached if the actual 1-year PFS was at least 35%. Secondary end points included OS, objective response rate (ORR), and tolerability. Exploratory biomarker analyses were conducted in pretreatment specimens. RESULTS Median follow-up was 29.1 months (IQR, 18.1-33.5). Grade 3-4 adverse events related to atezolizumab or RT were observed in 3/32 (9.4%) and 13/20 (65%) patients, respectively. One-year PFS was 12.5% (95% CI, 5.0 to 31.3), which did not meet the study's primary end point. Median OS was 11.3 months (95% CI, 5.5 to 18.7). In the objective response-evaluable population (n = 30; 93.8%), the ORR was 16.7% (95% CI, 6 to 35), including 2 (6.7%) complete responders and 3 (10%) partial responders. Improved PFS was observed in patients with high-risk human papillomavirus (hrHPV)–positive tumors ( P = .003) and those with high infiltration of intratumoral CD3+CD8+ T cells ( P = .037). CONCLUSION Although the primary end point of 1-year PFS was not met, durable antitumor activity to atezolizumab was observed in a subset of patients. Biomarkers, such as hrHPV and intratumoral CD3+CD8+ T-cell infiltration, may help to better select responders.

Characterization of T cell receptor repertoire in penile cancer

“…In our study, we demonstrated the association between TCR clonality and the number of CD8 + T cells infiltrating into PSCC tissue. Since higher CD8 + T cell infiltration is associated with better clinical prognosis in patients with PSCC [ 6 , 44 ], TCR clonality may be an important biomarker for predicting the therapeutic response to immunotherapy in patients with PSCC, which needs further investigation.…”

“…Although cisplatin-based chemotherapy offers better outcomes, long-term remission is rare, with overall survival lower than 12 months [ 5 ]. Significant response to immunotherapy with atezolizumab has been observed in a group of PSCC patients with high-risk human papillomavirus (HPV) and high infiltration of intratumoral CD3 + CD8 + T cells [ 6 ], evidencing the importance of tumor‑infiltrating T lymphocytes in PSCC.…”

“…Studies have characterized the signatures of TCR repertoire in different cancers and confirmed that it could serve as a biomarker for immune response and possess important diagnostic and prognostic value [ 11 – 13 ]. Although some studies have shown that CD8 + T cell infiltration is associated with better clinical prognosis in patients with PSCC [ 6 ], the characteristics of the TCR repertoire in patients with PSCC and the relationship between the TCR repertoire and clinical features remain unknown.…”

Genomic Profiles and Clinical Outcomes of Penile Squamous Cell Carcinoma With Elevated Tumor Mutational Burden

“…Conversely, no partial response was reported in 5 patients included in another study of nivolumab plus ipilimumab (2 stable disease and 3 progressive disease) . Atezolizumab was investigated as monotherapy or in combination with locoregional radiotherapy in a phase 2 trial including stage IV PSCC: the ORR was 44% with combination therapy and 17% with monotherapy . Finally, various ICI regimens tested in a heterogeneous population of chemotherapy-naive and chemotherapy-treated PSCC were included in a retrospective study sponsored by the Global Society of Rare Genitourinary Cancers: the pooled ORR was 13%, with a median progression-free survival of 3.2 months .…”

Penile Cancer: EAU-ASCO Collaborative Guidelines Update Q and A

“…Preliminary data for anti-PD(L)1 monotherapy trials reported an ORR of 14%-17%, including the first published dedicated prospective phase 2 study. 41,42 Basket studies testing combination immunotherapies have yielded preliminary data for subsets of patients with penile SCC. 43,44 Currently actionable genomic alterations appear rare in penile SCC.…”