Data from a phase 2 trial of atezolizumab with or without radiotherapy showed some antitumor activity in advanced squamous cell carcinoma of the penis, despite failing to meet the primary end point of progression-free survival.
Data from the phase 2 PERICLES trial (NCT03686332) of atezolizumab (Tecentriq) with or without radiotherapy for patients with advanced squamous cell penile cancerwere reported at the 2022 Genitourinary Cancers Symposium with mixed results after the trial failed to meet the primary end point of progression-free survival (PFS) at 1 year.1
At a median follow-up of 22 months in patients with stage IV disease, the 1-year PFS rate was 12.5% (95% CI, 5.0-31.3).
The study investigated whether immunotherapy would be effective against advanced squamous cell carcinoma of the penis based on preclinical data suggesting patients had high rates of intratumoral CD8 T cells and 40% to 60% PD-L1 positivity. Patients in 1 of the 2 arms of the study were also to receive radiotherapy to control locoregional lymph node disease.
“Advanced penile cancer has a very poor prognosis, especially for those patients with stage IV disease, and these patients have limited options…for treatment,” said de Hielke Martijn de Vries, MD, of Netherlands Cancer Institute, in a presentation.
According to de Vries, his institution ran 2 previous studies in this setting. A trial of neoadjuvant chemotherapy with docetaxel, cisplatin, and 5-fluorouracil was judged to have high toxicity and early relapses, with 23% of patients discontinuing treatment.2 A trial of chemoradiation resulted in less toxicity and better PFS than chemotherapy, but this study was not restricted to advanced-stage disease.3 Neither trial included patients with distant metastases.
In the PERICLES trial, patients in both arms received 1200 mg of atezolizumab every 3 weeks, while the radiotherapy arm also received 33 fractions of 1.5 Gy (locoregional affected lymph nodes) and 1.8 Gy (macroscopic tumor and margin) irradiation.1 There were 12 patients in the atezolizumab arm and 20 patients in the atezolizumab plus radiotherapy arm.
All patients had stage IV disease with an inoperable primary tumor and a World Health Organization performance status of 0 or 1. Patients were allowed to have received any previous treatment besides immunotherapy; only 25% had no prior treatment. The percentage of patients with distant metastases was 59%.
In addition to the primary end point of PFS of 35% or greater at 1 year (to exclude 15%), there was a secondary end point of 2-year overall survival rate in both arms combined.
The median PFS was 2.5 months with no significant difference between the treatment arms.1 Patients with PD-L1 positivity, as well as those who were positive for human papilloma virus (HPV), showed slightly higher PFS. “It’s interesting here to notice that the 2 patients in arm B who responded well to treatment were both PD-L1 positive and high-risk HPV-positive,” de Vries said in his presentation.
The median overall survival (OS) was 12 months (95% CI, 5.5-19.7) and the 1-year OS rate was 43.4% (95 CI, 28.4-66.1), though further follow-up is needed, according to de Vries.
Response to treatment was evaluated according to RECIST1.1 with 12-weekly scans of the abdomen and thorax. While some durable responses and complete responses (CRs) were observed, including 2 patients with pulmonary metastases achieved CRs, overall response rates were low. Out of 30 evaluable patients in both arms, there were 7 (23%) partial responses (PRs) and 3 (10%) CR. In the radiotherapy arm (n = 18), there were 6 PRs and 2 CRs, while there was only 1 PR and 1 CR in the arm that received atezolizumab (n = 12).
In terms of toxicity, 20 patients (63%) across both arms experienced any grade of immunotherapy-related adverse events (AEs) while 3 (9.4%) experienced grade 3 or 4 AEs. In the radiotherapy arm, 18 patients (90%) experienced radiotherapy-related AEs, with 13 (65.0%) being grade 3 or 4.
Despite some evidence of antitumor activity from atezolizumab, the trial did not meet its goals. The combination with radiotherapy did not improve outcomes of immunotherapy, though de Vries noted that a more optimal radiotherapy schedule might increase efficacy. De Vries suggested that further investigation could assess not only the biomarkers associated with improved response but those linked to resistance to the treatment.
“We also saw in this trial an incomplete immunological activity and early resistance to atezolizumab… and we’re currently looking at pre- and on-treatment biopsies to see if there are other biomarkers for response and which combination therapies would be best to overcome this resistance,” de Vries said. “So while there is still a lot of work to be done, we’re quite enthusiastic about immunotherapy for the treatment of advanced penile cancer.”