Immunotherapy Agent Misses Study Survival Goal in Advanced Penile Cancer

In a clinical trial evaluating Tecentriq (atezolizumab) in patients with advanced squamous cell carcinoma of the penis, the immunotherapy agent failed to meet its survival goals — regardless of whether it was given with or without radiotherapy, according to data presented by Dr. Hielke Martijn de Vries, of Netherlands Cancer Institute, at the 2022 ASCO Genitourinary Cancers Symposium.

The phase 2 PERICLES trial of Tecentriq with or without radiotherapy in patients with stage 4 cancer did not meet its primary end point of one-year progression-free survival (PFS; meaning that patients were able to live for one year without their disease getting worse). At an average follow-up of 22 months, only 12.5% of patients had a PFS of one year or more.

The 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 intratumoral CD8 T cells and 40% to 60% PD-L1 positivity. Patients in one of the two arms of the study were also to receive radiotherapy to control locoregional lymph node disease, which is disease that stayed within the original area.

“Advanced penile cancer has a very poor prognosis, especially for those patients with stage 4 disease, and these patients have limited options,” said de Vries in his presentation.

According to de Vries, his institution ran two 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. A trial of chemoradiation resulted in fewer side effects and better PFS than the chemotherapy, but this study was not restricted to advanced-stage disease.Neither trial included patients with metastases that have spread to distant parts of the body.

In the PERICLES trial, patients in both arms received 1,200 mg of Tecentriq every three 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. There were 12 patients in the Tecentriq arm and 20 patients in the Tecentriq plus radiotherapy arm.

All patients had stage 4 disease with an inoperable primary tumor and a World Health Organization performance status of 0 or 1, meaning that their disease resulted in little to no restrictions to their daily life. 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 one year (to exclude 15%), there was a secondary end point of two-year overall survival rate in both groups combined.

The median PFS was 2.5 months with no significant difference between the treatment groups.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 two 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 average overall survival (OS) was 12 months, and the one-year OS rate was 43.4%, though further follow-up is needed, according to de Vries.

Response to treatment was evaluated with 12-weekly scans of the abdomen and thorax. While some durable responses and complete responses (CRs; where there is no detectable traces of cancer) were observed, including two patients with pulmonary metastases achieved CRs, overall response rates were low.

Out of 30 evaluable patients in both groups, there were seven (23%) partial responses (PRs) and three (10%) CR. In the radiotherapy groups (18 patients), there were six PRs and two CRs, while there was only one PR and one CR in the arm that received atezolizumab (12 patients).

In terms of side effects, 20 patients (63%) across both groups experienced any grade of immunotherapy-related side effects while three (9.4%) experienced severe (grade 3 or 4) side effects. In the radiotherapy arm, 18 patients (90%) experienced radiotherapy-related side effects, with 13 (65.0%) being grade 3 or 4.

Despite some evidence of antitumor activity from Tecentriq in this patient population, 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 (Tecentriq) … 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.”

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This article was originally published on Urology Times as, “Atezolizumab Fails to Improve PFS in Advanced Squamous Cell Penile Cancer.”