Karl D. Lewis, MD
Patients with advanced basal cell carcinoma (BCC) who experience progression on or are intolerant to hedgehog pathway inhibitor therapy have no approved therapeutic options. An ongoing phase II study evaluating the PD-1 inhibitor cemiplimab (Libtayo) in this population may prove efficacious based on its activity in other advanced malignancies.
The primary objective of this ongoing study (NCT03132636), which was presented at the 2018 ESMO Congress, is overall response rate (ORR) for groups 1 and 2 per central review. Group 1 is patients with metastatic BCC (nodal or distant), and group 2 consists of patients with locally advanced BCC who are contraindicated for or have not achieved disease control with surgery or radiation.
Both groups will receive cemiplimab at 350 mg every 3 weeks for up to 93 weeks. Patients will be assessed for response at the end of each treatment cycle. The first treatment cycle is 9 weeks, then there are 4 subsequent 12-week cycles, investigators noted. Tumor response will be assessed by an independent central review committee.
“Cemiplimab, a monoclonal antibody to PD-1, has demonstrated efficacy with a safety profile comparable with that of other anti–PD-1 agents in advanced malignancies, including cutaneous squamous cell carcinoma (CSCC),” principal investigator Karl D. Lewis, MD, associate professor at the University of Colorado, Denver School of Medicine, and co-investigators wrote. “Several lines of evidence suggest that patients with advanced BCC may benefit from therapies that inhibit the PD-1 pathway.”
Although most patients with BCC have a good prognosis of recurrence-free survival with surgery, there remains a population that develop advanced and metastatic disease. These patients are often treated successfully with hedgehog inhibitors, such as vismodegib (Erivedge) and sonidegib (Odomzo), which are both FDA approved, but there are no approved agents following progression.
The investigators noted that the rationale for this study was based on the high mutational burden of BCC tumors and the responsiveness to immune modulators. These factors, in conjunction with the high potency and antitumor activity of cemiplimab, contributed to the thought that immunotherapy could be beneficial for patients with advanced BCC.
Secondary objectives include investigator-assessed ORR, progression-free survival and complete response by central and investigator review, overall survival, duration of response, safety and tolerability of cemiplimab, pharmacokinetics, and immunogenicity. Additionally, investigators will use the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and Skindex-16 to assess the impact of cemiplimab on quality of life.
Cemiplimab was approved by the FDA in September 2018 for the treatment of patients with metastatic cutaneous squamous cell carcinoma (CSCC) or for patients with locally advanced CSCC who are not candidates for curative surgery or curative radiation.
Investigators are looking to enroll up to 137 patients, with at least 50 patients in group 1 and at least 80 in group 2, in order to provide at least 85% power to reject a null hypothesis of an ORR of 15% and 20%, respectively. This is at a 2-sided significant level of 5% if the true ORR is 34% for group 1 and 35% for group 2.
Key inclusion criteria include a histologically confirmed diagnosis of invasive BCC; prior progression of disease on a hedgehog inhibitor; intolerance of prior hedgehog inhibitor therapy, defined as any grade 3 or 4 treatment-related adverse events or grade 2 muscle spasms, myalgia, dysgeusia, anorexia, diarrhea or nausea following ≤3 months of therapy; at least 1 measurable lesion; adequate hepatic, renal and bone marrow function; and an ECOG performance status ≤1.
Patients previously treated with an anti–PD-1/PD-L1 agent are excluded from this trial, as well as those with ongoing or recent evidence of significant autoimmune disease, investigators noted. Other exclusion criteria are untreated active brain metastases, history of solid organ transplant, and history of pneumonitis within the last 5 years.
Those enrolled on this phase II, nonrandomized, multicenter study will receive treatment until the end of the 93-week treatment period, until disease progression, unacceptable toxicity, withdrawal of concert, or confirmed complete response.
Lewis KD, Fury MG, Stankevich E, et al. Phase II study of cemiplimab, a human monoclonal anti-PD-1, in patients with advanced basal cell carcinoma (BCC) who experienced progression of disease on, or were intolerant of prior hedgehog pathway inhibitor (HHI) therapy [published online October 29, 2018]. Ann Oncol. doi: 10.1093/annonc/mdy288.111.