Cemiplimab After Hedgehog Inhibition Demonstrates Clinical Benefit in Locally Advanced Basal Cell Carcinoma

Alexander Stratigos, MD

In a phase 2 clinical trial (NCT03132636), promising clinical activity was observed with cemiplimab (Libtayo) in patients with locally advanced basal cell carcinoma (BCC) who progress on or are intolerant to hedgehog inhibitors, regardless of PD-L1 expression, according to findings presented at the 2020 European Society of Medical Oncology (ESMO) Virtual Congress.¹

Findings showed that, at a median follow-up of 15 months, the objective response rate (ORR) via independent central review (ICR) was 31% (95% CI, 21.3%-42.0%) in patients with locally advanced BCC who received cemiplimab, which included 5 (6.0%) complete responses (CRs) and 21 (25.0%) partial responses (PRs).

The updated data show an increase from the 29% ORR reported in the topline findings from the trial that were released in May 2020, and 2 additional responses have been confirmed since the initial analysis.²

“Cemiplimab is the first systemic therapy to show clinical benefit in [patients with] locally advanced basal cell carcinoma after hedgehog inhibitor therapy,” lead study author Alexander Stratigos, MD, professor of dermatology — venereology, the University of Athens Medical School, at Andreas Sygros Hospital, stated in a virtual presentation during the meeting. “These results provide strong rationale for cemiplimab as a treatment option for patients with locally advanced BCC who otherwise have no options after hedgehog inhibitor failure.”

Currently, no approved treatment options are available for patients with locally advanced BCC following hedgehog inhibition. Cemiplimab is available for use as a treatment for patients with metastatic cutaneous squamous cell carcinoma (CSCC) or patients with locally advanced CSCC who are not candidates for curative surgery or curative radiation.

Both BCC and CSCC are defined as keratinocytic tumors that have high mutational burden because of ultraviolent mutagenesis, with rationale that they respond to immunotherapy.

The phase 2 trial had 2 cohorts: adult patients with metastatic (nodal and distant) BCC and adult patients with locally advanced BCC. In the second cohort, which comprised the data presented at the 2020 Virtual ESMO Congress, 84 patients with locally advanced BCC were treated with 350 mg of cemiplimab delivered intravenously every 3 weeks for up to 93 weeks or until disease progression. Tumor assessments were conducted in cycles 1 through 5 every 9 weeks, and then every 12 weeks for cycles 6 through 9. Tumor response assessments by ICR were conducted via RECIST v1.1 criteria and/or modified World Health Organization criteria.

To be eligible for enrollment, patients must have had a histologically confirmed diagnosis of invasive BCC, prior progression or intolerance on hedgehog inhibition, or have no better state than stable disease (SD) after being on hedgehog inhibitor therapy for 9 months. Patients also needed to have at least 1 measurable baseline lesion and an ECOG performance status of 0 or 1.

Those with ongoing or recent autoimmune disease requiring systemic immunosuppression, who previously received anti–PD-1/PD-L1 therapy or who had a concurrent malignancy other than BCC were not eligible to participate. Additionally, patients with a prior malignancy other than BCC within 3 years of the first planned cemiplimab dose, except for tumors with negligible risk of metastasis or death, were excluded from enrolling on the trial.

A total 66.7% of patients were male, and the median age was 70 years (range, 42-89). More than half of patients (60.7%) had an ECOG performance status of 0, and the primary site of tumor in the majority of patients (89.3%) was in the head and neck. Additionally, 71.4% of patients discontinued prior hedgehog inhibition due to disease progression, 38.1% were intolerant to vismodegib (Erivedge), 4.8% were intolerant to sonidegib (Odomzo), and 8.3% had no better than SD following 9 months on a hedgehog inhibitor.

The primary end point of the trial was ORR by independent central review; secondary end points included safety and tolerability, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and complete response by ICR.

At a median follow-up of 15 months (range, 0.5-25), additional data showed that 48.8% (n = 41) of patients had SD, 10.7% (n = 9) had progressive disease (PD), and 9.5% (n = 8) were not evaluable. Additionally, the median Kaplan Meier–estimated DOR per ICR had not yet been reached. However, investigators noted an estimated probability of DOR of 90.9% (95% CI, 68.3%-97.6%) at 6 months and 85.2% (95% CI, 60.5%-95.0%) at 12 months.

The estimated median PFS was 19.3 months (95% CI, 8.6–not estimable [NE]) with an estimated 12-month event-free probability of 56.5% (95% CI, 44.3%-67.0%). The estimated median OS was not reached (95% CI, NE–NE), with an estimated 12-month probability of survival of 92.3% (95% CI, 83.6%-96.5%).

Overall responses were observed regardless of PD-L1 expression levels. For patients with evaluable PD-L1 less than 1% (n = 35), the ORR was 26% (95% CI, 13%-43%), with 2 CRs, 7 PRs, and 18 patients having SD. Five patients had PD and 3 patients were not evaluable.

In those with evaluable PD-L1 status 1% or higher (n = 15), the ORR was 27% (95% CI, 8%-55%), with 2 CRs, 2 PRs, and 9 patients had SD. One patient had PD and 1 patient was not evaluable.

Finally, in patients who had no evaluable PD-L1 expression status (n = 34), the ORR was 38% (95% CI, 22%-56%), which included 1 CR and 12 PRs. Fourteen patients had SD, 3 had PD, and 4 were unevaluable.

The disease control rates (DCRs) in patients with a PD-L1 expression of less than 1%, 1% or higher, or no evaluable PD-L1 expression were 77%, 87%, and 79%, respectively. The durable DCRs were 51%, 53%, and 71%, respectively.

Regarding safety, the most common, any-grade treatment-emergent adverse effects (TEAEs) were fatigue (30%), diarrhea (24%), pruritus (21%), and asthenia (20%). Grade 3 or higher TEAEs included hypertension (5%), fatigue (4%), urinary tract infection (4%), and asthenia, anemia, decreased appetite, headache, and nausea (n = 1 each).

The most common treatment-related adverse effects (TRAEs) were fatigue (25%), pruritus (14%), and asthenia (14%); at grade 3 or higher, these were colitis (n = 4), fatigue (n = 2), and adrenal insufficiency (n = 2). Additionally, all-grade and grade 3 or higher immune-related adverse effects (irAEs) occurred in 25% and 10% of patients (colitis and adrenal insufficiency), respectively; no grade 4/5 irAEs were reported. The most common any-grade irAEs were hypothyroidism (10%) and colitis (6%).

Any-grade and grade 3 or higher serious adverse effects occurred in 35% and 26% of patients, respectively. Seventeen percent of patients discontinued treatment to AEs; 4 TEAEs were associated with death.

“There were no treatment-related deaths,” concluded Stratigos. “The overall safety profile is consistent with previously reported experience with cemiplimab.”

_References:

_{1. Stratigos AJ, Sekulic A, Peris K, et al. Primary analysis of phase II results for cemiplimab in patients (pts) with locally advanced basal cell carcinoma (laBCC) who progress on or are intolerant to hedgehog inhibitors (HHIs). Presented at 2020 Virtual ESMO Congress; September 19-October 21, 2020; Virtual. Abstract LBA47.}

_{2. Libtayo (cemiplimab) shows clinically meaningful and durable responses in second-line advanced basal cell carcinoma. News release. Sanofi. May 5, 2020. Accessed September 18, 2020. https://bit.ly/2RHLZbm.}