U.S. Food and Drug Administration (FDA)-Approved Indications

Cutaneous Squamous Cell Carcinoma (CSCC)

Libtayo is indicated for the treatment of patients with metastatic CSCC or locally advanced CSCC who are not candidates for curative surgery or curative radiation.

Basal Cell Carcinoma (BCC)

Non-Small Cell Lung Cancer (NSCLC)

Libtayo, as a single agent, is indicated for the first-line treatment of adult patients with non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression [Tumor Proportion Score (TPS) > 50%] as determined by an FDA-approved test, with no EGFR, ALK or ROS1 aberrations, and is:

Libtayo, in combination with platinum-based chemotherapy, is indicated for the first-line treatment of adult patients with NSCLC with no EGFR, ALK, or ROS1 aberrations and is:

Compendial Uses

Cemiplimab-rwlc is available as Libtayo (Regeneron Pharmaceuticals, Inc.) and is a recombinant human immunoglobulin G4 (IgG4) monoclonal antibody that binds to programmed death receptor-1 (PD-1) and blocks its interaction with PD-ligand 1 (PD-L1) and PD-ligand 2 (PD-L2) resulting in the inhibition of T-cell proliferation and cytokine production. In syngeneic mouse tumor models, PD-1 activity blockade resulted in decreased tumor growth (Regeneron Pharmaceuticals, 2022).

According to the prescribing information, Libtayo carries the following warnings and precautions:

Per the prescribing information, Libtayo carries the following adverse reactions:

Refer to full prescribing information for Libtayo for use in specific populations.

Cutaneous Squamous Cell Carcinoma

In the U.S., cutaneous squamous cell carcinoma (CSCC) is the second most frequently occurring skin cancer and accounts for approximately 7,000 deaths annually. Newly diagnosed are anticipated to rise every year. CSCC that penetrates deeper layers of the skin or adjacent tissues is known as locally advanced. Once it spreads to other distant parts of the body, it is categorized as metastatic (Regeneron Pharmaceuticals, 2018).

On September 28, 2018, the U.S. Food and Drug Administration (FDA) approved Libtayo cemiplimab-rwlc for the treatment of patients with metastatic cutaneous squamous cell carcinoma (CSCC

or locally advanced CSCC who are not candidates for curative surgery or curative radiation. This is the first FDA approval of a drug specifically for advanced CSCC. The safety and efficacy of Libtayo was studied in 2 open-label clinical trials. A total of 108 patients (75 with metastatic disease and 33 with locally-advanced disease) were included in the efficacy evaluation. The study’s primary end-point was objective response rate (ORR), or the percentage of patients who experienced partial shrinkage or complete disappearance of their tumor(s) following treatment. Results showed that 47.2 % of all patients treated with Libtayo had their tumors shrunk or disappeared. The majority of these patients had ongoing responses at the time of data analysis. Common AEs associated with the use of Libtayo included diarrhea, fatigue, and rash. Libtayo can cause the immune system to attack normal organs and tissues in any area of the body and can affect the way they work. These reactions can sometimes become severe or life-threatening and can result in death. These reactions entailed the risk of immune-mediated AEs including colitis, dermatologic adverse reactions, endocrinopathies, hepatitis, pneumonitis, as well as nephritis and renal dysfunction. Patients should also be monitored for infusion-related reactions. Libtayo can also cause harm to a developing fetus; thus, women should be advised of the potential risk to the fetus and to use effective contraception; and women should avoid breast-feeding (Regeneron Pharmaceuticals, 2018).

16; Migden et al., 2018; Sidaway

Migden and colleagues (2018) stated that no systemic therapies have been approved for the treatment of advanced CSCC. This cancer may be responsive to immune therapy because the mutation burden of the tumor is high and the disease risk is strongly associated with immunosuppression. In the dose-escalation portion of the phase-I clinical trial of cemiplimab, a deep and durable response was observed in a patient with metastatic CSCC. These investigators reported the results of the phase-I clinical trial of cemiplimab for expansion cohorts of patients with locally advanced or metastatic CSCC, as well as the results of the pivotal phase-II clinical trial for a cohort of patients with metastatic disease (metastatic-disease cohort). In both studies, the patients received an intravenous dose of cemiplimab (3 mg/ kg of body weight) every 2 weeks and were assessed for a response every 8 weeks. In the phase-II study, the primary end-point was the response rate, as assessed by independent central review. In the expansion cohorts of the phase-I study, a response to cemiplimab was observed in 13 of 26 patients (50 %; 95 % confidence interval [CI]: 30 to 70). In the metastatic-disease cohort of the phase-II study, a response was observed in 28 of 59 patients (47 %; 95 % CI: 34 to 61). The median follow-up was 7.9 months in the metastatic-disease cohort of the phase-II study. Among the 28 patients who had a response, the duration of response exceeded 6 months in 57 %, and 82 % continued to have a response and to receive cemiplimab at the time of data cut-off. Adverse events (AEs) that occurred in at least 15 % of the patients in the metastatic-disease cohort of the phase-II study were diarrhea, fatigue, nausea, constipation, and rash; 7 % of the patients discontinued treatment because of an AE. The authors concluded that among patients with advanced CSCC, cemiplimab induced a response in approximately 50 % of the patients and was associated with AEs that usually occur with immune checkpoint inhibitors.

Basal Cell Carcinoma

In the U.S., basal cell carcinoma (BCC) is the most frequently occurring skin cancer with approximately two million new cases diagnosed annually. Although a great majority of BCCs are detected early and cured with surgery and radiation, a small fraction of tumors can become invasive and advance deep into surrounding tissues (locally advanced). Once it spreads to other parts of the body (metastasized), it becomes more challenging to treat (Regeneron Pharmaceuticals, 2021a).

On February 9, 2021, the U.S Food and Drug Administration (FDA) approved Libtayo (cemiplimab-rwlc) as the first immunotherapy for the treatment of patients with advanced basal cell carcinoma (BCC) previously treated with an hedgehog pathway inhibitor (HHI) or for whom an HHI is inappropriate. Full approval was given for patients with locally advanced BCC and accelerated approved was given for patients with metastatic BCC. Additionally, the approval of Libtayo was based on FDA Priority Review and on a pivotal open-label, multicenter, non-randomized Phase 2 trial consisting of 132 patients of which 112 patients with unresectable locally advanced BCC (n=28) or metastatic BCC (n=84) (nodal and distant) were included in the efficacy analysis. Libtayo was administered as 350 mg every 3 weeks by intravenous infusion for up to 93 weeks until disease progression, unacceptable toxicity, or completion of planned treatment. Patients in both cohorts either worsened on HHI therapy, had not had an objective response after 9 months on HHI therapy, or experienced intolerance with prior HHI therapy. The primary efficacy endpoint was confirmed objective response rate (ORR) and a notable secondary endpoint was duration of response (DOR). The confirmed ORR results in the locally advanced BCC patients were ORR 29% (n=24), complete response (CR) 6% (n=5), and partial response (PR) 23% (n=19), whereas in the metastatic BCC patients were ORR 21% (n=6), complete response 0%, and partial response 21% (n=6). The median DOR results in the locally advanced BCC patients was not reached (2-21 months) and in the metastatic BCC patients was not reached (9-23 months). It should be noted that ongoing assessment of DOR is being performed for both patient groups. Safety evaluation was conducted in 132 patients with serious adverse reactions occurring in 32% of patients. It was concluded that this study was clinically meaningful and durable (Regeneron Pharmaceuticals, 2021a).

Cervical Cancer

Minion and Tewari (2018) noted that vascular endothelial growth factor (VEGF) has emerged as a therapeutic target in several malignancies, including cervical cancer. Chemotherapy doublets combined with the fully humanized monoclonal antibody, bevacizumab, now constitute first-line therapy for women struggling with recurrent/metastatic cervical carcinoma. Regulatory approval for this indication was based on the phase-III randomized trial, GOG 240, which demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) when bevacizumab was added to chemotherapy: 17.0 versus 13.3 months; hazard ratio [HR] 0.71; 98 % CI: 0.54 to 0.95; p = 0.004. Incorporation of bevacizumab resulted in significant improvements in progression-free survival (PFS) and response. These benefits were not accompanied by deterioration in quality of life (QOL). GOG 240 identified vaginal fistula as a new AE associated with bevacizumab use. All fistulas occurred in women who had received prior pelvic radiotherapy, and none resulted in emergency surgery, sepsis, or death. Final protocol-specified analysis demonstrated continued separation of the survival curves favoring VEGF inhibition: 16.8 versus 13.3 months; HR 0.77; 95 % CI: 0.62 to 9.95; p = 0.007; PFS was not significantly different between the arms in GOG 240. Moving forward, immunotherapy has now entered the clinical trial arena to address the high unmet clinical need for effective and tolerable second-line therapies in this patient population. Targeting the PD- 1/programmed death ligand 1 (PD-L1) pathway using checkpoint inhibitors to break immunologic tolerance is promising. The immunologic landscape involving human papillomavirus (HPV)-positive head and neck carcinoma and CSCC can be informative when considering feasibility of checkpoint blockade in advanced cervical cancer. The authors concluded that phase-II clinical trials using anti-PD-1 molecules, nivolumab and pembrolizumab are ongoing, and GOG 3016, the first phase-III randomized trial of a checkpoint inhibitor (cemiplimab) in cervical cancer, was recently activated.

Cohen and associates (2020) noted that while screening programs and HPV vaccination have decreased the incidence of cervical cancer, still over 13,000 cases occur in the U.S. annually. Early-stage cervical cancer has an excellent long-term prognosis, with 5-year survival for localized disease being greater than 90 %. Survival decreases markedly for both locally advanced and metastatic disease, and both are associated with a higher risk of recurrence. Few effective therapeutic options exist for persistent, recurrent, or metastatic cervical cancer. In 2014, the anti-VEGF antibody bevacizumab was approved in combination with chemotherapy based on the results of the phase-III GOG-240 study. As the majority of cervical cancers have a viral etiology, which impairs the immune system, immunotherapy using checkpoint inhibitors and other agents, appears to be a promising approach. In June 2018, the FDA approved the anti-PD1 antibody pembrolizumab for recurrent or metastatic cervical cancer with PD-L1 expression that progressed after 1 or more lines of chemotherapy. Another anti-PD1 antibody, cemiplimab also shows potential in this setting, either as monotherapy or combined with radiotherapy, and it is currently being evaluated in a phase-III clinical trial. Additional checkpoint inhibitors including nivolumab, durvalumab, atezolizumab, and camrelizumab are in different stages of clinical development for the disease. Finally, an additional targeted approach being pursued involves PARP inhibitors (rucaparib and olaparib are both in phase II) based on earlier study results.

Marjolin Ulcer

Shalhout and colleagues (2021) stated that immunotherapy has revolutionized the treatment of advanced CSCC. However, the role of immune checkpoint inhibitors (ICIs) for the treatment of Marjolin ulcer (MU), a rare cutaneous malignancy that arises from previously traumatized and chronically inflamed skin, is not well-defined. In a retrospective, single-center, case-series study, these researchers examined the effectiveness and clinical response to immunotherapy in patients with MU. This trial included patients with MU treated with anti-PD-1 therapy at Massachusetts General Hospital between 2016 and 2020. A total of 5 subjects with this rare presentation met inclusion criteria and were treated with pembrolizumab (n = 2) or cemiplimab (n = 3); 4 participants received immunotherapy in the 1st-line setting. Notably, 1 patient had durable disease control for 1 year while on immunotherapy, with continued disease control after the cessation of anti-PD-1 therapy. Of the 4 subjects who progressed on anti-PD-1 therapy, disease control at 5 months was achieved in 2 patients. Furthermore, 60 % OS (3 patients) was observed in this limited cohort at 12 months after initiating anti-PD-1 therapy for MU.

Non-Small Cell Lung Cancer

Lung cancer is the worldwide leader in the cause of cancer deaths. In 2020, it was approximated that 2.2 million and 225,000 new cases were diagnosed worldwide and in the U.S., respectively. An estimated 84% of all lung cancers are non-small cell lung cancer (NSCLC), of which 75% of cases are diagnosed in advanced stages and approximately 25% to 30% of cases anticipated to test positive for PD-L1 in ≥50% of tumor cells (Regeneron Pharmaceuticals, 2021b).

On February 22, 2021, the U.S. Food and Drug Administration approved Libtayo (cemiplimab-rwlc) for the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression (tumor proportion score ≥50%), as confirmed by an FDA-approved test. In addition, patients had metastatic or locally advanced tumors that were not candidates for surgical resection or definitive chemoradiation, and the tumors did not have EGFR, ALK or ROS1 aberrations. This third approval for Libtayo was based on a Priority Review by the FDA and supported by data from the EMPOWER-Lung 1 study (Regeneron Pharmaceuticals, 2021b).

This study was an open-label, randomized, multi-center Phase 3 trial where Sezer and colleagues (2021) investigated the first-line treatment of Libtayo monotherapy compared to platinum-doublet chemotherapy in patients with advanced NSCLC who were positive for PD-L1 in ≥50% of tumor cells and without EGFR, ALK or ROS1 aberrations. The trial consisted of 710 patients with either previously untreated metastatic NSCLC (Stage IV) or locally advanced NSCLC (Stage IIIB/C) who were not candidates for surgical resection or definitive chemoradiation or who had progressed after treatment with definitive chemoradiation. Patient randomization was (1:1) for Libtayo 350 mg intravenously every 3 weeks for up to 108 weeks or a platinum-doublet chemotherapy regimen for 4 to 6 cycles with subsequent optional pemetrexed maintenance for patients with non-squamous histology who received a pemetrexed containing regimen. The primary endpoints included overall survival (OS) and progression-free survival (PFS), and secondary endpoints were overall response rate, duration of response and quality of life. Libtayo reduced the risk of death by 32% compared to chemotherapy. An additional analysis conducted in 563 patients with proven PD-L1 expression of ≥50% demonstrated that Libtayo reduced the risk of death by 43% compared to chemotherapy. It was concluded that Libtayo showed a statistically significant improvement in OS and PFS for patients randomized to Libtayo as compared with chemotherapy (Regeneron Pharmaceuticals, 2021b).

On November 8, 2022, the U.S. Food and Drug Administration (FDA) approved cemiplimab-rwlc (Libtayo) in combination with platinum-based chemotherapy for adult patients with advanced non-small cell lung cancer with no epidermal growth factor gene, anaplastic lymphoma kinase, or ROS-1 aberrations. The FDA approval was based on supporting data from Study 16113 (FDA, 2022).

In Study 16113, a randomized, multicenter, double-blind, active-controlled phase 3 trial, Gogishvili and colleagues (2022) evaluated the efficacy of cemiplimab-rwlc plus platinum-doublet chemotherapy as first-line treatment for advanced non-small cell lung cancer (aNSCLC), regardless of programmed death-ligand 1 (PD-L1) expression or histology. This study consisted of 466 patients with stage III/IV aNSCLC without EGFR, ALK or ROS1 genomic tumor aberrations and who had not received prior systemic treatment. Randomization was 2:1 where patients received cemiplimab-rwlc 350 mg (n=312) or placebo (n=154) every 3 weeks for up to 108 weeks in combination with four cycles of platinum-doublet chemotherapy (followed by pemetrexed maintenance as indicated). In all, 57.1% (266/466 patients) had non-squamous NSCLC, and 85.2% (397/466 patients) had stage IV disease. The primary efficacy outcome was overall survival (OS). Additional efficacy outcome measures included progression-free survival (PFS) and overall response rate (ORR). The trial concluded early per recommendation of the independent data monitoring committee, due to achieving preset OS efficacy criteria: median OS was 21.9 months (95% confidence interval [CI], 15.5-not evaluable) with cemiplimab-rwlc plus chemotherapy versus 13.0 months (95% CI, 11.9-16.1) with placebo plus chemotherapy (hazard ratio [HR] = 0.71; 95% CI, 0.53-0.93; p = 0.014). Median PFS per blinded independent central review was 8.2 months in the cemiplimab-rwlc plus chemotherapy arm and 5.0 months in the placebo plus chemotherapy arm. Established overall response rate per blinded independent central review was 43% and 23%, respectively. Grade ≥3 adverse events were noted with cemiplimab-rwlc plus chemotherapy (43.6%. 136/312 patients) and placebo plus chemotherapy (31.4%, 48/153 patients) (FDA, 2022; Gogishvili, et al., 2022).

Other Solid Tumors Except CSCC

In a first-in-human study, Papadopoulos and colleagues (2020) examined the safety, tolerability, dose-limiting toxicities (DLTs), anti-tumor activity, and pharmacokinetics of cemiplimab as monotherapy and in combination with hypo-fractionated radiotherapy (hfRT) and/or cyclophosphamide (CPA) in patients with advanced solid tumors. Patients were enrolled in 1 of 10 dose escalation cohorts and received cemiplimab 1, 3, or 10 mg/kg every 2 weeks intravenously for up to 48 weeks. Depending on the cohort, patients received hfRT and/or low-dose (200 mg/m2) CPA. Safety was evaluated. Anti-tumor activity was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. A total of 60 patients were enrolled. The median duration of follow-up was 19.3 weeks (range of 2.3 to 84.3). There were no DLTs. The most common treatment-emergent AEs (TEAEs) of any grade were fatigue (45.0 %), nausea (36.7 %), and vomiting (25.0 %). The most common immune-related AEs (irAEs) of any grade were arthralgia (10.0 %), hypothyroidism (8.3 %), and maculo-papular rash (8.3 %). Cemiplimab pharmacokinetic parameters increased in a close to dose-proportional manner and were similar regardless of combination therapy regimen; 2 patients (1 with CSCC and 1 with cervical cancer) experienced a complete response (CR); 7 had a partial response (PR). Observed duration of response was greater than or equal to 12 months in 6 patients. The authors concluded that the safety profile of cemiplimab was comparable with other anti-PD-1 agents. Addition of hfRT and/or CPA did not appear to increase grade greater than or equal to 3 irAEs. Cemiplimab exhibited encouraging anti-tumor activity and durable responses.

Rare Tumors

Petrelli and colleagues (2021) noted that rare cancers, as defined by the European Union, occur in fewer than 15 out of 100,000 individuals each year. The International Rare Cancer Consortium defines rare cancer incidence as less than 6 per 100,000 per year. There is a growing number of reports on the effectiveness of ICI therapy in patients with rare tumors. These researchers caried out a comprehensive review to examine the available literature. They performed a literature search of PubMed on January 31, 2021, using the following ICI names as keywords: ipilimumab, tremelimumab, cemiplimab, nivolumab, pembrolizumab, avelumab, atezolizumab, and durvalumab. Studies on patients with rare tumors who were being treated with ICIs were included. They plotted the ORR against the corresponding median survival across a variety of cancer types using linear regression. From 1,255 publications retrieved during the primary search, 62 articles were selected (with a total of 4,620 patients). Only 4 were randomized trials; and a minority were 1st-line studies, while the remaining were studies in which ICIs were delivered as salvage therapy in pre-treated patients. There was a good correlation between response rate and OS (Spearman R2 > 0.9) in skin cancers, mesothelioma, and sarcomas. The authors concluded that treatment of advanced-stage rare tumors with ICI therapy was found to be associated with significant activity in some orphan diseases (e.g., Merkel cell carcinoma) and hepatocellular carcinoma (HCC). Moreover, these researchers stated that several ongoing prospective clinical trials will expand the knowledge on the safety and effectiveness of ICI therapy in patients with these rare cancers. Furthermore, they stated that multi-parameter analysis of biomarkers that are predictive of the potential activity of ICIs in rare cancers and in common cancers will open new avenues for better selection of patients who may benefit from immunotherapy.

Denis and associates (2021) stated that relapsed locally advanced or metastatic penile cancer is a rare disease and systemic treatment is cisplatin-based chemotherapy (CT). These investigators reported on the case of a 75-year-old man who presented with metastatic, SCC of the penis whose disease had progressed after radiotherapy (RT) and CT. A strong PD-L1 expression as well as a CDKN2A mutation was documented, and he was administered cemiplimab every 3 weeks at time of disease progression; CR was shown after 10 cycles, and no toxicity was reported. However, this treatment was stopped after 13 cycles when the patient developed moderate severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pneumonitis that required a 2-week hospitalization for oxygen support. Six months later, he remained in CR. The authors concluded that, to their knowledge, this was the 1st demonstration of a CR with cemiplimab in a metastatic penile SCC patient previously treated with CT and RT for relapse. Furthermore, the patient remained disease-free despite cemiplimab was withdrawn due to SARS-CoV-2 pneumonitis. These researchers stated that this report had drawbacks: it was a single case-study, and the follow-up was short.

Xeroderma Pigmentosum

Rubatto and colleagues (2021) noted that xeroderma pigmentosum (XP) is a rare genetic disorder with a poor prognosis due to high photosensitivity in affected patients. These researchers described the 1st case of the use of cemiplimab in a patient with XP, a 19-year-old girl who presented with locally advanced SCC of the right peri-orbital and nasal region. This treatment has been undertaken after a cycle of proton beam RT (PBRT). Furthermore, reported a few cases in the literature that described the effectiveness of immunotherapy on skin cancers in XP-patients. This case was in line with those reported, underlining how anti-PD1 monoclonal antibodies may be a promising treatment in this genodermatosis. Moreover, these researchers stated that given the limited data on the disease, further studies are needed to identify the correct dosage and infusion rate of anti PD-1 drugs.

: Requires Precertification:

Precertification of cemiplimab-rwlc (Libtayo) is required of all Aetna participating providers and members in applicable plan designs. For precertification of cemiplimab-rwlc (Libtayo), call (866) 752-7021 (Commercial), or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see

.

For Medicare Part B plans, call (866) 503-0857, or fax (844) 268-7263.

: Site of Care Utilization Management Policy applies for cemiplimab-rwlc (Libtayo). For information on site of service, see

.

Exclusions

Aetna will not provide coverage for members who have experienced disease progression while on programmed death receptor-1 (PD-1) [e.g., pembrolizumab (Keytruda), nivolumab (Opdivo), and cemiplimab (Libtayo)] or programmed death ligand 1 (PD-L1) [e.g., atezolizumab (Tecentriq), avelumab (Bavencio), durvalumab (Imfinzi)] inhibitor therapy.

Criteria for Initial Approval

Aetna considers cemiplimab-rwlc (Libtayo) therapy medically necessary for

of the following indications:

Cutaneous Squamous Cell Carcinoma (CSCC)

When

of the following criteria are met:

The disease is

of the following:

Basal Cell Carcinoma (BCC)

For single-agent treatment of advanced, recurrent, or metastatic basal cell carcinoma in members who have received a hedgehog pathway inhibitor (e.g., vismodegib [Erivedge], sonidegib [Odomzo]) or for whom a hedgehog pathway inhibitor is not appropriate;

Non-Small Cell Lung Cancer (NSCLC)

For treatment of recurrent, advanced, or metastatic non-small cell lung cancer (NSCLC) when

of the following criteria are met:

The requested medication will be used as first-line therapy and the tumor does not have EGFR exon 19 deletions or L858R mutations, ALK rearrangements, or ROS1 aberrations (unless testing is not feasible due to insufficient tissue) as

The requested medication will be used as maintenance therapy following first-line cemiplimab-rwlc therapy and the tumor does not have EGFR exon 19 deletions or L858R mutations, ALK rearrangements, or ROS1 aberrations (unless testing is not feasible due to insufficient tissue) as

The requested medication will be used as subsequent therapy in combination with platinum-based chemotherapy for

of the following biomarkers:

Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

Continuation of Therapy

Aetna considers continuation of cemiplimab-rwlc (Libtayo) therapy medically necessary in members requesting reauthorization for an indication listed in Section II when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Dosage and Administration

Cemiplimab-rwlc is available as Libtayo as a 350 mg/7 mL (50 mg/mL) solution in a single-dose vial for intravenous infusion.

The recommended dosage of Libtayo is 350 mg as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity.

Refer to full prescribing information for Libtayo for preparation and administration instructions and dosage modifications for adverse reactions.

Source:Regeneron Pharmaceuticals, 2022

Experimental and Investigational

Aetna considers cemiplimab-rwlc (Libtayo) experimental and investigational for all other indications, including the following (not an all-inclusive list) because its effectiveness for these indications has not been established: