Cemiplimab (Libtayo)

Number: 0942

Policy

Note: REQUIRES PRECERTIFICATION. Precertification of Libtayo is required of all Aetna participating providers and members in applicable plan designs.  For precertification of Libtayo, call (866) 752-7021 (Commercial), (866) 503-0857 (Medicare), or fax (866) 267-3277.

Note: Site of Care Utilization Management Policy applies for cemiplimab (Libtayo). For information on site of service, see Utilization Management Policy on Site of Care for Specialty Drug Infusions.

Aetna considers cemiplimab (Libtayo) medically necessary for the treatment of members with cutaneous squamous cell carcinoma (CSCC) when all of the following criteria are met:

1. The disease is one of the following:
   
   
   1. Metastatic; or
   2. Locally advanced; or
   3. Regional and inoperable or incompletely resected; and
2. The member is not a candidate for curative surgery or curative radiation.

Aetna considers continued treatment with cemiplimab medically necessary in members requesting reauthorization for a medically necessary indication when there is no evidence of unacceptable toxicity or disease progression while on the current regimen. 

Aetna considers cemiplimab experimental and investigational if disease progresses while on prior anti-PD-1 therapy (e.g., pembrolizumab (Keytruda), nivolumab (Opdivo), and cemiplimab (Libtayo) or anti-PD-L1 therapy (e.g., atezolizumab (Tecentriq), avelumab (Bavencio), durvalumab (Imfinzi)

Aetna considers cemiplimab experimental and investigational for all other indications (e.g., cervical cancer and other solid tumors except for CSCC).

Dosing Recommendations

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

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

Source: Regeneron Pharmaceuticals, Inc., 2020.

Background

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

• Libtayo is indicated 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.

Compendial Uses

• Inoperable or incompletely resected regional squamous cell skin cancer

The prognosis of patients with metastatic cutaneous melanoma is poor.  Recently, new classes of drugs have significantly improved patient prognosis, which has markedly altered the therapeutic options of melanoma.  Basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (CSCC) share exposure to ultra-violet light as the dominant risk factor, thus, these tumors harbor high mutation burdens.  In other malignancies, high mutation burden has been associated with clinical benefit from therapy with antibodies directed against the programmed death 1 (PD-1) immune checkpoint receptor.  Highly mutated tumors are more likely to express immunogenic tumor neo-antigens that attract effector T cells, which could be unleashed by blockade of the PD-1 immune checkpoint; and PD-1 blockade with cemiplimab has been reported to be effective in effective in CSCC with adverse events (AEs) similar to other PD-1 inhibitors (Falchook et al, 2016; Sidaway, 2018; and no authors listed, 2018).

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. 

On September 28, 2018, the Food and Drug Administration (FDA) approved cemiplimab-rwlc (Libtayo) for the treatment of patients with metastatic 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.

Experimental Indications

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.

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.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
Other CPT codes related to the CPB:
96401 - 96450	Chemotherapy administration
HCPCS codes covered if selection criteria are met:
J9119	Injection, cemiplimab-rwlc,1 mg
Other HCPCS codes related to the CPB:
J9022	Injection, atezolizumab, 10 mg.
J9023	Injection, avelumab, 10 mg.
J9271	Injection, pembrolizumab, 1 mg
J9299	Injection, nivolumab, 1 mg.
ICD-10 codes covered if selection criteria are met:
C44.02	Squamous cell carcinoma of skin of lip
C44.121 - C44.1292	Squamous cell carcinoma of skin of eyelid, including canthus
C44.221 - C44.229	Squamous cell carcinoma of skin of ear and external auricular canal
C44.320 - C44.329	Squamous cell carcinoma of skin of other and unspecified parts of face
C44.42	Squamous cell carcinoma of skin of scalp and neck
C44.520 - C44.529	Squamous cell carcinoma of skin of trunk
C44.621 - C44.629	Squamous cell carcinoma of skin of upper limb, including shoulder
C44.721 - C44.729	Squamous cell carcinoma of skin of lower limb, including hip
C44.82	Squamous cell carcinoma of overlapping sites of skin
C44.92	Squamous cell carcinoma of skin, unspecified
ICD-10 codes not covered for indications listed in the CPB:
C11.0 - C11.9	Malignant neoplasm of nasopharynx
C12	Malignant neoplasm of pyriform sinus
C13.0 - C13.9	Malignant neoplasm of hypopharynx
C14.0 - C14.8	Malignant neoplasm of other and ill-defined sites in the lip, oral cavity and pharynx
C15.3 - C15.9	Malignant neoplasm of esophagus
C16.0 - C16.9	Malignant neoplasm of stomach
C17.0 - C17.9	Malignant neoplasm of small intestine
C18.0 - C18.9	Malignant neoplasm of colon
C19 - C21.8	Malignant neoplasm of rectosigmoid junction, rectum, anus and anal canal
C22.0	Liver cell carcinoma
C22.1	Intrahepatic bile duct carcinoma
C23 - C24.9	Malignant neoplasm of gall bladder and other and unspecified parts of biliary tract
C25.0 - C25.9	Malignant neoplasm of pancreas
C26.0 - C26.9	Malignant neoplasm of other and ill-defined digestive organs
C30.0 - C30.1	Malignant neoplasm of nasal cavity and middle ear
C31.0 - C31.9	Malignant neoplasm of accessory sinuses (paranasal)
C33 - C34.92	Malignant neoplasm trachea, bronchus, and lung
C37	Malignant neoplasm of thymus
C38.0 - C38.8	Malignant neoplasm of heart, mediastinum and pleura
C39.0 - C39.9	Malignant neoplasm of other and ill-defined sites in the respiratory system and intrathoracic organs
C40.00 - C40.92	Malignant neoplasm of bone and articular cartilage of limbs
C41.0 - C41.9	Malignant neoplasm of bone and articular cartilage of other and unspecified sites
C43.0 - C43.9	Malignant melanoma of skin
C46.1	Kaposi's sarcoma of soft tissue
C47.0 - C47.9	Malignant neoplasm of peripheral nerves and autonomic nervous system
C48.0 - C48.8	Malignant neoplasm of retroperitoneum and peritoneum
C49.0 - C49.9	Malignant neoplasm of other connective and soft tissue
C50.011 - C50.929	Malignant neoplasm of female and male breast
C51.0 - C51.9	Malignant neoplasm of vulva
C52	Malignant neoplasm of vagina
C53.0 - C53.9	Malignant neoplasm of cervix uteri
C54.0 - C54.9	Malignant neoplasm of corpus uteri
C55	Malignant neoplasm of uterus, part unspecified
C56.1 - C56.9	Malignant neoplasm of ovary
C57.00 - C57.02	Malignant neoplasm of fallopian tube
C58	Malignant neoplasm of placenta
C60.0 - C60.9	Malignant neoplasm of penis
C61	Malignant neoplasm of prostate
C62.00 - C62.92	Malignant neoplasm of testis
C63.00 - C63.9	Malignant neoplasm of other and unspecified male genital organs
C64.1 - C68.9	Malignant neoplasm of kidney and other and unspecified urinary organs
C69.00 - C69.92	Malignant neoplasm of eye and adnexa
C70.0 - C70.9	Malignant neoplasm of meninges
C71.0 - C71.9	Malignant neoplasm of brain
C72.0 - C72.9	Malignant neoplasm of spinal cord, cranial nerves and other parts of central nervous system
C73	Malignant neoplasm of thyroid gland
C7A.1 - C7A.8	Malignant poorly differentiated neuroendocrine tumors

The above policy is based on the following references: