Medicare Advantage

Medical Policy

Title:

Penpulimab-kcqx

Policy #:

MA08.186b

Policy

In the absence of coverage criteria from applicable Medicare statutes, regulations, NCDs, LCDs, CMS manuals, or other Medicare coverage documents, this policy uses internal coverage criteria developed by the Company in consideration of peer-reviewed medical literature, clinical practice guidelines, and/or regulatory status.

The Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member's medical needs and condition.

MEDICALLY NECESSARY

ANAL CARCINOMA
Penpulimab-kcqx is considered medically necessary and, therefore, covered for the treatment of anal carcinoma in EITHER of the following:

Used in combination with paclitaxel and carboplatin for ANY of the following:

Treatment of inguinal node recurrence
Primary treatment of metastatic disease
First-line treatment of metastatic disease if persistent or progressive locoregional disease

As a single agent as second-line (National Comprehensive Cancer Network [NCCN] preferred) and subsequent therapy for metastatic disease if no prior immunotherapy received

APPENDICEAL CANCERS
Penpulimab-kcqx, as a single agent, is considered medically necessary and, therefore, covered for the treatment of appendiceal cancer when BOTH of the following are met:

For ONE of the following:

Deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H)
Polymerase epsilon/delta (POLE/POLD1) mutation with ultrahypermutated phenotype (e.g., tumor mutational burden [TMB] > 50 mutations/megabase [mut/Mb])

If no previous treatment with a checkpoint inhibitor in ANY of the following:

As neoadjuvant systemic therapy for biopsy-proven recurrence of high-risk disease and no previous cytoreductive surgery
As neoadjuvant systemic therapy for peritoneal-only metastatic disease
For recurrence with serial tumor marker elevation or radiographic progression and progressive or positive findings
For biopsy-proven recurrence of high-risk disease if cytoreductive surgery was previously received or not possible
For progressive disease or inadequate response after neoadjuvant systemic therapy for metastatic peritoneal-only disease
For extraperitoneal disease

HEAD AND NECK CANCERS
Nasopharyngeal carcinoma

Initial Therapy
Penpulimab-kcqx, in combination with either cisplatin or carboplatin and gemcitabine, is considered medically necessary and, therefore, covered as first-line or subsequent-line (if not previously used) treatment of adults with recurrent or metastatic nonkeratinizing nasopharyngeal carcinoma (NPC) when ALL of the following are met:

Tumor is staged as T1-4, N0-3, M1
Disease is ONE of the following:

Oligometastatic disease and Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2
Widely metastatic disease and good PS (0-2)

Subsequent Therapy
Penpulimab-kcqx, as a single agent, is considered medically necessary and, therefore, covered for the subsequent-line treatment of adults with metastatic nonkeratinizing NPC with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy when ALL of the following are met:

Tumor is staged as T1-4, N0-3, M1
Disease is ONE of the following:

Oligometastatic disease and PS 0-2
Widely metastatic disease and good PS (0-2)

Very Advanced Head and Neck Cancer

Penpulimab-kcqx, in combination with either cisplatin or carboplatin and gemcitabine (if not previously given), is considered medically necessary and, therefore, covered as subsequent-line systemic therapy (if not previously used) for very advanced nonkeratinizing NPC and PS 0-1 for ONE of the following:

Unresectable locoregional recurrence with prior radiation therapy (RT)
Unresectable second primary with prior RT
Unresectable persistent disease with prior RT
Recurrent/persistent disease with distant metastases

SMALL BOWEL ADENOCARCINOMA
Penpulimab-kcqx, as a single agent, is considered medically necessary and, therefore, covered as neoadjuvant therapy for small bowel adenocarcinoma when ONE of the following is met:

Resectable disease that is T4
Has a bulky primary with ONE of the following:

dMMR/MSI-H
POLE/POLD1 mutation with ultrahypermutated phenotype (e.g., TMB >50 mut/Mb)

Penpulimab-kcqx, as a single agent, is considered medically necessary and, therefore, covered as primary treatment for small bowel adenocarcinoma in ANY of the following:

Locally unresectable
Medically inoperable
dMMR/MSI-H
POLE/POLD1 mutation with ultrahypermutated phenotype (e.g., TMB >50 mut/Mb)

Penpulimab-kcqx, as a single agent, is considered medically necessary and, therefore, covered for advanced or metastatic small bowel adenocarcinoma, if no previous treatment with a checkpoint inhibitor, for any line of therapy in EITHER of the following:

dMMR/MSI-H
POLE/POLD1 mutation with ultrahypermutated phenotype (e.g., TMB >50 mut/Mb)

EXPERIMENTAL/INVESTIGATIONAL

All other uses for penpulimab-kcqx are considered experimental/investigational and, therefore, not covered unless the indication is supported as an accepted off-label use, as defined in the Company medical policy on Off-Label Coverage for Prescription Drugs and Biologics.

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the drug.

Guidelines

There is no Medicare coverage determination addressing penpulimab-kcqx; therefore, the Company policy is applicable.

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, penpulimab-kcqx is covered under the medical benefits of the Company's products when the medical necessity criteria listed in this medical policy are met.

THE EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE STATUS

The Eastern Cooperative Oncology Group (ECOG), established in 1955, was one of the first groups to coordinate multicenter cancer clinical trials. The National Cancer Institute (NCI) is the primary funding source, and ECOG has evolved from a small consortium of institutions in the eastern United States to one of the largest clinical cancer research organizations in the country. As part of their work in the treatment of cancer, ECOG has developed the ECOG Performance Status (PS), originally published in 1982 in the American Journal of Clinical Oncology. The use of the scales and the criteria in the ECOG PS allows clinicians and researchers to determine an individual’s disease progression in terms of how the activities of daily living (ADL) are affected.

ECOG Performance Status
Grade	ECOG
0	Fully active, able to carry on all pre-disease performance without restriction
1	Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (e.g., light housework, office work)
2	Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50 percent of waking hours
3	Capable of only limited self-care, confined to bed or chair more than 50 percent of waking hours
4	Completely disabled. Cannot carry on any self-care: totally confined to bed or chair
5	Dead

Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-655.

VERY ADVANCED HEAD AND NECK CANCERS

According to the National Comprehensive Cancer Network (NCCN), very advanced head and neck cancers include the following:

Newly diagnosed (M0) locally advanced T4b, N0-3
Newly diagnosed unresectable regional nodal disease
Individuals unfit for surgery
Metastatic disease at initial presentation (M1)
Recurrent or persistent disease with or without distant metastases

US FOOD AND DRUG ADMINISTRATION STATUS

The US Food and Drug Administration (FDA) approved penpulimab-kcqx on April 23, 2025, in combination with either cisplatin or carboplatin and gemcitabine for the first-line treatment of adults with recurrent or metastatic nonkeratinizing nasopharyngeal carcinoma (NPC). At the same time, penpulimab-kcqx was approved as a single agent for the treatment of adults with metastatic NPC with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy.

PEDIATRIC USE
The safety and effectiveness of penpulimab-kcqx in pediatric individuals have not been established.

Description

NASOPHARYNGEAL CARCINOMA

Nasopharyngeal carcinoma (NPC) is a type of head and neck cancer that starts in the upper part of the throat (nasopharynx) behind the nose. The nasopharynx is the beginning part of the passageway for air traveling from the nose to the lungs. There are multiple types of NPC: keratinizing squamous cell carcinoma, nonkeratinizing differentiated carcinoma, nonkeratinizing undifferentiated carcinoma, and basaloid squamous cell carcinoma. NPC is a rare cancer in most parts of the world, including the United States, with fewer than one case for every 100,000 individuals. In parts of South Asia, North Africa, the Arctic, and the Middle East, however, there may be 15 to 30 cases per 100,000 individuals. The exact causes of NPC are not yet known, but there seem to be some risk factors that may play a role in the development of the cancer including diet, smoking, heavy alcohol use, genetics, and past infection with either the Epstein-Barr virus (EBV) or certain types of the human papillomavirus (HPV). Treatment usually includes pharmacologic therapy with or without radiation therapy. Surgery is not usually an initial treatment, but may occur later in the course of therapy.

PENPULIMAB-KCQX

Penpulimab-kcqx is a programmed death-1 (PD-1) receptor blocking IgG1 antibody. When the PD-1 receptor is bound by programmed death-ligand 1 or 2 (PD-L1, PD-L2) on the T cells, the T-cell immune surveillance of tumors will be inhibited, allowing tumors to grow. By binding to the PD-1 site, penpulimab-kcqx prevents the T cell from interacting with PD-L1 or PD-L2, and allows the T cell to continue its antitumor immune response.

CLINICAL TRIALS

FIRST LINE WITH PLATINUM AND GEMCITABINE
The efficacy and safety of penpulimab-kcqx, in combination with platinum and gemcitabine, as first-line therapy for recurrent or metastatic NPC was evaluated in a multicenter, randomized, double-blind, phase III clinical trial (NCT04974398). Participants were randomly assigned 1:1 to receive either systemic penpulimab-kcqx or placebo in combination with a platinum agent (cisplatin or carboplatin) and gemcitabine every 3 weeks for up to six cycles, followed by maintenance therapy with either penpulimab-kcqx or placebo. If any individual in the placebo cohort was confirmed to have progressive disease, they were allowed to change to therapy with penpulimab-kcqx. The primary endpoint was progression-free survival (PFS). Key secondary endpoints were overall survival (OS), objective response rate (ORR), and duration of response (DOR).

A total of 291 individuals were randomly assigned, with 144 receiving penpulimab-kcqx and 147 receiving placebo. At a median follow-up of 19.1 months, the median PFS for the penpulimab-kcqx cohort was 9.6 months versus 7.0 months for the placebo cohort (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.33–0.62; P<0.0001). OS was not mature. Confirmed ORR was 68.1% for the penpulimab-kcqx cohort and 63.9% for the placebo cohort. DOR was 9.8 months for the penpulimab-kcqx cohort and 5.7% for the placebo cohort (HR, 0.4, 95% CI, 0.27–0.59). Treatment-related adverse events (TRAE) of grade 3 or higher were experienced by 89.0% of individuals in the penpulimab-kcqx cohort and 85.9% of individuals in the placebo cohort.

THIRD LINE AS A SINGLE AGENT
The efficacy and safety of penpulimab-kcqx, as a single agent, for the treatment of individuals with metastatic non-keratinizing NPC with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy were evaluated in a multicenter, single-arm, open-label, phase II clinical trial (NCT03866967). Participants received penpulimab-kcqx every 2 weeks until disease progression or intolerable toxicities occurred. The primary endpoint was ORR. Key secondary endpoints were PFS, OS, and DOR.

A total of 125 individuals were enrolled. The ORR was 28% with one complete response and 27 partial responses. The median PFS was 3.6 months. The median OS was 22.8 months. The median DOR was not matured. TRAE were experienced by 71.5% of enrolled individuals.

OFF-LABEL INDICATIONS

There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company's off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.

References

American Cancer Society (ACS). Nasopharyngeal cancer. [ACS Web site]. 06/25/2025. Available at: https://www.cancer.org/cancer/types/nasopharyngeal-cancer.html. Accessed February 3, 2026.

American Hospital Formulary Service (AHFS). Penpulimab-kcqx. AHFS Drug Information. [UpToDate Lexidrug Web site]. 01/21/2026. Available at: https://online.lexi.com/lco/action/home [via subscription only]. Accessed February 3, 2026.

Chen X, Wang W, Zou Q, et al. Penpulimab, an anti-PD-1 antibody, for heavily pretreated metastatic nasopharyngeal carcinoma: a single-arm phase II study. Signal Transduct Target Ther. 2024 Jun 19;9(1):148.

ClinicalTrials.gov. A study of anti-PD-1 AK105 in patients with metastatic nasopharyngeal carcinoma. ClinicalTrials.gov Identifier: NCT03866967. First Posted: March 7, 2019. Last Update Posted: February 27, 2025. Available at: https://clinicaltrials.gov/. Accessed February 3, 2026.

ClinicalTrials.gov. A study of penpulimab (AK105) in the first-line treatment of recurrent or metastatic nasopharyngeal carcinoma. ClinicalTrials.gov Identifier: NCT04974398. First Posted: July 23, 2021. Last Update Posted: April 13, 2025. Available at: https://clinicaltrials.gov/. Accessed February 3, 2026.

Elsevier's Clinical Pharmacology Compendium. Penpulimab-kcqx. [Clinical Key Web site]. 07/16/2025. Available at: https://www.clinicalkey.com/#!/ [via subscription only]. Accessed February 3, 2026.

Hu C, Chen X, Xu T, et al. Penpulimab versus placebo in combination with chemotherapy as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma: a global, multicenter, randomized, double-blind, phase 3 trial (AK105-304) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT011. Available at: https://aacrjournals.org/cancerres/article/85/8_Supplement_2/CT011/761700. Accessed February 3, 2026.

Merative Micromedex^® DRUGDEX^® (electronic version). Penpulimab-kcqx. [Micromedex Web site]. 08/20/2025. Available at: https://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed February 3, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology^®. Anal carcinoma, V1.2026. [NCCN Web site]. 01/22/2026. Available from: https://www.nccn.org/professionals/physician_gls/pdf/anal.pdf. [via subscription only]. Accessed February 3, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology^®. Appendiceal neoplasms and cancers, V1.2026. [NCCN Web site]. 10/30/2025. Available from: https://www.nccn.org/professionals/physician_gls/pdf/appendiceal.pdf. [via subscription only]. Accessed February 3, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology^®. Head and neck cancers, V1.2026. [NCCN Web site]. 12/08/2025. Available from: https://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf. [via subscription only]. Accessed February 3, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology^®. Small bowel adenocarcinoma, V1.2026. [NCCN Web site]. 01/22/2026. Available from: https://www.nccn.org/professionals/physician_gls/pdf/small_bowel.pdf. [via subscription only]. Accessed February 3, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Drugs & Biologics Compendium^®. [NCCN Web site]. Penpulimab-kcqx. Available at: https://www.nccn.org/professionals/drug_compendium/content/ [via subscription only]. Accessed February 3, 2026.

Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-655.

UpToDate^® Lexidrug^TM. Penpulimab-kcqx. [UpToDate Lexidrug Web site]. 01/08/2026. Available at: https://online.lexi.com/lco/action/home [via subscription only]. Accessed February 3, 2026.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Penpulimab-kcqx. Prescribing information. [FDA Web site]. 04/23/2025. Available at https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm. Accessed February 3, 2026.

Coding

CPT Procedure Code Number(s)

N/A

ICD - 10 Procedure Code Number(s)

N/A

ICD - 10 Diagnosis Code Number(s)

C11.0 Malignant neoplasm of superior wall of nasopharynx

C11.1 Malignant neoplasm of posterior wall of nasopharynx

C11.2 Malignant neoplasm of lateral wall of nasopharynx

C11.3 Malignant neoplasm of anterior wall of nasopharynx

C11.8 Malignant neoplasm of overlapping sites of nasopharynx

C11.9 Malignant neoplasm of nasopharynx, unspecified

C14.0 Malignant neoplasm of pharynx, unspecified

C14.2 Malignant neoplasm of Waldeyer's ring

C17.0 Malignant neoplasm of duodenum

C17.1 Malignant neoplasm of jejunum

C17.2 Malignant neoplasm of ileum

C17.3 Meckel's diverticulum, malignant

C17.8 Malignant neoplasm of overlapping sites of small intestine

C17.9 Malignant neoplasm of small intestine, unspecified

C18.1 Malignant neoplasm of appendix

C21.0 Malignant neoplasm of anus, unspecified

C21.1 Malignant neoplasm of anal canal

C21.2 Malignant neoplasm of cloacogenic zone

C21.8 Malignant neoplasm of overlapping sites of rectum, anus and anal canal

C30.0 Malignant neoplasm of nasal cavity

C31.0 Malignant neoplasm of maxillary sinus

C31.1 Malignant neoplasm of ethmoidal sinus

C78.32 Secondary malignant neoplasm of pharynx

C79.89 Secondary malignant neoplasm of other specified sites

D37.05 Neoplasm of uncertain behavior of pharynx

D37.3 Neoplasm of uncertain behavior of appendix

D38.5 Neoplasm of uncertain behavior of other respiratory organs

D38.6 Neoplasm of uncertain behavior of respiratory organ, unspecified

HCPCS Level II Code Number(s)

THE FOLLOWING CODES ARE USED TO REPRESENT penpulimab-kcqx

C9399 Unclassified drugs or biologicals

J3590 Unclassified biologics

Revenue Code Number(s)

N/A

MPMiscCodesNarrativesPub

Coding and Billing Requirements

Cross Reference

Policy History

Revisions From MA08.186b

10/01/2026	This version of the policy will become effective 10/01/2026. Inclusion of a policy in a Code Update memo does not imply that a full review of the policy was completed at this time. The following ICD-10 code has been added to this policy: C78.32 Secondary malignant neoplasm of pharynx

Revisions From MA08.186a:

06/01/2026

This policy will become effective 06/01/2026.

The following policy criteria have been added as medically necessary to this policy in accordance the National Comprehensive Cancer Network (NCCN):

Anal carcinoma
Appendiceal cancers
Small bowel adenocarcinoma

The following policy criteria have been revised in accordance with the US Food and Drug Administration (FDA) and NCCN:

Head and neck cancers

The following ICD-10 codes have been added to this policy:

C17.0 Malignant neoplasm of duodenum
C17.1 Malignant neoplasm of jejunum
C17.2 Malignant neoplasm of ileum
C17.3 Meckel's diverticulum, malignant
C17.8 Malignant neoplasm of overlapping sites of small intestine
C17.9 Malignant neoplasm of small intestine, unspecified
C18.1 Malignant neoplasm of appendix
C21.0 Malignant neoplasm of anus, unspecified
C21.1 Malignant neoplasm of anal canal
C21.2 Malignant neoplasm of cloacogenic zone
C21.8 Malignant neoplasm of overlapping sites of rectum, anus and anal canal
C31.0 Malignant neoplasm of maxillary sinus
C31.1 Malignant neoplasm of ethmoidal sinus