Medical Policy

Policy Num:      02.003.021
Policy Name:    Tumor-Infiltrating Lymphocytes for Advanced Melanoma
Policy ID:          [02.003.021]  [Ac /B / M+ / P+]  [5.01.51]

Last Review:      September 20, 2024
Next Review:      September 20, 2025
 

Related Policies:

2.04.146 - Gene Expression Profiling for Cutaneous Melanoma
2.04.44 - Germline Genetic Testing for Familial Cutaneous Malignant Melanoma (CDKN2A, CDK4)
2.04.77 - Somatic Genetic Testing to Select Individuals with Melanoma or Glioma for Targeted Therapy (BRAF)
8.01.01 - Adoptive Immunotherapy

Tumor-Infiltrating Lymphocytes for Advanced Melanoma

Summary

Description

The spontaneous regression of certain cancers (eg, melanoma) supports the idea that an affected individual's immune system can delay tumor progression and, on rare occasions, eliminate tumors altogether. These observations have led to research into various immunologic therapies designed to stimulate a person's own immune system. Adoptive immunotherapy is a method of activating lymphocytes and/or other types of cells for the treatment of cancer and other diseases. This particular type of therapy removes cells from the affected individual, processes them for a period of time, and then infuses them back into the individual. This review focuses specifically on adoptive immunotherapy using tumor-infiltrating lymphocytes in individuals with melanoma.

Summary of Evidence

For individuals with melanoma who receive tumor infiltrating lymphocytes (TILs), the evidence includes the Phase 2 approval trial. Relevant outcomes are overall survival (OS), disease-specific survival, quality of life, and treatment-related mortality and morbidity. The Phase 2, single-arm, international study demonstrated the efficacy and safety of lifileucel, an autologous TIL product, demonstrating a clinically meaningful response (complete or partial response) in 31.4% of patients with advanced melanoma who were refractory to prior immune checkpoint inhibitors and, if BRAF V600 mutation-positive, BRAF or BRAF/MEK inhibitors. This Phase 2 trial data led to accelerated U.S. Food and Drug Administration-approval of lifileucel in February 2024 for this patient population, addressing an unmet need in patients with refractory, difficult-to-treat advanced disease. Continued approval may be contingent upon verification of clinical benefit in additional confirmatory trials. Ideally, multicentric comparative trials of lifileucel, with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as a control arm showing treatment benefits, should be conducted. For use as a second line agent, in patients who have failed anti-programmed death (PD)-1 and targeted therapy, the evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

Objective

The objective of this evidence review is to assess whether the use of tumor-infiltrating lymphocytes in individuals with melanoma improves the net health outcome.

Policy Statements

Tumor-infiltrating lymphocyte (TIL) therapy with an indication approved by the U.S. Food and Drug Administration (FDA) (e.g. lifileucel) may be considered medically necessary as a second-line treatment option in individuals with unresectable or metastatic melanoma previously treated with anti-programmed cell death-1 and, if BRAF V600 mutation positive, a BRAF inhibitor with or without a MEK inhibitor.

The use of lifileucel for all other indications is considered investigational.

Policy Guidelines

The lifelucel product label recommends that individuals receive treatment in an inpatient setting where specialists skilled in cardiopulmonary or intensive care medicine are available.

The product label contains several boxed warnings:

• Monitor individuals for prolonged severe cytopenia and monitor for internal organ hemorrhage.

• Administer filgrastim or a biosimilar product to patients beginning Day 1 after lifileucel and continue daily until the absolute neutrophil count is greater than 1000 per mm³ for 3 consecutive days, or per institutional standard.

• Treat severe infections.

• Monitor cardiopulmonary and renal functions throughout the treatment course.

Coding

See the Codes table for details.

Benefit Application

BlueCard/National Account Issues

Adoptive immunotherapy is a specialized service that may require an out-of-network referral.

Some plans may participate in voluntary programs offering coverage for individuals participating in the National Institutes of Health approved clinical trials of cancer chemotherapies, including adoptive immunotherapy.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

Background

Melanoma

Overall incidence rates for melanoma have been increasing for at least 30 years. In 2024, there will be an estimated 100,640 new cases of melanoma in the United States, with 8,290 estimated deaths.^1, In advanced (stage IV) melanoma, the disease has spread beyond the original area of skin and nearby lymph nodes. Although only a small proportion of cases are stage IV at diagnosis, the prognosis is extremely poor; 5-year survival is 15% to 35%.

Adoptive Immunotherapy

Adoptive immunotherapy uses “activated” lymphocytes or other immune cells as a treatment modality.^2, Both nonspecific and specific lymphocyte activation are used therapeutically. The nonspecific, polyclonal proliferation of lymphocytes by cytokines (immune system growth factors), also called autolymphocyte therapy, increases the number of activated lymphocytes.

T Lymphocytes and Killer Cells

Initially, this treatment was performed by harvesting peripheral lymphokine-activated killer cells and activating them in vitro with the T-cell growth factor interleukin (IL)-2 and other cytokines. More recent techniques have yielded select populations of cytotoxic T lymphocytes with specific reactivity to tumor antigens. Peripheral lymphocytes are propagated in vitro with antigen-presenting dendritic cells (DC) that have been pulsed with tumor antigens. Alternatively, innate tumor-infiltrating lymphocytes (TIL) from the tumor biopsy are propagated in vitro with IL-2 and anti-CD3 antibody, a T-cell activator. The expansion of TIL for clinical use is labor-intensive and requires laboratory expertise. Only a few cancers are infiltrated by T cells in significant numbers; of these, TIL can be expanded in only approximately 50% of cases. These factors limit the widespread applicability of TIL treatment.

Regulatory Status

The first product within the scope of this review that has been approved by the U.S. Food and Drug Administration (FDA) is the TIL product lifileucel (Amtagvi, Iovance Biotherapeutics, Inc.).^3, Lifileucel was granted accelerated approval in February 2024 for adult patients with unresectable or metastatic melanoma previously treated with a programmed cell death-1 blocking antibody, and if BRAF V600 positive, a BRAF inhibitor with or without a MEK inhibitor. The approval was based on objective response rate to treatment, as evaluated in a multicenter clinical trial. Continued approval may be contingent upon verification of clinical benefit in confirmatory trials.

Rationale

This evidence review was created in July 2024 with a search of the PubMed database. The most recent literature update was performed through July 11, 2024.

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1 

Tumor-Infiltrating Lymphocytes for Advanced Melanoma

Clinical Context and Therapy Purpose

The purpose of tumor-infiltrating lymphocytes (TIL) in individuals who have advanced melanoma is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population(s) of interest is individuals with unresectable or metastatic melanoma who are refractory to prior immune checkpoint inhibitors and, if BRAF V600 mutation-positive, BRAF or BRAF/MEK inhibitors.

Interventions

The therapy being considered is TIL with an indication approved by the U.S. Food and Drug Administration (FDA).

Comparators

The following therapies are currently being used to make decisions about melanoma: standard of care.

Outcomes

The general outcomes of interest are overall survival (OS), disease-specific survival (DSS), quality of life (QOL), treatment-related mortality, and treatment-related morbidity.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Randomized Controlled Trials and Key Approval Trials

In 2022, a pooled analysis of cohorts enrolled in the phase 2 C-144-01 trial (NCT02360579) was published by Chesney et al.^4, This analysis included data previously published by Sarnaik et al (2021)^5, (Cohort 2, n=66) and previously unreported data from Cohort 4 (n=87). Cohort 1 included patients receiving non-cryopreserved TIL generated using a different manufacturing process than lifileucel and Cohort 3 included patients from Cohorts 1, 2, and 4, who were retreated with lifileucel, and were not included in the analysis by Chesney et al (2022). In patients with advanced non-uveal melanoma who had received a median 3 prior lines of therapy, lifileucel demonstrated an objective response rate (ORR) of 31.4% which was significantly better (p<.001) than a pre-specified historical threshold of 10% ORR.^6, A total of 54 (34.6%) of participants had 1 or more serious adverse events through 30-days post-infusion, and 29 (18.6%) had a serious adverse event from 30-days post-infusion through 6 months follow-up. Of the study participants, 105 (67.3%) died following lifileucel infusion. The primary causes of death were disease progression (79%) and adverse events (11%). Follow-up is ongoing for up to 5 years or until disease progression or start of new anticancer therapy. Trial characteristics are described in Table 1 and results are described in Table 2.

Table 1. Summary of Key TIL Study Characteristics

EU: European Union; ICI; immune checkpoint inhibitors; IL-2: interleukin-2; IV: intravenous; NA: not applicable; OL: open-label; PD: programmed cell death; RCT: randomized controlled trial; TIL: tumor-infiltrating lymphocyte.

Table 2. Summary of Key TIL Study Results

CI: confidence interval; DOR: duration of response; HR: hazard ratio; MD: mean difference; ORR: objective response rate; OS: overall survival; PFS: progression-free survival; RCT: randomized controlled trial; TEAE: treatment-emergent adverse event; TIL: tumor-infiltrating lymphocyte.aDefined as any adverse event with onset after lifileucel infusion through day 30 post-infusion b8 complete responses and 40 partial responsesc41.7% of the patients had responses maintained for ≥18 months, and 39.6% of responses were ongoing at time of data cut

The purpose of the study limitations tables (see Tables 3 and 4) is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of evidence supporting the position statement.

Table 3. Study Relevance Limitations

FDA: U.S. Food and Drug Administration; TIL: tumor-infiltrating lymphocyte.The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Population key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4, Enrolled populations do not reflect relevant diversity; 5. Other.b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest (e.g., proposed as an adjunct but not tested as such); 5: Other.c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively; 5. Other.d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. Incomplete reporting of harms; 4. Not establish and validated measurements; 5. Clinically significant difference not prespecified; 6. Clinically significant difference not supported; 7. Other.e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms; 3. Other.

Table 4. Study Design and Conduct Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias; 5. Other.b Blinding key: 1. Participants or study staff not blinded; 2. Outcome assessors not blinded; 3. Outcome assessed by treating physician; 4. Other.c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication; 4. Other.d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials); 7. Other.e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference; 4. Other.f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated; 5. Other.

Section Summary: Tumor-Infiltrating Lymphocytes for Advanced Melanoma

A Phase 2, single-arm, international study demonstrated efficacy and safety of lifileucel, an autologous TIL product, demonstrating a clinically meaningful response (complete or partial response) in 31.4% of patients with advanced melanoma who were refractory to prior immune checkpoint inhibitors and, if BRAF V600 mutation-positive, BRAF or BRAF/MEK inhibitors. This Phase 2 trial data led to accelerated FDA-approval of lifileucel in February 2024 for this patient population, addressing an unmet need in patients with refractory, difficult-to-treat advanced disease. Continued approval may be contingent upon verification of clinical benefit in additional confirmatory trials. Ideally, multicentric comparative trials of lifileucel, with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as a control arm showing treatment benefits, should be conducted. However, in patients who have failed anti-PD-1 and targeted therapy, when appropriate, lifileucel can be considered as a second-line treatment option.

Summary of Evidence

For individuals with melanoma who receive tumor infiltrating lymphocytes (TILs), the evidence includes the Phase 2 approval trial. Relevant outcomes are overall survival (OS), disease-specific survival, quality of life, and treatment-related mortality and morbidity. The Phase 2, single-arm, international study demonstrated the efficacy and safety of lifileucel, an autologous TIL product, demonstrating a clinically meaningful response (complete or partial response) in 31.4% of patients with advanced melanoma who were refractory to prior immune checkpoint inhibitors and, if BRAF V600 mutation-positive, BRAF or BRAF/MEK inhibitors. This Phase 2 trial data led to accelerated U.S. Food and Drug Administration-approval of lifileucel in February 2024 for this patient population, addressing an unmet need in patients with refractory, difficult-to-treat advanced disease. Continued approval may be contingent upon verification of clinical benefit in additional confirmatory trials. Ideally, multicentric comparative trials of lifileucel, with adequate randomization procedures, blinded assessments, centralized oversight, and the use of an appropriate standard of care as a control arm showing treatment benefits, should be conducted. For use as a second line agent, in patients who have failed anti-programmed death (PD)-1 and targeted therapy, the evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Supplemental Information

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in 'Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

National Comprehensive Cancer Network

The National Comprehensive Cancer Network (NCCN) guidelines on melanoma (v.2.2024) were updated to include tumor-infiltrating lymphocyte (TIL) therapy as a treatment option after the approval of lifileucel by the U.S. Food and Drug Administration.^7, Specifically, the guidelines state: "For patients with good performance status who have progressed on anti-PD-1 [programmed cell death-1] based therapy and BRAF/MEK inhibition (if BRAF V600 mutation present), TIL therapy should be considered, based on favorable durable response rates in anti-PD-1 refractory melanoma. TIL therapy should not be considered for patients with inadequate cardiac, pulmonary, and/or renal function, poor performance status, or with untreated or active brain metastases. TIL therapy currently requires a resectable metastasis for TIL harvesting and includes the use of nonmyeloablative chemotherapy and high-dose IL-2 [interleukin-2]. Referral to a TIL authorized treatment center is recommended [category 2A recommendation]." Evidence to support this recommendation included the Chesney et al (2022) clinical trial.^4,

U.S. Preventive Services Task Force Recommendations

Not applicable

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently ongoing and unpublished trials that might influence this review are listed in Table 5.

Table 5. Summary of Key Trials

NCT: national clinical trial.a Denotes industry-sponsored or cosponsored trial.

References

1. Cancer stat facts: melanoma of the skin. National Cancer Institute. https://seer.cancer.gov/statfacts/html/melan.html. Accessed July 12, 2024.
2. Olson DJ, Odunsi K. Adoptive Cell Therapy for Nonhematologic Solid Tumors. J Clin Oncol. Jun 20 2023; 41(18): 3397-3407. PMID 37104722
3. U.S. Food and Drug Administration. FDA News Release: FDA approves first cellular therapy to treat patients with unresectable or metastatic melanoma. February 16, 2024; https://www.fda.gov/news-events/press-announcements/fda-approves-first-cellular-therapy-treat-patients-unresectable-or-metastatic-melanoma. Accessed June 3, 2024.
4. Chesney J, Lewis KD, Kluger H, et al. Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: pooled analysis of consecutive cohorts of the C-144-01 study. J Immunother Cancer. Dec 2022; 10(12). PMID 36600653
5. Sarnaik AA, Hamid O, Khushalani NI, et al. Lifileucel, a Tumor-Infiltrating Lymphocyte Therapy, in Metastatic Melanoma. J Clin Oncol. Aug 20 2021; 39(24): 2656-2666. PMID 33979178
6. U.S. Food and Drug Administration. Amtagvi (lifileucel) Statistical Review. Nov, 2023. https://www.fda.gov/media/176947/download?attachment. Accessed July 1, 2024
7. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: melanoma: cutaneous. Version 2.2024. Updated April 3, 2024. https://www.nccn.org/professionals/physician_gls/pdf/cutaneous_melanoma.pdf. Accessed July 11, 2024.

Codes

Policy History