Consistent Durable Responses Are Observed for Lifileucel in Melanoma Regardless of IL-2 Doses

Jessica C. Hassel, MD

Findings from a post hoc analysis of the phase 2 C-144-01 trial (NCT02360579) suggest that regardless of the number of IL-2 doses administered, lifileucel (LN-144) delivered durable and objective responses in patients with advanced melanoma. These data were presented during the 2022 European Society for Medical Oncology Immuno-Oncology Congress.¹

In the overall population (n = 153), the objective response rate (ORR) for patients who received up to 6 doses of IL-2 following lifi leucel was 31.4% (95% CI, 24.1%-39.4%) by RECIST 1.1 criteria and independent review committee (IRC) assessment.¹ Those who received 1 to 2 doses of IL-2 had a slightly higher ORR of 37.5% (95% CI, 15.2%-64.6%) vs those who received 3 to 4 doses (30.8%; 95% CI, 14.3%-51.8%) or 5 to 6 doses (31.2%; 95% CI, 22.7%-40.8%). However, there was no statistical signifi cant difference in ORR associated with the number of IL-2 doses received (P =.87).¹

Moreover, there was no significant difference in duration of response (DOR) by number of IL-2 doses received (P =.25). The median DOR was not reached (NR) in patients who received up to 6 IL-2 doses (95% CI, 8.3-NR), those administered 1 to 2 doses (95% CI, 2.7-NR), and those administered 3 to 4 doses (95% CI, 8.3-NR). In those who received 5 to 6 doses of IL-2, the median DOR was 24.6 months (95% CI, 4.1-NR).¹

“Most of the patients tolerated 6 doses of IL-2 after lifi leucel infusion. If patients were not able to receive 6 doses and received [fewer], at least there was no impact on clinical outcome," said lead study author Jessica C. Hassel, MD, associate professor and section head of dermato-oncology in the Department of Dermatology at the National Center for Tumor Diseases at Heidelberg University Hospital in Germany, in a presentation of the data. "This is supported by the T-cell receptor [TCR] clonality data that showed similar clonal expansion and persistence of TIL [tumor-infiltrating lymphocyte]-derived clones in the different IL-2 dose groups. Hence, protocol-guided, tolerance-guided, abbreviated highdose IL-2 dosing is feasible in TIL therapy."

High-dose IL-2 is approved for use as a single agent in patients with metastatic melanoma. However, the agent induces limited efficacy and is known to have considerable toxicity.

Previous data from cohorts 2 and 4 of the C-144-01 trial (n = 153) shared during the 2022 Society for Immunotherapy of Cancer Annual Meeting showed that lifi leucel, the polyclonal 1-time TIL therapy, elicited an ORR of 31.4% (95% CI, 24.1%-39.4%) per IRC assessment. Notably, these patients had progressed on immune checkpoint inhibitors and targeted therapy. At a median follow-up of 36.5 months, the median DOR in these patients (n = 48) had not yet been reached (95% CI, 8.3-NR).²

In the post hoc analysis presented at the Congress, investigators evaluated the association between the number of IL-2 doses and clinical outcomes achieved with lifi leucel.¹

In C-144-01, patients were screened and enrolled and/or underwent surgical resection prior to receiving nonmyeloablative lymphodepletion therapy with cyclophosphamide from day –7 to day –6, followed by fludarabine from day –5 to day –1. IL-2 was administered 3 to 24 hours after lifileucel infusion and approximately every 8 to 12 hours for up to 6 doses.¹

The IL-2 dosing per trial protocol allowed for IL-2 toxicity management for up to 4 days after lifileucel infusion. The number of IL-2 doses received was based on tolerance. If patients experienced toxicities that could be easily reversed within 24 hours via supportive measures, then additional doses of IL-2 were administered.¹

The key objective of the post hoc analysis was to understand the association of the number of IL-2 doses with the ORR, DOR, and safety achieved with lifileucel. Investigators also explored the TCR repertoire. The TCR repertoire of tumors, TIL infusion product, and pre- and post-lifileucel blood samples were assessed via RNA sequencing.¹

In the full analysis set of 153 patients, the median age was 56.0 years (range, 20-79); 54.2% of patients were male, and 75.8% of patients had more than 3 target and nontarget lesions at baseline. Moreover, 35.3% of patients had lactate dehydrogenase levels that were 1 to 2 times the upper limit of normal (ULN); 19.0% had lactate dehydrogenase levels that were more than 2 times the ULN. The median number of therapies received was 3 (range, 1-9).¹

Moreover, the median number of IL-2 doses received in the lifi leucel regimen was 6 (range, 0-6); 10.5% of patients (n = 16) received a median of 1 to 2 doses, 17.0% (n = 26) received a median of 3 to 4, and 71.2% (n = 109) received a median of 5 to 6. The median cumulative IL-2 dose was 352,830 IU/kg and the median relative dose intensity was 100%. Additional data showed that 5 patients who previously received IL-2 in the metastatic setting and had progressedon or after the therapy experienced an ORR of 40% with study treatment.¹

In the overall patient population who received up to 6 doses of IL-6, 54.2% experienced a DOR that lasted for 12 months or longer; these rates were 66.7%, 75.0%, and 47.1% in those who received 1 to 2 doses, 3 to 4 doses, and 5 to 6 doses, respectively.¹

IL-2 discontinuation was guided by clinical tolerance, which limited safety comparisons across dose groups, according to Hassel.

Grade 3/4 adverse effects (AEs), as well asgrade 3/4 lab hematologic abnormalities, were similar irrespective of the number of IL-2 doses received. All patients developedgrade 3/4 lymphopenia following lymphodepletion therapy on days 0 to 4.¹

Hassel added that any-grade hypotension (50.0%), dyspnea (37.5%), and somnolence (18.8%) were highest in those who received 1 to 2 doses of IL-2 vs other dose levels. These effects led to treatment discontinuation.

Three grade 5 treatment-emergent toxicities were reported; all of them occurred in the group of patients who received 5 to 6 doses of IL-2. These effects comprised pneumonia, acute respiratory failure, and intra-abdominal hemorrhage (each, n = 1).¹

Polyclonality was comparable between the IL-2 dose groups within each sample type. Over time, TCR clonal expansion and persistence was noted in all dose groups. Hassel added that uCDR3 clonotypes that were identified in the tumor and the TIL product likely reflect tumor-associated clonotypes that were captured in the TIL product.

In August 2022, Iovance Biotherapeutics-submitted a rolling biologics license application (BLA) seeing approval for the TIL product in patients with advanced melanoma who progressed on or after a prior PD-1/PD-L1 inhibitor. The BLA was supported by earlier data from the C-144-01 trial.³

After the FDA provided Iovance with feedback pertaining to supplemental assay validation information and comparability data for the TIL therapy, the company announced that it planned to address the comments and complete the application during the first quarter of 2023.⁴

_REFERENCES:

_{1. Hassel JC, Sarnaik A, Chesney J, et al. Number of IL-2 doses and clinical outcomes of tumor-infi ltrating lymphocyte (TIL) cell therapy: post hoc analysis of the C-144-01 trial of lifileucel in patients with advanced melanoma. Immuno-oncol Technol. 2022;16(suppl 1):100140. doi:10.1016/j.iotech.2022.100140}

_{2. Sarnaik A, Lewis K, Kluger H, et al. Lifileucel TIL cell monotherapy in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapy: pooled analysis of consecutive cohorts (C-144- 01 study). J Immunother Cancer. 2022;10(suppl 2):A821. doi:10.1136/jitc-2022-SITC2022.0789}

_{3. Iovance Biotherapeutics initiates biologics license application (BLA) submission for lifileucel in advanced melanoma. News release. Iovance Biotherapeutics, Inc. August 25, 2022. Accessed January 11, 2023. bit.ly/3QSNyR1}

_{4. Iovance Biotherapeutics provides update on biologics license application submission for lifileucel in advanced melanoma. News release. Iovance Biotherapeutics, Inc. November 18, 2022. Accessed January 11, 2023..bit.ly/3TNGoya}