Lifileucel Induces Response in Metastatic Melanoma Independent of Number of IL-2 Doses Received

Lifileucel (LN-44) achieved safety and efficacy irrespective of the number of aldesleukin (IL-2) doses administered to patients with advanced melanoma, according to data from a post-hoc analysis of the phase 2 C-144-01 trial (NCT02360579) presented at the 2022 ESMO Immuno-Oncology Annual 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 lifileucel was 31.4% (95% CI, 24.1%-39.4%) by RECIST v1.1 criteria and independent review committee (IRC) assessment. 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 significant difference in ORR associated with the number of IL-2 doses received (P = .87).

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 yet reached (NR) in those who received up to 6 IL-2 doses (95% CI, 8.3-NR), those given 1 to 2 doses (95% CI, 2.7-NR), and those given 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).

“Most of the patients tolerated 6 doses of IL-2 after lifileucel infusion. If patients were not able to receive 6 doses and received less, at least there was no impact on clinical outcome,” lead study author Jennifer C. Hassel, MD, associate professor and section head of dermato-oncology in the Department of Dermatology at the National Center for Tumor Diseases of University Hospital Heidelberg 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-derived clones in the different IL-2 dose groups. Hence, protocol-guided, tolerance-guided, abbreviated high-dose 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 SITC Annual Meeting showed that lifileucel, the polyclonal one-time tumor-infiltrating lymphocyte (TIL) therapy, elicited an ORR of 31.4% (95% CI, 24.1%-39.4%) per IRC assessment.2 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).

Treatment with lifileucel includes an abbreviated course of high-dose IL-2 at 600,000 IU/kg for a maximum of 6 to promote T-cell activity.

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 lifileucel.

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.

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.

The key objective of the post-hoc analysis was to understand the association of 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.

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 that was 1 to 2 times the upper limit of normal (ULN); 19.0% had LDH that was more than 2 times the ULN. The median number of therapies received was 3 (range, 1-9).

Moreover, the median number of IL-2 doses received in the lifileucel 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 doses, and 71.2% (n = 109) received a median of 5 to 6 doses. The median cumulative IL-2 dose was 3528.3 x 103 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 progressed on or after the therapy, experienced an ORR of 40% with study treatment.

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.

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 as grade 3/4 lab hematologic abnormalities, were similar irrespective of the number of IL-2 doses received. All patients developed grade 3/4 lymphopenia following lymphodepletion therapy on days 0 to 4.

Hassel added that grade 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 proved to be reasons for 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 (n = 1, each).

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) seeking the approval of the TIL product in patients with advanced melanoma who progressed on or after a prior PD-1/PD-L1 inhibitor.³ The BLA was supported by earlier data from C-144-01.

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 plans 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-infiltrating lymphocyte (TIL) cell therapy: Post hoc analysis of the C-144-01 trial of lifileucel in patients with advanced melanoma. Presented at: ESMO Immuno-Oncology Congress 2022; December 7-10, 2022; Geneva, Switzerland. Abstract LBA2
2. Sarnaik A, Lewis KD, 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). Presented at: 2022 SITC Annual Meeting; November 8-12, 2022; Boston, MA. Abstract 789
3. Iovance Biotherapeutics initiates biologics license application (BLA) submission for lifileucel in advanced melanoma. News release. Iovance Biotherapeutics, Inc. August 25, 2022. Accessed December 8, 2022. https://bit.ly/3QSNyR1
4. Iovance Biotherapeutics provides update on biologics license application submission for lifileucel in advanced melanoma. News release. November 18, 2022. Accessed December 8, 2022. http://bit.ly/3TNGoya