Maximized Benefit of Lifileucel in Melanoma Potentially Seen Following Anti–PD-1 Progression

With further follow-up, lifileucel (LN-144) continued to show durable responses in patients with heavily pretreated advanced or metastatic melanoma who have progressed on multiple therapies, including prior anti–PD-1/PD-L1 therapy, according to updated results from a cohort of the phase 2 C-144-01 trial (NCT02360579) presented at the 2021 ASCO Annual Meeting.¹

At 33.1 months follow-up with a data cutoff of April 22, 2021, the median duration of response (DOR) still had not been reached (range, 2.2-38.5+ months).

Additionally, treatment with lifileucel was found to be more beneficial among patients with melanoma who had primary resistance to prior anti–PD-1/PD-L1 therapy or a shorter duration of treatment with anti–PD-1/PD-L1 therapy.

“All newly diagnosed patients should be closely monitored for progression on anti–PD-1 therapy. Early intervention with lifileucel at the time of initial progression on anti–PD-1 agents may maximize the benefit,” said James M. G. Larkin, MD, FRCP, PhD, of the Royal Marsden Hospital NHS and Foundation Trust, when presenting the findings.

Similar to prior results presented at the 2021 AACR Annual Meeting,² the objective response rate (ORR) was 36.4% of patients (24/66), consisting of complete response (CR) in 4.5% and partial response (PR) in 31.8% of patients. Twenty-nine patients (43.9%) had stable disease for a disease control rate of 80.3%.

Eighty-one percent of patients (50/62) had a reduction in tumor burden, and 11 patients (17.7%) had a deepening of response from an earlier data cutoff point. One PR even converted to a CR 2 years after treatment.

Among responders, 79% had received prior ipilimumab (Yervoy) and 46% had received a combination of anti–PD-1 and anti–CTLA-4 therapy. One patient that Larkin called attention to had progressed on 4 prior treatment regimens but with lifileucel he achieved a PR at day 42 that became a CR by day 84, which was still ongoing as of data cutoff.

By univariate analysis, ORR was not predicted by any patient or disease characteristics analyzed. In an analysis of DOR, however, the cumulative duration of treatment with prior anti–PD-1/PD-L1 therapy was associated with DOR. Those who had a lower treatment duration on prior immunotherapy (less than 5.06 months), had a better duration of response to lifileucel (HR, 0.218; 95% CI, 0.056-0.854), which, Larkin said, was suggestive of statistical significance.

Upon multivariable analysis, baseline lactate dehydrogenase (LDH) levels and cumulative duration on prior anti–PD-1/PD-L1 therapy were both identified as being independent predictors of DOR to lifileucel. For baseline LDH below or at the upper limit of normal (ULN) compared to LDH above the ULN, the hazard ratio was 0.201 (95% CI, 0.040-0.996; P = .049). With prior anti–PD-1/PD-L1 treatment, for each 3-month decrease in exposure, the hazard ratio was 0.715 (95% CI, 0.518-0.987) and 0.511 (95% CI, 0.268-0.974) with every 6-month decrease (P = .041). “This means that for each 6-month decrease in exposure to prior anti–PD-1/PD-L1 therapy, the median duration of response to lifileucel will be nearly doubled,” Larkin explained.

The mean number of tumor-infiltrating lymphocyte (TIL) cells infused was 27.3 x 109. Sufficient TILs were manufactured regardless of the tumor resection site, Larkin noted.

No correlation was found with tumor shrinkage based on total cell dose or CD4/CD8 TIL ratio, tumor reductions were seen across all ranges.

Treatment-emergent adverse events (TEAEs) were reported in all patients treated with lifileucel; grade 3/4 events were observed in 97.0%, but only 2 events were grade 5. The most common grade 3/4 TEAEs were thrombocytopenia (81.8%), anemia (56.1%), febrile neutropenia (54.5%), and neutropenia (39.4%).

“The adverse event profile was consistent with the underlying advanced disease and the safety profile of the conditioning and IL-2 regimens,” Larkin said. “The decreasing frequency of AEs over time is reflective of the potential benefit of a one-time treatment with lifileucel and no new safety risks were identified for lifileucel during long-term follow-up.”

C-144-01 is a multicenter, open-label, multi-cohort phase 2 study exploring the safety and efficacy of TIL therapy lifileucel in adult patients with advanced melanoma. The study enrolled patients with unresectable or metastatic melanoma who had been treated with at least 1 prior systemic therapy, including an anti–PD-1 therapy and if BRAF V600–mutant, BRAF/MEK inhibitors. Patients were required to have radiographic confirmation of progression, at least 1 resectable tumor lesion for TIL generation and at least one target lesion for response assessment, and an ECOG performance status of 0 to 1.

Patients were enrolled into 4 cohorts. Cohort 1 looked at patients treated with non-cryopreserved TIL product, generation 1; cohort 2 looked at patients treated with cryopreserved second-generation TIL product, and the pivotal cohort 4 looked at patients treated with cryopreserved second-generation TIL product. Cohort 3, which is looking at re-treatment with TIL therapy in 10 patients, is still enrolling. Larkin’s ASCO presentation focused on the patients in the second cohort.

These patients were predominantly male (59%) and had an ECOG score of 0 (56%). The median age was 55 years (range, 20-79). About a quarter of patients (26%) had BRAF V600E or V600K mutations and 68% were wild-type; positive PD-L1 expression (tumor proportion score ≥5%) was observed in 35%. LDH levels were above the ULN in 59% of patients. The mean number of lesions was 6, representing a high tumor burden. Liver and/or brain metastases were also reported in 42% of patients at baseline.

The mean number of prior therapies was 3.3 (range, 1-9). Ninety-nine percent of patients had progression on anti–PD-1/PD-L1 therapy and 77% had progressive disease on anti–CTLA-4.

In the trial, tissue was procured and shipped to a central facility for TIL generation with a processing time of 22 days. Patients were then given non-myeloablative lymphodepleting chemotherapy of cyclophosphamide followed by fludarabine. Lifileucel was then infused as a one-time treatment, followed by interleukin-2 administration of up to 6 doses before the patient could be discharged.

_References

1. _{Larkin J, Sarnaik A, Chesney JA, et al. Lifileucel (LN-144), a cryopreserved autologous tumor infiltrating lymphocyte (TIL) therapy in patients with advanced melanoma: Evaluation of impact of prior anti-PD-1 therapy. J Clin Oncol. 2021;39(suppl 15):9505. doi:10.1200/JCO.2021.39.15_suppl.9505}
2. _{Chesney JA, Larkin JMG, Kirkwood JM, et al. Lifileucel (LN-144), a cryopreserved autologous tumor infiltrating lymphocyte (TIL) therapy in patients with advanced (unresectable or metastatic) melanoma: durable duration of response at 28 month follow up. Presented at: 2021 American Association for Cancer Research Annual Meeting; April 10-15, 2021; Virtual. Abstract CT008.}
3. _{Sarnaik A, Khushalani NI, Chesney JA, et al. Long-term follow up of lifileucel (LN-144) cryopreserved autologous tumor infiltrating lymphocyte therapy in patients with advanced melanoma progressed on multiple prior therapies. J Clin Oncol. 2020;38(suppl 15):10006. doi:10.1200/JCO.2020.38.15_suppl.10006}