Melanoma Resistant to Anti-PD-1 Responds to Tumor Infiltrating Lymphocytes

Almost a third of post-immunotherapy melanomas responded to cellular therapy with tumor-infiltrating lymphocytes (TILs), data from a multicohort study showed.

Overall, 31.4% of 153 patients responded to lifileucel TILs (LN-144), including nine complete responses. Almost half of the patients had stable disease as best response, and 79% of evaluable patients had some degree of tumor shrinkage.

Most patients had at least one grade ≥3 treatment-emergent adverse event, but the safety profile was consistent with known effects of nonmyeloablative lymphodepletion (NMA-LD) and interleukin-2 (IL-2), which patients received along with the TILs, reported Amod Sarnaik, MD, of Moffitt Cancer Center in Tampa, Florida, during the Society for Immunotherapy of Cancer meeting in Boston.

“Patients achieving a response at 6 weeks had a statistically superior overall survival [OS] compared to those not achieving a response at 6 weeks, demonstrating that early responses do have prognostic value,” he said. “Lifileucel exhibited a manageable safety profile with durable efficacy. Median duration of response was not reached at a median follow-up of 36.5 months, and responses were observed across all subgroups, including immune checkpoint inhibitor-primary refractory disease.”

Despite unprecedented progress in treatment of advanced melanoma, patients still have limited options following lack of response or progression during or after an immune checkpoint inhibitor (ICI). Autologous TILs recognize and target multiple patient-specific neoantigens to media tumor cell death. Three decades of data from patients not exposed to ICIs have provided evidence of TIL efficacy, said Sarnaik.

More recently, a phase III European study showed a higher response rate with non-cryopreserved TIL cellular therapy versus ipilimumab (Yervoy) in previously treated melanoma, including patients exposed to anti-PD-1/L1 therapy.

Lifileucel is an investigational adoptive cell therapy consisting of cryopreserved autologous TILs. In a phase II multicohort trial, lifileucel led to a response rate of 36.4% in patients with previously treated advanced melanoma. Sarnaik presented data from two cohorts in the same trial, involving a total of 153 patients — the largest study to date of cell therapy for advanced melanoma in the post-ICI setting.

Eligible patients had at least one resectable lesion for TIL production and one target tumor lesion for response assessment. Tumor samples were processed at a central facility, involving a 22-day production process. All patients received NMA-LD, a single infusion of lifileucel, and as many as six doses of IL-2.

About half the patients had cutaneous melanoma, a fourth had BRAF-mutant disease, and half had a PD-L1 tumor proportional score ≥1%. About 70% of patients had three or more metastatic sites. The patients had received a median of three prior regimens, and 71% of the patients had primary resistance to anti-PD-1/L1 therapy. The median time from resection to lifileucel infusion was 33 days.

Grade 3/4 hematologic abnormalities were near universal, including leukopenia, lymphopenia, and neutropenia in 100% of patients; thrombocytopenia in 94%; and anemia in 71%. Grade 3/4 nonhematologic toxicity included febrile neutropenia in 41.7% of patients, hypophosphatemia in 26.3%, and pyrexia and hypotension in 10.9%.

The objective response rate by independent review was 34.8% (23 of 66) in one cohort and 28.7% (25 of 87) in the second cohort, resulting in an overall response rate of 31.4%. Additionally, 24 and 47 patients in the two cohorts had stable disease (46.4%). Comparison of independent and investigator-assessed responses showed 91% concordance, said Sarnaik.

The median time from TIL infusion to best response was 1.5 months. Responses deepened over time, as seven partial responses eventually became complete responses, and four conversions from partial to complete response occurred more than a year after lifileucel infusion, including two conversions after 2 years, said Sarnaik. Additionally, 10 patients improved from stable disease to partial response.

The two cohorts combined had a median OS of 13.9 months. An analysis of OS by response category showed that patients who responded within the first 6 weeks after lifileucel infusion had yet to reach median OS as compared with a median OS of 10.3 months for patients who did not meet response criteria within 6 weeks (P<0.0001).

During a discussion that followed the presentation, Sarnaik said the magnitude of benefit did not differ between patients who had intrinsic versus acquired resistance to anti-PD-1/L1 therapy.

“I think this highlights that the mechanism of TIL therapy is completely independent of immune checkpoint inhibitors,” he added.