Patients with heavily pretreated metastatic melanoma treated with adoptive cell therapy based on tumor-infiltrating lymphocytes achieved a response rate of 36%, a disease control rate of 80%, and a median duration of response that had not been reached by 18 months in the global open-label phase II trial C-144-01 trial. These findings were reported during the ASCO20 Virtual Scientific Program by Amod Sarnaik, MD, of Moffitt Cancer Center, Tampa, Florida.¹

Amod Sarnaik, MD

“Notably, responses tended to deepen over time. These data demonstrate the potential efficacy and durability of response in a patient population with severely limited treatment options,” Dr. Sarnaik said. He also reminded listeners that after patients experience disease progression on a checkpoint inhibitor or BRAF/MEK inhibitor, responses to any further treatment are “dismal,” and median overall survival is less than 8 months.

Adoptive cell therapy with cryopreserved tumor-infiltrating lymphocytes is a novel approach that may improve outcomes in these patients, according to results with lifileucel. The product is manufactured centrally in about 3 weeks and then infused intravenously after preparative lymphodepleting chemotherapy.

Phase II Results

Dr. Sarnaik presented the results for Cohort 2 of C-144-01, which is evaluating lifileucel in four cohorts of 175 patients total with heavily pretreated advanced or metastatic melanoma. Cohort 2 included 66 patients (median age, 55 years) with at least one tumor ≥ 1.5 cm that could be resected for the purpose of generating tumor-infiltrating lymphocytes and at least one residual tumor that was not resected but served as a target lesion for response assessment. All patients underwent resection followed by infusion of lifileucel.

Patients had been treated with a median of 3.3 prior lines, which included a programmed cell death protein 1 (PD-1) antibody in all cases and ipilimumab in 80%. Of 17 patients with BRAF V600 mutations, 15 had received BRAF/MEK inhibitors.

The median lactate dehydrogenase level was 244 U/L. The mean sum of target lesion diameters was 106 mm. Three-quarters of patients had more than three target and nontarget lesions at baseline, with a mean of six. Almost half had liver and/or brain metastases.

“These characteristics indicate this cohort of patients had a relatively high disease burden, in addition to having disease that was refractory to the available standard-of-care treatments,” noted Dr. Sarnaik.

Treatment Details

After tumor resection, tissue was shipped to a central manufacturing facility. During a 22-day process, the cryo­preserved infusion product—lifileucel—was generated. Patients underwent nonmyeloablative lymphodepletion (cyclophosphamide, followed by fludarabine) and then received one infusion of expanded and activated lifileucel, followed by up to six doses of infusional bolus interleukin-2 (IL-2) to enhance the immune response. In Cohort 2, the mean number of tumor-infiltrating lymphocytes infused was 27.3 billion.

Adverse events were typical for a treatment regimen that includes lymphodepleting chemotherapy and IL-2. There were two deaths within 30 days of infusion: one due to intra-abdominal hemorrhage and one from acute respiratory failure.

Peak onset for toxicities was relatively soon after infusion, with few new adverse events emerging after 14 days post-infusion. “This relative lack of new toxicity after 14 days may reflect an inherent advantage of the one-time single treatment of lifileucel compared with other antimelanoma therapies that require multiple cycles,” he suggested.

Disease Control Rate of 80%

"These data indicate that responses from lifileucel therapy are achievable for subjects across a relatively broad range of clinical and pathologic features.”

— Amod Sarnaik, MD

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In the 66 patients, the objective response rate was 36.4% (3% complete responses). Another 43.9% achieved stable disease, for a disease control rate of 80.3%. More than 80% had some reduction in tumor burden, Dr. Sarnaik reported.

After a median follow-up of more than 18 months, the median duration of response had not been reached. “Excellent durability” overall has been seen, he noted, with 16 responses extending beyond 1 year. The investigators could identify no factors significantly associated with response or lack of response.

“Responses have generally deepened over time,” Dr. Sarnaik added. “One responder experienced disease progression after maintaining a response beyond 1 year, and one died of a noncompeting cause after achieving an unconfirmed complete response.”

“Overall, these data indicate that responses from lifileucel therapy are achievable for subjects across a relatively broad range of clinical and pathologic features,” he observed. “The majority of responders had progression of disease as their best response to prior anti–PD-1 treatment. This indicates that lifileucel therapy can result in responses for those who have metastatic melanoma that is primarily refractory to PD-1 antibody therapy.”

An additional cohort has recently completed enrollment in support of lifileucel’s registration. 

DISCLOSURE: The study was sponsored by Iovance Biotherapeutics. Dr. Sarnaik has served as a consultant or advisor to B4CC and Iovance Biotherapeutics and holds patents, royalties, or other intellectual property for compositions and methods for improving interleukins for adoptive cell therapy.

REFERENCE

1. 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. ASCO20 Virtual Scientific Program. Abstract 10006.