Future Promise for Advanced Melanoma Seen With Lifileucel TIL Therapy

Advanced melanoma has been a diagnosis that clinicians have struggled to find the right treatments. Many patients often find themselves using a multitude of treatments to try and find one that works. In fact, many patients will fail the traditional lines of therapy.

“As many advances as we’ve made for the treatment of advanced melanoma over the last 5 to 10 years, unfortunately, all the data still points out the fact that about half the patients will fail [on] standard therapies. As optimistic as we are, and as amazing as the advances have been, we still need to find better answers for almost half the people with advanced melanoma,” Eric D. Whitman, MD, a cutaneous surgical oncologist and Medical Director of the oncology service line for Atlantic Health System, said during an interview with CancerNetwork®.

One such treatment that is showing potential in this space is lifileucel (LN-144), an autologous tumor-infiltrating lymphocyte (TIL) therapy. Recently published data from a phase 2 trial (NCT02360579) examined the agent specifically for patients who had previously been treated with checkpoint inhibitors and BRAF plus or minus MEK agents with lifileucel producing durable responses.

In the interview, Whitman discusses potential treatments for metastatic melanoma, details of the clinical trial, and ongoing research.

Systemic Therapy Resistance

Systemic therapy resistance is experienced by a majority of patients with melanoma. Approximately 40% to 65% of patients with advanced melanoma have a primary resistance to immune checkpoint inhibitors, and 30% to 40% develop and acquired resistance.¹

Whitman said standard investigative approaches for finding better therapy regimens usually involves using an experimental drug in addition to a standard drug to see if patients with resistance will respond. Since the “buildup” of resistance is something happens to many patients, physicians will approach their patients with, “here’s this drug that works for most people, but for whatever reason, it’s not working for you. Let’s add on our experimental drug to the standard drug, and let’s see if we can make a difference for you. Let’s see if we can change your nonresponse to a response, [or] let’s see if we can salvage your care and have a much better outcome.”

For those with advanced melanoma, there have been no approved treatment options for those with BRAF wild–type disease who progressed after 1 line of immune checkpoint inhibitor therapy or with BRAF V600–positive disease and progression following 2 lines of therapy.

History of TILs for Melanoma

TILs have been examined in the setting of advanced melanoma following failed lines of therapy for decades. According to Whitman, TILs were originally developed at the National Cancer Institute through the 1980s and 1990s and were used in combination with interleukin-2 (IL-2), an immunotherapy that served as an immune stimulator in combination was eventually approved alone to treat metastatic melanoma.

The science behind TILs is similar to other autologous cellular therapies where clinicians harvest tumor cells from a patient, remove the lymphocytes, grow them in a laboratory, and then reinfuse them into the immune system. However, Whitman said the modality never found its footing and, “never quite got to the point where it was consistently beneficial. It also required expensive infrastructure that most hospitals and universities and care sites could not afford, but the federal government could.”

However, since this protocol was created, investigators have found a way to make TILs more accessible where any hospital can harvest the tumor for processing, send it out to a lab for the TILs to grow, and return it to the patient.

Lifileucel follows this specific protocol, and patients treated on clinical trials are beginning to see responses from it. The creators of the therapy have submitted a biologics license application to the FDA for approval, but additional data have been requested on the treatment’s potency assays.²

“The fascinating thing for lifileucel is that these are patients [whose disease has failed on] everything, all the standard therapies, and now they are getting TILs with IL-2 and preparatory chemotherapy and they’re responding. We’re cutting into that 50% failure rate with lifileucel plus high-dose interleukin-2,” said Whitman.

Current Research

A recent study of lifileucel involved 66 patients who previously received both immune checkpoint inhibitors and BRAF-targeted therapy in prior lines who were given TIL infusions between 1 × 109 but less than 150 × 109 cells.³ The median number lines of prior therapy was 3.3. A total of 64% of patients had progressive disease as their best response to anti–PD-1 or PD-L1 therapy. There were 40 patients (61%) who had target lesion sum of diameters of more than 70 mm 51 (71%) had more than 3 target lesions at baseline. Twenty-seven (41%) had baseline lactate dehydrogenase levels higher than the institutional upper limit of normal.

The median number of cyclophosphamide and fludarabine doses were 2 (range, 1-2) and 5 (range, 2-5), respectively, with a mean number of TIL cells infused at 27.3 × 109 (range, 1.2 × 109-99.5 × 109). The median number of IL-2 doses administered was 5.5.

At the median follow-up of 18.7 months, the investigator-assessed overall response rate (ORR) was 36% (95% CI, 25%-49%) and the disease control rate (DCR) was 80% (95% CI, 69%-89%) with 2 patients (3%) having a complete response (CR), 22 (33%) having a partial response (PR), and 29 (44%) showing stable disease (SD). Additionally, 81% of patients had a reduction in tumor burden.

The median time from lifileucel infusion to best response was 1.4 months (range, 1.3-8.7). Nineteen out of 24 patients reached response by the time of first planned assessment, and only 25% of patients progressed after response.

The median duration of response (DOR) has not been met (95% CI, 11.8 months-not reached [NR]), but the 1-year DOR rate was 69% (95% CI, 46%-84%). The median overall survival was 17.4 months (95% CI, 11.0 months-NR). Additionally, of those patients who achieved SD and PR or CR, overall survival of more than 1 year was achieved by 38% and 92%, respectively.

The efficacy analysis for the primary-refractory patient subset consisted of 42 patients who had initial resistance to anti–PD-1 or anti–PD-L1 therapy. The ORR was 41% (95% CI, 26%-57%), with 2 patients (5%) having CRs and 15 (36%) having PRs; the DCR rate was 81% (95% CI, 66%-91%). Of these patients, 41% (n = 17) had SD, 12% (n = 5) had progressive disease, and 3 were nonvaluable. The median DOR was not reached.

The most common grade 3 or 4 treatment-emergent adverse effects were thrombocytopenia (82%), anemia (56%), febrile neutropenia (55%), and neutropenia (39%). One patient each died because of intra-abdominal tumor hemorrhage that was possibly related to TILs and acute respiratory failure that was not related to TIL.

Over time, grade 3 or 4 adverse effects rapidly decreased, with no lifileucel-related serious adverse effect after 6 months. Patients did not experience immune-related adverse effect reoccurrence related to prior immune checkpoint inhibitors.

Moving Forward

Whitman again commented about the potential for this treatment to work in heavily pretreated patients, “In advanced melanoma, there are a number of drugs that have been approved over the past 5 to 10 years that have made a difference for people, having increased their outlook and their hope for survival. About half of them will still fail these great treatments… If nothing else works, we’re hoping that we’ll be able to give [patients] this next line of therapy, which, when approved, potentially could be lifileucel TIL therapy.”

Atlantic Health System is currently participating in a phase 2 trial (NCT02360579) of lifileucel for patients with metastatic melanoma who have progressed on at least 1 prior systemic therapy, with patients receiving adoptive cell therapy via infusion of lifileucel followed by IL-2 after a nonmyeloablative lymphodepletion preconditioning regimen. 

Since TILs inception, the treatment has come a long way in the treatment of certain patient populations with cancer. “This is something I saw years ago, when I was still in training, that we were hopeful would help patients. It’s really been a long evolution from only being available at the National Cancer Institute, and now hopefully at some point, being commercially available to patients at their home hospital,” Whitman concluded.

References

1. Sarnaik AA, Hamid O, Khushalani NI, et al. Lifileucel, a tumor-infiltrating lymphocyte therapy, in metastatic melanoma. J Clin Oncol. 2021;39(24):2656-2666. doi:10.1200/JCO.21.00612. Published correction appears in J Clin Oncol. 10;39(26):2972

2. Iovance Biotherapeutics provides regulatory update for lifileucel potency assays. News Release. Iovance Biotherapeutics. May 18, 2021. Accessed October 25, 2021. https://bit.ly/3jAH62x

3. Verdegaal E, van der Kooij MK, Visser M, et al. Low-dose interferon-alpha preconditioning and adoptive cell therapy in patients with metastatic melanoma refractory to standard (immune) therapies: a phase I/II study. J Immunother Cancer. 2020;8(1):e000166. doi:10.1136/jitc-2019-000166