Patients with metastatic melanoma who were previously treated with PD-1 or MAPK inhibition are significantly less likely to develop durable objective responses to adoptive cell transfer of tumor-infiltrating lymphocytes (ACT-TIL) than patients naive to these treatments, according to a study published by Seitter et al in Clinical Cancer Research. While ACT-TIL is a strategy now being studied for patients with treatment-refractory metastatic melanoma, the data suggest that ACT-TIL could be considered as a first-line therapy for select patients, noted the study authors.

Although melanoma accounts for about 1% of all skin cancers diagnosed in the United States, it causes most of the deaths from skin cancer. According to the Centers for Disease Control and Prevention, melanoma incidence has doubled over the past 3 decades, and is one of the most common cancers diagnosed in young adults. This year, it is estimated that about 106,110 people with be diagnosed with the disease, and approximately 7,200 will die from melanoma.

Advances in the treatment of metastatic melanoma—especially the development and U.S. Food and Drug Administration approval of immune checkpoint inhibitors including ipilimumab, nivolumab, and pembrolizumab, as well as targeted therapies like BRAF inhibitors and mediators of the MAPK pathway—have altered the management of metastatic melanoma. Despite these improvements in treatment options, many patients will develop resistance to these therapies.

Study Methodology

The researchers studied the outcome of 226 patients from four completed ACT-TIL clinical trials spanning almost 2 decades, with an emphasis on the effect of prior systemic therapy on patients and treatment characteristics associated with response. Eighty-three percent of the patients had disease that had relapsed on a prior therapy. The researchers examined differences in response based on characteristics such as age, sex, tumor size and location, and prior therapies.

Results

The study found that adoptive transfer of TILs mediated an objective response rate of 56% (108 of 192) and median melanoma-specific survival of 28.5 months in patients naive to anti–PD-1 therapy compared with 24% (8 of 34) and 11.6 months in patients refractory to anti–PD-1 therapy. Among patients with BRAF V600E/K–mutated disease, prior treatment with targeted molecular therapy was also associated with a decreased response rate (21% vs 60%) and decreased survival (9.3 vs 50.7 months) when compared with those patients naive to targeted therapy. With a median potential follow-up of 89 months, 46 of 48 complete responders in the anti–PD-1–naive cohort have ongoing responses after a single treatment, and a 10-year melanoma-specific survival of 96%.

“Patients previously treated with PD-1 or MAPK inhibitors are significantly less likely to develop durable objective responses to ACT-TIL. While ACT-TIL is currently being investigated for treatment-refractory patients, it should also be considered as an initial treatment option for eligible patients with metastatic melanoma,” concluded the study authors.

Translational Relevance

Stephanie L. Goff, MD

While ACT-TIL is a strategy now pursued solely for patients with treatment-refractory metastatic melanoma, according to the researchers, the data suggest that ACT-TIL could be considered as a first-line strategy for select patients.

“The data in this manuscript demonstrate that if you wait to use ACT-TIL as a later-line therapy, you may not get the same durable responses as when you use it upfront,” said principal study investigator Stephanie L. Goff, MD, Associate Research Physician in the Surgery Branch of the National Cancer Institute, in a statement. “We should think about utilizing TILs earlier in the disease course.”

Disclosure: Funding for this study was provided by the National Cancer Institute and a cooperative research and development agreement with Iovance Biotherapeutics. For full disclosures of the study authors, visit clincancerres.aacrjournals.org.