Prior therapy may reduce efficacy of tumor-infiltrating lymphocytes for advanced melanoma
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Prior treatment with newer-generation therapies appeared associated with significantly lower objective response rates among patients who received tumor-infiltrating lymphocytes for metastatic melanoma, according to study findings.
Early clinical trials of adoptive tumor-infiltrating lymphocytes (TILs) for metastatic melanoma showed consistent objective response rates of approximately 50%, Stephanie L. Goff, MD, FACS, associate research physician with the surgery branch at NCI, told Healio.
Goff and colleagues noticed a shift toward lower response rates in trials that began treating patients around 2010 or later. This trend coincided with the approval and increased use of new immunotherapies and molecularly targeted treatments.
“We wanted to go back and look at why our initial approximate 50% overall response rate was not holding true in the era of newer treatments,” Goff said. “We didn't want to just assume it was because of the availability of these new drugs and find a holistic way to demonstrate their effects on TIL therapy.”
Background and methodology
Researchers from NCI retrospectively analyzed 224 patients (median age, 47 years; 66% male) with metastatic melanoma to determine whether previous systemic therapies affected responses to adoptive TIL therapy.
All patients underwent surgical resection of their tumors to generate TILs for subsequent treatment at NCI between 2000 and 2018. The treatment regimen included preconditioning lymphodepletion chemotherapy followed by TIL infusion and IV interleukin-2 to promote TIL activity.
Key findings
Goff and colleagues examined a subset of patients (n = 34) refractory to PD-1 inhibitors. These patients achieved a significantly lower objective response rate to TIL therapy than patients (n = 192) who had not previously received a PD-1 inhibitor (24% vs. 56%; P = .0006).
Patients who previously received a PD-1 inhibitor also achieved significantly shorter median melanoma-specific survival (11.6 months vs. 28.5 months; P = .001) and shorter median PFS (3.2 months vs. 6.5 months; P < .0001).
At median follow-up of 89 months, nearly all (96%) of the 48 patients who had not received a PD-1 inhibitor prior to TIL therapy achieved 10-year melanoma-specific survival.
The investigators also evaluated the effect of previous BRAF/MEK inhibitor use among 62 patients whose tumors expressed BRAF V600E/V600K. Results showed a significantly lower ORR (21% vs. 60%; P = .0057) and shorter median OS (9.3 months vs. 50.7 months; P .0001) among patients who received targeted molecular therapy than those who did not.
Researchers observed no association between duration of prior PD-1 or BRAF/MEK inhibitor therapy and response to TIL therapy.
Clinical implications
“Treatment with either one of the newer classes of medication — anti-PD-1 or BRAF/MEK inhibitors — diminishes the likelihood of developing a response to TIL therapy,” Goff said.
Prior treatment with other therapies has a deleterious effect on T-cell quality.
Most patients undergo surgery for melanoma prior to developing advanced disease.
Given the results of this study, using excised tumors to develop more potent TILs would be a logical step prior to treatment with newer therapies, Goff said.
“Patients who develop a complete response to TIL therapy will likely never need another treatment for their melanoma and go on to lead a cancer-free life,” Goff told Healio. “We often underestimate the toll that constant therapy takes on patients.”
For more information:
Stephanie L. Goff, MD, can be reached at stephanie.goff@nih.gov.
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