NEW YORK – In a long-term retrospective study published Thursday in Clinical Cancer Research, researchers from the National Cancer Institute found that metastatic melanoma patients treated with autologous tumor-infiltrating lymphocyte, or TIL, therapy experienced a greater survival benefit when they had not previously received anti-PD-1 immunotherapy or targeted molecular therapy.
The analysis is significant in that, to date, the approach to autologous TIL therapy — that is, harvesting TILs from patients' resected tumors, expanding them ex vivo, and reinfusing them as a one-time treatment — has been largely reserved for the later line, refractory setting. Because the analysis demonstrated that patients were less likely to achieve durable benefit from the cell therapy after prior immunotherapy or targeted treatment, the researchers suggested there may be a rationale for moving TIL therapy to a frontline setting in this population.
The study considered 226 patients who underwent autologous TIL therapy over the course of nearly two decades. The overall response rate among the full group was 51 percent, and the complete response rate was 22 percent. The median overall survival time was 20.6 months, and the estimated three-, five-, and 10-year survival rates were 41 percent, 35 percent, and 32 percent, respectively.
Most of the patients considered in the analysis — 83 percent — had received at least one previous line of systemic therapy, and one-third of them had experienced disease progression after treatment with a checkpoint inhibitor. Of the patients who had previously received anti-PD-1 therapy specifically, the objective response rate was 24 percent, which was significantly lower than the 56 percent response rate observed among those who had not received anti-PD-1 therapy. Melanoma-specific survival times were also decreased among the anti-PD-1 immunotherapy-treated patients with a median survival time of 11.6 months compared with 28.5 months among those who had not received these previous treatments. The median progression-free survival time among these groups was 3.2 months versus 6.5 months, respectively.
The researchers considered the impact of prior targeted treatment on TIL therapy benefit, too. Among 62 patients whose cancers harbored known BRAF v600E/K mutations, 19 had received targeted treatment with MAPK inhibitors. These patients also experienced decreased survival benefit, with median melanoma-specific survival times of 9.3 months versus 50.7 months among those who had not received the prior targeted therapies. The progression-free survival times were 2.5 months versus 6.6 months, respectively. Importantly, the fact that these patients' tumors harbored BRAF v600E/K mutations in the first place did not intrinsically impact outcomes on TIL therapy; survival times were comparable between patients with and without these molecular alterations.
The researchers considered a host of other factors in their retrospective analysis that may have played a role in these outcome differences. Certain factors related to the TIL product itself, such as the absolute number of CD8-positive TILs that patients received and the site of the tumors resected for TIL harvesting, played into the outcomes, but baseline factors like age, sex, and mutation status did not.
Importantly, the researchers, including lead investigator Stephanie Goff of the NCI surgery branch, emphasized that, while the degree of benefit differed, a good number of patients who had previously received these treatments did still benefit from TIL therapy, meaning that the later-line approach shouldn't be abandoned. According to Goff and colleagues, "The low response rates after prior treatment with anti-PD-1 therapy or BRAF/MEK inhibition suggest that first-line [TIL] should be considered."
The findings could play into drugmakers' development plans for TIL products in their pipelines. Unlike autologous CAR T-cell therapy, which has received US Food and Drug Administration approval across multiple indications, autologous TIL therapy has yet to enter the commercial landscape. The prospect of an approval may not be far off, though; the company Iovance has a biologics license application pending with the FDA for lifileucel, a similar treatment as the one evaluated in the NCI study, for metastatic melanoma patients.
The firm's lifileucel application has hit a few roadblocks due to questions surrounding the firm's potency assays, but given the encouraging response rates seen in these industry-sponsored studies, the field has been anticipating a regulatory approval on the horizon. Iovance, though, is specifically seeking approval for later-line treatment. Because there are already established treatment options for these patients in the earlier setting, including anti-PD-1 immunotherapy and, contingent on biomarker status, targeted therapy, seeking earlier-line approval would likely be more difficult from the onset.
Usually, a later-line approval precedes a frontline approach, and if a frontline approach follows, it goes hand in hand with randomized studies demonstrating direct survival benefit versus the other therapies already validated in the frontline setting.
"The window to establish [TIL] as front-line therapy for metastatic melanoma faces many logistical obstacles," wrote Goff and colleagues.
Yet, the NCI's findings from this new retrospective analysis could urge the field to consider frontline TIL as a potential therapeutic strategy, especially in patients unlikely to respond well to anti-PD-1 or targeted therapy, and to plan accordingly for such studies. "As the field moves forward with biomarkers that more accurately predict response to checkpoint inhibition, those patients unlikely to derive benefit from first-line therapy may view adoptive transfer as a more viable option," Goff and colleagues wrote. "When creating treatment plans for patients with metastatic melanoma, the response rates and durability provide a basis for [TIL therapy] to be considered earlier in the disease course for eligible patients with access to the strategy."
Additionally, the findings beg the question as to whether harvesting the TILs from patients' tumors prior to anti-PD-1 or targeted therapy — then preserving them for future treatment in the event of disease progression — could overcome the decreased survival benefit they observed.
"Consideration should be given to studying the effectiveness of [TIL therapy] obtained from tumors prior to systemic therapy for delivery after progression on approved treatments," the researchers wrote. "This strategy might answer whether the reduced effectiveness of TIL after exposure to other therapies is a consequence of simple patient selection, tumor immunoediting, or active compromise of the TIL repertoire."