Durability of lifileucel linked to duration of immune checkpoint inhibitor use in melanoma
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Each 6-month decrease in exposure to immune checkpoint inhibitors nearly doubled the duration of response to therapy with lifileucel among patients with metastatic melanoma, according to long-term results of a phase 2 study.
The results — presented during the virtual ASCO Annual Meeting — suggest that patients may derive greater, more durable benefit from the investigational cell therapy if it were provided at the time of initial disease progression when patients are receiving anti-PD-1/PD-L1 therapies, according to the investigators.
Lifileucel (LN-144, Iovance Biotherapeutics) is an adoptive cell therapy derived by isolating tumor-infiltrating lymphocytes (TILs) from a resected portion of a patient’s tumor and multiplying them in a laboratory.
Researchers conducted the multivariable cohort analysis in response to growing concern about the effects of overtreatment with immune checkpoint inhibitors prescribed by physicians when patients with metastatic melanoma run out of treatment options, according to Jason A. Chesney, MD, PhD, director of James Graham Brown Cancer Center and associate vice president for health affairs at University of Louisville.
“Our group thought it would make sense to understand the impact of prior immune checkpoint inhibitor therapy on the durability of responses,” Chesney told Healio. “We wanted to see if prolonged exposure to immune checkpoint inhibitors had any impact on the durability of response and clinical benefits of TILs.”
Chesney and colleagues presented updated results from cohort 2 of an open-label, phase 2 study to determine the efficacy and safety of lifileucel among patients with unresectable metastatic melanoma. All participants experienced disease progression after receiving anti-PD-1 therapy, as well as BRAF/MEK inhibitors if they had BRAF V600-mutant disease.
The cohort included 66 patients (median age, 55 years; range, 20-79; 59% men) who received a mean 3.3 (range, 1-9) previous lines of therapy. In addition to anti-PD-1/anti-PD-L1 therapy, 80% previously received anti-CTLA-4 therapy.
The study regimen started with 1 week of nonmyeloablative lymphodepletion with 60 mg/kg IV cyclophosphamide and 25 mg/m2 fludarabine, followed by a single infusion of lifileucel. Patients then received up to six doses of interleukin (IL)-2 (600,000 IU/kg/dose) to promote TIL activity.
Efficacy as determined by the investigator-assessed objective response rate (ORR) served as the primary endpoint for the cohort 2 analysis. Secondary endpoints included safety and additional efficacy measurements.
Patients received a mean dose of 27.3 × 109 TIL cells, in addition to a median five doses of IL-2.
Median follow-up was 33.1 months, with a data cutoff date of April 22, 2021.
Results showed an ORR of 36.4%, with a complete response rate of 4.5%.
Forty-four percent of patients had stable disease after the regimen, for a disease control rate of 80.3%.
Median duration of response had not been reached (range, 2.2-38.5+ months).
Nearly all patients (97%) experienced at least one grade 3 or grade 4 treatment-related adverse event during the study, with the most common being cytopenias. Two treatment-related deaths occurred during the study.
A univariate analysis showed no predictors of ORR for lifileucel according to patient or clinical characteristics. However, a multivariate analysis of responders using a Cox proportional hazards regression model showed an HR of 0.71 (95% CI, 0.51-0.98) for each 3-month decrease in exposure to previous anti-PD-1/PD-L1 therapy, and an HR of 0.51 (95% CI, 0.26-0.97) for each 6-month decrease.
“There was a very nice correlation — for each 6-month decrease in exposure to prior anti-PD-1/PD-L1, the median duration of response to lifileucel nearly doubled,” Chesney told Healio. “In other words, the less you are exposed to [immune checkpoint inhibitors], the more durable the response is to TIL therapy, such as lifileucel.”
The multivariable analysis also showed an association between increased baseline lactate dehydrogenase (LDH) levels and shorter duration of response to lifileucel (HR = 0.2; 95% CI, 0.04-0.99).
This observation — typically indicative of a more aggressive disease type that is resistant to treatment — has been observed in previous studies, according to James M.G. Larkin, MD, PhD, FRCP, professor and consultant medical oncologist at Royal Marsden NHS Foundation Trust.
Larkin — a U.K.-based researcher also involved with the study — said the headline from these updated results is that duration of response to lifileucel seems to be linked to prior duration of anti-PD-1/PD-L1 therapy, meaning that less previous exposure increases the duration of response.
“It's an interesting observation,” he told Healio. “I don't think we can explain it at the moment, and nothing can be confirmed without further follow-up.”
Chesney agreed and said the next step for their group is to examine the impact of prior anti-PD-1/PD-L1 therapy on the TIL phenotype to see if it can cause changes in the T cells themselves.
“These results are important for any oncologist who takes care of patients with melanoma,” Chesney added. “If you have a patient who progresses — even modestly — after immune checkpoint inhibitor therapy, that patient should be referred to one of the active, open clinical trials for TILs or lifileucel.”
Larkin said the results seen with immune checkpoint inhibitors among patients with melanoma have been “incredible,” yet a large proportion of patients still experience disease progression while receiving this treatment.
“In my view, this is the biggest unmet medical need that we have in the disease today,” he said. “To have an active therapy like lifileucel in that setting is undoubtedly big news.”
Perspective
Back to TopJason J. Luke, MD, FACP
With lymphodepletion and IL-2 as part of the treatment regimen, a substantial population of patients who are either elderly or have brain metastases with edema, poor performance status or concurrent cardiopulmonary disease will be excluded from treatment with lifileucel. Nevertheless, the duration of response reported by these investigators is quite impressive, given that the median has not been reached over a long follow-up period.
Additionally, it appears that this therapy is predominantly active in patients who initially progressed when receiving anti-PD-1 therapy and in many patients who had tumors with low PD-L1 expression.
Determining the mechanism of action and how we select patients is still an open area of investigation. Larkin and colleagues observed that baseline LDH was possibly related to duration of response, whereas cumulative time on anti-PD-1 therapy clearly had an impact on duration of response. These will be important points as we think about how to use this therapy in the future.
This is clearly an active regimen in the post-PD-1/CTLA-4 setting. It differentiates mechanistically from other systemic therapies. The response rate for lifileucel appears to be approximately similar to previous reports of pembrolizumab (Keytruda, Merck) and low-dose ipilimumab (Yervoy, Bristol Myers Squibb) in the post-PD-1 setting.
An optimal approach might be front-line anti-PD-1 plus, perhaps, LAG-3. If patients progress on this, they should undergo TIL harvest. Patients could then be treated with anti-PD-1 and low-dose CTLA-4 and have TILs available so that they could be reinfused if they progress on that regimen.
UPMC Hillman Cancer Center
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Larkin JMG, et al. Abstract 9505. Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.
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