Prior Treatment Confers Reduced Responses With Adoptive Transfer of TIL Therapy in Metastatic Melanoma

Prior treatment with PD-1 or MAPK inhibitors resulted in lower objective response rates (ORRs) with adoptive cell transfer (ACT) of autologous tumor-infiltrating lymphocytes (TILs) in patients with metastatic melanoma vs patients who were naïve to these agents, according to findings from a retrospective analysis that were published in Clinical Cancer Research.¹

Adoptive transfer of TILs elicited an ORR of 56% in patients with metastatic melanoma who were naïve to PD-1 inhibitors compared with 24% in patients refractory to PD-1 inhibitors (P = .0006). The median melanoma-specific survival was 28.5 months vs 11.6 months, respectively (P = .0010).

In patients with BRAF V600E–/K–mutated melanoma, the ORR was 60% in patients naïve to targeted therapy vs 21% in refractory patients (P = .0057). The median melanoma-specific survival was 50.7 months vs 9.3 months, respectively (P ≤ .0001).

Additionally, at a median estimated follow-up of 89 months, 46 of 48 PD-1 inhibitor–naïve patients who derived a complete response (CR) had an ongoing response after a single treatment. Their 10-year melanoma-specific survival rate was 96%.

“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 up front,” said senior study author Stephanie L. Goff, MD, an associate research physician in the Surgery Branch of the National Cancer Institute’s (NCI’s) Center for Cancer Research, in a press release.² “We should think about utilizing TILs earlier in the disease course.”

The incorporation of immunotherapy and targeted therapy into the melanoma armamentarium has significantly shifted the clinical paradigm of metastatic melanoma treatment from palliative resection and chemotherapy to more individualized approaches. However, ACT-TILs have continued to demonstrated responses among this patient population.

“The advancements demonstrated by these clinical trials have begun to decrease the number of annual deaths from melanoma but also highlight the need for ongoing development of treatment options for patients with advanced and metastatic disease,” wrote lead study author Samantha J. Seitter, DO, MS, an immunotherapy/surgical oncology research fellow at the NCI, and coauthors in the study publication.1

The retrospective analysis included 226 patients with metastatic melanoma treated over nearly 2 decades on single-arm, early-phase, or randomized later-phase clinical trials. All patients had an ECOG performance status of 0 or 1, a life expectancy of at least 3 months, and no evidence of active major medical, cardiovascular, or immunodeficient diseases. Patients with small volume brain metastases of 3 of fewer deposits that were less than 1 cm in diameter were included.

Overall, patients were a median age of 47 years, and the majority were male (n = 148; 66%). Most patients had stage M1C disease (n = 107; 47%). Approximately half of patients (n = 65; 52%) were BRAF V600E negative.

Regarding prior treatment, 83% of patients (n = 188) underwent at least 1 systemic therapy prior to ACT-TIL; 34% (n = 77) received at least 1 checkpoint inhibitor prior to enrollment.

Patients had TILs sourced from subcutaneous deposits (n = 86; 38%), lymph nodes (n = 80; 36%), and viscera (n = 58; 26%).

All patients received a lymphodepleting chemotherapy regimen prior to ACT-TIL infusion on day 0. The regimen consisted of 60 mg/kg of daily cyclophosphamide on days -7 and -6 and 25 mg/m2 of daily fludarabine for 5 consecutive days starting on day -7 or -5. Cell infusions consisted of a maximum 2e11 lymphocytes on day 0, followed by aldesleukin given intravenously given at 720,000 IU/kg every 8 hours to tolerance and. Total body irradiation was given in some patients to augment lymphodepletion.

Further results revealed that the ORR in the overall patient population was 51% and 22% of patients achieved CRs. Patients treated in the context of a randomized trial (n = 133), including those who underwent surgical resection for TIL generation but were unable to proceed with treatment (n = 25), had an ORR of 41% and a CR rate of 18%.

The median overall survival (OS) in the overall cohort was 20.6 months. The estimated 3-, 5-, and 10-year survival rates were 41%, 35%, and 32%, respectively. The median melanoma-specific survival was 22.2 months (95% CI, 16.2-32.0) and the median progression-free survival was 5.5 months (95% CI, 4.1-7.1).

No significant differences were observed in the likelihood of response based on patient characteristics such as sex, age, baseline neutrophil-to-lymphocyte ratio, or platelet count. The presence or absence of BRAF V600E/K mutations also did not demonstrate a difference in response to ACT-TIL.

Patients with increasing disease stage were less likely to respond to ACT-TILs (P = .0058); this difference was likely driven by the low response rate observed in patients with brain metastases (n = 12). Patients with high baseline lactate dehydrogenase (LDH) had a higher rate of nonresponse to ACT-TIL compared with patients with lower baseline LDH (P = .040), but response rates did not differ based on degree of LDH elevation (P = .10). Finally, nonresponders to ACT-TILs had larger tumors compared with responders (P = .008).

Patients who received prior CTLA-4 inhibition, but not PD-1 inhibition (n = 43), did not demonstrate a difference in response rate compared with those naïve to any immunotherapy (P = .60).

“If we harvest the lymphocytes before they’ve seen any medications, we could potentially develop it into an effective later-line therapy with better response rates,” Goff concluded.2

References

1. Seitter SJ, Sherry RM, Yang JC, et al. Impact of prior treatment on the efficacy of adoptive transfer of tumor-infiltrating lymphocytes in patients with metastatic melanoma. Clin Cancer Res. Published online August 19, 2021. Accessed August 19, 2021. doi:10.1158/1078-0432.CCR-21-1171
2. Adoptive transfer of tumor-infiltrating lymphocytes may be less effective in patients with pretreated metastatic melanoma. News release. AACR. August 19, 2021. Accessed August 19, 2021. https://bit.ly/3mhpCtS