Cell therapy doubles survival, response rates in advanced melanoma
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A single infusion of tumor-infiltrating lymphocytes more than doubled PFS, OS and complete response rates compared with ipilimumab among patients with advanced, unresectable melanoma, study results presented at ESMO Congress showed.
This likely is the first randomized phase 3 study to show significant clinical benefit of a T-cell immunotherapy over standard-of-care therapy for a solid tumor, according to investigators.
Background
Prior studies showed tumor-infiltrating lymphocytes (TILs) manufactured using the protocol his group employed to be an effective and active anticancer agent for almost 2 decades, according to John Haanen, MD, PhD, professor of translational cancer immunotherapy at Leiden University Medical Center and leader of the cancer immunotherapy research group at Netherlands Cancer Institute.
Positive results for TILs in melanoma have been reproduced using the original NCI/NIH protocol by other academic centers through smaller phase 1 and phase 2 trials and, more recently, by commercial sponsors in a phase 2 trial.
“Our group decided about a decade ago to conduct a randomized phase 3 trial to determine whether TILs could become a standard-of-care treatment option,” Haanen told Healio.
The treatment landscape for melanoma has changed in the subsequent decade, given the approval and use of anti-PD-1 agents, which is why their study permitted their use prior to enrollment, Haanen said.
“TILs are a very viable option among patients with melanoma who have disease progression despite the use of a previous anti-PD-1 treatment,” Haanen said.
Methodology
The multicenter, open-label trial included 168 patients with unresectable stage IIIC to stage IV melanoma.
Researchers randomly assigned 84 study participants (median age, 59 years; 56% male) to a single infusion of TILs. The other 84 participants (median age, 58 years; 63.1% male) received up to four doses of ipilimumab (Yervoy, Bristol Myers Squibb) dosed at 3 mg/kg every 3 weeks.
The study included patients whose disease progressed after prior therapy but excluded patients who previously received ipilimumab.
More than 80% of patients in each treatment group experienced disease progression despite after either first-line or adjuvant anti-PD-1 therapy.
Patients who received TILs had tumor lesions surgically removed to produce TILs in laboratories located at the point of care. TIL recipients received preconditioning lymphodepletion followed by infusion at a dose of 5 × 109 to 2 × 1011 TILs, and subsequent infusions of high-dose interleukin-2 to promote TIL activity.
PFS in the intent-to-treat population served as the study’s primary endpoint. Secondary endpoints included overall response rate, complete response rate, OS and safety.
Median follow-up was 33.5 months for the TILs cohort and 33 months for the ipilimumab cohort.
Key findings
The study met its primary endpoint, as TILs significantly extended median PFS compared with ipilimumab (7.2 months vs. 3.1 months; HR = 0.5; 95% CI, 0.35-0.72) as second-line or later therapy.
Investigators reported 6-month PFS rates of 52.7% with TILs and 21.4% with ipilimumab.
TIL therapy also more than doubled the ORR (48.8% vs. 21.4%) and complete response rate (20.2% vs. 7.1%) compared with ipilimumab.
A higher percentage of patients who received TILS derived therapeutic clinical benefit (67.9% vs. 39.3%).
Investigators reported median OS of 25.8 months (95% CI, 18.2-not reached) for the TIL group vs. 18.9 months (95% CI, 13.8-32.6) for the ipilimumab group (HR = 0.83; 95% CI, 0.54-1.27).
All patients who received TILs experienced at least one grade 3 or higher treatment-related adverse event, compared with 57.3% of those in the ipilimumab group.
Clinical implications
The results showed treatment with TILs reduced the risk for disease progression or death by 50% compared with ipilimumab in an intention-to-treat population, Haanen told Healio.
He also noted the near tripling of complete responses with TILs compared with ipilimumab.
"We know from experience with other immunotherapies that patients who have complete responses typically have very good outcomes,” Haanen said.
As for treatment-related toxicity, TIL therapy is a one-time treatment with manageable side effects that are limited to the immediate post-infusion period, Haanen said.
“Eighty to ninety percent of patients recover from their side effects before leaving the hospital, with the rest recovering soon after returning home,” he said. “This is different from the use of checkpoint inhibitors, where toxicity may accumulate over the course of therapy or — sometimes — produce even life-long effects.”
Haanen’s group is examining the specificity of the cells they use in TIL infusions to improve overall efficiency of the treatment.
“We need to determine which portion of the cells we infuse are tumor-reactive,” he said. “This could allow for enrichment of a particular cell population to make TILs potentially more effective and cheaper.”
Perspective
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Maya Dimitrova, MD
This is the first phase 3 trial utilizing TILs in metastatic cancer with demonstrated benefit in the form of PFS.The results of this trial may fuel further research of TILs in other cancer types, potentially demonstrating benefit in many other solid tumors and expanding available treatments for patients.
Although immunotherapy can yield impressive long-term responses, a substantial percentage of patients will have no response — or no durable response — to checkpoint inhibitors. This is a much-needed study, as TIL therapy has proven effectiveness in melanoma; however, no phase 3 trials have been done to date to compare its effectiveness with a standard-of-care regimen. The results are consistent with past reports of an approximately 50% response rate, with an impressive 20% complete response rate in the TIL group. It will be important to determine the persistence of antitumor activity and whether there are biomarkers that could help with patient selection given the resource intensity of the therapy.
TIL therapy likely will become a new standard of care in metastatic melanoma refractory to immune checkpoint inhibitors.
Asignificant strength of this study is that it was an investigator-initiated trial, thus obviating the potential competing interests of pharmaceutical companies or industry sponsors. A challenge of using adoptive cellular therapies, however, is the significant lag time between harvesting the cells and infusing them into the patient, as well as the variable success rate of achieving the prerequisite number of cells. This is not a therapy that can be used for those with rapidly progressive or symptomatic disease, and it requires a resectable lesion as the source of the lymphocytes.It remains to be seen if the response rates reported are based on an intention-to-treat population or on the patient population successfully infused with TILs.
If commercially approved, this will establish a new standard of care for patients with metastatic disease who have progressed on or were unresponsive to immunotherapy or targeted therapies.
Adoptive cell therapy — including chimeric antigen receptor T cells — has revolutionized the treatment of some hematologic malignancies but has yet to make significant inroads in solid tumors. However, with the work of these authors and others in the field, TILs have an exciting role in the treatment of solid cancers and may offer significant benefit for a well-selected patient population.
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Haanen J, et al. Abstract LBA3. Presented at: European Society for Medical Oncology Congress. Sept. 9-13, 2022; Paris.
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