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Autologous TIL Therapy Benefits Rare, Difficult-to-Treat Melanoma Subset, ESMO Data Show

Infusion bags

NEW YORK – Iovance Biotherapeutics' autologous tumor-infiltrating lymphocyte (TIL) therapy led to what researchers at the European Society for Medical Oncology (ESMO) Congress on Saturday considered meaningful and encouraging responses in a small subset of patients with difficult-to-treat mucosal melanoma.

Evidio Musibay, an oncologist at the University of Minnesota Medical Center, shared data from 12 mucosal melanoma patients who received the autologous TIL therapy, lifileucel, in the Phase II C-144-01 clinical trial. On the whole, the trial enrolled patients with any type of advanced melanoma, except for uveal melanoma, who had received prior anti-PD-1 therapy. Iovance previously reported an overall response rate of 31.4 percent in all 153 patients in the trial and submitted this data to the US Food and Drug Administration as part of its biologics licensing application for lifileucel, which is currently under review. But the results from the subset of mucosal melanoma patients was news to oncologists, who took a particular interest in the outcomes since this subtype of melanoma is tough to treat. 

Advanced mucosal melanoma is rare, comprising around 1 percent of all melanoma cases, with a five-year survival rate of less than 25 percent. Immunotherapy with checkpoint and CTLA4 inhibitors is now a standard first-line option for melanoma patients, but mucosal melanoma patients often don't fare well on these types of drugs. The response rates for anti-PD-1 therapy for these patients range from 19 percent to 23 percent, and the median overall survival tends to range from 11 months to 16 months.

In the Phase II C-144-01 trial, after undergoing TIL harvest — during which investigators removed part of the tumor and separated and expanded the immune cells infiltrating it — patients received a regimen of lymphodepleting chemotherapy and interleukin-2, followed by lifileucel, a one-time infusion of their own expanded TILs. It took about 22 days to make the treatment for each patient.

After a median follow-up of 35.7 months, the overall response rate among the 12 mucosal melanoma patients who received lifileucel was 50 percent. The median duration of response was not yet reached, nor was the median progression-free survival, though Musibay reported that four out of six patients who responded to the therapy had ongoing, durable responses at the time of data cutoff. The median overall survival was 19.4 months.

The 12 mucosal melanoma patients had received a median of two prior lines of treatment, and 42 percent had metastases in their livers or brains. Compared to cutaneous melanoma patients, those with mucosal melanoma had lower mean tumor mutational burden (TMB), 10.47 mutations per mega base versus 2.15 mutations per mega base, respectively. Studies have shown that the higher TMB is in certain types of cancer, the better patients do on immunotherapy.

The safety profile for lifileucel in mucosal melanoma patients was largely on track with that of the overall study population, Musibay added. Researchers observed adverse events that were mostly associated with lymphodepleting chemotherapy and high-dose interleukin-2, which patients received before their TIL infusions.

"These results further support the potential benefit of lifileucel as a one-time treatment that is differentiated from other immunotherapies," Musibay concluded. 

In a discussion following Musibay's presentation, Omid Hamid, chief of research and immune-oncology at the Angeles Clinic and Research Institute in California, asserted that based on this subset analysis, TIL therapy should be "the new standard for mucosal melanoma."

Both Musibay and Hamid acknowledged that the patient population was small and the follow-up wasn't long enough to know for sure whether these patients would have durable responses to TIL therapy. Additionally, Hamid said it would be nice to know which, if any, of the patients had previously received anti-CTLA4 immunotherapy in addition to prior anti-PD-1 therapy.

Hamid further noted that, at least in the overall melanoma population, "higher response rates have been seen when this type of [TIL] therapy has been introduced earlier," making him wonder about the potential for giving TILs to earlier-stage mucosal melanoma patients.

"As we think about this therapy … this data has shown that we can think about bringing it earlier and earlier into our thought process for patients with mucosal melanoma, given the high response rate and the tolerability," he said.

Iovance, for its part, has already been eyeing earlier-line indications for its TIL therapy in the Phase III TILVANCE-301 trial, which pits first-line lifileucel and Merck's checkpoint inhibitor Keytruda (pembrolizumab) against Keytruda alone in advanced, previously untreated melanoma patients.

When Iovance announced in June that it had randomized the first patient in TILVANCE-301, Friedrich Graf Finckenstein, the firm's chief medical officer, said he expected this trial to be "well underway" by the time lifileucel received accelerated approval in refractory melanoma.

That approval has been a long time coming. Iovance had previously expressed confidence that it would have its biologics license application submitted in 2021, but, thanks to a series of regulatory delays and potency assay complications, the San Carlos, California-based drugmaker didn't complete the submission until this May. Even then, the application has run into further speed bumps. Last month, Iovance said the FDA, which was originally expected to announce its decision on the BLA in late October, had moved its decision date to Feb. 24, 2024.

But the agency has "agreed to work with Iovance to expedite the remaining review for a potentially earlier approval date," Iovance said when it announced the most recent delay.

The trouble with netting regulatory approval for this cell therapy is that the path through the FDA is uncertain and untrodden. If Iovance is successful in getting FDA approval for lifileucel, it will be the first TIL therapy to achieve this.

Other autologous cell therapies on the market, such as CAR T-cell treatments, involve modified T cells. But the TIL product Iovance is trying to garner approval for doesn't involve any ex vivo modification, though the firm is also developing modified versions of autologous TILs, including TILs with PD-1 knockout. For regulatory purposes, it can be hard to define the marketed product for therapies like lifileucel, which involve infusing patients with more of their own cells. Moreover, given the rapid growth in the cell and gene therapy space in recent years, regulators at the FDA have been challenged to handle the volume of sponsor requests for the agency's guidance.

As Iovance continues to juggle its regulatory hurdles, though, oncologists are welcoming the new TIL therapy data as a promising sign of what's to come for this patient population. "Lifileucel in PD-1/PD-L1 refractory mucosal melanoma could become standard of care in the future, particularly due to the lack of responses with standard oncological treatment," Sophia Wong, a medical oncologist at the Royal Marsden NHS Foundation Trust, wrote in an email.

But Wong noted that the small patient population calls for additional confirmatory data, and acknowledged a reality that many other practicing oncologists have harped on when it comes to complex cell and gene therapies: A treatment can only benefit patients to the extent they can access it. "The practicalities and intense regulations in the delivery of these therapies are challenging," Wong said. "It would likely only be available in specialist centers."