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Amid FDA Holdup, Iovance's TIL Therapy Shows Strong Performance in Advanced Melanoma Trials

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NEW YORK – Despite recent registrational setbacks with the US Food and Drug Administration, Iovance Biotherapeutics' autologous tumor-infiltrating lymphocyte (TIL) treatment, lifileucel, is continuing to show durable anti-tumor activity in advanced solid tumors, most notably, in melanoma.

During the American Society of Clinical Oncology's virtual annual meeting, James Larkin, a medical oncologist specializing in melanoma treatment at the Royal Marsden NHS Foundation Trust, presented updated, 33-month data from a Phase II trial evaluating lifileucel as a treatment for patients with metastatic melanoma. Sixty-six patients were enrolled in the cohort presented at ASCO, all of whom had been treated with at least one prior line of therapy, including a PD-1 checkpoint inhibitor and, if the patients' tumors were BRAFV600 mutation-positive, a BRAF and MEK inhibitor.

Once enrolled in the trial, patients underwent a tumor tissue biopsy for harvesting TILs. Following cryopreservation and shipment to a manufacturing facility, the TILs were then expanded ex vivo, and, after patients received a non-myeloablative lymphodepleting regimen, reinfused with lifileucel as a one-time treatment together with interleukin-2.

The melanoma patients were heavily pretreated with a median of around three prior lines of therapy. After 33 months, 24 of these patients had responded to lifileucel, contributing to an objective response rate — the study's primary endpoint — of 36.4 percent. Three patients experienced complete responses following treatment, and as of the last data cutoff, the median duration of response had not been reached.

In terms of best overall response, 81 percent of patients experienced a reduction in tumor burden, and since the data cutoff, 11 patients have experienced further reductions tumor burden. Larkin highlighted these cases, as well as one patient who converted from a partial response to a complete response 24 months after infusion, as evidence that responses to lifileucel deepen over time.

"The duration of response is quite impressive given that the median has not been reached now over a long period of time," Jason Luke, the director of the Cancer Immunotherapeutics Center at the University of Pittsburgh Medical Center, said in a discussion of the new data. "Also interesting is that it appears that this therapy is predominantly active in those patients who progressed initially on anti-PD-1 therapy, and many of those patients had PD-L1-low tumors."

Indeed, in an exploratory analysis that Larkin presented at ASCO focusing on patients' clinical and biomarker characteristics, responses to lifileucel were not found to be contingent on factors such as PD-L1 expression status, BRAF mutation status, and whether patients received prior BRAF-MEK inhibitors or anti-CTLA4 checkpoint inhibitors.

Ultimately, however, the cumulative duration of patients' prior anti-PD-1 or anti-PD-L1 therapies did correlate with patients' duration of response to the TILs. For each six-month decrease in cumulative time on prior PD-1/PD-L1 checkpoint inhibitors, Larkin and colleagues found the median duration of response to lifileucel nearly doubled.

"All newly diagnosed patients should be closely monitored for progression on anti-PD-1 therapy, and early intervention with lifileucel at the time of initial progression on anti-PD-1 agents may maximize benefit," Larkin said. In his discussion of the data, Luke agreed and also noted that patients' baseline lactate dehydrogenase levels — the only other biomarker found to be correlated with duration of response — could be important considerations as the field considers how best to fit lifileucel into the treatment schema.

Considering Iovance's TIL data in the context of other melanoma therapies both experimental and FDA-approved, Luke suggested one potential "optimal approach" for advanced melanoma beginning with frontline anti-PD-1 therapy combined with anti-LAG3 therapy, such as Bristol Myers Squibb's investigational relatlimab. Then, Luke suggested a combination of anti-PD-1 therapy and low-dose CTLA4-targeted therapy, but anticipating progression, patients should also undergo TIL harvest so the TILs are available for infusion should they relapse.

Frontline immunotherapy combinations

Luke's proposed optimal approach, however, could be subject to change contingent on data from another Iovance clinical trial presented during ASCO.

This second trial, a Phase II basket trial of lifileucel combined with checkpoint inhibitors in multiple disease types and treatment settings, enrolled advanced, immune checkpoint inhibitor-naïve melanoma patients into one cohort and treated them with a combination of anti-PD-1 therapy and lifileucel at the same time. As of April, seven patients on that Phase II trial — five of whom had not received any prior treatments, and two of whom received either BRAF-MEK inhibition or chemotherapy — had received combination treatment with lifileucel and pembrolizumab (Merck's Keytruda).

Six out of seven patients had a confirmed objective response to the treatment, two patients had confirmed complete responses. According to Sajeve Thomas, a hematologist oncologist at the Orlando Health Cancer Institute who presented the data, the longest duration of response to the TIL-pembrolizumab combination so far is 16.8 months. The adverse events that occurred on the treatment, according to Thomas, were manageable, and mostly related to the lymphodepleting regimen and the IL-2 administration rather than the TILs themselves.

"We are encouraged by these data showing the potential feasibility and activity of combination lifileucel and pembrolizumab in the early-line treatment of patients with advanced, metastatic melanoma," Thomas said, adding that Iovance's basket trial is continuing to enroll not only melanoma patients, but also patients with cervical, head and neck, and non-small cell lung cancers.

Regulatory setbacks

Though autologous TILs have been used to treat patients at the National Cancer Institute and in academic settings for years, Iovance has been working toward FDA approval for lifileucel and is hoping to bring it into the commercial space. Oncologists and investors have been closely tracking Iovance's progress since 2019, when the company first announced plans to file a biologics license application for lifileucel in previously treated, metastatic melanoma with the FDA. But two years later, the BLA filing is still pending. 

The reason for the registrational delays, according to Iovance, is not related to the TIL product itself, but rather the potency assay that the drugmaker has developed to measure lifileucel's consistency. Several times now — including as recently as May 18 — Iovance has released statements indicating that the agency has requested additional data validating the potency assay. During an Iovance webcast following the ASCO presentation, Fred Vogt, Iovance's president and interim CEO, said, "All things are on the table with the FDA" including submitting all new potency assays to the agency either alone or in combination with prior assays evaluated by the agency.

Iovance remains optimistic that investigators working on the pivotal lifileucel trial will sort out the potency assay glitches soon and proceed as planned with the BLA filing. "We are confident that we can resolve the FDA's questions regarding our potency assays for our product's future commercial use," Vogt said. "We think we have an understanding of recent FDA feedback, and based on that, we are working on a path forward to complete additional assay work in the near-term."

Although in February, the firm's then-CEO Maria Fardis told Precision Oncology News she was confident that the lifileucel BLA filing would occur this year, according to the company's latest update, Iovance will meet again with the FDA during the second half of this year and expects to file its BLA in early 2022. 

The consecutive delays, combined with Fardis' abrupt resignation from her five-year tenure as Iovance's CEO, have raised questions about the regulatory prospects for TIL products. Iovance announced Fardis' resignation on May 19, the day after it announced the most recent FDA feedback.

Although the company hasn't said Fardis left because of the regulatory difficulties, the concurrent announcements spooked investors, and the firm's stock price dropped nearly 40 percent in the wake of the news. The data presented at ASCO has aided the stock's recovery a bit since the May plummet; as of June 10, the price was back up by just over 35 percent.

Regardless of the reasons for Fardis' resignation or the regulatory issues around a single BLA, the company has made clear that it remains committed to advancing its TIL therapies across the cancer care continuum. As Omar Hamid, chief of research and immune-oncology at the Angeles Clinic and Research Institute, said during Iovance's update call, "Iovance is not just waiting on the data to be evaluated by the FDA for single-agent [lifileucel] … they're moving further [into other settings]."