NEW YORK – Having recently announced pivotal data from its Phase II metastatic melanoma clinical trial, Iovance Biotherapeutics tried to assure investors last week that it is on track to file a biologics licensing application for the autologous tumor infiltrating lymphocyte (TIL) therapy lifileucel in August.
San Carlos, California-based Iovance has already postponed filing the BLA several times to iron out potency assay issues with the US Food and Drug Administration. However, according to the firm, it is now moving ahead with regulatory filing plans in the coming months, and the application will include data from cohort 4 of the Phase II C-144-01 clinical trial, as well as the more positive data from cohort 2 in the same trial.
In reporting the data from cohort 4 late last week, Iovance presented the findings as positive, especially given the heavily treated and refractory patient population. However, the latest results were not as positive as those reported last June from cohort 2 in the same trial, which involved patients with the same disease characteristics.
In cohort 4, 87 patients with advanced melanoma — all of whom had received prior treatment with anti-PD-1/L1 immune checkpoint inhibitors as well as prior BRAF or BRAF/MEK inhibitor therapy if their cancers harbored BRAF mutations — received lifileucel. The therapy involves several steps. First, patients' tumors are biopsied for TIL harvesting. Then, after these TILs are frozen and shipped to a manufacturing facility, they undergo ex vivo expansion. While this expansion is occurring, patients receive a non-myeloablative lymphodepleting regimen, after which they receive the TILs as a one-time infusion together with interleukin 2.
Of the 87 patients who received lifileucel, 29 percent responded. Three patients experienced a complete response and 22 had partial responses. After a median follow-up of 23.5 months, the median duration of response was 10.4 months.
In the previously reported data from cohort 2, meanwhile, 35 percent of 66 lifileucel-treated patients responded, and after a median follow-up of 36.6 months, the median duration of response had not yet been reached.
Investors homed in on the discrepancy in duration of response in these two cohorts, and after Iovance announced cohort 4 data, the firm's stock price plummeted by 50 percent. As of this Wednesday, the stock price has not recovered, despite Iovance's attempts to reassure investors during a conference call last week that the data were still positive relative to other treatments for refractory metastatic melanoma.
"From a regulatory perspective, we think this is very, very good data," Iovance interim CEO Frederick Vogt said on the call.
"We believe that the cohort 4 data, supported by cohort 2 data, may be the basis for approval," he added, indicating the firm's strategy to submit data from both cohorts to the FDA as part of its lifileucel BLA.
Iovance's plan, informed by FDA input, was always to use the cohort 4 objective response rate as the primary endpoint supporting registrational filing, and Vogt underscored that this is still the plan. However, the possibility of including the more impressive cohort 2 data in the application is based on recent FDA feedback.
"With the updated data … we are confident that we are on track with our planned BLA submission in August," he said.
Iovance's previously asserted regulatory plans have failed to materialize before. It was 2019 when the firm first announced plans to file a BLA for lifileucel in previously treated, metastatic melanoma. Years of consecutive delays have left investors wary. Still, the firm is adamant that autologous TIL therapy provides advanced melanoma patients with a much-improved outlook relative to the current treatment regimens available.
"There are no approved therapies for melanoma patients who progress after treatment with PD-1 therapy, [and] available care for patients with metastatic melanoma patients in this setting is chemotherapy," Friedrich Graf Finckenstein, Iovance's chief medical officer, reminded analysts and investors during the call, pointing out that chemo in this setting usually elicits responses in just 4 percent to 10 percent of patients that last around 3.5 months. He underscored that the cohort 4 results, while less promising than those seen in cohort 2, still represented a significant improvement over current standard of care.
Explaining cohort discrepancies
During the conference call, Vogt and Finckenstein attempted to account for the difference in response rates and duration of responses between the two cohorts, despite the identical eligibility requirements.
"Patients in cohort 4 had higher baseline disease burden in comparison to cohort 2," Finckenstein said. "This finding was supported by a higher proportion of cohort 4 patients with elevated baseline lactate dehydrogenase (LDH) levels, which is a well-known negative prognostic factor in melanoma."
Finckenstein added that patients in cohort 4 also had a greater number of tumor lesions at baseline and had undergone more intensive prior treatment. Cohort 2 patients had received about half the cumulative duration of anti-PD-1 therapy before lifileucel compared to cohort 4 patients. As the firm reported out last year, a shorter duration of anti-PD-1 therapy was associated with improved lifileucel response.
According to Vogt and Finckenstein, this difference in disease prognosis was not intentional, but rather a natural phenomenon that occurs as multi-cohort clinical trials like this one progress.
"The inclusion and exclusion criteria were exactly the same," Finckenstein said. "There was no enrichment of a different population in regards to tumor burden or LDH or prior therapy."
The fact that patients in cohort 2 may have been somewhat healthier than those in cohort 4 reflects how clinical trial investigators tend to enroll patients into trials for novel investigational treatments, he explained. Initially, investigators may have been cautious about enrolling patients with more advanced disease and worse prognoses, but then, as positive data emerged from cohort 2, they began enrolling patients more liberally in cohort 4.
"The expectation is, with a potential approval, this will be a second-line therapy, meaning we will be looking at patients with less prior therapy," he added. In the trial, patients did need a minimum number of prior therapies, but there was not a maximum. In the real world, if lifileucel is approved, Iovance hopes to see even better responses in patients who have had fewer lines of prior therapy.
The company plans to report additional data from these cohorts at a medical meeting in the second half of this year. In the meantime, at this year's American Society of Clinical Oncology annual meeting, which begins later this week, the firm will share translational data suggesting that patients' responses to lifileucel are likely independent of tumor mutational burden (TMB), a finding that is consistent with the treatment's "proposed immune checkpoint pathway-independent mechanism of action."
While it remains to be seen if Iovance will end up submitting its BLA in August as planned, at least one prior point of concern — the firm's chosen potency assay — seems to be in better shape than it was at this time last year.
Earlier this spring, Iovance said it received positive FDA feedback on its plan to use a potency assay matrix that includes multiple measures of potency to assure regulators that the TIL product will have consistent activity when produced on a commercial scale. The positive feedback comes after going back and forth with the agency several times on other potency assay approaches.