Make or break time for Iovance

After years of setbacks and delays Iovance will soon find out whether its TIL therapy lifileucel will become its first marketed product. The company’s filing faces a 24 February PDUFA date, and leads the list of the US regulator’s upcoming approval decisions.

The filing is for relapsed melanoma after PD-(L)1 blockade and targeted therapy, and its latest delay came when the FDA said it had insufficient resources to review it by the initially planned 25 November action date. Iovance’s stock has been volatile, and given lifileucel’s rollercoaster development history some still struggle to see it as an approvable product.

The TIL therapy had suffered numerous regulatory pushbacks, having initially been due to be filed in 2020. At that time the first major delay occurred, with the FDA and Iovance failing to agree on the potency assay necessary to satisfy a BLA submission.

The issue went to the heart of what a TIL (tumour-infiltrating lymphocyte) therapy actually was. Since TILs are simply extracted from a person’s tumour and expanded before being reinfused, therapy will vary from patient to patient, and the active targets are also likely to differ; such concerns came on top of questions over whether an unmodified project like this was even patentable.

Finally Iovance managed to start a rolling submission for lifileucel in 2022, but new questions on supplemental assay validation and comparative data delayed this further, and it wasn’t until May 2023 that a BLA was accepted.

Iovance’s TILs have faced other setbacks: NSCLC data from a basket study of LN-145 disappointed at the 2021 SITC meeting, while a separate filing plan, in cervical cancer, has gone to the back burner after competitor approvals. Lifileucel delays saw off one chief executive, Maria Fardis, who had taken over after her predecessor Manish Singh was forced to resign amid a stock promotion scandal.

Lifileucel’s melanoma filing is backed by the uncontrolled C-144-01 trial, whose headline finding was median overall survival of 19.4 months; its most recent analysis showed showed a landmark four-year overall survival rate of 22.2%, with the longest response ongoing at 59.9 months. If the FDA agrees to accelerated approval based on this, Iovance is already running Tilvance-301, a potentially confirmatory first-line trial testing lifileucel plus Keytruda versus Keytruda.

Upcoming US regulatory catalysts

Source: FDA calendar & OncologyPipeline.

While lifileucel’s is the only significant remaining oncology PDUFA date in February, the following month will see a crucial advisory panel discuss the expansion of anti-BCMA Car-T therapy into early-line multiple myeloma.

This concerns Bristol Myers Squibb’s Abecma and Johnson & Johnson’s Carvykti; the adcom caused the former’s PFUDA date in December to be missed, whereas the latter, earlier expected not to have needed an adcom, faces regulatory action in April.

A separate adcom will scrutinise Geron’s imetelstat, which after a US clinical hold and terminated alliance with J&J managed to score in the myelodysplastic syndromes study Imerge, and could become Geron’s first approved drug 34 years after that company was founded.

Investors will also be awaiting regulatory decisions on Regeneron’s controversial anti-CD20 T-cell engager odronextamab, and ImmunityBio’s Anktiva, which was hit by a complete response letter last year.

This story has been updated to correct the lifileucel rolling BLA submission date.