Tivdak success could make life even harder for Iovance

Success in Seagen/Genmab’s InnnovaTV-301 trial should see Tivdak formally approved for second-line cervical cancer. That’s the clearest takeaway from this study, which was toplined positive last night for overall survival; less obvious, but arguably more important, is what the outcome means for the competition in this fast-moving space.

Agenus investors, for instance, will recall the bombshell of Keytruda’s US green light in first and second-line cervical cancer, and one result of a full Tivdak approval could be the permanent shutting off of the accelerated pathway for all others. This should be a concern for Iovance’s lifileucel, notwithstanding that company earlier modifying its second-line strategy.

The situation illustrates the complexity of the metastatic cervical cancer treatment landscape. Until recently this had been the domain of chemo and Avastin, with Keytruda and Tivdak holding conditional second-line approvals. Agenus had filed balstilimab, an anti-PD-1 MAb, for accelerated second-line use on the basis of uncontrolled data, and had a December 2021 PDUFA date.

But then Keytruda’s first-line Keynote-826 trial read out positively, and in October 2021 the Merck & Co drug’s US label was formalised in the first and second-line settings alike, albeit only in PD-L1 ≥1% expressers. With a formally approved drug on the market the accelerated pathway closed for Agenus, and on the FDA’s recommendation the balstilimab filing was pulled.

Iovance next?

Iovance’s lifileucel, a TIL therapy, has not yet been filed for cervical cancer, but its life could be made difficult here by Tivdak’s success. Depending on how strong the InnovaTV-301 data are they could see the Seagen anti-tissue factor ADC formally approved in all-comers, putting up a roadblock to aspirants seeking PD-L1-negative patients as a possible accelerated way in.

That was part of Agenus’s argument when resisting the FDA’s recommendation to withdraw filing; however, even though balstilimab had shown some remissions in PD-L1-negatives, the sample size was too small to sway the regulator. PD-L1 status is important in cervical cancer, and notably Regeneron/Sanofi’s Libtayo filing – on controlled data – had to be pulled because the companies could not show whether there was efficacy in PD-L1-negative patients.

True, Iovance is pursuing a different tack, but given InnovaTV-301’s outcome this probably won't matter much. Though initially targeting a broad accelerated filing based on the uncontrolled second-line C-145-04 study, Iovance last year abandoned plans for a filing in PD-L1-naive second-line cervical cancer, and instead expanded cohort 2 of that study, which specifically enrols patients progressed after Keytruda and chemo.

Yet this seems to be precisely the same setting covered by InnovaTV-301, whose enrolment criteria mandate disease progression after chemo, Avastin and an anti-PD-(L)1 drug. Should the FDA grant Tivdak full approval here it seems likely that the accelerated approval for another drug in the same setting would not be appropriate.

If this happens it would spell yet another setback for Iovance, which has endured a litany of delays for lifileucel in its melanoma indication; filing here was put back from 2020 to 2021 and then 2022, before finally being made in May, and this now faces a 25 November PDUFA date. Meanwhile, Maria Fardis resigned as Iovance’s chief executive two years ago.

Among all this, metastatic cervical cancer does not represent a huge market, with Tivdak posting sales of $63m last year, and $41m in the first half of 2023. Companies’ attempts to fragment it into small niches seem destined to fall on stony ground.

Selected trials in metastatic cervical cancer

Note: AA=accelerated approval. Source: OncologyPipeline & company reports.