Immutep approaches Lag3 crunch time

Australia’s Immutep is fast approaching a crucial decision on the pivotal development plan for its Lag3 project eftilagimod alpha, expected some time this month. At roughly the same time, however, efti’s next big readout, the Tacti-003 study in first-line head and neck cancer, threatens to muddy the waters.

That’s because the initial readout of Tacti-003, which combines efti with Keytruda, is likely to paint a confusing picture, at least judging by Keytruda’s own registrational Keynote-048 trial. However, Immutep’s pivotal plan concerns first-line NSCLC, where efti’s uncontrolled Tacti-002 trial impressed at last year’s ESMO.

The basis for the excitement in NSCLC were ORR, PFS and OS figures for efti plus Keytruda. These seemed impressive across PD-L1 expression levels, though with no control cohort the comparison was on a cross-trial basis, namely against Keytruda’s Keynote-042 study.

Earlier this year, Immutep promised to give clarity about its phase 3 first-line NSCLC development plan by the end of March, including detail on trial size, PD-L1 expression levels and whether it would include chemo. Crucially, phase 3 depends on a licensing deal being struck – not only to provide a PD-(L)1 MAb to combine with efti, but also to help fund a study; Immutep only has some $65m in the bank.

Help or hindrance?

Among the various moving parts here is whether deal and/or financing prospects will be helped or hindered by the readout of Tacti-003, delayed from 2023 to the current first quarter.

Tacti-003 is a controlled phase 2 trial, primarily comparing efti plus Keytruda versus Keytruda alone in 138 first-line head and neck cancer patients with ≥1% PD-L1 expression. A separate cohort enrolled 33 PD-L1 non-expressers, and treated them with just the efti/Keytruda combo.

The trial measures ORR as primary endpoint, so this likely to be reported first, before survival measures (PFS and OS are listed as key secondaries) mature later.

And here the problem arises: Merck’s Keynote-048 study backed Keytruda’s US approval in this setting, but only on the basis of OS. ORR and PFS were either no different or numerically worse than Erbitux plus chemo control.

This is relevant not only because Keynote-048 will be held up against the Tacti-003 readout, but also since a similar dichotomy is possible in Immutep’s trial. Immutep might end up releasing ORR data that in Tacti-003 beat Keytruda, but which on a cross-trial basis look no better than Erbitux/chemo – and it could thus be left hoping for a survival benefit at some later point.

Tacti-003’s PD-L1 non-expressing cohort is something of a wild card. In front-line head and neck cancer Keytruda monotherapy is approved only in PD-L1 expressers, but the drug does have an all-comers label as part of a chemo combo. Still, there’s no obvious bar for Immutep’s combo to clear in PD-L1 non-expressing patients, in addition to the unreliability of the ORR endpoint.

Lag3 competitors

The Lag3 space is of interest because of the approval of Bristol Myers Squibb’s Opdualag in melanoma, and the progress being made by Regeneron’s fianlimab. However, efti has a different modality from the anti-Lag3 MAbs fianlimab and relatlimab, being a Lag3 fusion protein, and Immutep’s idea is that it can stimulate antigen-presenting cells.

Some backing for efti in head and neck cancer exists in the second-line setting, where a cohort of Tacti-002 showed better ORR with efti plus Keytruda than Keytruda had yielded in its failed Keynote-040 trial. However, again there was a disparity with survival: median PFS and OS numbers weren’t materially different versus the Merck trial.

It’s important to remember that head and neck and NSCLC are two very different cancers in terms of immunogenicity, so a potential partner might not care too much about initial Tacti-003 results. However, they have to be convinced that the mid-stage NSCLC data efti has generated so far can be repeated in a controlled, multicentre trial without a significant fall-off in activity.

What's the bar in first-line head & neck cancer? Summary data from Keynote-048

Source: OncologyPipeline.