Lazertinib and Tagrisso go head to head

Astrazeneca’s Tagrisso has cemented its status as the most successful targeted lung cancer drug of recent times, but a challenger is emerging. Johnson & Johnson’s Mariposa study, pitting lazertinib head to head against Tagrisso, should read out this year.

Lazertinib is a low-key third-generation asset, but J&J has increasingly been playing up its potential. However, Astra will vigorously defend Tagrisso’s status as its top-selling drug, and the imminent readout of its own Flaura2 trial could raise the bar and effectively neutralise the lazertinib threat.

Flaura2 is one of several large studies designed to expand Tagrisso’s use into early disease on the one hand, and enhance its benefit in existing indications on the other. It is unsurprising that Astra will not give up easily on a brand that sold $5.4bn last year.

Tagrisso was initially approved in lung cancer patients with the EGFR resistance mutation T790m, but the key to its dominance has been an expansion into earlier lines of NSCLC therapy. The drug is now established in common first-line EGFR mutations too, and is also approved in the adjuvant setting.

Interim hope

It is first-line EGFR-mutant NSCLC that is the battleground for J&J’s Mariposa trial. Technically this study is not due to end until April 2024, but J&J has been highlighting the possibility of an interim readout sometime this year.

Mariposa’s primary endpoint is progression-free survival, and the trial gives J&J two shots at beating Tagrisso. The first is a lazertinib monotherapy arm, while the second is a cohort that randomises patients to a combo of lazertinib with Rybrevant.

Rybrevant is a bispecific against EGFR and cMet, and is approved for the treatment of another type of EGFR mutation, called exon 20 insertion. Lazertinib, on the other hand, is a small molecule EGFR inhibitor that acts the same way as Tagrisso, but is not available in the west; in South Korea it has been approved as Leclaza for T790m-resistant second-line disease.

The logic here is that two drugs might hit more mutations than a single small molecule. In theory the combo could catch patients with common EGFR mutations, a de novo cMet abnormality or an exon 20 insertion that is resistant to typical EGFR drugs, as well as preventing the emergence of resistance via T790m.

The risk, of course, is that combining multiple pharmacologies in this way will result in unacceptable toxicity.

Wrong comparator?

An even bigger risk, however, is Astra’s Flaura2 trial, which is expected to read out imminently and lead to a second-half regulatory submission if positive.

Flaura2 tests front-line Tagrisso head to head against Tagrisso’s combination with one of two chemotherapies, and has PFS as primary endpoint. The goal is to show that combining Tagrisso with chemo can enhance efficacy, and Wolfe Research’s Tim Anderson reckons that, based on the earlier NEJ009 and Opal studies, a PFS advantage is likely.

Why is this a problem for J&J? Because, if Tagrisso plus chemo works better than Tagrisso and becomes a new standard combo, Astra could argue that Mariposa is irrelevant because it tests lazertinib (with or without Rybrevant) against the wrong comparator, namely Tagrisso monotherapy.

True, there is nuance here. Flaura2 might reduce the lazertinib threat but not eliminate it entirely; and the size of any benefit in Mariposa would also need to be considered, as on a cross-trial basis it might still look impressive compared with Flaura2.

In the absence of Flaura2 there is justified optimism about Mariposa. The Chrysalis-2 study at last year’s Asco showed Rybrevant plus lazertinib to have a 36% remission rate, though this was in patients relapsed on Tagrisso. And a late-breaker at December’s Esmo-Asia conference showed lazertinib monotherapy to have first-line potential in the Laser301 trial, albeit against the first-generation drug Iressa.

J&J licensed lazertinib from the South Korean group Yuhan in a little-noticed 2018 deal worth just $50m up front. That came after lazertinib showed its potential at Asco in NSCLC patients resistant to EGFR-targeting therapy.

Other ways in which Astra wants to expand Tagrisso’s potential include a combination with Hutchmed’s China-approved small-molecule cMet inhibitor Orpathys, though in contrast to J&J this seeks to broaden Tagrisso’s reach into cMet-driven disease.

Analysts clearly recognise the threat that Mariposa now poses to Tagrisso’s dominance, but Astra is not sitting on its hands, and 2023 should give investors a good idea how these settings play out.

After this article was published J&J pointed out that Mariposa's primary purpose was to evaluate the combination of Rybrevant with lazertinib versus Tagrisso, and to form the basis of regulatory submissions for this combo in patients with EGFR-mutated NSCLC.