Zepzelca’s pivotal surprise

Jazz’s PharmaMar-originated Zepzelca has quietly been carving out a presence in small-cell lung cancer, and Tuesday brought what might be its most significant win to date: a positive result in Imforte, a phase 3 first-line SCLC maintenance study, that will lead to regulatory filing next year.

Though no data have been released the result is important because it concerns an apparent win not just on PFS but on OS too; in July Jazz guided to a topline 2024 PFS readout from Imforte. The data are also significant because Zepzelca’s US approval is on an accelerated basis, based on ORR numbers alone, and the confirmatory Atlantis study failed in 2021.

With such uncertainty it might come as a surprise that Zepzelca is on course to sell over $300m this year, with first-half revenues climbing 14% to $156m. Depending on the extent of the Imforte win, the data could shore up the drug’s position.

That’s important in a SCLC space where combinations of chemotherapy with Tecentriq or Imfinzi dominate the front line, where Amgen’s Imdelltra was recently approved for use after platinum chemo, and where Daiichi Sankyo/Merck & Co’s ifinatamab deruxtecan is threatening.

Roche too

It’s also important to note that Imforte is a Roche-sponsored trial (Jazz is co-funding it), which represents the Swiss company’s corresponding attempt at shoring up Tecenriq’s SCLC position.

Though Tecentriq was the first anti-PD-(L)1 drug approved for first-line extensive-stage SCLC, it was soon joined by Imfinzi. The Astra drug is now gunning for expansion into limited-stage disease, based on the Adriatic study, whose data back a filing on which an FDA verdict is due in the current quarter.

Imforte took SCLC patients who were in response to, or had stable disease after, first-line Tecentriq plus chemo, and randomised them to Tecentriq with or without Zepzelca. On Tuesday Jazz said it hit both its co-primary endpoints of OS and PFS by independent review, and clearly the numerical size of the benefit will be scrutinised once data are presented.

Though not indicated as such, Tecentriq is used in SCLC maintenance, based on long-term data from the registrational first-line Impower-133 study, so the fact Zepzelca can improve on this is relevant. One consideration is how Tecentriq, with or without Zepzelca, might have performed after response on Imfinzi and chemo, though the Roche and Astra drugs boast very similar first-line data.

Accelerated approval

While Imforte should secure Zepzelca’s US-approved status, as well as possibly adding a new use, the drug in any case seemed unlikely to be pulled form the market, despite the Atlantis confirmatory trial failure.

That’s because Atlantis did show a small numerical OS benefit favouring Zepzelca, while clearly failing to demonstrate statistical significance, and might have suffered from reduced dosing. 2021 World Lung data suggested subgroup benefits in patients with CNS involvement, and in those with a chemo-free interval of 90 days or more, so perhaps the biggest risk was a narrowing of Zepzelca’s label rather than withdrawal.

Zepzelca’s relative safety was also highlighted. That’s important given the second-line SCLC challenge of Imdelltra, whose FDA review revealed problems with the registrational Dellphi-301 study, some relating to protocol deviations and the under-reporting of adverse events. 

Jazz paid PharmaMar $200m up front for Zepzelca in December 2020, and five years on that’s starting to look like money well spent.

Selected Zepzelca studies in SCLC

Notes: *phase 2, as all others are phase 3; CTFI=chemo-free interval. Source: OncologyPipeline.