ASCO 2024 – some Adriatic fears allayed

AstraZeneca’s ASCO double plenary today showcases two studies that aim to broaden the use of its lung cancer drugs Tagrisso and Imfinzi into settings featuring cancer that hasn’t metastasised extensively. While Tagrisso’s Laura trial today revealed a knockout on PFS with questions about OS, Imfimzi’s Adriatic study delivered significant wins on both metrics.

A key difference between the studies, however, was that Laura allowed placebo patient crossover on progression, whereas Adriatic didn’t. Lack of crossover would clearly be expected to flatter an OS result, and an ASCO press briefing before today’s plenary heard that in Adriatic this came in at an impressive-looking median benefit of nearly two years in favour of Imfinzi.

Adriatic concerned small-cell lung cancer. Here Imfinzi is approved for metastatic extensive-stage disease on the back of the Caspian trial, but Adriatic looked at earlier use – limited-stage disease – which is pre-metastatic (stage I-III), with the cancer generally confined to one lung; patients had to be in response to chemoradiation, akin to a first-line maintenance setting.

22.5-month median survival benefit

A topline win on both of Adriatic’s co-primary endpoints of OS and PFS had already been declared last month, but it was only today that Dr David Spigel, of the Sarah Cannon Research Institute, told ASCO of the extent of this: risk of death was cut by 27% for Imfinzi versus placebo, and risk of progression or death by 24%, with median OS coming in at 55.9 versus 33.4 months.

This is subject to future revision, however, and the fact that much of the OS benefit develops late on in the survival curves explains why the 0.73 hazard ratio is a less impressive number than the medians might suggest. Astra cited median duration of follow-up in censored patients of 37.2 months.

Nevertheless, the extent of the median OS benefit was highlighted at the ASCO press briefing; this is relevant given that two technically positive studies in front-line extensive-stage SCLC, Imfinzi’s Caspian and Roche’s Impower-133 trial of Tecentriq, both yielded somewhat marginal absolute OS benefits.

Adverse events in Adriatic led to treatment discontinuation in 16% of Imfinzi versus 11% of placebo patients, and two subjects given the Astra drug died, one of encephalopathy and the other of pneumonitis. Nevertheless, Spigel hailed Adriatic as establishing Imfinzi as a new standard of care as a consolidation therapy; regulatory filing is planned this year.

Source: Dr David Spigel & ASCO.

The Adriatic data presented at ASCO concerned the trial’s first planned interim analysis, which only related to its Imfinzi monotherapy cohort. Adriatic also tests Imfinzi plus the anti-CTLA-4 drug Imjudo, but this arm appears to have been deprioritised.

Spigel said Adriatic had started with the aim of enrolling 600 patients evenly across the three cohorts. Later, however, the monotherapy and placebo arms were expanded (to 264 and 266 patients respectively), and the co-primary endpoints for monotherapy versus placebo became the focus for Adriatic’s primary analysis.

The statistical analysis plan will see the combo tested for survival versus placebo as a secondary analysis, but for now nothing is known about how that arm, still with an enrolment target of 200, has performed. Adriatic’s readout had been delayed, but it’s not clear why Astra decided it needed to raise its chances of success with Imfinzi monotherapy but make no change to the combo arm, which now looks like it might be underpowered.

Until Imfinzi plus Imjudo scored in the Himalaya trial in first-line liver cancer the anti-CTLA-4 MAb had a long list of setbacks behind it, and Astra attributed its later success to an amended dosing regimen it calls Stride.

One result of Adriatic is that it could give Astra an advantage over Roche, after the companies appeared to be neck and neck in the extensive-stage SCLC setting. Ultimately it looks like Imfinzi alone might allow Astra to achieve this without Imjudo’s help.