Astra goes early in small cell

Having matched Roche with an approval in front-line extensive-stage small-cell lung cancer AstraZeneca is hoping to go one up: today the group toplined a win for Imfinzi in the delayed Adriatic study, concerning the earlier SCLC setting of limited-stage disease.

This could give Imfinzi first-mover advantage in a space where Tecentriq isn’t being tested, and which features phase 3 trials of just four other anti-PD-(L)1 drugs, according to OncologyPipeline. However, much will depend on the size of the apparent win in Adriatic, especially given the precedent of the marginal benefits shown in the registrational Caspian and Impower-133 studies.

Those two trials support the approved chemo combos of Imfinzi and Tecentriq respectively in extensive-stage SCLC, but show a median overall survival benefit of just two to three months. A separate sign of the intractability of SCLC is that Keytruda and Opdivo have both failed here, in the phase 3 Keynote-604 and Checkmate-451 trials respectively.

Filings possible

Now Astra is pinning hopes on limited-stage SCLC, and says it plans to discuss the Adriatic data with regulators with a view to approval; full data are being held back for a scientific meeting.

Adriatic enrolled first-line patients in response to chemoradiation, and compared Imfinzi, with or without Imjudo, against placebo. It’s said to have succeeded on the co-primary endpoints of OS and PFS, but so far only for Imfinzi monotherapy; the Imjudo combo arm continues blinded. Notably, in Caspian only Imfinzi plus chemo succeeded, while an Imjudo-containing triplet failed.

Limited-stage SCLC is defined as pre-metastatic disease (stage I-III), where the cancer is generally confined to one lung. In contrast, extensive-stage SCLC represents a more advanced setting, involving both lungs, lymph nodes and/or metastasis to other parts of the body.

Astra’s strategy here is broadly similar to what the group achieved in NSCLC. In the metastatic setting Imfinzi was late to the game behind Keytruda, but the Pacific trial, in stage III NSCLC, scored an important win and opened up the unbroken ground of pre-metastatic disease, a setting in which Keytruda ended up playing catch-up.

Any competition?

Depending on the extent of the Adriatic win a similar scenario could unfold in limited-stage SCLC, where perhaps the most notable challenger is not an anti-PD-(L)1 project but Amgen’s anti-DLL-3 T-cell engager tarlatamab; in February this started the phase 3 Dellphi-306 study, testing a setting similar to Adriatic's where front-line patients are in response to chemoradiation.

Only one other trial features this setting, involving Coherus/Shanghai Junshi’s toripalimab given with or without Junshi’s tifcemalimab (this seems to be the industry’s only MAb targeting BTLA, a lymphocyte inhibitory receptor with some similarities to CTLA-4). Three anti-PD-(L)1 MAbs are in purely first-line studies, given on top of chemoradiation, and the first of these, the Astrum-020 trial of Fosun/Shanghai Henlius’s serplulimab, should end this year.

The first-line limited-stage SCLC setting also features the Keylynk-013 study of Keytruda with or without Lynparza, but given the setbacks across the Keylynk programme its chances of success appear slim.

Phase 3 studies in first-line/maintenance limited-stage SCLC

Notes: *China study; ^anti-BTLA MAb; ^^PARP inhibitor; *anti-DLL3 TCE, others are anti-PD-(L)1 MAbs. Source: OncologyPipeline.