Johnson & Johnson’s amivantamab has cemented its status as the industry’s leading project for treating lung cancer driven by a rare and intractable mutation, exon 20 insertion, with highly positive data presented at the weekend’s World Lung conference.
The meeting also allowed an interesting cross-trial comparison with the industry’s next most advanced exon 20-targeting asset, Takeda’s mobocertinib. J&J comes out on top, but there is an important distinction: while amivantamab is a bispecific antibody, mobocertinib is a targeted small molecule, which naturally will come with convenience and cost of goods advantages.
In this respect amivantamab is an anomaly. NSCLC tumours with specific driver mutations – EGFR, Alk and the like – are the domain of small-molecule kinase inhibitors like Iressa, Tagrisso and Xalkori. This has been the approach taken by Takeda with mobocertinib, and by other competitors specifically targeting exon 20 insertions, such as Spectrum’s poziotinib and Rain Therapeutics’ tarloxotinib.
J&J, however, says that because amivantamab is an antibody it binds extracellularly to EGRF, preventing ligand binding and exerting immune cell responses, and could thus have use in a range of EGFR-driven lung cancers, also including exon 19 deletion, T790M and cMet amplification.
Thus exon 20-insertion NSCLC, an area with no specifically approved current treatments, is just amivantamab’s initial use. Such is the unmet need here that J&J’s December filings were based on phase I data, and it was these results, from part of the Chrysalis trial, that featured at World Lung over the weekend.
These concerned post-platinum chemo patients preselected for exon 20 insertion, and in an efficacy analysis numbering 81 subjects J&J boasted overall remission of 40% and median progression-free survival of 8.3 months.
This allows a fairly clean, albeit cross-trial, comparison with Takeda’s mobocertinib, the most advanced TKI. Takeda’s study here is complex, but the key data presented at World Lung concerned 114 post-platinum subjects, comprising the first of six cohorts plus a phase II extension arm.
This yielded a 26% ORR, and median PFS of 7.3 months. Not only did this study underperform amivantamab’s, it also showed the J&J project in a better light as regards severe treatment-related adverse events.
|A comparison of EGFR exon 20 insertion-driven NSCLC data at World Lung 2020|
|Company||Johnson & Johnson||Takeda|
|Mech||EGFR-Met bispecific antibody||Oral TKI targeting EGFR exon 20 in-frame insertion mutations|
|Cohort||Post-platinum chemo, confirmed exon 20 ins (monotherapy cohort)||Post-platinum chemo, confirmed exon 20 ins (cohorts 1 & Exclaim extension)|
|ORR||32/81 (40%)||30/114 (26%)|
|mPFS||8.3 mth (6.5-10.9)||7.3mth (5.5-10.2)|
|mOS||22.8 mth (14.6-NR)||Not given|
|Grade ≥3 AEs||18/114 (16%)||53/114 (46%)|
|TRAEs leading to death||0||1 (1%)|
Like mobocertinib, Spectrum’s exon 20-mutant NSCLC contender poziotinib is being studied in a possibly registrational study with numerous cohorts.
This is called Zenith20, but so far both its EGFR exon 20 arms, in front-line and relapsed patients, have failed. Only one cohort, in Her2 exon 20 insertions, had proved successful, and Spectrum plans a filing this year based on this, giving amivantamab and mobocertinib a clear run at the EGFR setting.
J&J is also targeting front-line use, where it wants to combine amivantamab with the EGFR-targeting TKI lazertinib, detailing a separate cohort of the Chrysalis trial at last year’s Esmo meeting (Esmo 2020 – J&J goes for broke with lung cancer bispecific, September 23, 2020). But a front-line filing needs phase III data, which are to come from the Mariposa study.
Piper Jaffray reckons exon 20 insertion in EGFR drives just 4% of NSCLC tumours. However, Astrazeneca succeeded in using T790M, an acquired resistance mutation, as a gateway to Tagrisso becoming a blockbuster, and J&J probably has similar ideas, especially as exon 20 mutations are associated with de novo resistance.
If amivantamab gets approved all J&J will have to do is convince prescribers that a biological approach has a role to play here.