Shanghai Junshi and Coherus celebrating the success of their anti-PD-1 MAb toripalimab in first-line lung cancer yesterday raises a key question: will the FDA approve a drug on the basis of a trial run entirely in China?
The tori study in question, Choice-01, was run in just one Chinese hospital, and the question is relevant not only because Chinese and US patients might exhibit different characteristics, but also because Choice-01 did not offer control subjects a key US standard of care, Merck & Co’s Keytruda. An answer might soon come from a separate tori filing, and will surely have a political dimension given Coherus’s low-cost strategy.
There will be some agitating for tori to be approved as quickly as possible in the US: Coherus is one company that has a stated mission of launching “cost-effective medicines ... to deliver significant savings”. This is especially apt in immuno-oncology, whose tally of US-approved anti-PD-(L)1 drugs is seven and counting.
Still, it is not at all clear that Choice-01 is a US-approvable study, as according to clinicaltrials.gov it was conducted at a single Chinese centre, the Cancer Hospital Chinese Academy of Medical Sciences in Beijing.
Toripalimab met its primary endpoint, increasing median progression-free survival to 8.3 months, versus 5.6 for chemo, with a highly statistically significant 41% reduction in risk of progression across all-comers. But if chemo is an appropriate comparator in China, where Keytruda might not yet be established as first-line standard, this is not the case in the US.
Indeed, it would be very difficult ethically to run a US trial in which control cohort subjects were denied Keytruda, and some say this fact justifies carrying out such studies elsewhere. Nevertheless, Choice-01 does not appear to reflect a US patient’s reality.
Coherus bulls will now look for a precedent. One exists with Sanofi/Regeneron’s latecomer Libtayo, which got US approval this year in first-line ≥50% PD-L1-expressing NSCLC on the strength of a study run largely in Asia, east Europe and South America.
And earlier this month Beyondspring argued that the FDA was amenable to a US filing based on a study that comprised only 20% recruitment in the US, as long as pharmacokinetic data for US and Asia patients were similar.
Where this leaves another two metastatic NSCLC laggards, Astrazeneca’s Imfinzi and Merck KGaA/Pfizer’s Bavencio, is a separate question. Both are in pivotal first-line NSCLC trials that do include the US, but which have been extensively redesigned, upsized and delayed. Perhaps the increasing use of Keytruda is playing havoc here, but in any case their chances of success seem low.
|Selected trials of anti-PD-(L)1 MAbs in 1st-line NSCLC|
|Product||Company||Study||Regional scope||Primary endpoint(s)/result||US outcome|
|Keytruda||Merck & Co||Keynote-042||Global, incl US||Positive for mOS vs chemo in PD-L1 ≥1%*||Approved for PD-L1 ≥1%|
|Tecentriq||Roche||Impower-110||Global, incl US||Positive for mOS vs chemo in PD-L1 ≥50%**||Approved for PD-L1 ≥50%|
|Libtayo||Sanofi/Regeneron||Empower-Lung 1||Australia, Asia, east Europe & S America||Positive for mOS & mPFS vs chemo in PD-L1 ≥50%||Approved for PD-L1 ≥50%|
|Tuoyi (toripalimab)||Shanghai Junshi/Coherus||Choice-01||China||mPFS 8.3mth vs 5.6mth for chemo (HR=0.58, p=0.0001) in all-comers||NA|
|Bavencio||Merck KGaA/Pfizer||Javelin Lung 100||Global, incl US||PFS & OS in PD-L1 expressers; completion Oct 2021^||NA|
|Imfinzi||Astrazeneca||Pearl||Australia, Asia, east Europe & US (1 centre)||OS in PD-L1 ≥25%; completion Oct 2021, data H1 2022^^||NA|
|Notes: *failed secondary mPFS endpoint; **positive for secondary mPFS endpoint; ^completion was originally Apr 2019, and all-comers PFS was original sole primary endpoint; ^^completion was originally Jul 2020, and PFS was a co-primary endpoint. Source: clinicaltrials.gov & company statements.|
Tori, which is already approved in China as Tuoyi, will itself give a big clue to the FDA’s thinking when the US regulator reviews its expected BLA for nasopharyngeal carcinoma – backed by the Asian Polaris-02 and Jupiter-02 trials.
Before that bulls will point at the high quality of the Choice-01 data, which appear to back tori irrespective of patients' PD-L1 expression. In the US, Keytruda monotherapy is approved in PD-L1 ≥1% expressers, and as part of a chemo combo in all-comers, while the other front-line monotherapy player, Roche’s Tecentriq, has a ≥50% PD-L1 expression stipulation.
So another question for tori is how it performed in PD-L1-negative subjects, since it is possible that its all-comers benefit was simply driven by expressers. Investors do not have long to wait: Choice-01 data are to be presented in full at next month’s World Lung conference.