Bristol’s filing withdrawal sets up another US vs EU conflict
Blink and you will have missed the significance of Bristol-Myers Squibb’s decision to pull its EU filing for Opdivo plus Yervoy in first-line lung cancer. The move, revealed after market close on Friday, on the face of it looks like a predictable acknowledgement of the uselessness of analysing the combo’s Checkmate-227 study based on patients’ tumour mutation burden; similar considerations saw a US submission pulled a year ago. Not so: Bristol quietly revealed that it had added to the EU filing data from Checkmate-227’s original part 1a – but the EMA rejected this, citing the study’s “multiple protocol changes”. Apparently the US FDA has no such qualms, given that it has agreed to review Opdivo/Yervoy based on a pooled result of part 1 of the study, an even shakier exploratory dataset than part 1a. Yet again the US FDA seems to be behaving more leniently than its EU opposite number. Those who still rate Bristol’s EU chances might have another hope: the company has vowed to file on the basis of Checkmate-9LA, which yielded a survival benefit favouring Opdivo plus Yervoy last October (Bristol might play a role in front-line lung cancer after all, October 23, 2019).
| The Checkmate-227 timeline | |
|---|---|
| Date | Note |
| (Initial study design) |
Part 1a: O+Y or O mono, vs chemo, in PD-L1+ve |
| Part 1b: O+Y or O+chemo, vs chemo, in PD-L1-ve | |
| Part 2: O+chemo, vs chemo, in all comers | |
| Feb 2018 | Bristol claims PFS win in TMB-high patients on O+Y from part 1 combined |
| May 2018 | EMA accepts filing in TMB-high patients |
| Jun 2018 | US FDA accepts filing in TMB-high patients; Feb 2019 action date |
| Mid-2018 | EMA requests OS analysis in TMB-low subjects – and this is almost equal to that in TMB-high cohort |
| Oct 2018 | US FDA considers OS data in TMB-low subjects, and delays action date to May 2019 |
| Jan 2019 | Bristol pulls US filing (TMB-high) |
| Jul 2019 | Part 2 fails |
| Sep 2019 | Exploratory analysis of part 1 in O+Y all comers is numerically positive for OS |
| 2019 | Part 1a analysis (OS for O+Y in PD-L1 ≥1%) added to EMA filing |
| Jan 2020 | FDA accepts part 1-based filng; May 2020 action date |
| Jan 2020 | Bristol pulls EMA filing (TMB-high & part 1a) |
| Other 1st-line NSCLC studies due to report | |||||
|---|---|---|---|---|---|
| Study (sponsor) | Intervention | Population | Primary endpt | Data | Note |
| Javelin Lung 100 (Merck KGaA/ Pfizer) | Bavencio monotherapy vs various chemos | PDL1 +ve | PFS , OS | Jun 2020 | Upsized from 420 to 1,095 to 1,224; all-comers PFS used to be sole primary; completion delayed from Apr to Oct 2019, then to Jun 2020 |
| Pearl (Astrazeneca) | Imfinzi monotherapy vs various chemos | PD-L1 ≥25% | OS | Jan 2021 | Upsized from 440 to 669; PFS used to be co-primary; completion delayed from Jul 2020 |
| NCT03631706 (Merck KGaA) | Bintrafusp alfa vs Keytruda | High PD-L1 | ORR, PFS | Mar 2022 | – |
| NCT03088540 (Sanofi/ Regeneron) | Libtayo vs chemo | PD-L1 ≥50% | PFS , OS | Feb 2023 | Upsized from 300 to 700; completion delayed from Nov 2021; no Keytruda in comparator arm |
| Keynote-598 (Merck & Co) | Keytruda + Yervoy, vs Keytruda | PD-L1 ≥50% | PFS , OS | Feb 2023 | Completion delayed from Apr 2022 |
