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

Share This Article