The US FDA gets tough

Tecentriq follows Opdivo, Imfinzi and Keytruda in having a US approved use knocked out.

An industry-wide review of US accelerated approvals whose confirmatory trials have failed, quietly begun by the FDA a few months ago, has now seen off four previously approved uses for anti-PD-(L)1 drugs.

Today Roche’s Tecentriq became the latest to be pulled, in its case in a bladder cancer setting that had remained in place despite the 2017 failure of a confirmatory trial. Evaluate Vantage recently highlighted a surge in accelerated approvals, an alarming number of which remain unconfirmed; though it has taken a long time for the agency to act, this is a case of better late than never.

It should be stressed that, formally at least, all four withdrawals have been voluntary. But they have followed discussions between drug makers and the FDA, and while the regulator might have risked losing face had it moved to force an anti-PD-(L)1 drug off the market it likely gave companies little choice but to pull the plug.

Front-line unaffected

Roche says it is pulling Tecentriq’s US urothelial bladder cancer use after platinum chemo, but surprisingly the decision has no bearing on an even broader setting: a Roche spokesperson told Vantage that “the withdrawal does not affect the US indication in first-line metastatic urothelial carcinoma”.

Urothelial bladder cancer was Tecentriq’s first US approval, back in May 2016, on the basis of the Imvigor-210 trial. This was broadened a year later, on the basis of the same study, to encompass front-line bladder cancer in patients ineligible for cisplatin chemotherapy; like the second-line label this was an accelerated approval subject to a confirmatory trial.

However, on May 10, 2017 Roche’s controlled phase III trial in the second-line setting, Imvigor-211, showed Tecentriq to have no advantage over chemo in terms of survival or response rates. Even then the FDA did not rescind approval, instead calling for Tecentriq to continue to be prescribed according to its label.

There was concern over interim data from Imvigor-130, which suggested that low PD-L1 expressers would live longer on chemo than if given Tecentriq monotherapy. Data later presented at Esmo appeared to back this up (Esmo 2019 – PD-L1 status moves centre stage in bladder cancer, September 30, 2019).

Still, it was only in 2018 that Tecentriq’s label was narrowed, the FDA saying the drug should be given front line to cisplatin-ineligible patients only if these expressed PD-L1 at ≥5%. Those ineligible for any platinum chemo could still get the drug first line, irrespective of their tumours’ PD-L1 expression.


This was the state of play until today. An FDA spokesperson told Vantage that the agency’s Oncology Center of Excellence was reassessing oncology accelerated approvals as part of a broad, industry-wide evaluation.

This has now seen four anti-PD-(L)1 drugs withdrawn in short order, Bristol Myers Squibb’s Opdivo and Merck & Co’s Keytruda, both in small-cell lung cancer, and Astrazeneca’s Imfinzi in bladder, before today’s Tecentriq move.

Those wondering which indication is next to go might look at Keytruda in bladder cancer, and Keytruda and Opdivo in liver cancer. Tecentriq in ≥1% PD-L1 triple-negative breast cancer might be safe as the Impassion-130 trial that backed its approval did show a numerical overall survival benefit, but this was not tested statistically for technical reasons.

And all remaining accelerated approvals with failed confirmatory trials still have other studies running that could in future serve for confirmation. Not that this saved Tecentriq, of course: final Imvigor-130 data are still awaited but Pfizer’s Bavencio has been approved in post-platinum maintenance, and Roche says it decided to withdraw because the landscape had evolved.

Anti-PD-(L)1 drugs with accelerated US approvals and failed confirmatory trials
Drug (company) Indication Failed potentially confirmatory trial(s) Regulatory outcome Advanced potentially confirmatory trials remaining?
Keytruda (Merck & Co) Urothelial bladder cancer (2L/1L) Keynote-361 (1L) US label narrowed 3 Jul 2018 Keynote-676 (BCG combo in non-muscle invasive bladder cancer)
Liver cancer (2L) Keynote-240 (2L) None Keynote-394 (2nd-line Asian patients)
Gastric/GEJ adenocarcinoma (3L) Keynote-061 (2L) & 062 (1L, inconclusive) None Keynote-585 (neoadjuvant/adjuvant chemo combo)
SCLC (3L) Keynote-604 (1L) Withdrawn 1 Mar 2021 No
Tecentriq (Roche) Urothelial bladder cancer (1L) Imvigor-211 (2L) US label narrowed 3 Jul 2018; withdrawn 8 Mar 2021 Imvigor-130 final readout
TNBC (1L) Impassion-131 (1L) None Impassion-132 (note OS benefit in Impassion-130 not statistically tested)
Opdivo (BMS) Liver cancer (2L) Checkmate-459 (1L) None Checkmate-9DX (adjuvant)
SCLC (3L) Checkmate-331 (2L) & 451 (1L) Withdrawn 29 Dec 2020 No
Imfinzi (Astrazeneca) Urothelial bladder cancer (2L) Danube (1L, tremelimumab combo) Withdrawn 22 Feb 2021 Nile (tremelimumab combo)
Source: company information.

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