Lilly edges towards the bladder cancer queue

The industry’s PD-1/L1 assets might be charging towards the market in bladder cancer, but Eli Lilly confirmed today that other novel mechanisms should not be ruled out. The company’s anti-VEGF antibody Cyramza has succeeded in extending progression-free survival in a large phase III study in the second-line setting.

This is something that Keytruda failed to do in a similar trial, but more importantly the Merck antibody extended overall survival – the US regulator granted full approval in the second-line setting earlier this month. Thus Lilly must wait until next year for the survival read-out from its trial to judge whether a path to market is possible.

Lilly said today that the Range study of Cyramza (ramucirumab) plus docetaxel yielded a statistically significant improvement in PFS over patients treated with the chemo agent alone. These patients had advanced urothelial carcinoma – bladder cancer accounts for the majority of these cases – and had already failed on platinum-based therapy.

Lilly’s boast that Range is the first phase III study to show superior PFS over chemotherapy in second-line disease could prove to be irrelevant, given the Keytruda result in Keynote-045. This trial also recruited platinum failures, testing Keytruda monotherapy against physician’s choice of chemotherapy agents.

Although PFS was no different between treatment groups survival was extended by around three months and the study was stopped early for efficacy.

Keytruda OS results in second-line bladder cancer
Study   All comers   PD-L1-high patients
Keynote-045   (NCT02256436) 10.3mth vs 7.4mth (21.1% ORR) 8.0mth vs 5.2mth (21.6% ORR)

This therefore would seem to be the bar for Range to cross when it comes to the survival read out, which Lilly expects in mid-2018. As has been shown frequently in the past, a hit on PFS is no guarantee of success down the line.

Cyramza is a pretty big deal for Lilly – EvaluatePharma ranks it as the company’s fifth most important sales growth driver – and alongside abemaciclib the antibody is hugely important for its oncology efforts. Approvals in lung, gastric and colorectal cancers are already in the bag; extension into bladder cancer would strengthen the franchise further.

Sales are forecast to hit $1.2bn by 2022, consensus data show, with bladder already representing some of this expected growth.

The danger for the anti-angiogenic agent – in bladder but also other indications – is that it might become irrelevant as immuno-oncology approaches encroach (Therapy focus – Immunotherapy crowds bladder cancer space, May 2, 2017).

In bladder cancer Astrazeneca’s Imfinzi and Bristol-Myers Squibb’s Opdivo are on the market in a second-line setting and Roche’s Tecentriq and Keytruda have first-line labels. All of these are conditional approvals based on response rates, and it is not inconceivable that solid survival data in randomised phase III trials will emerge.

Some of those read outs are not too far off, although the failure of Roche's Imvigor-211 trial earlier this month shows success is not guaranteed. The study failed to extend survival over chemotherapy, with the Swiss firm hinting at a strong performance in the chemotherapy arm (Tecentriq failure puts accelerated approval in a spin, May 10, 2017)

Consensus for Cyramza sales in 2022 has already shrunk by 25% over the last 12 months. The final Range data need to be hugely impressive for the drug to hold off these worthy challengers.

On-going PD-1/L1 bladder cancer phase III trials 
Drug/study Setting Primary completion date Trial ID
Tecentriq      
Imvigor-211 Second-line; vs chemo  Mar 2017 NCT02302807
Imvigor-010 Adjuvant; vs observation Jun 2017 NCT02450331
Imvigor-130 First-line; +/- chemo  Dec 2018 NCT02807636
Imfinzi      
Danube  First-line; +/- tremelimumab vs chemo  Apr 2018 NCT02516241
Keytruda      
Keynote-361 First-line; +/- chemo vs chemo Jan 2019 NCT02853305
Opdivo      
Checkmate-901 First-line; + Yervoy vs chemo Apr 2020 NCT03036098

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