Therapy focus – Immunotherapy crowds bladder cancer space

Astrazeneca’s durvalumab, now called Imfinzi, received its first approval yesterday in second-line bladder cancer; but a number of other agents are all vying for position in this relatively small patient population (see table).

Roche’s Tecentriq is the one to beat after cementing a win in first line last month – the first immunotherapy to do so. Bristol-Myers Squibb’s Opdivo is approved for second line, while Merck’s Keytruda boasts a survival benefit and is up before the regulators mid-year. As more agents reach the market in this space efficacy will need to doubly impress for a new drug to make headway.

First past the post

Tecentriq, an anti-PD-L1, initially had the second-line market all to itself with US approval last year. The green light was based on the results of Cohort 2 in the Imvigor-210 trial, which showed a 14.8% objective response rate (ORR) – strongly driven by patients whose tumours had PD-L1 expression of over 5%, among whom the ORR was 26.0%.

Its more recent first-line approval in patients ineligible for chemotherapy came off the back of Cohort 1 data from the same Imvigor-210 trial. In 119 patients the ORR was 23.5%, and 28.1% in patients with over 5% PD-L1 expression.

At last year’s Asco the company showed a median OS of 7.9 months in second line and 14.8 months in first line, although as a single-arm trial these data come with caveats.

In 2016 Roche reported Tecentriq sales of $159m but that number also includes sales from its October approval in second-line non small cell lung cancer. In bladder cancer sales are forecast at $793m by 2022. While this figure confirms its top seller position analysts are starting to factor in the competition; 2022 sales sat at $1.5bn when EP Vantage looked at the space at the end of last year (SITC – Roche and Bristol face bladder cancer threats, November 14, 2016).

Second line competition

Opdivo, an anti-PD-1, was second to market with approval in the second-line setting earlier this year. With the caveat of cross-trial comparisons, Opdivo’s ORR in the Checkmate-275 trial was 19.6%, again increasing to 28.4% in PD-L1 patients with over 5% expression. The median OS was 8.74 months in all treated patients.

Data from Checkmate-032 in second-line patients given a combination of Opdivo and Yervoy showed an impressive ORR of 38.5% when the higher of two Yervoy doses was used. ORR was 26% in the lower dose group. However, Yervoy comes with toxicity issues, with 30.8% of patients suffering grade 3-4 adverse events in the higher dose group.

A first-line combination trial called Checkmate-901 is ongoing versus standard of care with a primary completion date of 2020. Opdivo can claim a victory in Europe, the drug becoming the first to receive a positive CHMP opinion in second-line use last month. 

Astra’s Imfinzi, another anti-PD-L1, received approval yesterday in the second-line setting. In study 1108 the ORR was 17% and 26.3% in patients whose tumours express 25% or more PD-L1. In PD-L1 low or negative the ORR was 4.1%. Analysts had thought the label could be restricted to PD-L1 high expressers, but approval was granted regardless of PD-L1 status.

A first-line trial called Danube is enrolling both chemo-eligible and -ineligible patients testing Imfinzi in combination with tremelimumab, Astra’s CTLA4 antibody, with data expected early next year. Astra appears to be leading the development in the chemo-eligible population, which UBS analysts note makes up around 70% of patients.

One aspect that could also contribute to use is Tecentriq’s administration – a 30 minute infusion every three weeks while Opdivo and Imfinzi require a 60 minute infusion every two weeks.


Merck's Keytruda, another anti-PD-1, should come before the regulators by June 14 in both first and second-line settings. It has the edge by boasting a survival benefit over chemotherapy, which will likely be on the label.

In the second line Keynote-045 trial it showed a median OS of 10.3 months versus 7.4 months for chemotherapy. In high PD-L1 expressers (10% or more) the median OS was 8.0 months versus 5.2 months. The ORR was 21.1% with Keytruda versus 11.4% in chemotherapy. In high expressers it was 21.6% with immunotherapy and 6.7% with chemotherapy.

Its first line setting is based on the Keynote-052 trial in chemo-ineligible patients. In data presented at last year’s Esmo Merck reported an ORR of 24% and 36.7% in high PD-L1 expressors.

Its OS advantage is reflected in consensus forecasts with sales of $439m by 2022 according to EvaluatePharma, putting it in second place behind Tecentriq and way ahead of Opdivo's $128m.

Available ORR results in bladder cancer* 
Product  Study  Setting  All comers  PD-L1-high pts** 
Tecentriq  Imvigor-210  Cohort 2 2nd-line 14.8%  26.0% 
Tecentriq Imvigor-210  Cohort 1 1st line 23.5% 28.1%
Opdivo  Checkmate-275  2nd-line 19.6%  28.4% 
Opdivo +Yervoy  Checkmate-032  2nd-line 38.5%  NA 
Imfinzi Study 1108 2nd-line 17.0% 26.3%
Keytruda  Keynote-045  2nd-line 21.1% (OS 10.3mth vs 7.4mth)  21.6% (OS 8.0mth vs 5.2mth) 
Keytruda  Keynote-052 1st line 24.0% 36.7%
Note: *across-study comparisons; **different assays and PD-L1 expression cutoffs are used

Finally Pfizer’s Bavencio, known generically as avelumab, will hear from the US regulator in August as a maintenance treatment in the first-line setting. The filing was based on the Javelin Bladder 100 trial that tests Bavencio and best supportive care versus BSC alone, in patients that did not progress after first-line chemotherapy. The target population is limited, and no sales are currently assigned to the bladder indication.

Catching up

Competition is fierce in this relatively small market opportunity. Last year in the US 77,000 patients were diagnosed with bladder cancer and at diagnosis around 10% of cases are at the advanced stage, according to UBS analysts.

In first line use, the biggest market, Merck is shaping up for battle with Roche, although over time Astrazeneca and Bristol could catch up if their combination strategies bear fruit. Emerging survival benefits could ultimately determine who leads the pack in years to come.

Advanced bladder cancer PD-1/L1 pipeline      
Status Product  Company  US Approvals  Treatment  Trial ID  WW 2022 indication sales ($m) 
Marketed  Tecentriq  Roche  19 May 16 2L 1L chemo ineligible monotherapy IMVigor210 (Cohort 1) NCT02951767 793 
18 April 17 1L (chemo-ineligible) 1L +/- Gem/Carbo IMvigor 130 NCT02807636
(EU decision Q2?)  2L mono IMvigor 210 (Cohort 2) NCT02108652
2L mono  IMvigor 211 NCT02302807 
Opdivo*  BMS/Ono 2 Feb 17 2L 1L Opdivo +Yervoy CheckMate-901 NCT03036098 128 
(CHMP positive opinion 21 Apr 17 2L)  2L mono CheckMate-275 NCT02387996
2L mono  CheckMate-032 NCT01928394 
Approved Imfinzi Astrazeneca  1 May 17 2L  1L +/- Treme chemo-eligible and ineligible patients Danube NCT02516241 417**
2L mono  Study 1108 NCT01693562
Filed Keytruda*  Merck & Co  PDUFA 1L (chemo-ineligible) and 2L 14 June 17  1L chemo ineligible mono KeyNote-052 NCT02335424 439 
1L +/- Pt-based chemo KeyNote-361 NCT02853305
2L mono KeyNote-045 NCT02256436
2L +/- ACP-196  KeyNote-143 NCT02351739 
Bavencio  Pfizer/Merck KGaA  PDUFA 2L 27 Aug 17  Maintenance treatment w/ BSC  Javelin Bladder 100 NCT02603432 
*Anti-PD-1 MAb, remainder are anti-PD-L1; ** consensus prior to approval; source: EvaluatePharma

To contact the writer of this story email Joanne Fagg in London at [email protected] or follow @ByJoFagg on Twitter

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