SITC – Roche and Bristol face bladder cancer threats

While checkpoint-blocking antibodies do battle over large indications like lung and head and neck cancers, a slightly less lucrative tumour type – bladder cancer – seized the limelight at the SITC meeting over the weekend.

The most important data came from Merck & Co’s Keynote-045, halted for efficacy last month, the first study to demonstrate the survival benefit of an anti-PD-1/PD-L1 agent in bladder cancer. This will put pressure on Roche’s marketed drug Tecentriq, and could threaten the approvability of Bristol-Myers Squibb’s Opdivo – though another trial has shown the promise of a Yervoy combination (see table below).

That said, Roche is not about to loosen its grip on this indication. It is running three large phase III studies in bladder cancer in over 2,000 patients combined, including the Imvigor-211 trial measuring overall survival as primary endpoint, which is due to yield data early next year.


In the meantime, a survival benchmark has been set by Keytruda, whose Keytnote-045 trial featured as a late-breaker at the SITC (Society for Immunotherapy of Cancer) meeting on Saturday.

Here Keytruda showed a 3.4-month median OS increase versus chemo alone, with a 27% reduction in risk of death (p=0.002), which surprisingly seemed not to have been driven by PD-L1-positive patients. Also surprising was the lack of a progression-free survival benefit, suggesting that patients were living longer with the cancer.

Overall remission was 21.1% in all comers, and 21.6% in PD-L1-positives; Tecentriq was approved on the strength of the Imvigor-210 trial, showing 14.8% ORR – strongly driven by patients whose tumours had PD-L1 expression of over 5%, where ORR was 26.0%.

The fact that these are across-trial comparisons is, of course, a major caveat, as is that varying methods of measuring PD-L1 expression are used. But investors now know what survival benefit Tecentriq is up against in Imvigor-211, and will closely watch data in PD-L1-low patients.

Overall survival results from Keynote-045 have also thrown into doubt the approvability of Roche’s second competitor, Bristol’s Opdivo, which is awaiting approval in bladder cancer, with a March 2, 2017, FDA action date, but is for now armed only with remission data. The Checkmate-275 trial at Esmo showed ORR of 19.6%, rising to 28.4% in PD-L1-high patients.

Now that Keytruda has shown a survival benefit, ORR data alone might not be enough for Opdivo. At a separate SITC late-breaker Bristol did raise the stakes, however, courtesy of the Checkmate-032 trial of Opdivo plus Yervoy showing a very impressive ORR of 38.5% with the higher of two Yervoy doses, irrespective of PD-L1 expression.

As always with Yervoy there is a price in terms of toxicity, and Bristol said 30.8% of patients suffered grade 3 or 4 treatment-related adverse events, though it insisted that Checkmate-032 showed no new safety signals.

Checkpoint inhibitor MAbs in bladder cancer
Available results*
Product Study Trial ID Setting All comers PD-L1-high pts** PD-L1-low pts** 2022e sales***
Tecentriq Imvigor-210 NCT02108652 310 pts in 2nd-line group ORR 14.8% ORR 26.0% ORR 9.5% $1,529m
Tecentriq Imvigor-211 NCT02302807 932 pts – measures OS Data in Jan 2017
Tecentriq Imvigor-130 NCT02807636 435 1st-line pts Data in Jun 2020
Tecentriq Imvigor-010 NCT02450331 700 PD-L1+ve pts Data in Apr 2022
Keytruda Keynote-045 NCT02256436 542 2nd-line pts ORR 21.1% (OS 10.3mth vs 7.4mth) ORR 21.6% (OS 8.0mth vs 5.2mth) NA $337m
Opdivo Checkmate-275 NCT02387996 270 2nd-line pts ORR 19.6% ORR 28.4% ORR 15.8% $153m
Opdivo + Yervoy Checkmate-032 NCT01928394 208 2nd-line pt cohort ORR 38.5% NA NA
Note: *across-study comparisons; **different assays and PD-L1 expression cutoffs are used; ***from EvaluatePharma sales by indication module.

As long as toxicity can be managed a Yervoy combo offers the possibility of treating patients with lower levels of PD-L1 expression, though the Keytruda monotherapy data in PD-L1-low patients are intriguing.

Tecentriq’s accelerated approval in bladder cancer is irrespective of PD-L1 status, though its label cites Imvigor-210, so prescribers will know that its effect beyond PD-L1-high expressers is scant. Moreover, as with most oncology indications, overall survival remains the gold standard, and no real comparisons can be made between the various agents until each has generated OS data.

A further threat in this setting could come from Astrazeneca’s durvalumab and Pfizer’s avelumab though, given how far behind these are, their large phase III trials will have to generate knockout data to break the current checkpoint inhibitors’ stranglehold.

To contact the writer of this story email Jacob Plieth in London at [email protected] or follow @JacobPlieth on Twitter

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