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Executive Summary
Merck's filings in bladder cancer span first-line and second-line treatment and include overall survival data. Roche also is getting ready to move Tecentriq to the frontline setting.
Bristol-Myers Squibb Co. has secured yet another approval for Opdivo – in second-line bladder cancer – but competitor Merck & Co. Inc. is once again nipping at its heels with a broader filing strategy for Keytruda in the indication, while first-to-market Roche is gearing up to move Tecentriq into the frontline with Phase III data close at hand.
Roche's PD-L1 inhibitor Tecentriq (atezolizumab) has the clear lead in the bladder cancer market, following approval as a second-line therapy in May 2016. But it now faces competition: Bristol’s PD-1 inhibitor Opdivo (nivolumab) cleared FDA Feb. 2 with accelerated approval for urothelial cancer after progression on platinum-based chemotherapy or after progression on neoadjuvant or adjuvant chemotherapy.
The filing, which had breakthrough therapy designation, was supported by the CheckMate 275 study of 270 patients, in which there was a 19.6% response rate, including 2.6% with complete responses. The median duration of response was 10.3 months.
The drug has benefited from broad labeling, now with eight indications.
Bristol declined to comment on its regulatory strategy for filing in first-line bladder cancer. It did note that it is running two Phase III studies – CheckMate 274 of Opdivo vs. placebo in the adjuvant setting, which is due to report in the fourth quarter of 2020, and CheckMate 901 of Opdivo with the firm’s CTLA-4 checkpoint inhibitor Yervoy (ipilimumab) in first-line bladder cancer, which is due to report in the third quarter of 2020.
Merck Shoots For First- And Second-Line
For the time being, Opdivo has a lead in the indication over Merck's PD-1 inhibitor Keytruda (pembrolizumab). Merck announced Feb. 3 that FDA has accepted two filings for Keytruda in bladder cancer, both of which have priority review. One covers first-line patients who are ineligible for cisplatin-containing therapy. And a second, which has breakthrough designation, covers patients with disease progression on or after platinum-containing chemotherapy. Both applications have a user fee date of June 14.
Merck's filings are supported by the Phase II KEYNOTE-052 first-line study and the Phase III KEYNOTE-045 second-line study. The firm stressed that the drug demonstrated an overall survival benefit compared to chemotherapy in the KEYNOTE-045 trial, while acknowledging that it did not improve progression-free survival.
Merck has been stealing a lead over Bristol in some important respects in recent months. Keytruda is approved as a monotherapy for first-line non-small cell lung cancer and is under review at FDA for use in combination with chemotherapy in first-line NSCLC. Bristol's introduction of Opdivo in first-line NSCLC faced a major setback with the failure of the CheckMate 026 monotherapy study and the company's recently announced decision not to file for accelerated approval of Opdivo with Yervoy in first-line NSCLC.
Keytruda's gains relative to Opdivo, however, haven't made their mark on sales yet – Merck reported $1.4bn in 2016. (Also see "Merck's Keytruda Reaches Blockbuster Status, But Still Lags In Lung Cancer" - Scrip, 3 Feb, 2017.) Including all indications, Bristol reported $3.77bn for Opdivo in 2016. (Also see "Under Fire, Bristol Plans To Pick Up The IO Pieces" - Scrip, 26 Jan, 2017.) Opdivo brought in sales of $1.3bn in the fourth quarter of 2016, but US sales were flat from the prior quarter as the drug faced more competition from Roche's Tecentriq in second-line NSCLC; Roche’s PD-L1 inhibitor was cleared for that indication in October 2016.
Bristol's response to the lung cancer setbacks was to highlight development in a wide range of indications, both for Opdivo as a monotherapy and Opdivo in combination with Yervoy.
Taking On Tecentriq
Roche reported better than expected uptake of Tecentriq during its fourth quarter earnings call on Feb. 1. (Also see "Cautious Roche Stresses: 'It's Not Only About APHINITY'" - Scrip, 2 Feb, 2017.) According to Roche, the drug already has a 60% share of the market, which had not seen the introduction of a new treatment in decade, and brought in CHF157m ($158m) in sales for 2016.
The Phase II IMvigor210 study, which used objective response rate as a primary endpoint, supported the second-line filing and also a new filing in first-line patients ineligible for cisplatin-based chemotherapy or who had disease progression at least 12 months after neoadjuvant or adjuvant chemotherapy. The first-line filing is under priority review at FDA with a user fee date of April 30.
Roche expects to report confirmatory trial results from the Phase III IMvigor211 second-line bladder cancer study this year, possibly in time for the American Society of Clinical Oncology annual meeting in June. IMvigor211 tested Tecentriq against chemotherapy, with overall survival as a primary endpoint. The company is also looking to expand the drug into even earlier-stage settings through other trials.
Morningstar analyst Damien Conover commented to Scrip that Roche's first-mover advantage will support Tecentriq's leading market share, but "relatively strong data from Bristol and Merck will likely mean those companies will get the majority of the rest of the market," which his firm expects will drive PD-1/L1 drug sales close to $3bn annually in bladder cancer.
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