FDA Flags Lower Efficacy For Merck's Keytruda, Roche's Tecentriq In Frontline Bladder Cancer Trials

In patients with previously untreated metastatic bladder cancer with low PD-L1 expression, PD-1 drugs alone don't work as well as chemo.

The US FDA issued an alert on May 18 that said first-line monotherapy treatment with Merck & Co. Inc.'s Keytruda and Roche's Tecentriq in metastatic urothelial cancer (mUC) trials was linked with decreased survival in patients with low expression of the PD-L1 biomarker compared with chemotherapy, though this was not due to adverse events.

Keytruda (pembrolizumab), a PD-1 inhibitor, and Tecentriq (atezolizumab), a PD-L1 inhibitor, both were cleared under FDA's accelerated approval process for previously untreated metastatic bladder cancer in patients who are not eligible for cisplatin-based chemotherapy – about 40% to 60% of the first-line population.

Keytruda and Tecentriq as well as the three other PD-1/L1 drugs on the market – Pfizer Inc./Merck KGAA's Bavencio (avelumab), AstraZeneca PLC's Imfinzi (durvalumab) and Bristol-Myers Squibb Co.'s Opdivo (nivolumab) – were all approved based on response rate data for second-line use after platinum-based chemotherapy. Keytruda is the only one so far that has gone on to secure full approval in that indication after showing a survival benefit.  (Also see "Kalydeco Expands Indication Without Clinical Data; Keytruda Is Latest Bladder Cancer Approval" - Pink Sheet, 21 May, 2017.) However, Tecentriq failed to show a survival benefit in its Phase III confirmatory IMvigor211 second-line study. (Also see "Could Tecentriq's Bladder Cancer Setback Be A Class Effect?" - Scrip, 12 May, 2017.)

Bladder cancer is a relatively modest-sized market for PD-1/L1 checkpoint inhibitors, worth an estimated $2bn versus $14.8bn for non-small cell lung cancer indications and $30bn for all tumor types in 2022, according to Morningstar Research projections. Morningstar has projected that in 2022, Merck would take a 45% share of the bladder cancer market, followed by Roche with 30% and Bristol with 12%.

Decreased Survival In Trials

FDA issued an alert to health-care professionals, cancer trial investigators and the public about the use of the checkpoint inhibitors in first-line metastatic urothelial cancer studies following early reviews by data monitoring committees of two studies – the KEYNOTE-361 study (NCT02853305) of Keytruda and the IMvigor-130 trial (NCT02807636) for Tecentriq, both of which tested the drugs with or without platinum-based chemotherapy versus chemotherapy alone.

The agency said that in the monotherapy arms of both trials, patients with low PD-L1 had decreased survival compared to those taking cisplatin or carboplatin-based chemotherapy. This was attributed to a difference in efficacy, not a safety problem.

"There was no change in the adverse event profile of Keytruda or Tecentriq," FDA noted.

Low PD-L1 expression is defined as immune cell staining of less than 1% in Roche's study.

Merck's study defines low PD-L1 expression as a combined positive score (CPS), the percent of tumor or infiltrating immune cells, of less than 10.

On the recommendation of data monitoring committees, Merck and Roche have stopped enrolling patients with low PD-L1 into the monotherapy arms of the studies, but low PD-L1 patients may continue to participate in the PD-1/chemo combination and standalone chemotherapy arms of the trials.

Roche subsidiary Genentech noted that participants already randomized and treated with Tecentriq monotherapy may still continue to receive treatment.

FDA said it is reviewing the findings of the ongoing clinical trials and will communicate new information as necessary.

Following Labeling

The agency's statement notes that the patients enrolled in the trials were eligible for platinum-based chemotherapy and therefore different from the populations tested in trials supporting accelerated approvals in first-line metastatic urothelial cancer.

"We continue to believe in the efficacy and safety of Tecentriq monotherapy in people with locally advanced or mUC who are not eligible for cisplatin-containing chemotherapy," Genentech said in a statement provided to Scrip.

FDA recommended that providers select patients for treatment using criteria in the clinical studies section of drug's each label.

Keytruda's labeling in bladder cancer has no mention of PD-L1 expression status. While claims of the other PD-1/L1 drugs in bladder cancer have not specified a PD-L1 threshold in the indication, the clinical trials sections split out efficacy data by PD-L1 expression. (Also see "Kalydeco Expands Indication Without Clinical Data; Keytruda Is Latest Bladder Cancer Approval" - Pink Sheet, 21 May, 2017.)

Trials Continue

Merck said its KEYNOTE-361 study is ongoing and the company continues to work closely with regulatory agencies as additional data are generated in the course of the trial.

Roche's trial also continues and the company said there are no changes to other ongoing studies at this time.

Genentech is blinded to the IMvigor130 data and therefore it is challenging to extrapolate to other diseases.

FDA's statement did not reference late-stage first-line bladder cancer studies of other PD-1 inhibitors.

Bristol is testing its PD-1 inhibitor Opdivo in combination with its CTLA-4 inhibitor Yervoy (ipilimumab) or standard of care chemotherapy compared to the standard of care chemotherapy alone in the CheckMate 901 study of previously untreated metastatic urothelial cancer.

AstraZeneca is testing its PD-L1 inhibitor Imfinzi with or without its CTLA-4 inhibitor tremelimumab versus standard of care chemotherapy in advanced urothelial cancer.