Since the arrival of cancer immunotherapies Keytruda and Opdivo eight years ago, drugmakers have sought to repeat their success by finding new ways to direct the body's defenses against tumors.
But that goal has proved elusive. Merck, Bristol Myers Squibb and Roche have all backed out of projects or partnerships meant to find the next immunotherapy after clinical trial disappointments in recent years.
Now Roche is at the vanguard of research into a new type of immune-activating treatment with an experimental drug called tiragolumab. While early testing showed promise, more recent data from two late-stage trials in lung cancer has disappointed, raising questions among experts whether tiragolumab will live up to expectations. Roche's results also impact other drugmakers like Bristol Myers, Gilead, GSK and Novartis, which have poured hundreds of millions of dollars into researching drugs like tiragolumab.
Roche has invested heavily, too, having already launched five Phase 3 trials pairing tiragolumab with its immunotherapy Tecentriq in lung and esophageal cancer. Tiragolumab targets a protein called TIGIT that is thought to influence how immune cells recognize and attack tumor cells. Blocking TIGIT, the thinking goes, could work well with Tecentriq and other cancer immunotherapies aimed at proteins called PD-1 and PD-L1, which have been proven to help some patients with a range of cancers live longer.
Often, cancer drug developers seek to gain speedy approvals based on whether their treatments can shrink the size of tumors, and then follow up with larger trials that measure how long they help patients live. They typically choose to test their experimental therapies after other, already proven drugs have failed, too.
With tiragolumab, however, Roche is trying to clear a high bar first, testing it in combination with Tecentriq as a initial treatment and measuring its impact on disease progression and survival.
This has led to the early tiragolumab disappointments in two challenging lung cancers. In extensive-stage small cell lung cancer, a tumor type for which Tecentriq is already approved, the addition of tiragolumab didn't delay disease progression or help patients live longer than Tecentriq alone. Detailed data on this trial, called SKYSCRAPER-02, was revealed at the American Society of Clinical Oncology meeting on Sunday.
"Based on these data, our conclusion is targeting TIGIT in extensive-stage small cell lung cancer does not appear to be therapeutically relevant," said Charles Rudin, a medical oncologist at Memorial Sloan Kettering Cancer Center who presented the data at ASCO.
In the other lung cancer trial, which tested the two drugs in a more common tumor type called non-small cell, the addition of tiragolumab didn't significantly delay disease progression over Tecentriq alone in newly diagnosed patients expressing high levels of PD-L1. However, Roche hasn't gathered enough data yet to determine whether patients lived longer, nor has it released anything other than summary data on disease progression.
Roche executives acknowledge the approach taken in SKYSCRAPER-02 carried with it the danger of failure. But they said they hoped to provide another option in a disease that, apart from Tecentriq and AstraZeneca's immunotherapy Imfinzi, primarily has only older chemotherapies as treatments.
"We went into SKYSCRAPER-02 knowing it was a calculated high risk, and also that it wasn’t a referendum on tiragolumab," Charles Fuchs, Roche's senior vice president and global head of oncology and hematology drug development, said in an interview.
Indeed, the Swiss drugmaker's executives have spoken confidently about the numerical advantage their research team has measured for the tiragolumab combination on survival and disease progression in the non-small cell lung cancer trial, although neither has yet met the bar for success over Tecentriq.
Reviewing the data from SKYSCRAPER-02, Wall Street analysts noted a small detail in Roche's statistical analysis that could bode well for the non-small cell trial, which is called SKYSCRAPER-01. In simple terms, Roche's research team put greater emphasis on measuring an improvement in overall survival, so its assessment of disease progression — a yardstick called "progression-free survival" — needed to meet a higher threshold before the trial's statisticians could call it significant.
If SKYSCRAPER-01 is designed the same way, the overall survival result could end up differing from the initial progression-free survival data. "These tidbits raise our confidence that there is a real chance Roche can hit on a subsequent [overall survival] analysis," Evercore ISI analyst Umer Raffat wrote in a June 5 note to clients.
Overall survival is the Food and Drug Administration's gold standard for approval, while progression-free survival can be used in certain circumstances, such as if subsequent treatments might affect measurements of overall survival.
Based on the statistical analysis Roche chose, analysts questioned why Roche even set progression-free survival as a trial goal. Executives, however, said it was included because positive data could have led to a more immediate FDA application, if the tiragolumab combination was dramatically effective.