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 proved elusive. Merck, Bristol Myers Squibb and Roche have all abandoned projects or partnerships to find the next immunotherapy after clinical trial disappointments in recent years.
Today, Roche is at the forefront of research into a new type of immune-activating treatment with an experimental drug called tiragolumab. While early tests showed promise, more recent data from two late-stage lung cancer trials have disappointed, raising questions among experts about whether tiragolumab will live up to expectations. Roche’s findings also impact other drugmakers like Bristol Myers, Gilead, GSK and Novartiswho have invested hundreds of millions of dollars in research into drugs like tiragolumab.
Roche has also invested heavily, having already launched five phase 3 trials combining tiragolumab with its immunotherapy Tecentriq in lung and esophageal cancer. Tiragolumab targets a protein called TIGIT which is thought to influence how immune cells recognize and attack tumor cells. Blocking TIGIT, it is thought, could work well with Tecentriq and other cancer immunotherapies targeting proteins called PD-1 and PD-L1, which have been shown to help some patients with various cancers to to live longer.
Often, cancer drug developers seek to gain rapid approvals based on the ability of their treatments to shrink tumors, then follow up with larger trials that measure how long patients live. They usually choose to test their experimental therapies after other proven drugs have failed.
With tiragolumab, however, Roche is trying to raise the high bar first, testing it in combination with Tecentriq as an initial treatment and measuring its impact on disease progression and survival.
This led to tiragolumab’s first disappointments in two difficult lung cancers. In extensive-stage small cell lung cancer, a tumor type for which Tecentriq is already approved, the addition of tiragolumab did not 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 finding targeting TIGIT in extensive-stage small cell lung cancer does not appear to be therapeutically relevant,” said Charles Rudin, medical oncologist at Memorial Sloan Kettering Cancer Center, who has presented the data to ASCO.
In the other lung cancer trial, which tested both drugs in a more common type of tumor called non-small cell, adding tiragolumab did not significantly delay disease progression compared to to Tecentriq alone in newly diagnosed patients expressing elevated levels of PD-L1. However, Roche has not yet collected enough data to determine whether patients lived longer, nor has it published anything other than summary data on disease progression.
Roche executives acknowledge that the approach taken in SKYSCRAPER-02 carried a risk of failure. But they said they hoped to offer another option in a disease that, aside from Tecentriq and AstraZeneca’s Imfinzi immunotherapy, mostly only has older chemotherapies as treatments.
“We entered SKYSCRAPER-02 knowing that this was a calculated high risk, and also that this was not a referendum on tiragolumab,” said Charles Fuchs, vice president. Roche’s senior and global head of drug development in oncology and hematology, in an interview.
Indeed, executives at the Swiss drugmaker spoke with confidence about the numerical advantage their research team measured for the tiragolumab combination on survival and disease progression in the non-human lung cancer trial. cells, although none have yet reached the bar of success compared to Tecentriq.
Reviewing the SKYSCRAPER-02 data, Wall Street analysts noted a small detail in Roche’s statistical analysis that could bode well for the non-small cell trial, called SKYSCRAPER-01. Simply put, the Roche research team has placed more emphasis on measuring an improvement in overall survival, so their assessment of disease progression – an endpoint called “progression-free survival” – had to reach a higher threshold before the trial statisticians could qualify it as significant.
If SKYSCRAPER-01 is designed in the same way, the overall survival result could end up differing from the initial progression-free survival data. “This information reinforces our confidence that there is a real chance that Roche could strike on a next [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 may be used in certain circumstances, such as if subsequent treatments may affect measures of overall survival.
Based on the statistical analysis chosen by Roche, analysts wondered why Roche had even set progression-free survival as a trial goal. The executives, however, said it was included because positive data could have led to a more immediate request from the FDA, if the tiragolumab combination was extremely effective.