Though drugmakers have spent considerable resources trying to expand the reach of immunotherapy through new drug combinations, success has been hard to find. Multiple high-profile projects, most notably ones from Incyte and Nektar Therapeutics, have failed or fallen short of expectations.
But the potential rewards are significant, given the fast growing use of immunotherapies across cancer types and the lucrative businesses drugmakers have built on that adoption. So far, medicines aimed at TIGIT have emerged as among the most promising, making them some of the most closely watched research programs in oncology.
Over the past several years, Roche, Merck & Co., Bristol Myers Squibb, GlaxoSmithKline and Gilead have all developed or acquired such drugs. Early clinical data has shown potential for them to boost the effects of checkpoint inhibitors — immunotherapies that have been proven effective in many different cancers but still, depending on the tumor type, may only help a minority of patients.
Roche’s tiragolumab is one of the most advanced drug candidates of the TIGIT class. The latest update comes after a median of two and a half years of follow-up for the 135 patients enrolled in a Phase 2 study known as CITYSCAPE. Results showed that patients on the drug combination are living longer than those given Tecentriq and a placebo.
The drug’s effects seem strongest in patients whose tumors express high levels of a protein, PD-L1, that’s known to be associated with immunotherapy response. In participants with lower levels, tiragolumab doesn’t appear to add much, if any, benefit over Tecentriq monotherapy.
Across the study overall, patients on Tecentriq and tiragolumab lived a median of over 23 months, versus more than 14 months for people who only received Tecentriq. Median survival hasn’t yet been reached, however, after nearly 31 months for combination recipients whose tumors have a lot of PD-L1 expressed. Among this group, study volunteers on only Tecentriq lived a median of 13 months.
That result equates to a roughly 77% reduction in risk of death, which “compares favorably” with the findings underlying Merck’s standard-of-care lung cancer regimen of Keytruda and chemotherapy, wrote Peter Welford, an analyst at Jefferies, in a note to clients.
In the KEYNOTE-189 study, which Merck used to support first-line lung cancer use of Keytruda and chemotherapy together, study participants with high PD-L1 lived a median of 28 months after treatment, versus 10 for chemo alone.
The risk of disease worsening or death was also cut by 71% for people with high PD-L1 on tiragolumab and Tecentriq, as tumors were held in check for a median of almost 17 months, versus just over four months for those who only received Tecentriq. Results were more modest — a 38% risk reduction — for the overall population, and the combination actually appeared to perform worse than Tecentriq alone among those with low PD-L1 expression.
Roche said the combination was generally well-tolerated, with infusion reactions, stiffness, dry skin, fatigue and rash the most common side effects. Rates of serious side effect were comparable between the two groups.
Two patients, however, died from treatment-related side effects in the combination group, compared to none who got only Tecentriq. Roche didn’t disclose further details on either death in its statement Friday.
SKYSCRAPER-01, Roche’s Phase 3 study, is assessing tiragolumab and Tecentriq only in people with high PD-L1 expression. Four other late-stage trials are ongoing in lung and esophageal cancers.