Finding A New Role For Yervoy

Academics question whether Yervoy would enjoy broader use at a lower dose in a combination with PD-1 or in a sequential protocol to minimize severe side effects and costs, and boost use in the community setting.

Determining the role of Bristol’s once ground-breaking CTLA-4 inhibitor Yervoy is more complicated following the release of new data at the recent American Society of Clinical Oncology meeting.

Data from the combination CheckMate 067 study show that the combination of Yervoy with Bristol’s Opdivo offers the best response and progression-free survival rates, but at the cost of many more severe side effects.

Opdivo monotherapy also outperformed Yervoy alone, so Yervoy by itself is no longer the standard of care for first-line treatment, but it will be used in combination first-line or as a monotherapy in second-line treatment, melanoma expert Steven O’Day commented, on behalf of ASCO.

Experts note there have been differences in treatment for academic and community settings, so the impact will be different based on the setting. Clinicians at academic centers were quick to embrace Yervoy as a front-line treatment, regardless of mutation status, if patients had some time to wait for treatment to work, to give patients a shot at the durable response demonstrated by immunotherapy.

Part of the attraction for that strategy is that Yervoy was given in a fixed set of four treatments, Memorial Sloan Kettering oncologist Paul Chapman explained. If that was unsuccessful, mutation-positive patients could then get BRAF/MEK. PD-1 inhibitors have been rapidly adopted in the academic setting following their approval, Chapman said.

Community oncologists, on the other hand, have been more reticent to use Yervoy due to its side effects.

Immuno-oncology veteran researcher Michael Atkins noted that a lower dose of Yervoy could make the combination with PD-1 better tolerated in the future, and therefore more usable in the community setting. It’s also possible that a class with a better tolerability profile, like IDO, 4-1BB or OX40 could emerge as a substitute for Yervoy in combination treatment in the future, Atkins said in an interview after the ASCO annual meeting in late May-early June. The clinician also said that he believes that the combination of Yervoy/Opdivo will be adopted in academic centers and that there is no longer a role for Yervoy monotherapy.

However, others see open questions regarding the use of Yervoy. Melanoma Research Foundation executive director Tim Turnham commented that Yervoy works very well in some, and has the fixed duration of treatment. The problem is that one can’t know who the responders will be. Bristol said it continues exploratory research for a Yervoy biomarker, but to date none have been consistently effective.

Chapman, who was closely involved in the CheckMate 067 study combining Yervoy and Opdivo, noted the lack of overall survival data in the trial as yet. Furthermore, and very importantly, investigators do not know if the combination is better for patients than giving one drug followed by the other sequentially if necessary, Chapman said.

“That strategy may be even better than giving everyone the combination upfront,” Chapman said.

BioMedTracker analysts noted that an important implication emerging from ASCO is “a biological model in which CTLA-4 exposure actually increases T-cell infiltration into tumors thus making them more sensitive to PD-1 inhibition.” While that has the effect of growing the PD-1/L1 market, it also creates a new role for Yervoy.