Checkpoint therapies before surgery? MD Anderson team reports encouraging efficacy but worries about toxicity
Days after the Nobel committee honored immunotherapy in this year’s medicine prize, MD Anderson, where Nobel winner Jim Allison currently works, has some new human data — and lessons — about a novel way to use checkpoint inhibitors.
While checkpoint drugs like Opdivo (nivolumab) and Yervoy (ipilimumab) are often given to melanoma patients after surgery or when their cancer is unresectable, researchers wanted to know if administering them before surgery could be an effective approach.
The short answer is yes — but with a big asterisk.
In a Phase II study involving patients who have reached high-risk stage 3 of the deadly skin cancer, MD Anderson researchers gave 12 patients the PD-1 inhibitor nivolumab and another 11 a combination of nivolumab and ipilimumab, which targets CTLA-4.
Investigators observed that combined checkpoint blockade was “much more effective,” with 8 patients in the arm seeing their tumor shrink and 5 of them showing no evidence of disease at surgery. It’s however a result marred by notable toxicity — 8 experienced grade 3 side effects, causing delays in dosing and surgery.
The single-agent anti-PD-1 group, meanwhile, showed “modest response rates” at 25% tumor shrinkage or disappearance. Only 1 patient in the group had grade 3 side effects, but 2 others progressed to stage 4 metastatic melanoma before they could get to surgery — a cause for concern.
“It is clear from this trial that we need to further optimize this treatment approach,” said Rodabe Amaria, co-first author and assistant professor at MD Anderson’s department of melanoma medical oncology.
Why does it matter whether the checkpoint drugs are given before or after surgery? Here Michael Tetzlaff, a pathology professor and senior author on the study, explains:
The advantage of a neoadjuvant approach in this setting is that it enables an interval evaluation of the tumor cells after therapy to determine the extent to which those tumor cells responded to the therapy in real time and predict which patients are likely to experience durable responses going forward. It also provides us the tissue resources to determine why tumors may not respond to therapy and thus tailor therapies going forward as we learn more about resistance.
The high occurrence of side effects forced investigators to close the trial early, but they note that overall survival at 24 months was 100% in the combo arm and 75% in the nivolumab arm. In a redesigned study, they replaced ipilimumab with relatlimab (an LAG3 inhibitor from Bristol-Myers Squibb) anticipating a better safety profile.