because of the risk of increased toxicity.
Sotorasib is indicated for adults with locally advanced or metastatic NSCLC who carry a KRASG12C mutation, which occurs in about 13% of cases.
Since its approval in 2021, sotorasib has emerged as “a new standard of care” for such patients after chemotherapy and anti–PD-L1 failure, the investigators say.
The new warning comes after the team compared 48 patients who received an anti–PD-L1 – most often pembrolizumab alone or in combination with platinum-based chemotherapy – before sotorasib with a control group of 54 patients who either didn’t receive an anti–PD-L1 before sotorasib or had at least one other treatment in between.
The team found that sequential anti–PD-L1 and sotorasib therapy significantly increased the risk of severe sotorasib-related hepatotoxicity and also the risk of non-liver adverse events, typically in patients who received sotorasib within 30 days of an anti–PD-L1.
“We suggest avoiding starting sotorasib within 30 days from the last anti–PD-(L)1 infusion,” say senior author Michaël Duruisseaux, MD, PhD, Louis Pradel Hospital, Bron, France, and collegues.
The findings should also “prompt a close monitoring for the development of hepatotoxicity and non-liver AEs [in] patients who receive sotorasib after anti–PD-(L)1,” they add.
The study was published in the Journal of Thoracic Oncology.
Actionable findings
“I consider the results to be highly credible and informative to my own practice,” said Jack West, MD, a thoracic medical oncologist at the City of Hope outside of Los Angeles, said in an interview.
The findings “may lead me to favor a trial of docetaxel as an intervening therapy for patients who have very recently discontinued immunotherapy, deferring sotorasib at least a few weeks and ideally several months,” Dr. West commented. “I think this is a particularly reasonable approach when we remember that sotorasib conferred no improvement in overall survival at all over docetaxel in the CodeBreaK 200 trial in KRASG12C-mutated NSCLC.”
Overall, the study “corroborates what we’ve seen in the limited first-line experience of sotorasib combined with immunotherapy and also echoes our experience of other targeted therapies, such as osimertinib administered in the weeks just after patients received immunotherapy, which is known to be associated with life-threatening pneumonitis,” he said.
Jared Weiss, MD, a thoracic medical oncologist at the University of North Carolina, Chapel Hill, said that given the long half-life of immune checkpoint inhibitors, “it is quite understandable that the toxicity challenges we previously saw with concurrent administration of immunotherapy and certain targeted therapies would be recapitulated in patients who had a relatively short interval between prior checkpoint inhibitor therapy and sotorasib.”
Even so, because of the aggressiveness of NSCLC, long treatment delays between immunotherapy and sotorasib therapy are “not a favored option.”
Like Dr. West, Dr. Weiss said docetaxel (with or without ramucirumab) is a sound intervening alternative.
Another option is to use adagrasib in the second line instead of sotorasib, Dr. Weiss suggested. It’s also a KRASG12C inhibitor but hasn’t so far been associated with severe hepatotoxicity, he said.
Hossein Borghaei, DO, a thoracic medical oncologist at Fox Chase Cancer Center, Philadelphia, agrees with his colleagues and thinks that what the French team found “is real.”
As the investigators suggest, “it might be that sotorasib leads to an inflammatory microenvironment that causes hepatotoxicity in the presence of a checkpoint inhibitor. In that case,” a lower dose of sotorasib might help reduce toxicity while remaining effective, Dr. Broghaei suggested.