After surprising clinical observations of a patient with ALK fusion–positive lung cancer who had an exceptional response to an insulin-like growth factor 1 receptor (IGF-1R)-specific antibody, a team of researchers from Vanderbilt University, Tennessee, developed a therapeutic synergism between ALK and IGF-1R inhibitors that could benefit patients suffering from this particular type of lung cancer.
In the study entitled “Rationale for co-targeting IGF-1R and ALK in ALK fusion–positive lung cancer” and published in the Nature Medicine journal, the researchers analyzed the clinical outcome of a female patient with advanced lung cancer who remained on anti-IGF-1R therapy for 17 months, an immunotherapy stopping cancer cells from proliferating and surviving.
This patient had a dramatic response to the experimental therapy, leading the team to test the patient for gene mutations and finding the tumor was positive for an ALK gene fusion, an event occurring in about 5% of all lung cancer patients.
“ALK kinase gene fusions in lung cancer were discovered after the patient enrolled on the IGF-1R study. So there was no reason to think in advance that a patient with ALK+ lung cancer would benefit from this experimental therapy, since ALK gene fusions in lung cancer had not even been discovered when the trial was initially conceived,” Christine Lovly, M.D., Ph.D., assistant professor of Medicine and Cancer Biology and lead author of the study said in a University press release. “Since this patient had such a dramatic and unexpected response to the IGF-1R directed therapy, and was later noted to have an ALK gene fusion in her tumor, we became interested in understanding the potential interplay between ALK and IGF-1R to try to explain this patient’s exceptional response to the IGF-1R inhibitor.”
Following the analysis, the patient was enrolled in a clinical trial testing crizotinib, a drug targeting ALK rearrangements, which resulted in delayed cancer progression for several months.
These surprising results led researchers to test the efficacy of IGF-1R inhibitor therapies alone or in combination with ALK inhibitors, to stop ALK+ lung cancer growth and overcome acquired resistance to these inhibitor therapies.
Using in vitro cell lines, in vivo mouse models and ex vivo patient lung tumor cells, they found that combination therapy was capable of inhibiting ALK+ lung cancer cell proliferation.
“We need better tools to treat diseases like lung cancer that traditionally have been resistant to therapy, and increasingly, we are finding that combination therapies may be necessary to improve outcomes for our patients. The activity of this new combination therapy is encouraging,” Dr. Lovly added in the press release.
