The future role of checkpoint inhibitors in melanoma has been the topic of recent discussion amongst oncologists, as reported in a recent OncLive video debate.
Tolerability and the development of predictive biomarkers guiding treatment selection could be a crucial determinant, according to Omid Hamid, MD, Director, Melanoma Program The Angeles Clinic and Research Institute, Santa Monica, California.
Past clinical trials have stressed the toxicity involved in combining BRAF (MAP kinase inhibitor) and CTLA-4 therapies, especially elevated ALT/AST, an indicator of liver damage, and bowel perforation. Moreover, nivolumab (anti-PD-1 receptor monoclonal antibody) and ipilimumab (anti-CTLA-4 monoclonal antibody) combination therapy also created concerning side effects, a problem that was not verified upon ipilimumab and T-VEC (an anti-cancer viral vaccine) combination.
There is still not enough research to understand which patients are more susceptible to suffer higher toxicity and at which point in time these side effects occur, leaving an open gap towards optimal treatment.
Through recent clinical trials, researchers and physicians have gained empirical knowledge as to which and when side effects would occur, indicating that time could provide critical clues for the success of these combined immunotherapies.
However, Dr. Hamid believes that biomarker development is the answer for both benefit and toxicity in this type of therapies.
According to Louis M. Weiner, MD, Director, Georgetown Lombardi Comprehensive Cancer Center, Dept. of Oncology, Georgetown University Medical Center, it is important to understand the added toxicity with combination drugs, since it is common practice to create individualized experimental regimens to approach melanoma treatments.
There are still few clinical trials specifically focused on understanding this problem, and the majority of the ongoing trials necessary to provide critical clues on combinations and biomarkers are already accumulating patients. Furthermore, drugs that proved efficient in treating melanoma are being administered as either adjuvant or in combination.
Another important and unsolved question concerns the unresponsiveness of patients to current therapies, with the answer lying once more in additional biomarker research, as stated by Dr. Weiner.
Even though PD-1 ligand, a protein involved in suppressing immune responses, has been used as a biomarker for the design of melanoma treatments, this ligand by itself may not be the only necessary marker, since patients who are negative for PD-1 ligand in clinical trials still respond to treatment.
To address this problem, studies examining MPDL3280A, an experimental anti-PD-1 ligand antibody, are analyzing markers of T cell activation, changes in PD-L1 staining and gene arrays.
The conclusion from ongoing debates within the medical and research community are extremely important to find the direction that future studies may take to optimize outcomes in treating melanoma patients.