Jason J. Luke, MD, discusses potential new methods for determining prognostic markers in melanoma and the challenges of balancing toxicity with efficacy in designing combination regimens.
Jason J. Luke, MD, FACP
Although nivolumab (Opdivo) and ipilimumab (Yervoy) together demonstrate superior survival in previously untreated patients with advanced melanoma, the combination comes with additional toxicity and an increased price tag, says Jason Luke, MD, assistant professor of Medicine at the University of Chicago Medicine.
“There have been several studies designed around trying to predict which patients are most likely to benefit from anti—PD-1 or immunotherapy combinations. I really think that is going to be an essential part of the future approach to treatment, says Luke. “Not all patients respond to these treatments. There are additional toxicities with the combinations, and there are also cost issues because of how catastrophically expensive these drugs are. We really need to know which patients are most likely to respond and which aren’t.”
The phase III CheckMate-067 trial found that, after 9 months of follow-up, the median progression-free survival (PFS) was 11.5 months with the combination of nivolumab and ipilimumab, 6.9 months for nivolumab monotherapy, and 2.9 months for single-agent ipilimumab. The combination reduced the risk of progression by 58% compared with ipilimumab (HR, 0.42; P <.0001).
The ORR was 57.6% with the combination compared with 43.7% and 19% for single-agent nivolumab and ipilimumab, respectively. In the combination arm, the complete response rate was 11.5% versus 8.9% and 2.2% with single-agent nivolumab and ipilimumab.
All-grade adverse events (AEs) were 95.5% for the combination, 82.1% for nivolumab, and 86.2% for ipilimumab. Rates of treatment-related discontinuations with the combination and single-agent nivolumab and ipilimumab arms were 36.4%, 7.7%, and 14.8%, respectively.
The FDA granted an accelerated approval to the combination of nivolumab and ipilimumab as a treatment for patients with BRAF V600 wild-type unresectable or metastatic melanoma, based on findings from the phase II CheckMate-069 study.
A supplemental biologics license application was submitted for the combination, as well as single-agent nivolumab, for the frontline treatment of BRAF-mutant advanced melanoma, based on the CheckMate-067 results. This application was granted a priority review, with a decision deadline of January 23, 2016.
To better understand which patients will benefit from nivolumab and ipilimumab as well as other immunotherapy combinations, biomarker development is critical, says Luke.
In an interview with OncLive, Luke discusses potential new methods for determining prognostic markers and the challenges of balancing toxicity with efficacy in designing combination regimens.Luke: Several recently presented studies examined the impact of tumor-infiltrating lymphocytes (TILs) as a prognostic marker for immunotherapy, as well as PD-L1. A lot of people are talking about that, and I think it is very important.
Several years ago, our group published a paper showing that the trafficking of CD8-positive T cells in the tumor generates all of the inflammation. We are very interested in a broader look at the tumor microenvironment, and we are doing that through gene expression profiling. Instead of looking at just one gene or one set of cells, we would rather examine the full transcriptome of the tumor and determine which genes are up or down. This provides a much bigger picture of whether immunotherapy is likely to work. We find that those patients who have a T-cell inflamed tumor microenvironment to be much more responsive to immunotherapy. On the flip side, if a patient does not have a T-cell¬—inflamed tumor, immunotherapy basically does not work. This is a better model, but it is just a bit more complicated and has not become a clinical grade diagnostic but, over time, perhaps it could.We absolutely think so. If we had a useful clinical grade test, perhaps those patients who are the most highly T-cell inflamed in their tumor might be candidates for an anti—PD-1 antibody alone, as opposed to those who have less inflammation who may perhaps need the combination upfront of CTLA-4 and PD-1 blockades together. As we go forward into the next generation of combination strategies, we are going to be able to better piece out how much push we need to give the patient.In the frontline setting, the combination of ipilimumab and nivolumab is highly efficacious with more than a 50% response rate. The issue is that there is more than a 50% grade III or IV adverse event rate. In my practice, it really becomes essential to understand who is going to respond to anti—PD-1 alone so we can avoid giving patients the toxicity associated with the combination if they do not need it. We really don’t know that yet. The future will likely be trying to look at sequencing of these agents. Could we administer the combination as a second-line therapy? Are there certain patients who will benefit enough? Those will be the future questions.The combination of CTLA-4 and PD-L1 antibodies has generated a very high response rate and that has been the most recent approval. In clinical trials, however, there are other combinations being investigated, including PD-1 antibodies with oncolytic viruses or IDO inhibitors. Both of these approaches look very promising with much less toxicity. We really don’t know which will be the best yet, but there are underpinning rationales for each that suggests that we should pursue them.The future is going to be focused on combination immunotherapy strategies, either with small-molecule inhibitors or other immunotherapeutic agents that, perhaps, we haven’t yet seen in the clinic. Despite making so much progress in the past few years in immunotherapy, we have barely scratched the surface on what we can do. Resting our laurels and accepting that the drugs we have are the best we can do is going to do a disservice to our patients. We really need to push forward with these clinical trials to find optimal efficacy with minimal toxicity, and we are not there yet.