Charles L. Sawyers, MD

The combination of kinase inhibitors and checkpoint inhibitors could be a fantastic idea, because kinase inhibitors would liberate the gold mine of tumor antigens present in the tumor cells so that the immune system can see them if enabled by a checkpoint inhibitor.

As we have seen in trials presented at AACR, triple therapy with immunotherapy plus kinase inhibitors is superior to kinase inhibitors alone.

The most impressive part of the result is the durability of response and the tail on the PFS curve. This is perhaps an expected result based on the tails we see with checkpoint blockade alone.

Another big point is that, since these trials started, the standard of care for these patients has changed. That’s based on the remarkable benefit of giving combined checkpoint blockade with checkpoint inhibitors targeting PD-1.

The real reason this abstract is interesting for a translational scientist is that is offers an opportunity to answer whether MEK-plus-BRAF inhibition releases a gold mine of tumor antigens. The answer is, we don’t know for sure. But, we have hints that it could. One is the T-cell infiltrate is known to increase in patients who get just the kinase inhibitors, so they are going from “warm” to “hot” tumors. Furthermore, there is a side benefit of MEK inhibition — it can increase the expression of HLA class 1 molecules in tumor cells. So, in theory, it could improve antigen presentation to T cells.

I am quite excited by the development of technology that allows us to obtain tumor samples in a trial like this and study them much more accurately using single-cell RNA sequencing and spatial transcriptomics.

Another possible explanation for the benefit seen here is the hypothesis of patient-to patient variability, which shows some patients benefit because they respond better to drug A and others respond better to drug B without there being any synergy. Time will tell whether that is true or not.

Immuno-oncology combinations with kinase inhibitors have already spread to kidney cancers, and there is the possibility this will work in prostate cancer.

Kim Margolin, MD

These results appear to confirm an important and favorable immunomodulatory interaction between double MAPK inhibition and immune checkpoint blockade. A previous trial that used a similar design showed comparable results in a smaller, randomized phase 2 design with dabrafenib (Tafinlar, Novartis) and trametinib (Mekinist, Novartis) plus pembrolizumab (Keytruda, Merck) or placebo, but that trial was insufficiently powered to demonstrate significant benefits for the combination. In the current trial, what is most interesting and may lead to statistically significant survival benefit for the combination is the late separation of the OS curves, suggesting that after a period in which the molecularly targeted therapies are the primary drivers of benefit, the immunotherapy effect kicks in and predominates. 

Lacking in these studies was a cohort of patients randomly assigned to the immunotherapy alone, either single agent PD-1 blockade or the currently best available immunotherapy for melanoma, which is a combination of ipilimumab (Yervoy, Bristol-Myers Squibb) and nivolumab (Opdivo, Bristol-Myers Squibb) either at standard or reversed doses that are associated with comparable activity and less toxicity. It also will be very important to understand sequence questions because OS benefit can only occur if patients who progress on the protocol regimen do not achieve equal benefit from whatever therapy they receive after progression. Conversely, it would be important to know whether sequences rather than combinations can provide similar or greater benefits at the cost of less toxicity, as well as better ability to identify and manage toxicities.

The data have been reported for both the investigator-assessed outcomes and those of an independent review committee, which essentially always comes up with slightly less favorable results in all cohorts compared with the investigator assessments. It doesn’t mean the investigators are biased or dishonest but may simply mean that the investigators know the clinical picture and may exercise their judgment in the interpretation of questionable lesions that may arise on tumor assessments. This is particularly important for reactive inflammatory nodes that occur frequently in patients on immunotherapy regimens or for transient abnormalities that turn out to be infectious or otherwise nonmalignant.