Ryan J. Sullivan, MD: Inhibiting BRAF-mutated melanoma typically is—we use 2 drugs. We use an inhibitor BRAF itself, targeting the oncogene specifically, and then we inhibit a downstream protein called MEK.
These drugs actually were developed individually. So BRAF inhibitors and MEK inhibitors were developed essentially on separate paths. The first BRAF inhibitors to get into patients were actually RAF inhibitors generally, and they tended not to have specificity for BRAF or the mutated BRAF and weren’t particularly effective. These drugs go by the names of sorafenib, which is actually FDA approved for kidney cancer and hepatocellular carcinoma, and a drug called RAF265, which was tested for melanoma.
Moving on from that, the development of more specific BRAF inhibitors occurred, and the first of those drugs to get into humans was a drug called vemurafenib. Vemurafenib is a highly potent and specific inhibitor of both the normal and the wild type—I’m sorry, the normal and the mutated version of BRAF. And the importance of that is that the adverse effects are actually related to inhibiting BRAF.
An interesting thing happens when you inhibit BRAF. When you inhibit the mutated version of BRAF, you shut down the pathway that BRAF mutation triggers, called the MAP kinase pathway. And it produces tumor growth, and on average 6 to 8 months, there’s control of disease, and then most patients will progress after that.
When you inhibit the wild-type version of BRAF, or the normal BRAF, you end up getting paradoxical activation of the pathway. So these very specific BRAF inhibitors actually paradoxically activate the pathway, and so you end up with adverse effects that are associated with too much signaling of the MAP kinase pathway. This typically leads to thickening of calluses on the hands and the feet, which can be quite tender. It can lead to hypertrophic changes in skin generally. It can actually lead to secondary skin cancers like squamous cell carcinoma of the skin, and even secondary melanomas. But all because it’s driving the pathway and so if there’s a premalignant cell that just needs a little push, this paradox with activation can actually drive tumor growth in a different type of cancer. And so in the phase I study of vemurafenib, the rate of secondary malignancies, specifically secondary skin cancers, was close to 20%.
Now, that’s a far cry from dying from melanoma, so we didn’t worry so much about it. And more importantly, what we learned is that you could just either cut them out or freeze them or just stop the BRAF inhibitor, and the skin cancer would go away. And so it was a treatable adverse effect but an interesting one and sort of does get to the types of adverse effects that these drugs drive.
Other types of adverse effects are that BRAF inhibitors, any small-molecule inhibitor, can cause nausea and vomiting, can cause diarrhea. There are characteristics. Rashes—I mentioned the thickening rash that can be on the hands and the feet. But there can be more widespread rashes. And so we involved our dermatologist all the time when we were giving these drugs as single agents because it was very common for patients to have developed rash.
Additionally, vemurafenib is associated with photosensitivity, which is to say that people are much more sensitive to sunlight. And so an amount of exposure that most people, even very pale people, wouldn’t even think twice about—like 5 minutes outside talking to a friend, or writing on a card and having your arm up on the kind of the side panel—would…come through the window, or the sun from just a short exposure could cause very serious blistering sunburns.
So we learned that it was very important to have our patients wear sunscreen, not necessarily because we were trying to prevent their next melanoma, but because we were trying to prevent their next sunburn, which is much more likely to happen on BRAF-targeted therapy, or on BRAF-inhibited therapy specifically.
With the development of MEK inhibitors, they cause adverse effects that actually are related to blocking the pathway, so they work by blocking the pathway, just as BRAF inhibitors do in mutant cells. But they also block the pathway in normal cells. And so the adverse effects of MEK inhibitors are what you would get if you block MAP kinase, and that also leads to rash, but the rash is a much more characteristic acneiform rash, which is very common with EGFR-mutation inhibitors. And so the strategies to treat that typically are topical steroids, or topical antibiotics, or oral steroids, or oral antibiotics.
We also see nausea and vomiting and diarrhea because it’s a small-molecule inhibitor, and all small-molecule inhibitors can cause those adverse effects. And then there are a few other very characteristic adverse effects from MEK inhibitors. We can see swelling of the legs; really edema anywhere, but the lower extremities are most common. We can see eye toxicity. Very specifically a condition called central serous retinopathy, which is, for lack of a better term, a benign retinal detachment that’s reversible—sometimes with continued use, sometimes you have to stop and then it gets better and you can resume therapy. We can see a weakening of the heart muscle, so-called cardiomyopathy, related to MEK inhibitors, so it’s important for patients to be followed very closely with echocardiography during the course of their treatment.
So those, and then there’s actually another eye condition called central serous retinopathy that’s pretty problematic.
Those are the major adverse effects of BRAF inhibitors and MEK inhibitors. When we combine them we see something very interesting. The dominant skin findings from both drugs are actually mitigated by the exposure of the other drug. As I mentioned, BRAF inhibitors activate the pathway in normal cells. MEK inhibitors block the pathway in normal cells. And so any tissue where the inhibitors are having an effect, if they’re both having an effect in that tissue, the adverse effects actually usually cancel each other out, which is really interesting and cool and allows for the use of these drugs at full dose without a lot of therapeutic consequences.
We see toxicity, of course. The adverse effects related to MEK inhibitors—like swelling and effects on the eyes and effects on the heart—still happen, and they happen at a very similar rate, so that’s not mitigated. But those don’t happen very commonly. And the adverse effects of BRAF inhibitors, like photosensitivity, still happen with vemurafenib containing BRAF/MEK inhibitor regimens.
And we see interestingly in combinations some characteristic adverse effects with regimens. There are 3 BRAF/MEK inhibitor regimens that are approved by the FDA: dabrafenib-trametinib, vemurafenib-cobimetinib, encorafenib-binimetinib.
Dabrafenib-trametinib causes fever in over 50% of patients. And that fever can range from annoying, like you need to go to the hospital and get IV fluids because you’ve lost so much in sweat, to insensible losses of fluid. Vemurafenib-cobimetinib has a major adverse effect that can affect the liver a little bit, but it’s major adverse effect is that photosensitivity, which we see with vemurafenib. It seems to be augmented a little bit. With encorafenib-binimetinib, we see characteristic toxicities, probably a little bit more nausea, maybe a little bit more elevation of liver function testing. But we don’t see the photosensitivity, and we don’t see the fever, and so if somebody has been suffering from those types of toxicities, we can usually get away with that other therapy.
Geoffrey Thomas Gibney, MD: In the clinical trials with BRAF and MEK inhibitors in combinations for melanoma, the majority of patients have experienced or reported some form of adverse events. However, most patients tolerate the drugs very well. In approximately 30% to 40% of patients, there’s either a dose interruption or modification. Most patients can then go back on the drugs. Depending on which study you quote, the rates for permanent discontinuation are very low. Most studies have shown it to be in around 13% to 14% overall, and it may be actually lower when you’re looking at the events that are truly attributed to adverse effects. And those numbers in some cases have been reported to be even lower.
Transcript Edited for Clarity.