Promising results announced at the recent ASCO Annual Meeting from studies with BRAF and MEK inhibitors have made headlines, but only one of these agents—the BRAF inhibitor vemurafenib (Zelboraf)—has been approved by the FDA. The others are still investigational. Patients interested in gaining access to these drugs through clinical trials should be aware of clinical evidence suggesting that patients may develop resistance to BRAF inhibitors and that BRAF and MEK inhibitors used singly or together have adverse effects.

Secondary Squamous Cell Carcinoma

The use of BRAF inhibitors in patients with advanced melanoma has been associated with secondary squamous cell carcinoma. “There are no documented cases yet of another cancer, but we are obviously keeping our eyes open to that as we treat patients,” noted Keith T. Flaherty, MD, Director of Developmental Therapeutics at Massachusetts General Hospital Cancer Center and Associate Professor of Medicine at Harvard Medical School in Boston.

In the metastatic setting, this is not a concern. “These patients are dealing with a life-threatening circumstance, and the possibility of other tumors forming beyond these skin tumors is not a reason to not offer the therapy,” Dr. Flaherty said. “In the adjuvant setting, the stakes are a little different. If there is any protumor effect happening in a subgroup of patients on these trials who aren’t destined to have their melanoma show up again, there’s a harm there that obviously causes us to have much greater concern. The FDA and practitioners are in high surveillance mode on that topic,” Dr. Flaherty noted. “The MEK inhibitor doesn’t raise that concern,” he added.

Adverse effects of the MEK inhibitor trametinib, as reported in phase III trials, are mainly skin rash, diarrhea, edema, hypertension, fatigue, and chorioretinopathy. These are clinical class effects that can be expected of all MEK inhibitors, according to Dr. Flaherty.

Fever and Chills from Combined Use

In a phase I/II trial combining the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib, the rate of fever of any grade in the phase I group was 52%. Focusing on the group that received full doses of both drugs, 58% of patients had fever, but only 8% were grade 3. Similarly, in the overall phase I group, 38% of patients had chills of any grade (37% of the patients receiving full doses of both drugs), and 1% of patients had grade 3 chills.

 For the phase III trials, efforts are being made to increase awareness and early recognition of these effects, while instructing patients on how to manage them, Dr. Flaherty said. “It is fairly clear that it you intervene quickly, even with Tylenol, you can help prevent that sort of escalation. If Tylenol won’t handle it, then you quickly start holding the doses,” he added, and the fever will resolve fairly rapidly.

“When we were first working with the combination, we didn’t know to expect this as such a frequent or bothersome issue, so patients were continuing dosing and we’d hear about it after they had been dealing with it for several days,” Dr. Flaherty said. “But a much more proactive stance evolved as that trial continued.”

In a few patients with recurring fever despite dose interruptions, low-dose prednisone was successfully used to stop the fever. “But we are a little cautious in these patients about just using steroids,” Dr. Flaherty said, “because we feel like that could potentially compromise treatment outcomes. We like to hold that in reserve.” The phase III trial, he noted, includes “a much more well-fleshed-out algorithm” for managing fever and chills. ■