Clinical Experience With Dabrafenib/Trametinib in NSCLC

Mark A. Socinski, MD: In terms of the toxicity of the combination of dabrafenib and trametinib, one of the more common adverse events is fever. We manage that with the usual antipyretic therapy. Sometimes, it does require dose reduction or dose interruption. Other toxicities include cytopenias. Anemia has been reported, neutropenia has been reported, and GI toxicities that we see with most of the TKIs can be present. I think in terms of looking at the higher-grade toxicities, pyrexia leads the list, but all the other ones are, in terms of grade 3 or 4 toxicities, in the single digits. Many of us would, in this situation, characterize these as manageable. Again, we’ve had this regimen out in the melanoma population, and it’s used quite frequently in that population. I’m not aware if there are any different safety signals in the lung cancer population, relative to the melanoma population with this combination.

The use of agents such as acetaminophen or steroids is important, or to give patients a break from therapy to let them resolve the toxicity. It’s not a very common reason to have to discontinue the regimen, so I think you can work with dose, as well as the anti-pyretics so that patients can stay on the therapy, which is important if they’re having a response. I’m thinking, in the majority of the cases, it will be more of an inconvenience than it is a reason that the patient can’t continue on treatment.

One of the initial experiences I had with this combination was with a relatively young lady who was highly symptomatic from her recurrent pleural effusion from the lung disease. This was a lady who lived in a relatively rural area, and one of the things that she enjoyed doing was walking her dogs. When you live in a rural area, sometimes your mailbox is a ways away from where the house is, and there was a river she would walk the dogs around, but she got so symptomatic that she could not get the mail or take her dogs for a walk, so she ended up really being housebound. We saw her, and we were aware that she had theV600E BRAFmutation.

We enrolled her on the clinical trial for the combination of dabrafenib and trametinib, she started on treatment, and we saw her back a week or 2 later. And she said that within 3 days of starting this therapy, she was able to get the mail; she felt that this was a miracle. It was a very touching moment when she looked at me and she said, “I never thought I was going to be able to leave my house again or walk my dogs, but I’m doing it again, and I feel so much better just taking these pills.” And so, that’s the kind of experience you can have. For all of us who treat lung cancer for a living, when you start to find theseEGFR,ALK,ROS1,BRAF, orMETexon 14skip mutations, these patients can be very sick—and within a matter of days with the appropriate targeted agent, you can turn them around. That’s very gratifying from a treating physician point of view. In thisBRAFpatient, it was one of the most remarkable stories that I’ve heard.

Subsequently, for every medical student I had, I’d have her tell her story, just so medical students would get the impression that lung cancer is a potentially treatable disease. Lung cancer is very heterogeneous, and you have to look for these patients. Patients aren’t going to tell you, “Hey, I’mBRAF-positive.” You have to get enough tissue to test for it, and know to test for it, and I think that’s the lesson learned.

In this patient, again, I think she should be treated with the combination of dabrafenib and trametinib. We don’t know; we don’t believe it’s curative therapy. At some point, she’s going to progress. My sense would be to treat her in the third-line setting with immunotherapy. She did not have any contraindications in her history that suggest she couldn’t get immunotherapy. Even though she was PD-L1-negative to start with, we know, for instance, that the drug atezolizumab—whether you’re PD-L1-positive or PD-L1-negative—seems to have a similar effect. We know from the nivolumab studies that there’s activity in the PD-L1-negative population. PD-L1 is a complicated biomarker, and we clearly do see activity of the immunotherapy agents—to a lesser degree, but still, there is activity there in the PD-L1-negative population. So, following progression on this case in the third-line setting, I would recommend probably either atezolizumab or nivolumab as her next choice.

Transcript edited for clarity.

• 67-year-old female, former smoker (30 pack-years, quit 10 years ago) presented to her pulmonologist with increased cough, dyspnea and hemoptysis.
• Past medical history of mild COPD.
• Patient swims three times a week and is continuing normal activities.
• ECOG PS was assessed as 1.
• CT scan of chest and abdomen show a lower right lobe lung nodule with several small liver lesions.
• PET/CT scan indicated lung cancer with liver metastases.
• Core needle biopsy was performed in the liver. Pathology report showed adenocarcinoma consistent with non-small cell lung cancer (NSCLC).
• Mutation testing showed aBRAF V600Emutation.
• PD-L1 status was negative.
• Patient was started on pemetrexed and carboplatin.
• After 3 of 6 planned cycles patient showed worsening signs of dyspnea with a weight loss of 10%.
• Repeat CT scan showed progression of primary lesion.
• Patient was started on dabrafenib + trametinib.