[Suzanne McGettigan]

Kathy–
It will be so interesting to learn more about the influences of the microbiome on responses to immunotherapy and even other therapies that we are using.

Bri–
I haven’t had this exact scenario but have seen a lot of esophagitis in my immunotherapy patients. Generally have treated as described above with use of corticosteroids in addition to typical supportive care therapies utilized in this setting (PPI, H2 blocker, coating agents at maximum doses to start and then tapering along with steroids as symptoms improve).

[Suzanne McGettigan]

Hi Kathy–
Such an interesting case. My experience with xerostomia and mucositis has been similar to your prior experience. Generally it has resolved quickly with supportive care therapies, including salt water rinses, the Biotene products, GelClair, Muguard, or decadron mouth rinses. I have also had a patient where culturing one of their ulcers did indicate a herpetic infection and the addition of an antiviral therapy seemed to help. Good to know that infliximab is also effective in this refractory case.
thanks for sharing,
Suzanne

[Suzanne McGettigan]

Hi All–
I do agree with Kathy that the majority of fevers from dabrafenib/trametinib do tend be in the 101-103 range–luckily not too many over 104, but these certainly are possible.

There was a publication recently from the Australian Melanoma group which delineates their management strategies for pyrexia. This management guide is definitely more in line with my practice.
I will include a link to it here: https://doi.org/10.1111/ajco.12656

In this guideline, patients would hold both dabrafenib and trametinib with onset of fever > 100.5 degrees Farenheit. They would initiate anti-pyretic agents (acetominophen, NSAIDs) as well other supportive care measures (adequate hydration). They could resume both agents once fever free and asymptomatic for at least 24-48 hours. However, if symptoms do not improve within 24 hours, they would be instructed to initiate corticosteroid (i.e. prednisone 10-25 mg daily) as an anti-inflammatory to reduce fever and to continue as prophylaxis against pyrexia/pyrexia syndrome with resumption of dabrafenib/trametinib. The corticosteroid dose could be tapered after approximately one month if the patient remained fever-free.

I would certainly be interested in how you all manage these as well.
thanks,
suzanne

[Suzanne McGettigan]

Hi Kathy–
Yes, I have a few patients who were switched from an alternate BRAF/MEK combination to encorafenib/binimetinib who have experienced fever, flu like symptoms, complex pyrexia. I have utilized the processes that we have previously used and were recently published by the Australlian group including holding both therapies, starting with non-steroidal anti-inflammatories, but quickly moving to corticosteroids if not responding to the non-steroidal alternatives, or not effectively responding. Also, making sure that in this setting that patients are staying adequately hydrated with water as well as electrolyte rich beverages. Once they are fever free for ~ 48 hours, then resuming full dose.
I haven’t had to dose reduce anyone yet, but that may be coming.
I have had some patients experience GI side effects from these combo regimens. In my practice, it has seemed to wax and wane a little over the course of their therapy and has generally responded to anti-diarrheal and anti-emetic therapies temporarily.
Great discussion!
Suzanne

[Suzanne McGettigan]

Hi Lisa–
We have had several patients develop new or worsening sensorineural hearing loss, characterized by tinnitus. We have not seen or recognized other types of hearing loss.
For two patients, tubes were surprisingly effective–both of those had developed very early on in treatment.
For the remainder, effective treatment has been a little more elusive.
Oral corticosteroids have been effective in a small portion patients, but not in most. We have attempted holding further immunotherapy in a few patients with possible improvement. With this symptom, it is hard to tell if the tinnitus is actually better or if lifestyle modifications as a result have led to improvement in the tolerability of this symptom.
It is a tough one.
thanks for bringing this up.
Suzanne

[Suzanne McGettigan]

I would concur with Rajni that it does seem like more patients are experiencing those temporary flu-like symptoms on the 480 mg dose, but it is hard to definitively quantify. They do seem to be mild, when they do occur.

[Suzanne McGettigan]

Such a great question.
to add onto this conversation thread…

Not only have we seen many non-target mutations in known target-able genes such as BRAF, but also with some of the broader spectrum molecular panels available (either commercially or institution based) we are identifying a lot of mutations that we can’t necessarily target right now, outside of a clinical trial.

[Suzanne McGettigan]

Rajni–
such a good point.
In the melanoma world, we have been lulled into this sense that every year there will be new treatments for melanoma. The last five years have been amazing, with so many new therapies and new combinations of therapies that have truly changed the way we manage melanoma. This year was the first in which it seemed like it slowed down.

[Suzanne McGettigan]

Hi Lisa–
such a great question. I agree with Rajni. The oral targeted therapies are very challenging for many patients. There will definitely be a select group of patients in which these agents are used in the adjuvant setting, but the pyrexia and febrile syndrome make them quite challenging in more advanced melanoma patients.

[Suzanne McGettigan]

I do not routinely premedicate prior to TVEC.
However, if a patient has experienced significant flu-like symptoms following a treatment, then would advise them to take acetominophen/ibuprofen for the first 24-48 hours to prevent similar symptoms with subsequent treatments. These symptoms do seem to lessen over time.

There is one exception to that. Patients who have developed adrenal insufficiency, from a prior immunotherapy treatment, do seem more prone to these flu-like symptoms. Additionally, their adrenal glands cannot compensate for the sick-day/physiologic stress of these symptoms. Therefore, in those patients, I do have them premedicate and take anti-pyretics for the first 24 hours following TVEC administration. Additionally, they sometimes do have to follow their sick-day rules for the day of the TVEC treatment and possibly the next day.

[Suzanne McGettigan]

Hi Kathy–
what an interesting article.
We have not initiated therapy beyond steroids for the rashes we’ve managed from the ICIs. We have definitely utilized alternate therapies such as methotrexate and hydroxychloroquine for some of the immune related arthritis symptoms resulting from ICIs. As Molly mentioned, these have typically been initiated by a rheumatologist to whom we’ve referred a patient due to complications from the ICI therapy.
thanks for letting us know about this article!
Suzanne

[Suzanne McGettigan]

None right now. We are trialing an app for some of the complicated oral chemotherapy regimens, where a patient may be required to take different drugs on different days, but have not expanded the use of this technology to daily chemotherapy or targeted therapy regimens. It would be helpful depending on how tech savy a patient was…

[Suzanne McGettigan]

I can only ditto what others have said.
We, too, have a centralized radiology pre-cert team, made up of non-clinical staff. They submit the initial request for prior authorization, along with labs/path/most recent progress note. When it still requires a peer to peer discussion (with the MD/NP/PA), we receive these requests very close to the time of the scan. Since these discussions now have to be “scheduled”, it is more and more challenging to have them completed prior to the original scheduled time of the scan and these often have to be rescheduled, along with the patient’s office visit.
PET/CTs have become almost impossible to get approved other than at the time of initial diagnosis or as a follow up to equivocal findings on “standard” imaging. We have updated our clinical pathways to reflect this restriction and utilize CT c/a/p +/- neck or extremity for surveillance imaging in NED patients and for monitoring response to therapy in other patients.

[Suzanne McGettigan]

I was not aware of the medicare issues with reimbursement. Thank you for sharing!

[Suzanne McGettigan]

Hi Krita–
We have utilized infliximab for a number of steroid-refractory immune related toxicities, including pneumonitis and myocarditis.
For hepatitis, we do not use infliximab and have used mycophenylate in the steroid-refractory setting.

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