Lung Toxicities: Management of irAEs Guideline (Part 5)

An interview with Dr. Jarushka Naidoo from Johns Hopkins University, author on "Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update." She discusses the identification, evaluation, and management of lung toxicities in patients receiving ICPis, focusing on pneumonitis in Part 5 of this 13-part series. For more information visit www.asco.org/supportive-care-guidelines

TRANSCRIPT

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SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

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BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network-- a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts.

My name is Brittany Harvey, and today we're continuing our series on the management of immune-related adverse events. I am joined by Dr. Jarushka Naidoo from Johns Hopkins University in Baltimore, Maryland, author on Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update and Management of Immune-Related Adverse Events in Patients Treated with Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline. And, today, we're focusing on lung toxicities in patients treated with immune checkpoint inhibitor therapy. Thank you for being here, Dr. Naidoo.

JARUSHKA NAIDOO: Thank you. It's my pleasure to share updates on this guideline.

BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with a publication of the guidelines in the Journal of Clinical Oncology. Dr. Naidoo, do you have any relevant disclosures that are directly related to these guidelines?

JARUSHKA NAIDOO: Yes. So I have research funding in the last two years from Merck, AstraZeneca, and Bristol Myers Squibb. And I also have served in a consulting role-- or an advisory board capacity-- for Merck, AstraZeneca, Bristol Myers. And not specifically related to this work, but also Pfizer, Takeda, Daiichi Sankyo, and Kaleido Biosciences.

BRITTANY HARVEY: OK. Thank you for those disclosures. Then-- getting into the content of this guideline-- what are the immune-related lung toxicities addressed in this guideline?

JARUSHKA NAIDOO: Thanks, Brittany. So the main lung toxicity that is addressed in this guideline is immune checkpoint inhibitor pneumonitis, which-- as this audience knows-- is an uncommon, but potentially fatal toxicity particularly associated with anti-PD-1 or PD-L1 monotherapy, but can also occur with combination immunotherapy approaches.

In the guideline, we go through what is known about the natural history, risk factors, and then, of course, our comprehensive approach to identifying, evaluating, and managing this toxicity, which is defined as a focal or diffuse inflammation of the lung parenchyma.

We also identify that, while pneumonitis is the quintessential lung toxicity that can occur with immune checkpoint inhibitors, we also note that there are some other lung toxicities that have been reported on, but for which known we relatively little.

And this includes sarcoid-like granulomatous reactions, including subpleural micronodular opacities and hilar lymphadenopathy, as well as pleural effusions. And these have been associated with both CTLA-4 and the PD-1, PD-L1 immune checkpoint inhibitor therapies.

BRITTANY HARVEY: I appreciate that overview. So then, you mentioned the main toxicity here is pneumonitis. What are the key recommendations for identification, evaluation, and management of pneumonitis?

JARUSHKA NAIDOO: Thanks, Brittany. So yeah, this is a key focus of the guideline. So, as we're aware, pneumonitis is defined as a focal or diffused inflammation of the lung parenchyma and is a toxicity that was identified as one of the early toxicities in the early clinical trials of the PD-1 inhibitors.

The incidence of this toxicity is estimated at anywhere between 0% and 10%, and in large meta analyses, looks to be around 2% to 3% in terms of incidence. In terms of how to evaluate patients with suspected immune-related pneumonitis, the common symptoms would be cough, shortness of breath, fever, and chest pain.

And in a patient who has suspected pneumonitis, some of the first tests to be done would be to take a pulse oximetry and to do some chest imaging. Chest imaging is preferable with a CT scan with contrast in order to rule out alternative etiology, such as pulmonary embolus

For patients who are symptomatic-- which means CTCAE grade 2 or greater-- we also recommend a standard infectious workup, which is guided by institutional guidelines. But based on our ASCO guideline, we outline that this should include, at a minimum, a nasal swab, sputum culture and sensitivity, blood culture and sensitivity, and urine culture and sensitivity, as well as a standard COVID-19 evaluation.

When we come to the diagnosis of pneumonitis, we then evaluate that in terms of CTCAE grade. Where the grade of pneumonitis refers, firstly, to whether a patient has symptoms, and the proportion of the lung parenchyma that may be involved with pneumonitis on chest imaging.

Broadly speaking, patients with grade 1 pneumonitis are asymptomatic and usually identified on radiographic imaging almost incidentally. For these patients, we would recommend either holding immunotherapy or proceeding with close monitoring.

And we recommend that patients should have weekly physical exams and pulse oximetry offered, and consideration of further chest imaging if the diagnosis is uncertain, or to follow progress-- usually around every three to four weeks-- or, if a patient becomes symptomatic, it may be more often than this.

We also recommend that we may consider doing spirometry or DLCO evaluation as a repeat in these patients. Broadly, again, in terms of the evaluation of patients-- if patients are symptomatic from pneumonitis, which means they have a symptom related to radiographic features, then this would be called grade 2.

And usually, radiographically, patients have more of the lung parenchyma involved-- greater than 25%-- and require a medical intervention. And the management would be prednisone, 1 to 2 milligrams per kilogram per day, that is then tapered over 4 to six weeks, and immunotherapy is held during that time.

Importantly, in order to knuckle down the diagnosis of pneumonitis, we recommend consideration of doing a bronchoscopy with bronchoalveolar lavage sampling in order to truly rule out alternative infectious diagnoses or lymphangitis carcinomatosis. And for this reason, a transbronchial biopsy can also be considered. In some cases, we also consider treating with empiric antibiotics to cover infection if we feel that this remains in the differential diagnosis.

If patients do not clinically improve after 48 to 72 hours on prednisone, then we recommend treating at a higher grade, meaning grade 3, where patients have severe symptoms, hospitalization is required, and a larger proportion of the lung parenchyma is involved.

For these patients who have grade 3 or greater pneumonitis, we recommend permanently discontinuing immunotherapy, administering a higher dose of steroids at methylprednisolone, 1 to 2 milligrams per kilogram per day. And, once again-- if there is no improvement after 48 hours, we recommend a range of potential additional immunosuppressive approaches, which include either infliximab, mycophenolate mofetil, intravenous immunoglobulin, or cyclophosphamide.

And there are currently no recommendations as to which may be the optimum immunosuppressive approach, but there are a number of clinical trials aiming to elucidate the answer to this. Importantly, overall in patients who are symptomatic, it may also be appropriate to consult pulmonary medicine and infectious diseases teams to weigh in on the diagnosis and management going forward.

BRITTANY HARVEY: Great. Thank you for that clear, step-wise approach to the evaluation and management of pneumonitis. So then, in your view, Dr. Naidoo-- how will these recommendations for the management of lung toxicities impact both clinicians and patients?

JARUSHKA NAIDOO: I think it's very important for both clinicians and patients to be aware of the potential side effects of the treatment that patients are receiving with immune checkpoint inhibitors. We know that some toxicities from immunotherapy tend to be mild and can be managed quite well with corticosteroids or other approaches.

What we understand about lung toxicities is that, thankfully-- in the majority of cases-- pneumonitis will be well-controlled with corticosteroids and holding of immunotherapy. However, in a proportion of patients, pneumonitis may become severe and may even lead to treatment-related deaths.

And for that reason, both patients and clinicians need to be aware of what to look out for in terms of the symptoms of pneumonitis, and how to diagnose and manage this toxicity quickly and efficiently in order to avoid poor outcomes.

BRITTANY HARVEY: Absolutely. Those are excellent points for both clinicians and patients to keep in mind. So I really want to thank you for all of your work on these guidelines and for taking the time to speak with me today, Dr. Naidoo.

JARUSHKA NAIDOO: You're very welcome, Brittany. And thank you to the ASCO oncology community for the opportunity to share this important work.

BRITTANY HARVEY: And thank you to all of our listeners for tuning into the ASCO Guidelines podcast series. Stay tuned for additional episodes on the management of immune-related adverse events. To read the full guideline, go to www.asco.org/supportive-care-guidelines.

You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

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