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Toxic effects of immunotherapy ‘a valid concern’ among oncology experts

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January 11, 2018

Combining nivolumab with epidermal growth factor receptor tyrosine kinase inhibitors increased the risk for interstitial pneumonitis among patients with non-small cell lung cancer, according to a database study published in JAMA Oncology.

In another study published in JAMA Oncology, researchers reported an association between receipt of immunotherapy and symptomatic radiation necrosis among patients undergoing stereotactic radiation for brain metastases.

“Although the combination of immuno-oncology agents with molecularly targeted agents or radiotherapy offers the potential for synergistic antitumor immune responses, a valid concern is increased risk [for] immune-mediated toxic effects,” Chad Tang, MD, assistant professor in the department of radiation oncology at The University of Texas MD Anderson Cancer Center, and colleagues wrote in a commentary that accompanied both studies. “The treatment of immune-related toxic effects centers around steroid use, which may curtail a budding immune response.”

Lung cancer standard of care

Nivolumab (Opdivo, Bristol-Myers Squibb) and EGFR TKIs are standard-of-care therapies in NSCLC. Researchers examined their association with interstitial pneumonitis, which can cause labored or difficult breathing.

Yasuo Oshima , MD, PhD, FACP, visiting scientist at the Institute of Medical Science at University of Tokyo, and colleagues analyzed data from 20,516 patients with NSCLC registered in the FDA Adverse Event Reporting System database from April 2015 until March 2017.

Of those patients, 5,707 (mean age, 68.86 years; 55.5% women) received an EGFR TKI alone and 70 (mean age, 64.43 years; 60% women) received an EGFR TKI with nivolumab. Another 5,108 patients (mean age, 66 years; 32.3% women) received nivolumab alone, and 9,634 (mean age, 63.38 years; 39.1% female) did not receive an EGFR TKI or nivolumab.

Interstitial pneumonitis developed in 985 patients (4.8%; 95% CI, 4.51-5.1).

Of the patients treated with EGFR TKI, 4.59% (95% CI, 4.06-5.16) developed interstitial pneumonitis, which included 25.7% (95%, 16.0-37.6) of the patients who received both EGFR TKI and nivolumab.

The adjusted OR for interstitial pneumonitis associated with EGFR TKI and nivolumab was 4.31 (95% CI, 2.37-7.86), suggesting the existence of an interaction. With further stratification, the OR for EGFR TKI-associated interstitial pneumonitis was 5.09 (95% CI, 2.87-9.03) with nivolumab compared with 1.22 (95% CI, 1-1.47) without nivolumab.

“Interstitial pneumonitis is one of the most serious adverse reactions related to EGFR TKI,” Oshima and colleagues wrote. “Furthermore, in phase 3 trials of nivolumab [among] patients with NSCLC, approximately 4% of the nivolumab treatment groups developed interstitial pneumonitis.”


Researchers noted that not all serious adverse events in drug-treated patients are captured by the FDA’s MedWatch program, resulting in reporting biases, and that reported events are not always confirmed in a standardized manner.

“Although not confirmed, careful consideration should be given to the possibility of an increased risk [for] interstitial pneumonitis when EGFR TKI is administered in combination with nivolumab, including both concomitant and sequential use,” Oshima and colleagues wrote, “and careful monitoring for interstitial pneumonitis is recommended.”

These data seem consistent with data from a phase 1b trial in which interstitial lung toxic effects rates reached 38% in the combined durvalumab (Imfinzi, AstraZeneca) and osimertinib (Tagrisso, AstraZeneca) arm vs. only 2% to 3% for either monotherapy, according to Tang and colleagues.

Treatment of brain metastases

Allison Marie Martin, MD , instructor of oncology at Johns Hopkins Medicine, and colleagues identified 480 patients with newly diagnosed brain metastases secondary to NSCLC (n = 294), melanoma (n = 145) and renal cell carcinoma (n = 41) treated with stereotactic radiation at Brigham and Women’s Hospital and Dana-Farber Cancer Institute between 2001 and 2015.

Of the participants, 115 received immunotherapeutic checkpoint inhibitors — ipilimumab (Yervoy, Bristol-Myers Squibb), pembrolizumab (Keytruda, Merck) or nivolumab — and 365 did not.

Symptomatic necrosis occurred in 23 of 115 patients (20%) who received immunotherapy and 25 of 365 patients (6.8%) who did not.

Receipt of immunotherapy appeared associated with symptomatic radiation necrosis after adjustment for tumor histology (HR = 2.56; 95% CI, 1.35-4.86), especially among patients with melanoma (HR = 4.02; 95% CI, 1.17-13.82).

Among patients with melanoma, receipt of ipilimumab compared with no immunotherapy increased risk for symptomatic necrosis (HR = 4.7; 95% CI, 1.36-16.19). Of the 23 patients who received immunotherapy and developed symptomatic necrosis, 18 (78%) received dexamethasone for a median duration of 1.8 months.

Limitations of the study included its retrospective nature and small sample size, which prevented use of a propensity score-matching analysis.

“Prospective studies are needed to better characterize the risks and benefits of combining brain-directed stereotactic radiation with immunotherapy in this population,” Martin and colleagues wrote.

Cause of toxicity

Tang and colleagues noted that although both studies highlight the key issues of increased toxic effects associated with immunotherapy-based combination regimens, they do not provide mechanistic insights into why such toxic effects develop.

At the molecular level, immune checkpoint inhibitors release effector T cells from immune suppressive mechanisms, thus leading to their activation, according to Tang and colleagues.


“As a result, treatment with immune checkpoint inhibitors promotes the expansion of low-affinity T cells, leading to an increased likelihood of tumor cell recognition, but also a higher risk [for] cross-reaction with normal tissue,” Tang and colleagues wrote. “This scenario creates a double-edged sword in which patients who are likely to demonstrate improved antitumor responses from immune checkpoint blockade are also at increased risk [for] developing immune-mediated adverse events, and vice-versa.” – by Chuck Gormley

Disclosures: Oshima reports personal fees from Novartis and Sanofi. Martin and Tang report no relevant financial disclosures. Please see the full studies and editorial for all other authors’ relevant financial disclosures.