Treatment-Related Adverse Events of PD-1 and PD-L1 Inhibitors in Clinical Trials

Wang, Yucai; Zhou, Shouhao; Yang, Fang; Qi, Xinyue; Wang, Xin; Guan, Xiaoxiang; Shen, Chan; Duma, Narjust; Aguilera, Jesus Vera; Chintakuntlawar, Ashish V.; Price, Katharine A.; Molina, Julian R.; Pagliaro, Lance C.; Halfdanarson, Thorvardur R.; Grothey, Axel; Markovic, Svetomir N.; Nowakowski, Grzegorz S.; Ansell, Stephen M.; Wang, Michael L.

doi:10.1001/jamaoncol.2019.0393

Cited by 564 publications

(497 citation statements)

References 143 publications

(145 reference statements)

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“…In comparison, a more recent meta-analysis of trAEs of PD-1 and PD-L1 inhibitors in clinical trials consisting of 125 clinical trials included 20 128 patients reported 66% of 18, 610 patients (n = 106 studies) developed at least 1 any-grade trAEs while 14.0% of 18 715 patients (n = 110 studies) developed at least 1 grade ≥ 3 trAEs. 51 These rates were comparable to those observed for trAEs among HNC patients. Whether anti-PD1 ICI therapy in HNC indeed have much higher rates of trAEs and irAEs than the same agents used in patients with other kinds of cancers remains to be further investigated.…”

Section: Discussionsupporting

confidence: 63%

“…These rates are much lower than reported for anti‐PD1 therapy for HNC patients. In comparison, a more recent meta‐analysis of trAEs of PD‐1 and PD‐L1 inhibitors in clinical trials consisting of 125 clinical trials included 20 128 patients reported 66% of 18, 610 patients (n = 106 studies) developed at least 1 any‐grade trAEs while 14.0% of 18 715 patients (n = 110 studies) developed at least 1 grade ≥ 3 trAEs . These rates were comparable to those observed for trAEs among HNC patients.…”

Section: Discussionmentioning

confidence: 81%

“…Similarly these systems were also the most commonly affected by ICI-induced adverse effects in other cancers. [51][52][53] Gastrointestinal and hepatic toxicities were less frequent for nivolumab than standard of care chemotherapy for HNC, whereas skin toxicities (15.7%), endocrinopathies (7.6%), and pneumonitis (2.1%) were more frequent in the Checkmate 141 study. 16 It is not yet clear how the rates of trAEs and irAEs of anti-PD1 therapy in HNC would compare with the rates in other cancers because the number of studies and the total number of HNC patients were still relatively small.…”

Section: Discussionmentioning

confidence: 97%

“…Anti‐PD1 agents in HNC had a wide variety of trAEs across several organ systems, with the endocrine, skin, gastrointestinal systems, and respiratory, being most commonly affected. Similarly these systems were also the most commonly affected by ICI‐induced adverse effects in other cancers . Gastrointestinal and hepatic toxicities were less frequent for nivolumab than standard of care chemotherapy for HNC, whereas skin toxicities (15.7%), endocrinopathies (7.6%), and pneumonitis (2.1%) were more frequent in the Checkmate 141 study …”

Section: Discussionmentioning

confidence: 99%

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Serious immune‐related adverse events in patients with head and neck cancer after checkpoint blockade: Systematic review

et al. 2019

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Background Immune checkpoint inhibitors confer significant clinical benefit by bolstering immune‐system activity, however, they also produce a spectrum of immune‐related adverse events (irAEs). Rapid recognition and timely treatment of these patients is essential for improved outcomes. Methods We conducted a systematic review of English‐language articles in MEDLINE, EMBASE, Web of Science, PubMed, and Cochrane CENTRAL databases on patients with head and neck cancer treated with immune checkpoint inhibitors who developed treatment‐related adverse events. Results Of 1715 unique citations, 11 studies met inclusion criteria. Eight patients with serious irAEs were reported from case reports and case series. Overall, 46 treatment‐related AEs were identified from the pooled 791 patients with at least 12 having potential relevance to irAEs. The most frequent AEs observed in patients receiving PD‐1 inhibitors involved the endocrine, cutaneous, and gastrointestinal systems. Conclusions Characterizing irAEs in longitudinal studies is needed for developing strategies for their prompt recognition and management.

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Section: Discussionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

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Serious immune‐related adverse events in patients with head and neck cancer after checkpoint blockade: Systematic review

et al. 2019

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“…The incidence of irAEs with single‐agent ICI varies by agent, tumor type, and disease setting. The incidence of any‐grade irAE in trials including patients with multiple solid tumor types has been reported at 72% with ipilimumab monotherapy and 66% with anti–PD‐1/anti–PD‐L1 monotherapy . The incidence of irAEs is higher with combined PD‐1 and CTLA‐4 blockade .…”

Section: Checkpoint Inhibitorsmentioning

confidence: 99%

A review of cancer immunotherapy toxicity

Kennedy

Salama

2020

CA A Cancer J Clinicians

825

628

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Cancer immunotherapies, including checkpoint inhibitors and adoptive cell therapy, manipulate the immune system to recognize and attack cancer cells. These therapies have the potential to induce durable responses in multiple solid and hematologic malignancies and thus have transformed treatment algorithms for numerous tumor types. Cancer immunotherapies lead to unique toxicity profiles distinct from the toxicities of other cancer therapies, depending on their mechanism of action. These toxicities often require specific management, which can include steroids and immune‐modulating therapy and for which consensus guidelines have been published. This review will focus on the toxicities of checkpoint inhibitors and chimeric antigen receptor T cells, including pathophysiology, diagnosis, and management.

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Systemic Therapy for Locally Advanced and Metastatic Non–Small Cell Lung Cancer

Arbour

Riely

2019

JAMA

794

658

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IMPORTANCE Non-small cell lung cancer remains the leading cause of cancer death in the United States. Until the last decade, the 5-year overall survival rate for patients with metastatic non-small cell lung cancer was less than 5%. Improved understanding of the biology of lung cancer has resulted in the development of new biomarker-targeted therapies and led to improvements in overall survival for patients with advanced or metastatic disease.OBSERVATIONS Systemic therapy for metastatic non-small cell lung cancer is selected according to the presence of specific biomarkers. Therefore, all patients with metastatic non-small cell lung cancer should undergo molecular testing for relevant mutations and expression of the protein PD-L1 (programmed death ligand 1). Molecular alterations that predict response to treatment (eg, EGFR mutations, ALK rearrangements, ROS1 rearrangements, and BRAF V600E mutations) are present in approximately 30% of patients with non-small cell lung cancer. Targeted therapy for these alterations improves progression-free survival compared with cytotoxic chemotherapy. For example, somatic activating mutations in the EGFR gene are present in approximately 20% of patients with advanced non-small cell lung cancer. Tyrosine kinase inhibitors such as gefitinib, erlotinib, and afatinib improve progression-free survival in patients with susceptible EGFR mutations. In patients with overexpression of ALK protein, the response rate was significantly better with crizotinib (a tyrosine kinase inhibitor) than with the combination of pemetrexed and either cisplatin or carboplatin (platinum-based chemotherapy) (74% vs 45%, respectively; P < .001) and progression-free survival (median, 10.9 months vs 7.0 months; P < .001). Subsequent generations of tyrosine kinase inhibitors have improved these agents. For patients without biomarkers indicating susceptibility to specific targeted treatments, immune checkpoint inhibitor-containing regimens either as monotherapy or in combination with chemotherapy are superior vs chemotherapy alone. These advances in biomarker-directed therapy have led to improvements in overall survival. For example, the 5-year overall survival rate currently exceeds 25% among patients whose tumors have high PD-L1 expression (tumor proportion score of Ն50%) and 40% among patients with ALK-positive tumors.CONCLUSIONS AND RELEVANCE Improved understanding of the biology and molecular subtypes of non-small cell lung cancer have led to more biomarker-directed therapies for patients with metastatic disease. These biomarker-directed therapies and newer empirical treatment regimens have improved overall survival for patients with metastatic non-small cell lung cancer.

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Treatment-Related Adverse Events of PD-1 and PD-L1 Inhibitors in Clinical Trials

Cited by 564 publications

References 143 publications

Serious immune‐related adverse events in patients with head and neck cancer after checkpoint blockade: Systematic review

Serious immune‐related adverse events in patients with head and neck cancer after checkpoint blockade: Systematic review

A review of cancer immunotherapy toxicity

Systemic Therapy for Locally Advanced and Metastatic Non–Small Cell Lung Cancer

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