Prospective evaluation of the prognostic value of immune-related adverse events in patients with non-melanoma solid tumour treated with PD-1/PD-L1 inhibitors alone and in combination with radiotherapy

Schweizer, Claudia; Schubert, Philipp; Rutzner, Sandra; Eckstein, Markus; Haderlein, Marlen; Lettmaier, Sebastian; Semrau, Sabine; Gostian, Antoniu‐Oreste; Frey, Benjamin; Gaipl, Udo S.; Zhou, Jianguo; Hecht, Markus

doi:10.1016/j.ejca.2020.09.001

Cited by 33 publications

(25 citation statements)

References 21 publications

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“…In contrast to past assumptions, treatment interruptions and glucocorticoid use for irAE management are no obstacle for the treatment success. Recent analyses of our ST-ICI trial and other trials indicate that patients with irAE have a superior prognosis compared to patients without irAE [13][14][15][16][17].…”

Section: Discussionmentioning

confidence: 87%

“…The ASCO Clinical Practice Guideline Summary presents a system-based toxicity diagnosis and management guideline, which recommends treatments depending on the affected system [11,12]. Several studies have shown that the occurrence of immune-related adverse events (irAE) might have a positive influence on tumor treatment response and the survival rate [13][14][15][16][17]. As a result, the onset of irAE represents a potentially beneficial clinical marker for ICI efficacy and should be further evaluated also in this respect.…”

Section: Introductionmentioning

confidence: 99%

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Questionnaire-based detection of immune-related adverse events in cancer patients treated with PD-1/PD-L1 immune checkpoint inhibitors

et al. 2021

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Background Immune checkpoint inhibitors (ICI) have become standard treatment in different tumor entities. However, safe treatment with ICI targeting the PD-1/PD-L1 axis requires early detection of immune-related adverse events (irAE). There exist different questionnaires of drug manufacturers for the detection of irAE that have not been validated so far. Methods The prospective non-interventional ST-ICI trial studied treatment with PD-1/PD-L1 ICI alone or combined with radiotherapy. In the current analysis, the detection rate of self-reported irAE with a patient questionnaire containing 41 different questions was compared to clinician-reported irAE. Results Between April 2017 and August 2019, a total of 104 patients were prospectively enrolled. NSCLC (44%) and HNSCC (42%) were the most frequent tumor entities. A total of 784 questionnaires were collected. A total of 29 irAE were reported by clinicians. The most frequent irAE was hypothyroidism (9%), followed by skin reactions (5%), hepatitis (4%), diarrhea (3%), and pneumonitis (3%). Questions that became significantly more often positive at time points of clinician-reported irAE were “weight change”, “difficulty to grip things”, “bloody or mucous stool” and “insomnia”. Self-reported organ-specific questions detected at least 50% of clinician-reported irAE of gastrointestinal, lung, endocrine, and skin irAE. It was not possible to detect hepatic irAE with the questionnaire. Conclusion Questionnaires can help to detect gastrointestinal, lung, endocrine, or skin irAE, but not hepatic irAE. Questions on “weight change” and “insomnia” may help to increase the detection rate of irAE, besides organ-specific questions. These results are a valuable contribution to the future development of a specific and practicable questionnaire for early self-reported detection of irAE during ICI therapy in cancer patients. Trial registration ClinicalTrials.gov, NCT03453892. Registered on 05 March 2018.

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Section: Discussionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Questionnaire-based detection of immune-related adverse events in cancer patients treated with PD-1/PD-L1 immune checkpoint inhibitors

et al. 2021

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“…Previous experience with irAEs has informed management guidelines, allowing for recovery for most patients and often immunotherapy rechallenge (Table 2). Some studies have suggested the development of irAEs may correlate with an improved response to therapy [58][59][60]. Limited data exists for the safety and efficacy of immunotherapy in immune-vulnerable populations, such as patients with pre-existing autoimmune conditions or HIV/AIDS, though generally it is favored to pursue immunotherapy in these patients if clinically appropriate [61].…”

Section: Immunotherapy Toxicitymentioning

confidence: 99%

Checkpoint inhibitor therapy for metastatic triple-negative breast cancer

Heeke

Tan

2021

Cancer Metastasis Rev

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Immunotherapy has become a mainstay of cancer treatment in many malignancies, though its application in breast cancer remains limited. Of the breast cancer subtypes, triple-negative breast cancers (TNBCs) are characterized by immune activation and infiltration and more commonly express biomarkers associated with response to immunotherapy. Checkpoint inhibitor therapy has shown promising activity in metastatic TNBC. In 2019, the US FDA granted accelerated approval of atezolizumab, a programmed death-ligand 1 (PD-L1) inhibitor, in combination with nab-paclitaxel for unresectable locally advanced or metastatic PD-L1-positive TNBC, based on the results of the phase III IMpassion130 trial. In 2020, the FDA also granted accelerated approval of pembrolizumab, a PD-1 inhibitor, in combination with chemotherapy for locally recurrent unresectable and metastatic PD-L1-positive TNBC, based on results of the phase III KEYNOTE-355 trial. Additional combination strategies are being explored in the treatment of metastatic TNBC, with the goal of augmenting antitumor activity. In this review, the clinical development of checkpoint inhibitors in the treatment of metastatic TNBC will be discussed, including clinical outcomes with monotherapy and combination therapy regimens, biomarkers that may predict for benefit, and future directions in the field.

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“…In some cases, the onset of irAEs may have a favorable impact on patients undergoing radioimmunotherapy. Recently, a prospective evaluation by Schweize et al reported metastatic melanoma patients developing irAEs to have a significantly prolonged overall survival than those who did not in the whole population under study and the subgroup treated with RT, with no differences in irAEs rate between the RT group and non-RT group ( Schweizer et al, 2020 ). A retrospective study on concurrent, palliative RT and a PD-1 inhibitor (usually 30–3 Gy/fraction using 3D conformal RT techniques) showed only 36% of grade 3 toxicities occurring within the radiation field, while all grade 4 and 5 toxicities occurred outside the field ( Parker et al, 2018 ).…”

Section: Radiotherapy and Immunotherapymentioning

confidence: 99%

Biological Bases of Immune-Related Adverse Events and Potential Crosslinks With Immunogenic Effects of Radiation

Bardoscia¹,

Pasinetti

Triggiani

et al. 2021

Front. Pharmacol.

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Immune checkpoint inhibitors have gained an established role in the treatment of different tumors. Indeed, their use has dramatically changed the landscape of cancer care, especially for tumor types traditionally known to have poor outcomes. However, stimulating anticancer immune responses may also elicit an unusual pattern of immune-related adverse events (irAEs), different from those of conventional chemotherapy, likely due to a self-tolerance impairment featuring the production of autoreactive lymphocytes and autoantibodies, or a non-specific autoinflammatory reaction. Ionizing radiation has proven to promote both positive pro-inflammatory and immunostimolatory activities, and negative anti-inflammatory and immunosuppressive mechanisms, as a result of cross-linked interactions among radiation dose, the tumor microenvironment and the host genetic predisposition. Several publications argue in favor of combining immunotherapy and a broad range of radiation schedules, based on the recent evidence of superior treatment responses and patient survival. The synergistic modulation of the immune response by radiation therapy and immunotherapeutics, particularly those manipulating T-cell activation, may also affect the type and severity of irAEs, suggesting a relationship between the positive antitumor and adverse autoimmune effects of these agents. As yet, information on factors that may help to predict immune toxicity is still lacking. The aim of our work is to provide an overview of the biological mechanisms underlying irAEs and possible crosslinks with radiation-induced anticancer immune responses. We believe such an overview may support the optimization of immunotherapy and radiotherapy as essential components of multimodal anticancer therapeutic approaches. Challenges in translating these to clinical practice are discussed.

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Prospective evaluation of the prognostic value of immune-related adverse events in patients with non-melanoma solid tumour treated with PD-1/PD-L1 inhibitors alone and in combination with radiotherapy

Cited by 33 publications

References 21 publications

Questionnaire-based detection of immune-related adverse events in cancer patients treated with PD-1/PD-L1 immune checkpoint inhibitors

Questionnaire-based detection of immune-related adverse events in cancer patients treated with PD-1/PD-L1 immune checkpoint inhibitors

Checkpoint inhibitor therapy for metastatic triple-negative breast cancer

Biological Bases of Immune-Related Adverse Events and Potential Crosslinks With Immunogenic Effects of Radiation

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