Improved survival and disease control following pembrolizumab-induced immune-related adverse events in high PD-L1 expressing non-small cell lung cancer with brain metastases

Zhang, Michael; Rodrigues, Adrian; Pollom, Erqi L.; Gibbs, Iris C.; Soltys, Scott G.; Hancock, Steven; Neal, Joel W.; Padda, Sukhmani K.; Ramchandran, Kavitha; Wakelee, Heather A.; Chang, Steven D.; Lim, Michael; Gephart, Melanie Hayden; Li, Gordon

doi:10.1007/s11060-020-03686-3

Cited by 7 publications

(6 citation statements)

References 28 publications

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“…Zhang et al 25 found, in another retrospective study with 63 patients, a significantly longer OS among patients with irAEs in a population with NSCLC with brain metastases.…”

Section: Discussionmentioning

confidence: 94%

“…Due to the above mentioned common mechanism responsible for both therapeutic action and toxicity, it is suggested that an increased toxicity might lead to a better response, observing improved ORR, PFS or OS 14–16. Several studies have supported this hypothesis, mainly in melanoma,17–20 but evidence is growing across all cancers, including NSCLC treated with nivolumab21–23 and, more recently, pembrolizumab 24 25…”

Section: Introductionmentioning

confidence: 99%

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Predictive value of immune-related adverse events during pembrolizumab treatment in non-small cell lung cancer

et al. 2022

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ObjectivesSeveral studies have reported the role of immune-related adverse events as a predictor of clinical benefit, but few have properly described these findings in advanced or metastatic non-small cell lung cancer treated with pembrolizumab. This study aimed to evaluate the association between immune-related adverse events development and clinical outcomes in the aforementioned group of patients.MethodsWe conducted a retrospective study in patients with advanced or metastatic non-small cell lung cancer treated with pembrolizumab. Overall response rate, progression-free survival and overall survival were evaluated according to the appearance, subtype and number of immune-related adverse events developed. We report the results of the immune-related adverse events analysis and the potential correlation between immune-related adverse events and clinical outcomes. Univariate and multivariate analyses were performed to evaluate this relationship.ResultsA total of 94 patients were analysed; 60 of them developed immune-related adverse events. Patients with immune-related adverse events had a significantly higher overall response rate compared with the non-immune-related adverse events group (34% vs 8.5%, χ2=0.005). Median progression-free survival was statistically significant in favour of patients with at least one immune-related adverse event (p=0.015). Median overall survival was not reached in patients with ≥1 immune-related adverse events, compared with 8 months (95% CI 0.6 to 15.4 months) in those without immune-related adverse events. Patients who developed ≥2 immune-related adverse events had longer median progression-free survival (11 vs 4 months, not statistically significant) and overall survival (not reached vs 11, p=0.022) compared with those with ≤1 immune-related adverse events.ConclusionsObtained data showed that patients with immune-related adverse events occurrence had significantly better overall response rate and longer progression-free survival and overall survival. This study highlights the role of immune-related adverse events as a predictor of survival in a real-life setting.

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“…Zhang et al 25 found, in another retrospective study with 63 patients, a significantly longer OS among patients with irAEs in a population with NSCLC with brain metastases.…”

Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Predictive value of immune-related adverse events during pembrolizumab treatment in non-small cell lung cancer

et al. 2022

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“…The number of patients undergoing combined SRS and immunotherapy with subsequent development of RN is likely to continue to increase. 31 It is therefore increasingly important to better understand the pathophysiology of RN and how treatment can be used more effectively. An upcoming trial at the University of Florida (NCT04187872) will investigate the immune effects of LITT and pembrolizumab in adult patients with brain metastases from melanoma, NSCLC, or renal cell carcinoma recurring post-SRS, primary cancers approved for treatment with immune-checkpoint inhibitors by the Food and Drug Administration ( https://clinicaltrials.gov ).…”

Section: Discussionmentioning

confidence: 99%

“…The immune cell composition of brain metastases is being increasingly studied and has been shown to contain a high number of lymphocytes subtypes of which can be influenced by local microenvironment and type of malignancy. [28][29][30][31][32] Immune regulatory molecules driving myeloid and lymphocytic cells (CD40L, IL6R, INHBA, AREG) are highly expressed, with specific increase in autoimmune inflammation mediators and specific enrichment of IL6 in microglia and TREM1 in microglia/macrophages. 28 RN histology also demonstrates marked inflammatory changes with abundant infiltration by CD3 1 T cells and CD68 1 macrophages but drivers of this process have been less well studied.…”

Section: Observationsmentioning

confidence: 99%

Histological changes associated with laser interstitial thermal therapy for radiation necrosis: illustrative cases

Fomchenko¹,

Leelatian

Darbinyan

et al. 2022

Journal of Neurosurgery: Case Lessons

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BACKGROUND Patients with lung cancer and melanoma remain the two largest groups to develop brain metastases. Immunotherapy has been approved for treatment of stage IV disease in both groups. Many of these patients are additionally treated with stereotactic radiosurgery for their brain metastases during ongoing immunotherapy. Use of immunotherapy has been reported to increase the rates of radiation necrosis (RN) after radiosurgery, causing neurological compromise due to growth of the enhancing lesion as well as worsening of associated cerebral edema. OBSERVATIONS Laser interstitial thermal therapy (LITT) is a surgical approach that has been shown effective in the management of RN, especially given its efficacy in early reduction of perilesional edema. However, little remains known about the pathology of the post-LITT lesions and how LITT works in this condition. Here, we present two patients who needed surgical decompression after LITT for RN. Clinical, histopathological, and imaging features of both patients are presented. LESSONS Criteria for selecting the best patients with RN for LITT therapy remains unclear. Given two similarly sized lesions and not too dissimilar clinical histories but with differing outcomes, further investigation is clearly needed to identify predictors of response to LITT in the setting of SRS and immunotherapy-induced RN.

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“…The association of irAEs and clinical outcomes in NSCLC patients with existing brain metastasis who received ICIs is also not well studied. A small retrospective review of 63 patients found that any grade irAEs were associated with longer OS (21 versus 10 months; p = 0.004) and delayed treatment failure (14 versus 5 months; p = 0.001), especially in patients with high PD-L1 expression [ 59 ].…”

Section: Tumour-specific Iraes and Clinical Outcomesmentioning

confidence: 99%

Defining the correlation between immune-checkpoint inhibitors-related adverse events and clinical outcomes: a narrative review

Abdihamid¹,

Omar²,

Rugambwa³

2021

ecancer

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Immune checkpoint inhibitors (ICIs) have increased modern anticancer armamentarium portfolios, with 15%–60% of cancer patients deriving clinical benefit while others progress, including some occurrences of accelerated progressions. ICIs have also introduced a new pattern of immune-related adverse events (irAEs). Recently, a mechanistic link was proposed in which patients who develop ICIs-related irAEs derive a survival benefit compared to those who do not, suggesting an overlap between toxicities and the treatment efficacy. Identifying predictive biomarkers to optimally identify patients who will benefit from ICIs is a contemporary research area in Oncology. However, the data remains sparse, with only several smaller studies showing a plausible direct proportionality of a therapeutic effect across tumours. In contrast, the overall survival and progression-free survival rate depend on the tumour type, degree of toxicities, duration of exposure, affected system/organs and inherent patient characteristics. Furthermore, the occurrence of irAEs appears to be more associated with a clinical benefit from programmed death 1 and programmed death-ligand 1 inhibitors than anti-cytotoxic T-lymphocyte-associated antigen 4. Several questions remain unanswered, including the association between survival benefit and specific type of organ system toxicities, toxicity grade, if the benefit is entirely due to immortal-time biases (ITBs), presence of patients confounding comorbidities like autoimmune diseases, and finally, immune heterogeneities. Considering ITB represents a key element in interpreting these studies since patients with precipitated death or with an earlier disease progresses rarely develop irAEs; in fact, such patients have not stayed in the study long enough to experience such irAEs. Conversely, patients that stayed in the study for a longer period have a higher risk of developing irAEs. Landmark analysis is key in these studies if a real association is to be found. Overall response and disease control rates are mainly higher in those who develop irAEs due to immune activation. So, this review aims to summarise the evidence from key studies that addressed this important clinical question.

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Improved survival and disease control following pembrolizumab-induced immune-related adverse events in high PD-L1 expressing non-small cell lung cancer with brain metastases

Cited by 7 publications

References 28 publications

Predictive value of immune-related adverse events during pembrolizumab treatment in non-small cell lung cancer

Predictive value of immune-related adverse events during pembrolizumab treatment in non-small cell lung cancer

Histological changes associated with laser interstitial thermal therapy for radiation necrosis: illustrative cases

Defining the correlation between immune-checkpoint inhibitors-related adverse events and clinical outcomes: a narrative review

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