Immune-related adverse events predict the therapeutic efficacy of anti–PD-1 antibodies in cancer patients

Rogado, Jacobo; Sánchez-Torres, J.M.; Romero-Laorden, Nuria; Ballesteros, Anabel; Pacheco-Barcía, Vilma; Ramos-Leví, Ana M.; Arranz, Reyes; Lorenzo, Antonino De; Gullón, Pedro; Donnay, O.; Adrados, Magdalena; Costas, Pablo; Aspa, Javier; Alfranca, Arántzazu; Mondéjar, Rebeca; Colomer, Ramón

doi:10.1016/j.ejca.2018.10.014

Cited by 200 publications

(167 citation statements)

References 34 publications

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“…This suggests that patients with previous rejection episodes exhibit lymphocyte subpopulations with a susceptibility to checkpoint inhibition. Some studies in the nontransplant population have highlighted a relationship between irAEs and favorable cancer outcome . We found no similar association between organ rejection and tumor response.…”

Section: Discussioncontrasting

confidence: 76%

Efficacy and tolerance of immune checkpoint inhibitors in transplant patients with cancer: A systematic review

d’Izarny-Gargas

Dürrbach

Zaidan

2020

American Journal of Transplantation

130

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Solid organ transplant (SOT) is frequently complicated by cancers, which render immunosuppression challenging. Immune checkpoint inhibitors have emerged as treatments for many cancers. Data are lacking regarding efficacy and rejection risk in the SOT population. We conducted a systematic literature review and analyzed 83 cases of immune checkpoint inhibitor use for cancer in SOT. Two thirds of these patients received anti–programmed death ligand 1 therapy, 15.7% received anti–cytotoxic T lymphocyte–associated protein 4 therapy, and 10.8% received a combination. Allograft rejection occurred in 39.8% of patients, leading to end‐stage organ failure in 71.0% of cases. Outcomes were similar across organs and immunotherapy regimens. The use of immunosuppressants other than steroids, time since transplant, and prior episodes of rejection were associated with the risk of rejection. The median overall survival of patients was 36 weeks. Most of the deaths were related to cancer progression. In nonkidney recipients, graft rejection was strongly associated with worse survival. At the end of the study, 19.3% of the patients were alive, free from rejection and tumor progression. This study highlights the difficult tradeoff facing oncologists and transplant specialists managing transplant recipients with cancer, and the need for prospective data and novel biomarkers for identifying the patients likely to benefit from immunotherapy in the SOT setting.

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Section: Discussioncontrasting

confidence: 76%

Efficacy and tolerance of immune checkpoint inhibitors in transplant patients with cancer: A systematic review

d’Izarny-Gargas

Dürrbach

Zaidan

2020

American Journal of Transplantation

130

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“…In patients with melanoma, 1-year OS and PFS were 49% [95%, CI 40-58] and 26% [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34], respectively (Supplementary Table 1). Median OS and PFS were 11.6 (iqr 3.4-29.6) and 3.9 (2.2-12.6) months, respectively.…”

Section: Efficacymentioning

confidence: 99%

“…The ORR was 33.9%. In patients with NSCLC, the 1-year OS and PFS were 44% [37-51] and 21% [16][17][18][19][20][21][22][23][24][25][26][27], respectively. Median OS and PFS were 9.1 (3.6-28.9) and 2.8 (1.6-10.4) months respectively.…”

Section: Efficacymentioning

confidence: 99%

The prognostic impact of immune-related adverse events during anti-PD1 treatment in melanoma and non–small-cell lung cancer: a real-life retrospective study

et al. 2019

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Background: Nivolumab and pembrolizumab, two PD1 inhibitors, trigger immune-related adverse events in approximately 50% of patients. Our objective was to determine whether these immunerelated adverse events are associated with patient outcomes. Patients and Methods: Retrospective cohort study, realized at the Institut Universitaire du Cancer de Toulouse, of all the patients treated with nivolumab or pembrolizumab off clinical trials. We included patients (i) diagnosed with unresectable stage III or stage IV melanoma or with recurrent stage IIIB or stage IV non-small cell lung cancer (ii) on nivolumab 3mg/kg or pembrolizumab 2mg/kg every 2 or 3 weeks respectively. Results: Of the 311 patients included (of 641 eligible subjects), 120 (38.6%) had melanoma and 191 (61.4%) had non-small cell lung cancer; 241 (77.5%) were treated with nivolumab with a median followup of 24 months (20-29). We observed 166 immune-related adverse events in 116 (37.3%) patients, categorized as "early" (onset before 12 weeks in melanoma and before 8 weeks in lung cancer) in 63 (54.3%) patients. Early and late adverse events were significantly associated with an increase in overall survival: adjusted hazard ratio 0.58 [0.41-0.84] (p = .003) and 0.28 [0.16-0.50] (p < .001) respectively. The overall response rate was significantly increased in patients with an immune-related adverse event (53.9% vs 12.9%, p < .001) Conclusions: This study validates the association between immune-related adverse events and anti-PD1 efficacy in real-life, especially if these events are delayed. Our results, along with further studies on the place of immunosuppressive drugs in the therapeutic strategy, could improve the management of these adverse events.

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“…We used the objective radiological response (ORR) and progression-free survival (PFS) as efficacy outcomes. Since we have recently reported that immune-related adverse events (irAEs) in patients treated with anti-PD-1 drugs is directly related to the response and an increase in PFS, 23 we also evaluated the influence of the development of irAEs in terms of ORR and PFS in the cohort of excess weight or normal weight patients.…”

Section: Introductionmentioning

confidence: 99%

Effect of excess weight and immune-related adverse events on the efficacy of cancer immunotherapy with anti-PD-1 antibodies

et al. 2020

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Immunotherapy is an effective treatment in advanced cancer, although predictors of response are limited. We studied whether excess weight influences the efficacy outcomes of immunotherapy. We have also evaluated the combined prognostic effect of excess weight and immune-related adverse events (irAEs). Efficacy of anti-PD-1 treatment was evaluated with both objective radiological response (ORR) rate and progression-free survival (PFS), and toxicity with irAEs. We studied the association between excess weight and ORR, PFS or irAEs. 132 patients diagnosed with advanced cancer were included. Median body mass index (BMI) was 24.9 kg/ m2. 64 patients had normal weight (BMI<25 kg/m2), and 64 patients had excess weight (BMI≥25 kg/m2). Four patients had underweight and were excluded from further analysis. ORR was achieved in 50 patients (38.0%), median PFS was 6 months. 44 patients developed irAEs (33.3%). ORR was higher in excess weight patients than in patients with normal weight (51.6% vs 25.0%; OR 3.45, p = .0009). PFS was improved in patients with excess weight (7.25 months vs 4 months, HR 1.72, p = .01). The incidence of IrAEs was not different in patients with excess weight (54.5% vs 43.2%, p = .21). When high BMI and irAEs were combined, we observed a marked prognostic trend in ORR rate (87.5% vs 6.2%; OR 161.0, p < .00001), and in PFS (14 months vs 3 months; HR 5.89, p < .0001). Excess weight patients with advanced cancer that receive single-agent anti-PD-1 antibody therapy exhibit a significantly improved clinical outcome compared with normal BMI patients. This association was especially marked when BMI and irAEs were considered combined.

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Immune-related adverse events predict the therapeutic efficacy of anti–PD-1 antibodies in cancer patients

Cited by 200 publications

References 34 publications

Efficacy and tolerance of immune checkpoint inhibitors in transplant patients with cancer: A systematic review

Efficacy and tolerance of immune checkpoint inhibitors in transplant patients with cancer: A systematic review

The prognostic impact of immune-related adverse events during anti-PD1 treatment in melanoma and non–small-cell lung cancer: a real-life retrospective study

Effect of excess weight and immune-related adverse events on the efficacy of cancer immunotherapy with anti-PD-1 antibodies

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