Safety evaluation of nivolumab added concurrently to radiotherapy in a standard first line chemo-radiotherapy regimen in stage III non-small cell lung cancer—The ETOP NICOLAS trial

Peters, Solange; Felip, Enriqueta; Dafni, Urania; Belka, Claus; Gückenberger, Matthias; Irigoyen, A.; Nadal, Ernest; Becker, Annemarie; Vees, Hansjörg; Pless, Miklos; Martinez-Martí, Alex; Tufman, Amanda; Lambrecht, Maarten; Andratschke, Nicolaus; Piguet, Anne‐Christine; Kassapian, Marie; Roschitzki-Voser, Heidi; Rabaglio-Poretti, Manuela; Stahel, Rolf A.; Vansteenkiste, Johan; Ruysscher, Dirk De

doi:10.1016/j.lungcan.2019.05.001

Cited by 126 publications

(116 citation statements)

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“…Our finding of a preferential location of IP to RT fields is of particular interest. Several trials have raised the interest of administering immunotherapy with other treatments, particularly RT, since their antitumoural effects may be enhanced when combined [2,[6][7][8][9]23].…”

Section: Discussionmentioning

confidence: 99%

“…ICIs interfere with this process, and reactivate the priming and effector phases of the immune response against the neoplastic cells, which has been shown to result in a systemic, complete and durable cancer response in a subset of patients. Recently, a synergistic effect of immunotherapy and radiotherapy (RT) has been suggested in selected patients, with several studies demonstrating a significant prolonged progression-free survival and overall survival when immunotherapy is combined with previous or concomitant RT [2][3][4][5][6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

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Relationship between pneumonitis induced by immune checkpoint inhibitors and the underlying parenchymal status: a retrospective study

et al. 2020

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In patients with primary or secondary lung tumour treated with immune checkpoint inhibitors, immune-related pneumonitis is a rare adverse event but may evolve to respiratory failure. Prompt management is required and usually consists of treatment interruption and immunosuppressive drug administration. The aim of this study was to evaluate relationships between immune-related pneumonitis and pre-existing parenchymal status, especially tumour location and history of chest radiotherapy.Computed tomography (CT) scans of patients with immune-related pneumonitis were retrospectively reviewed. Pattern, distribution and extent of pneumonitis were assessed in six lung regions. In patients who received radiotherapy, the extent of pneumonitis was evaluated according to the radiation field.Among 253 patients treated with immunotherapy, 15 cases of immune-related pneumonitis were identified. 10 had previous or concomitant chest radiotherapy in addition to immunotherapy. At CT scan, 29 (33%) out of 88 regions encompassed the primary tumour (n=4), a lung metastasis (n=4) and/or radiation fields (n=21). A significantly higher prevalence of parenchymal involvement by immune-related pneumonitis occurred within areas of primary or metastatic malignancy and/or radiation field (97%) as compared to other areas (3%, p=0.009). Lung regions affected by the primary tumour, metastasis or radiotherapy had a higher probability of immune-related pneumonitis than others (OR 10.8, p=0.024). An organising pneumonia (OP) pattern was more frequent after radiotherapy (70% versus 0%, p=0.024), whereas nonspecific interstitial pneumonia features were more commonly seen in radiotherapy-naive patients (100% versus 10%, p=0.002).In patients with primary or secondary lung tumour treated with immune checkpoint inhibitors, immune-related pneumonitis is preferentially located within lung areas involved by tumour and/or radiation fields.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Relationship between pneumonitis induced by immune checkpoint inhibitors and the underlying parenchymal status: a retrospective study

et al. 2020

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“…No clinically significant increase in the rate of side effects has been reported with the addition of immunotherapy compared with that of CCRT alone. 2,83 In the PACIFIC study, durvalumab immunotherapy was delivered after CCRT for up to 1 year. The rates of grade !3 events were similar in Table 2.…”

Section: Radiotherapy Techniques and Chemotherapy Adjustments To Prevmentioning

confidence: 99%

“…2 In the phase 2 NICOLAS study, which evaluated the safety of delivering nivolumab concurrently with CCRT and for up to 1 year after completion of treatment, no increased pneumonitis grade !3 was observed. 83 There is no evidence supporting modifications of routine radiotherapy techniques to prevent toxicity in the context of the use of immunotherapy. As advocated in the European Organization for Research and Treatment of Cancer (EORTC) recommendations for planning and delivery of radiotherapy for lung cancer, dose to thoracic organs at risk should be minimized, while maintaining target coverage.…”

Section: Radiotherapy Techniques and Chemotherapy Adjustments To Prevmentioning

confidence: 99%

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Recommendation for supportive care in patients receiving concurrent chemotherapy and radiotherapy for lung cancer

et al. 2020

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Concurrent chemotherapy and radiotherapy (CCRT) followed by durvalumab immune therapy in appropriate patients is considered to be the standard of care in most fit stage III non-small-cell lung cancer (NSCLC) patients. However, CCRT is a toxic treatment that affects all organ systems and may cause acute and permanent side effects, some of which may be lethal. Supportive care is therefore of utmost importance in this clinical setting. A group of experts from the European Society for Therapeutic Radiology and Oncology (ESTRO) and the European Society of Medical Oncology (ESMO) identified the following items of importance for further improvement of supportive care: smoking cessation; nutrition before and during CCRT (including treatment and prevention of anorexia); physical exercise before and during CCRT; prevention and treatment of acute esophagitis and dysphagia; treatment of cough and dyspnea; treatment of skin reactions; treatment of fatigue; prophylaxis of nausea and emesis; prevention, diagnosis, and treatment of cardiac disease and damage; and optimization of radiotherapy techniques and chemotherapy adjustments to reduce toxicity in the era of immune therapy. The resulting recommendations are summarized in this manuscript and knowledge gaps identified, in which future investments are needed to improve supportive care and hence quality of life and survival for our stage III NSCLC patients.

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Phase 1 Trial of Pembrolizumab Administered Concurrently With Chemoradiotherapy for Locally Advanced Non–Small Cell Lung Cancer

et al. 2020

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IMPORTANCE Consolidative programmed death ligand-1 (PD-L) inhibition after chemoradiotherapy improves overall survival and progression-free survival (PFS) for stage III non-small cell lung cancer (NSCLC) and requires safety evaluation for incorporation of programmed cell death 1 (PD-1) inhibition at the onset of chemoradiotherapy.OBJECTIVE To determine the safety and tolerability of PD-1 inhibition concurrently with definitive chemoradiotherapy for NSCLC. DESIGN, SETTING, AND PARTICIPANTSThis phase 1 prospective multicenter nonrandomized controlled trial using a 3 plus 3 design was performed from August 30, 2016, to October 24, 2018, with a median follow-up of 16.0 (95% CI, 12.0-22.6) months and data locked on July 25, 2019. Twenty-one participants had locally advanced, unresectable, stage III NSCLC as determined by multidisciplinary review, Eastern Cooperative Oncology Group performance status 0 or 1, and adequate hematologic, renal, and hepatic function. Data were analyzed from October 17, 2016, to July 19, 2019.INTERVENTIONS Pembrolizumab was combined with concurrent chemoradiotherapy (weekly carboplatin and paclitaxel with 60 Gy of radiation in 2 Gy per d). Dose cohorts evaluated included full-dose pembrolizumab (200 mg intravenously every 3 weeks) 2 to 6 weeks after chemoradiotherapy (cohort 1); reduced-dose pembrolizumab (100 mg intravenously every 3 weeks) starting day 29 of chemoradiotherapy (cohort 2); full-dose pembrolizumab starting day 29 of chemoradiotherapy (cohort 3); reduced-dose pembrolizumab starting day 1 of chemoradiotherapy (cohort 4); and full-dose pembrolizumab starting day 1 of chemoradiotherapy (cohort 5). A safety expansion cohort of 6 patients was planned based on the maximum tolerated dose of pembrolizumab. Dose-limiting toxic effects were defined as pneumonitis of at least grade 4 within cycle 1 of pembrolizumab treatment.MAIN OUTCOMES AND MEASURES Safety and tolerability of PD-1 inhibition with chemoradiotherapy for NSCLC. Secondary outcomes included PFS and pneumonitis rates. RESULTS Among the 21 patients included in the analysis (11 female [52%]; median age, 69.5 [range, 53.0-85.0] years), no dose-limiting toxic effects in any cohort were observed. One case of grade 5 pneumonitis occurred in the safety expansion cohort with the cohort 5 regimen. Immune-related adverse events of at least grade 3 occurred in 4 patients (18%). Median PFS for patients who received at least 1 dose of pembrolizumab (n = 21) was 18.7 (95% CI, 11.8-29.4) months, and 6-and 12-month PFS were 81.0% (95% CI, 64.1%-97.7%) and 69.7% (95% CI, 49.3%-90.2%), respectively. Median PFS for patients who received at least 2 doses of pembrolizumab (n = 19) was 21.0 (95% CI, 15.3 to infinity) months.CONCLUSIONS AND RELEVANCE These findings suggest that combined treatment with PD-1 inhibitors and chemoradiotherapy for stage III NSCLC is tolerable, with promising PFS of 69.7% at 12 months, and requires further study.

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Safety evaluation of nivolumab added concurrently to radiotherapy in a standard first line chemo-radiotherapy regimen in stage III non-small cell lung cancer—The ETOP NICOLAS trial

Cited by 126 publications

References 12 publications

Relationship between pneumonitis induced by immune checkpoint inhibitors and the underlying parenchymal status: a retrospective study

Relationship between pneumonitis induced by immune checkpoint inhibitors and the underlying parenchymal status: a retrospective study

Recommendation for supportive care in patients receiving concurrent chemotherapy and radiotherapy for lung cancer

Phase 1 Trial of Pembrolizumab Administered Concurrently With Chemoradiotherapy for Locally Advanced Non–Small Cell Lung Cancer

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