Safety of Combined PD-1 Pathway Inhibition and Intracranial Radiation Therapy in Non–Small Cell Lung Cancer

Hubbeling, Harper; Schapira, Emily; Horick, Nora; Goodwin, Kelly; Lin, Jessica J.; Oh, Kevin; Shaw, Alice T.; Mehan, William A.; Shih, Helen A.; Gainor, Justin F.

doi:10.1016/j.jtho.2018.01.012

Cited by 98 publications

(79 citation statements)

References 31 publications

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“…In addition, AE rates did not differ according to the timing of anti-PD-1 administration with respect to irradiation. 23 Our results also agreed with the Keynote-001 trial subset analysis of irradiated patients 26 and other retrospective series. 24,27 Only one patient experimented a grade III immune-related adverse event directly correlated to the irradiation field (immune esophagitis after a cervical irradiation).…”

Section: Discussionsupporting

confidence: 87%

“…This good tolerance of the combination of radiotherapy and anti-PD-1 has been found previously. 13,15,16,23,24 In a retrospective analysis of 163 patients with advanced NSCLCs and brain metastases, rates of all-grade AEs and grade ≥3 AEs did not differ significantly between patients, who received intracranial RT and were treated with or without anti-PD-1 (grade ≥3 AEs: 8% of anti-PD-1-naïve patients vs 9% of anti-PD-1-treated patients with SRS, P = 1.00; and 8% of anti-PD-1-naïve patients vs 0% of anti-PD-1-treated patients with wholebrain RT, P = 0.71). In addition, AE rates did not differ according to the timing of anti-PD-1 administration with respect to irradiation.…”

Section: Discussionmentioning

confidence: 99%

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Safety of combined PD‐1 pathway inhibition and radiation therapy for non‐small‐cell lung cancer: A multicentric retrospective study from the GFPC

et al. 2018

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IntroductionRandomized prospective studies on patients with metastatic non‐small‐cell lung cancers (NSCLCs) showed that anti‐programmed death‐1 (PD‐1) agents notably improved 2‐year overall survival (OS) rates, compared to docetaxel. NSCLC patients now receive nivolumab and irradiation, concurrently or not. However, little is known about the safety of this combination, even though the preclinical model suggested a possible synergic effect. We analyzed NSCLC patients treated with radiotherapy and nivolumab according to former's timing.MethodsWe retrospectively reviewed records of a large series of metastatic NSCLC patients from three French centers, irradiated during the 6 months preceding, concomitantly, or 3 months after nivolumab administration to assess nivolumab tolerance and outcomes.ResultsAmong 104 patients included (37 women; 67 men; median age 60.3 years; 67% with performance status <2; 93.2% were current or past smokers) and their 144 intra‐ or extracranial irradiation courses, any‐grade adverse events (AEs) were observed in 62 (59.6%), with 10 (9.6%) experiencing at least one grade 3/4 toxicity and 9 (8.7%) at least one grade 3/4 immune‐related AE (IRAE). Respective 1‐ and 2‐year OS rates were 48.8% and 29.1%, while 1‐ and 2‐year progression‐free survival (PFS) rates were 20.9% and 10.1%. PFS was significantly better for patients with IRAE(s) (P = 0.038) than those without and a trend toward better OS (P = 0.06). Delivering radiation before or during/after nivolumab administration was not associated with better OS or PFS.ConclusionRadiotherapy delivered during the 6 months before, during, or the three months following nivolumab for NSCLCs was not associated with an increased risk of severe or unexpected toxicities.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Safety of combined PD‐1 pathway inhibition and radiation therapy for non‐small‐cell lung cancer: A multicentric retrospective study from the GFPC

et al. 2018

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“…There was no significant difference in rates of all grades as well as severe AEs. Additionally, there was no difference in AE based on the timing of ICI administration with respect to radiation therapy [82].…”

Section: Combination Of Ici and Radiotherapy In Brain Metastasismentioning

confidence: 90%

“…These findings limit the extrapolation of the melanoma results to NSCLC as radiation necrosis seems dependent on pathology as well as ICI type [81]. Another retrospective study included 163 NSCLC patients with BM treated with cranial radiation therapy (94 SRT, 28 partial brain irradiation, and 101 WBRT) with (n = 50) or without (n = 113) an anti-PD (L)1 inhibitor [82]. Patients were assigned to three timing groups: radiation therapy > 4 weeks before ICI, > 4 weeks after ICI and < 4 weeks before or after ICI.…”

Section: Combination Of Ici and Radiotherapy In Brain Metastasismentioning

confidence: 99%

Non-small cell lung cancer brain metastases and the immune system: From brain metastases development to treatment

Rassy

Botticella

Kattan

et al. 2018

Cancer Treatment Reviews

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Brain metastases (BM) are diagnosed frequently in non-small cell lung cancer (NSCLC) patients. Despite the high incidence of BM (up to 40% in unselected patients), patients with untreated and/or unstable BM were excluded from pivotal immune checkpoint inhibitors (ICI) NSCLC trials. Percentage of patients with stable and treated BM in these trials ranged from 9.1 to 14.7% and ICI benefit over chemotherapy was not always demonstrated. Only small trials have been completed that demonstrated ICI efficacy in locally untreated, selected BM patients. With 33%, cranial objective response rate (ORR) was comparable to extracranial ORR and responses were often durable. With the promising survival benefits of ICI, in daily practice also unstable and/or untreated BM patients will often receive treatment with ICI and extrapolating clinical trial data to these patients can be challenging. In this review, we will summarize the preclinical rationale and potential concerns for the use of ICI in BM patients. Furthermore, we will summarize BM subgroup data from the pivotal NSCLC trials, retrospective series, the NSCLC BM specific ICI trials and the use of cranial radiation and ICI. Last, we provide an overview of response measurement criteria and future directions.

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“…A drawback is that in the majority of these trials there was no neurocognitive assessment, and there was no selection based on EGFR-mutation [29]. Retrospective series suggest that PD-(L)1 inhibitors can be safely combined with cranial irradiation, but detailed neurotoxicity assessment was lacking [30,31]. To evaluate the question whether TKI can be combined with cranial irradiation, a prospective observational Swiss registry (TOaSTT: any type of systemic treatment) and a Dutch multicentre platform trial (NL6518/NTR6707, TKI treatment) are currently enrolling patients; for ICI, several trials are ongoing (summarised above).…”

Section: Best Sequence Of Local and Systemic Therapymentioning

confidence: 99%

Current challenges in the management of nonsmall cell lung cancer brain metastases

2020

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Safety of Combined PD-1 Pathway Inhibition and Intracranial Radiation Therapy in Non–Small Cell Lung Cancer

Cited by 98 publications

References 31 publications

Safety of combined PD‐1 pathway inhibition and radiation therapy for non‐small‐cell lung cancer: A multicentric retrospective study from the GFPC

Safety of combined PD‐1 pathway inhibition and radiation therapy for non‐small‐cell lung cancer: A multicentric retrospective study from the GFPC

Non-small cell lung cancer brain metastases and the immune system: From brain metastases development to treatment

Current challenges in the management of nonsmall cell lung cancer brain metastases

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