Pembrolizumab with or without radiotherapy for metastatic non-small-cell lung cancer: a pooled analysis of two randomised trials

Theelen, Wendy; Chen, Fan; Verma, Vivek; Hobbs, Brian P.; Peulen, Heike M.U.; Aerts, Joachim; Bahce, Idris; Niemeijer, Anna-Larissa N.; Chang, Joe Y.; Groot, Patricia M. de; Nguyen, Quynh Nhu; Comeaux, Nathan; Simon, George R.; Skoulidis, Ferdinandos; Lin, Steven H.; He, Kewen; Patel, Roshal R.; Heymach, John V.; Baas, Paul; Welsh, James W.

doi:10.1016/s2213-2600(20)30391-x

Cited by 304 publications

(202 citation statements)

References 20 publications

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“…The results revealed that OS, PFS and ORR of non-irradiated lesion showed improved trends in the SBRT combination group without an increase in treatment-related adverse events ( 61 ). A pooled analysis of this study and another phase I/II study of SBRT in combination with pembrolizumab demonstrates the significant superiority of the SBRT combination group in non-irradiated tumor response and control rates, OS and PFS ( 62 ). Furthermore, in a prospective study of patients with metastatic melanoma treated with radiotherapy to one or two disease sites with concurrent ipilimumab, half of all patients had a clinical benefit during the observation period, including durable CR in 3 of 22 patients ( 63 ).…”

Section: Clinical Application Of the Combined Therapymentioning

confidence: 79%

The role of radiotherapy in the age of immunotherapy

Sato

Demaria

Ohno

2021

Japanese Journal of Clinical Oncology

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With the development of immune checkpoint inhibitors, the efficacy of immunotherapy as a cancer treatment that is effective against multiple tumor types has been established, and this modality came to be considered as the fourth pillar of cancer therapy. The clinical success of immunotherapy greatly changed the field of oncology by highlighting the importance of the immune system in cancer control and elimination. It has now become clear that research into, and the clinical application of, the immune response are important for effective cancer treatment. Moreover, it has become apparent that conventional cancer treatments, such as radiotherapy and chemotherapy, can modulate the cross-talk between the tumor and the immune system, and their efficacy depends, in part, on the ability to elicit antitumor immune response. The ability of radiotherapy to induce an immune response has become relevant in the immunotherapy age. Radiotherapy has been redefined as a partner for cancer immunotherapy, based on evidence indicating the potential synergistic effect of the combination of these therapeutic modalities. This review outlines the major findings reported to date on the immune response induced by radiotherapy and discusses the role of radiotherapy in combination with immunotherapy. Furthermore, we introduce research aimed at the clinical application of combination therapy and discuss its potential in clinical practice and future issues.

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Section: Clinical Application Of the Combined Therapymentioning

confidence: 79%

The role of radiotherapy in the age of immunotherapy

Sato

Demaria

Ohno

2021

Japanese Journal of Clinical Oncology

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“…The outcomes of the combination arm were better, but not significantly ( Table 4 ). Interestingly, Theelen et al made a pooled analysis of two random trials, 37 they found that the best out-of-field response rate (pembrolizumab alone group versus combination group) was 19.7% versus 41.7%, and the best abscopal disease control rate was 43.4% versus 65.3%. mPFS was 4.4 months versus 9.0 months, and mOS was 8.7 months versus 19.2 months.…”

Section: Discussionmentioning

confidence: 99%

Hypofractionated Low-Dose Radiotherapy Combined with Immune Checkpoint Inhibition in Metastatic Solid Tumors

Li¹,

Zhu²,

Zhou³

et al. 2021

OTT

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Background The combination of radiotherapy and immunotherapy can bring benefits to patients, especially advanced patients. However, conventional radiotherapy brings about great adverse reactions. How about the hypofractionated low-dose radiotherapy? Materials and Methods In this retrospective cohort study, we included 32 patients with metastatic solid tumors treated with hypofractionated radiotherapy combined with an immune checkpoint inhibitor. Patients underwent radiotherapy of 4Gy/Fx on day 1, 3, and 5, and received single-drug immunotherapy of PD-1 inhibitor on day 2. We evaluated the following outcomes: objective response rate (ORR), disease control rate (DCR), change of nonirradiated and irradiated lesions, quality of life, and symptom improvement. Results Among the 32 patients, the ORR was 9.4% (3/32) and the DCR was 56.25% (18/32). Hypofractionated radiotherapy combined with immunotherapy showed a remarkable efficacy of local control on metastatic tumor patients. Local masses irradiated in two patients (6.25%) were complete remission, partial response rate was 37.5% (12 patients), and 56.25% was stability (18 patients). Out of those 18 patients, 15 patients had the local masses shrank more or less. The ORR of local control reached 43.75%, and its DCR was 100%. In addition, the intratumor necrosis rate was 44.4% in the SD patients. Median progression-free survival was 3.8 months (95%Cl: 2.2–5.4). By treating the local mass, the symptoms of most patients were alleviated, and the quality of life was improved. Conclusion Our retrospective analysis revealed that hypofractionated radiotherapy combined with immunotherapy was effective in local control, it also relieved clinical symptoms and improved quality of life. The adverse effect rate was low. However, the incidence of abscopal effects was low either. This mode was suitable for the palliative treatment and expected to improve survival for patients with metastatic tumors.

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“…But the pooled analysis of PEMBRO-RT and MDACC trials demonstrated that adding radiotherapy to pembrolizumab provided significant survival benefit (57). Moreover, subgroup analysis showed that 50 Gy in four fractions were significantly associated with better PFS (57), which needs further validation by a randomized phase III trial. The most common adverse events (AEs) in both trials were fatigue, respiratory related symptoms, rash, pruritus and weight loss.…”

Section: Exploration Of the Dose And Fraction Size Of Radiotherapymentioning

confidence: 97%

“…In MDACC trial, where pembrolizumab was concurrently given with SBRT (50 Gy in four fractions) or HFRT (45 Gy in 15 daily fractions) as experimental group, no benefits in median PFS or OS were observed when compared with pembrolizumab without radiation therapy (56). But the pooled analysis of PEMBRO-RT and MDACC trials demonstrated that adding radiotherapy to pembrolizumab provided significant survival benefit (57). Moreover, subgroup analysis showed that 50 Gy in four fractions were significantly associated with better PFS (57), which needs further validation by a randomized phase III trial.…”

Section: Exploration Of the Dose And Fraction Size Of Radiotherapymentioning

confidence: 99%

Optimizing the Treatment Schedule of Radiotherapy Combined With Anti-PD-1/PD-L1 Immunotherapy in Metastatic Cancers

Kong

Zhao

et al. 2021

Front. Oncol.

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Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein-1 (PD-1), and programmed cell death ligand-1 (PD-L1) have been approved for a variety of malignant tumors and are widely used to treat patients with metastatic disease. However, the efficacy of PD-1 inhibitors is limited due to tumor heterogeneity, high tumor burden, and “cold” tumor microenvironment. Radiotherapy can improve the anti-tumor effects of PD-1/PD-L1 inhibitors in various ways. As a new radiotherapy method, stereotactic body radiotherapy (SBRT) or hypofractionated radiotherapy (HFRT) provides higher doses per fraction to the target lesions, thus achieving immune activation effects and overcoming tumor resistance to anti-PD-1/PD-L1 treatment, which significantly improves the local and distant control of tumors. However, for different metastatic situations, radiotherapy plays different roles in the combination therapy. In oligometastatic status, radiotherapy can be used as a local radical treatment aiming to eliminate cancers in cooperation with systemic PD-1 inhibitors. In other circumstances, like bulky metastasis or multiple metastatic tumors, radiotherapy can be used as adjuvant to systemic immunotherapy. This review focuses on the underlying mechanisms and optimization strategies for the combination of radiotherapy and anti-PD-1/PD-L1 therapy in metastatic disease.

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Pembrolizumab with or without radiotherapy for metastatic non-small-cell lung cancer: a pooled analysis of two randomised trials

Cited by 304 publications

References 20 publications

The role of radiotherapy in the age of immunotherapy

The role of radiotherapy in the age of immunotherapy

Hypofractionated Low-Dose Radiotherapy Combined with Immune Checkpoint Inhibition in Metastatic Solid Tumors

Optimizing the Treatment Schedule of Radiotherapy Combined With Anti-PD-1/PD-L1 Immunotherapy in Metastatic Cancers

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