Radiotherapy to reinvigorate immunotherapy activity after acquired resistance in metastatic non-small-cell lung cancer: A pooled analysis of two institutions prospective phase II single arm trials

Popp, Ilinca; Vaes, Rianne D.W.; Wieten, Lotte; Adebahr, Sonja; Hendriks, Lizza; Bavafaye Haghighi, Elham; Degens, Juliette; Schäfer, Henning; Greil, Christine; Peeters, Stéphanie; Waller, Cornelius F.; Houben, Ruud; Niedermann, Gabriele; Rawluk, Justyna; Gkika, Eleni; Duyster, Justus; Grosu, Anca-Ligia; De Ruysscher, Dirk

doi:10.1016/j.radonc.2023.110048

Cited by 4 publications

(5 citation statements)

References 44 publications

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“…This may be a more immunogenic tumor type and, therefore, more prone to present AR. PFS and OS are not comparable yet due to the short followup, but the fact that medians have not been reached suggests that I-SABR is useful to extend the clinical benefit of ICI as previously reported [7,10]. Given the good results in terms of response, LC and safety with subablative doses [10], we decided to use the same SABR fractionations for the present study.…”

Section: Discussionmentioning

confidence: 95%

“…Last ORR in cohort A was slightly higher compared to our previous study on a very similar patient population [10] (57.9% vs. 42%), but this is probably due to a much shorter follow-up in this analysis. A recent pooled analysis of two phase II trials has reported a 62.5% disease control rate at 3 months and median PFS of 4.4 months in patients with oligometastatic (1-4 lesions) NSCLC in progression to ICI [7]. In contrast, the randomized phase II STOP trial did not achieve its PFS endpoint.…”

Section: Discussionmentioning

confidence: 99%

“…This oligoprogression can be present in an already oligometastatic patient or be "induced" by systemic therapy in a polymetastatic patient. In this context, SABR is useful for maintaining the same line of systemic therapy and avoiding a change to less effective treatments [7]. In NSCLC with driver mutations, strong responses that allow for the continuation of targeted therapy have been reported after the addition of SABR [8].…”

Section: Introductionmentioning

confidence: 99%

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Novel Blood Biomarkers for Response Prediction and Monitoring of Stereotactic Ablative Radiotherapy and Immunotherapy in Metastatic Oligoprogressive Lung Cancer

Zafra,

Onieva,

Oliver

et al. 2024

IJMS

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Up to 80% of patients under immune checkpoint inhibitors (ICI) face resistance. In this context, stereotactic ablative radiotherapy (SABR) can induce an immune or abscopal response. However, its molecular determinants remain unknown. We present early results of a translational study assessing biomarkers of response to combined ICI and SABR (I-SABR) in liquid biopsy from oligoprogressive patients in a prospective observational multicenter study. Cohort A includes metastatic patients in oligoprogression to ICI maintaining the same ICI due to clinical benefit and who receive concomitant SABR. B is a comparative group of oligometastatic patients receiving only SABR. Blood samples are extracted at baseline (T1), after the first (T2) and last (T3) fraction, two months post-SABR (T4) and at further progression (TP). Response is evaluated by iRECIST and defined by the objective response rate (ORR)—complete and partial responses. We assess peripheral blood mononuclear cells (PBMCs), circulating cell-free DNA (cfDNA) and small RNA from extracellular vesicles. Twenty-seven patients could be analyzed (cohort A: n = 19; B: n = 8). Most were males with non-small cell lung cancer and one progressing lesion. With a median follow-up of 6 months, the last ORR was 63% (26% complete and 37% partial response). A decrease in cfDNA from T2 to T3 correlated with a good response. At T2, CD8+PD1+ and CD8+PDL1+ cells were increased in non-responders and responders, respectively. At T2, 27 microRNAs were differentially expressed. These are potential biomarkers of response to I-SABR in oligoprogressive disease.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Novel Blood Biomarkers for Response Prediction and Monitoring of Stereotactic Ablative Radiotherapy and Immunotherapy in Metastatic Oligoprogressive Lung Cancer

Zafra,

Onieva,

Oliver

et al. 2024

IJMS

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“…In a recent phase 2 trial, upfront local ablative therapy consisting of radiotherapy, surgery and radiofrequency ablation, combing with pembrolizumab, resulted in generally comparable incidence of treatment-related toxicities with those receiving pembrolizumab monotherapy in oligo-metastatic NSCLC [ 41 ]. Grade ≥ 2 treatment-related adverse events occurred in 25% of the patients receiving hypofractionated radiotherapy and immunotherapy in a pooled analysis of two prospective trials, which was generally manageable [ 44 ]. Similarly, a meta-analysis including 51 studies with 15,398 patients found comparable grade 3–4 toxicities in those receiving both immunotherapy and radiotherapy (16.3%; 95% CI, 11.1–22.3%) and those receiving immunotherapy alone (22.3%; 95% CI, 18.1–26.9%) [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

Oligo-residual disease in PD-1/PD-L1 inhibitor-treated metastatic non-small cell lung cancer: incidence, pattern of failure, and clinical value of local consolidative therapy

Zhang,

Gao,

Jiang

et al. 2024

Cancer Immunol Immunother

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Objectives To investigate the feasibility and potential clinical value of local consolidative therapy (LCT) in PD-1/PD-L1 inhibitor-treated metastatic non-small cell lung cancer (NSCLC). Materials and methods PD-1/PD-L1 inhibitor-treated metastatic NSCLC patients with measurable disease in three academic centers were screened and those with adequate follow-up were included. Oligo-residual disease (ORD) was defined as residual tumors limited to three organs and five lesions evaluated at the best response among patients with partial response or stable disease after PD-1/PD-L1 inhibitors. Oligometastatic and multiple-metastatic disease (OMD/MMD) were similarly classified at baseline. Locoregional interventions, administered after effective treatment of PD-1/PD-L1 inhibitors and before initial disease progression, were defined as LCT. Patterns of initial progressive disease (PD) were classified as involving only residual sites (RP), only new sites (NP), or a combination of both (BP). Results Among the 698 patients included, ORD was documented in 73 (47.1%) of 155 patients with baseline OMD and 60 (11.0%) of 543 patients with baseline MMD. With a median follow-up of 31.0 (range, 6.0–53.0) months, 108 patients with ORD developed initial PD, with RP, NP, and BP occurring in 51 (47%), 23 (21.3%), and 34 (31.5%), respectively. Among the 133 patients with ORD, those receiving LCT (n = 43) had longer progression-free survival (HR = 0.58, 95% CI 0.40–0.85, p = 0.01) and overall survival (HR = 0.49, 95% CI 0.30–0.79, p < 0.0001). Conclusion ORD occurs with a clinically relevant frequency among PD-1/PD-L1 inhibitor-treated metastatic NSCLC patients and LCT may provide extra survival benefits in those with ORD.

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“…This demonstrated an improvement in OS for patients with oligometastatic disease [ 58 , 59 ], with 35% of patients receiving SABR to bone metastases and 13% to liver metastases. Hypofractionated radiotherapy in a pooled analysis of two phase II trials has also demonstrated the ability to re-invigorate immunotherapy responses in patients with resistance to ICIs with NSCLC, leading to ongoing disease control [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

Site-Specific Response and Resistance Patterns in Patients with Advanced Non-Small-Cell Lung Cancer Treated with First-Line Systemic Therapy

Brown,

Ahn,

Gao

et al. 2024

Cancers

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Patients with advanced NSCLC have heterogenous responses to immune checkpoint inhibitors (ICIs) with or without chemotherapy. In NSCLC, the impact of the distribution of metastatic sites and the response to systemic therapy combinations remain poorly understood. In a retrospective cohort study of patients with unresectable stage III/IV NSCLC who received first-line systemic therapy, we sought to assess the association between the site of metastases with patterns of response and progression. Data regarding demographics, tumour characteristics (including site, size, and volume of metastases), treatment, and outcomes were examined at two cancer care centres. The endpoints included organ site-specific response rate, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Two-hundred and eighty-five patients were included in the analysis. In a multivariate analysis, patients with bone metastases had a reduced ORR, PFS, and OS. Primary resistance was also more likely in patients with bone metastases. Patients with bone or liver metastases had a shorter OS when receiving ICIs with or without chemotherapy, but not with chemotherapy alone, suggesting an immunological basis for therapeutic resistance. A directed assessment of the tumour microenvironment in these locations and a deeper understanding of the drivers of organ-specific resistance to immunotherapy are critical to optimise novel combination therapies and sequencing in these patients.

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Radiotherapy to reinvigorate immunotherapy activity after acquired resistance in metastatic non-small-cell lung cancer: A pooled analysis of two institutions prospective phase II single arm trials

Cited by 4 publications

References 44 publications

Novel Blood Biomarkers for Response Prediction and Monitoring of Stereotactic Ablative Radiotherapy and Immunotherapy in Metastatic Oligoprogressive Lung Cancer

Novel Blood Biomarkers for Response Prediction and Monitoring of Stereotactic Ablative Radiotherapy and Immunotherapy in Metastatic Oligoprogressive Lung Cancer

Oligo-residual disease in PD-1/PD-L1 inhibitor-treated metastatic non-small cell lung cancer: incidence, pattern of failure, and clinical value of local consolidative therapy

Site-Specific Response and Resistance Patterns in Patients with Advanced Non-Small-Cell Lung Cancer Treated with First-Line Systemic Therapy

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