Re-induction of a Systemic Immune Response After Initial Response With Immune Therapy With Single-dose Radiotherapy in Metastatic or Locally Recurrent Lung Cancer: A Prospective Phase II Trial (Re-Induce 2)
试验速览
- 阶段
- 2 期
- 状态
- 撤回
- 发起方
- 入组人数
- 82
- 试验地点
- 2
- 主要终点
- Progression-free
研究概览
简要总结
Patients with metastatic non-small cell lung cancer (NSCLC) who after an initial response to immunotherapy of chemo-immunotherapy show diffuse disease progression are treated with chemotherapy, with a median PFS of about 3 months and a high incidence of important toxicity or by continuation of immune therapy when the growth rate of the tumours is low. In a previous study, it was showed that irradiating a single metastatic lesion and continuation of immune therapy resulted in a median PFS time was 4.9 months (95% CI, 3.0-7.0 months). At three months of follow-up, the PFS rate was 62.5%, at six months 37.5% and at 12 months 17.9%. The median OS for all patients was 14.9 months (95% CI, 12.2-21.5 months). Toxicity was hardly observed. This was obtained with a few fractions of radiotherapy. There is biological rationale to deliver this radiation in a single fraction of 10 Gy.
Objective: The primary objective is to investigate if a single fraction of 10 Gy is not inferior to a more fractionated schedule, which would add to the convenience for the patient, even less toxicity and costs.
Study design: Prospective, single-arm phase II trial. Study population: Patients with stage IV NSCLC who initially showed a partial or complete remission under immune therapy alone or concurrent immune therapy and chemotherapy and now show progressive disease according to RECIST 1.1 criteria. At least two different lesions should show progressive disease. Patients should be able to continue the same immune therapy (i.e. no adverse events grade 3 or more).
Intervention: Patients continue the same immune therapy they already received and get radiotherapy to one progressing lesion. The lesion may or may not be symptomatic. The preferred radiotherapy dose is 10 Gy in 1 fraction, but other fractionation schedules (e.g. 24 Gy/ 3 fractions, 30 Gy/ 10 fractions, 20 Gy/ 5 fractions, 20-24 Gy / 1 fraction for stereotactic radiotherapy for brain metastases), including so-called isotoxic strategies are allowed if these are standard for a certain location or palliative indication in the body.
Main study parameters/endpoints: Progression-free survival (PFS).
详细描述
Metastatic non-small cell lung cancer (NSCLC) has always had a remarkably high mortality, with a 5-year overall survival (OS) rate of only 6%.However, immune checkpoint inhibitors (ICI) targeting the programmed death protein (PD-1)/programmed death-ligand 1 (PD-L1) axis have changed this outcome significantly. Patients with NSCLC who have been treated with ICI, either as monotherapy or in combination with chemotherapy, are surviving longer as compared to patients receiving chemotherapy alone,5-14 with 5-year OS rates as high as 15-30%.This has led to the implementation of ICI in clinical practice, namely in patients with metastatic NSCLC without specific gene alterations.
Despite overall improved survival rates, a considerable number of patients fail to achieve a response when treated with ICI (primary resistance) or develop resistance after an initial period of clinical and radiological response (acquired resistance). Resistance to ICI is thought to be the result of tumor cell intrinsic factors and an immunosuppressive tumor microenvironment, resulting in the suppression of effective anti-tumor immunity. Currently, treatment options in case of resistance to PD1/PD-L1 blockade are limited, with chemotherapy being standard of care outside clinical trials. The PFS and OS in fit patients receiving double-agent chemotherapy after progression are approximately 5 and 12 months, while for those receiving single-agent chemotherapy only 4 and 10 months, respectively. Therefore, exploring treatments for overcoming ICI resistance is warranted.
Radiation therapy (RT) is an effective and common treatment in advanced NSCLC, playing a major role in symptom control, improving quality of life and potentially survival in oligometastatic disease. Moderately hypofractionated RT to tumor or metastases, while sparing lymphoid tissues such as lymph nodes, bone marrow and the circulating blood pool, was shown to enhance the immune response with clinical benefit.
Acquired immunotherapy resistance is a common event in NSCLC, with most patients exhibiting progression within the first 6 months (20%) or the first year of treatment (35%). Clinical trials directed at overcoming immunotherapy resistance in NSCLC have mainly focused on the escalation of systemic therapy by dual checkpoint blockade or by addition of supporting substances. A phase II trial investigated the role of durvalumab plus tremelimumab in this setting and showed no benefit. In contrast, the randomized phase II study of ramucirumab and pembrolizumab showed improved OS of 14.5 months versus 11.6 months with standard of care. In other trials investigating chemotherapy plus immunotherapy after ICI-resistance, the continuation of immunotherapy beyond disease progression also resulted in improved outcomes compared to patients receiving chemotherapy alone.
Since previous works have demonstrated that the combination of ICI with RT in immunotherapy-naïve patients has a relevant impact on PFS, OS and rate of abscopal responses, local radiation has also been considered a viable option for overcoming immunotherapy resistance.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Stage IV NSCLC
- •An initial partial or complete remission under immune therapy alone or concurrent immune therapy and chemotherapy
- •Subsequently progressive disease according to RECIST 1.1 criteria
- •Considered by the treating physician to be able to continue the same immune treatment as standard of care
- •At least two different lesions should show progressive disease
- •At least one progressing lesion should be eligible for radiation
排除标准
- •Patients with any grade 3 or higher toxicity from previous therapy
- •Patients who are not eligible for continuation of the immune therapy according to standard practice
- •Corticosteroids in a dose above 10 mg prednisone or equivalent per day. Corticoids used as supportive therapy for systemic or radiotherapy are allowed
研究组 & 干预措施
Radiation
Radiation to one progressive lesion
干预措施: Radiation (Radiation)
结局指标
主要结局
Progression-free
时间窗: 3 months after radiotherapy
Progression-free survival (PFS)
次要结局
- Regression(3 months after radiotherapy)
- Remission rate(3 months after radiotherapy)
- Toxicity(3 months after radiotherapy)
- Overall survival(3 months after radiotherapy)
- PFS second course(3 months after radiotherapy)
- Number(3 months after radiotherapy)
- Relation between the growth rate of the fastest growing metastasis in the 3 months preceding radiotherapy and PFS(3 months after radiotherapy)