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Consolidative Radiotherapy for Limited Metastatic Non-Small-Cell Lung Cancer: A Phase 2 Randomized Clinical Trial.

ABSTRACT: Importance:Patterns-of-failure studies suggest that in metastatic non-small-cell lung cancer (NSCLC) sites of gross disease at presentation are the first to progress when treated with chemotherapy. This knowledge has led to increased adoption of local ablative radiation therapy in patients with stage IV NSCLC, though prospective randomized evidence is limited. Objective:To determine if intervening with noninvasive stereotactic ablative radiotherapy (SAbR) prior to maintenance chemotherapy in patients with non-progressive limited metastatic NSCLC after induction therapy led to significant improvements in progression-free survival (PFS). Design, Setting, and Participants:This is a single-institution randomized phase 2 study of maintenance chemotherapy alone vs SAbR followed by maintenance chemotherapy for patients with limited metastatic NSCLC (primary plus up to 5 metastatic sites) whose tumors did not possess EGFR-targetable or ALK-targetable mutations but did achieve a partial response or stable disease after induction chemotherapy. Interventions:Maintenance chemotherapy or SAbR to all sites of gross disease (including SAbR or hypofractionated radiation to the primary) followed by maintenance chemotherapy. Main Outcomes and Measures:The primary end point was PFS; secondary end points included toxic effects, local and distant tumor control, patterns of failure, and overall survival. Results:A total of 29 patients (9 women and 20 men) were enrolled; 14 patients (median [range] age, 63.5 [51.0-78.0] years) were allocated to the SAbR-plus-maintenance chemotherapy arm, and 15 patients (median [range] age, 70.0 [51.0-79.0] years) were allocated to the maintenance chemotherapy-alone arm. The trial was stopped to accrual early after an interim analysis found a significant improvement in PFS in the SAbR-plus-maintenance chemotherapy arm of 9.7 months vs 3.5 months in the maintenance chemotherapy-alone arm (P?=?.01). Toxic effects were similar in both arms. There were no in-field failures with fewer overall recurrences in the SAbR arm while those patients receiving maintenance therapy alone had progression at existing sites of disease and distantly. Conclusions and Relevance:Consolidative SAbR prior to maintenance chemotherapy appeared beneficial, nearly tripling PFS in patients with limited metastatic NSCLC compared with maintenance chemotherapy alone, with no difference in toxic effects. The irradiation prevented local failures in original disease, the most likely sites of first recurrence. Furthermore, PFS for patients with limited metastatic disease appeared similar to those patients with a greater metastatic burden, further arguing for the potential benefits of local therapy in limited metastatic settings. Trial Registration:clinicaltrials.gov Identifier: NCT02045446.

SUBMITTER: Iyengar P

PROVIDER: S-EPMC5833648 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Consolidative Radiotherapy for Limited Metastatic Non-Small-Cell Lung Cancer: A Phase 2 Randomized Clinical Trial.

Iyengar Puneeth P Wardak Zabi Z Gerber David E DE Tumati Vasu V Ahn Chul C Hughes Randall S RS Dowell Jonathan E JE Cheedella Naga N Nedzi Lucien L Westover Kenneth D KD Pulipparacharuvil Suprabha S Choy Hak H Timmerman Robert D RD

JAMA oncology 20180111 1

<h4>Importance</h4>Patterns-of-failure studies suggest that in metastatic non-small-cell lung cancer (NSCLC) sites of gross disease at presentation are the first to progress when treated with chemotherapy. This knowledge has led to increased adoption of local ablative radiation therapy in patients with stage IV NSCLC, though prospective randomized evidence is limited.<h4>Objective</h4>To determine if intervening with noninvasive stereotactic ablative radiotherapy (SAbR) prior to maintenance chem ...[more]

PMID: 28973074

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Project description:BackgroundNHS-IL2 (selectikine, EMD 521873, MSB0010445) consists of human NHS76 (antibody specific for necrotic DNA) fused to genetically modified human interleukin 2 (IL-2) and selectively activates the high-affinity IL-2 receptor. Based on an evolving investigational concept to prime the tumor microenvironment with ionizing radiation prior to initiating immunotherapy, 2 related studies were conducted and are reported here. The first, a preclinical study, tests the systemic effect of the immunocytokine NHS-IL2 and radiotherapy in a lung carcinoma animal model; the second, a phase Ib trial in patients with metastatic non-small cell lung carcinoma (NSCLC), was designed to determine the safety and tolerability of NHS-IL2 in combination with radiotherapy directly following first-line palliative chemotherapy.MethodsTumor-bearing C57Bl/6 mice were treated with NHS-IL2 alone (5 mg/kg; days 7-9), fractionated radiotherapy (3.6 Gy; days 0-4) plus cisplatin (4 mg/kg; day 0), or the triple combination. Metastatic NSCLC patients who achieved disease control with first-line palliative chemotherapy were enrolled in the phase Ib trial. Patients received local irradiation (5x 4 Gy) of a single pulmonary nodule. Dose-escalated NHS-IL2 was administered as 1-h intravenous infusion on 3 consecutive days every 3 weeks.ResultsNHS-IL2 plus radiotherapy induced immune response activation and complete tumor growth regressions in 80%-100% of mice. In patients with metastatic NSCLC treated with NHS-IL2 (3, 3, and 7 patients in the 0.15-mg/kg, 0.30-mg/kg, and 0.45-mg/kg cohorts, respectively), maximum tolerated dose was not reached. Most frequently reported adverse events were fatigue, anorexia, and rash. Transient increases in leukocyte subsets were observed. In 3 patients, thyroid gland dysfunction occurred. No objective responses were reported; long-term survival was observed in 2 patients, including 1 patient with long-term tumor control.ConclusionsCombining NHS-IL2 with radiotherapy achieved synergistic antitumor activity in preclinical studies, supporting the use in lung cancer patients. This combination was well tolerated and 2 of 13 patients achieved long-term survival.Trial registrationClinicalTrials.gov NCT00879866.

Project description:PurposeTo determine the safety, tolerability and maximum tolerated dose (MTD) of addition of erlotinib to bevacizumab and capecitabine-based definitive chemoradiation (CRT) in unresectable pancreatic cancer.MethodsSeventeen patients with CT-staged, biopsy-proven unresectable pancreatic cancer were enrolled between 3/2008 and 10/2010. Prior chemotherapy was permitted. Two patients each were enrolled at dose levels (DLs) 1-4 and 9 patients at DL 5. All patients received 50.4 Gy (GTV only) in 28 fractions with concurrent capecitabine, bevacizumab and erlotinib. Dose of each drug was escalated in 5 DLs using the continual reassessment method. Bevacizumab was escalated from 5mg/Kg q2weeks (DLs 1-4) to 10mg/Kg q2weeks (DL 5); daily erlotinib from 100mg/day (DLs 1-2) to 150 mg/Kg (DLs 3-5); and capecitabine from 400mg/m2 twice daily on days of radiation (DL 1) to 650mg/m2 (DLs 2-3) to 825 mg/m2 (DLs 4-5). Reassessment for potential resection was performed 6-8 weeks later.ResultsSixteen patients received gemcitabine-based chemotherapy prior to CRT. With a median clinical follow-up of 10 months, no grade 3 toxicities were observed in DLs 1-4. Three (33%) patients at DL 5 developed a grade 3 acute toxicity (2 diarrhea, 1 rash). No grade 4 or 5 toxicities were seen. DL 4 was selected as the MTD; therefore, the recommended doses in combination with radiation are: bevacizumab, 5mg/Kg q2weeks; erlotinib, 150 mg/Kg daily; and capecitabine, 825mg/m2 BID. Median survival was 17.4 months. Of the five patients who underwent resection, 4 were originally deemed locally advanced and 1 was borderline resectable. Three patients had excellent pathological response (2 complete response and 20% viable tumor) at surgery, and the 2 patients with complete response are still alive at 61 and 67 months of follow up with no local or distant failures.ConclusionsThis chemoradiation regimen at the recommended dose levels is safe and tolerable for patients with unresectable pancreatic cancer and merits further evaluation.

Project description:Controversies exists with regard to target volumes as far as thoracic radiotherapy (TRT) is concerned in the multimodality treatment for limited-stage small cell lung cancer (LSCLC). The aim of this study is to prospectively compare the local control rate, toxicity profiles, and overall survival (OS) between patients received different target volumes irradiation after induction chemotherapy.LSCLC patients received 2 cycles of etoposide and cisplatin (EP) induction chemotherapy and were randomly assigned to receive TRT to either the post- or pre-chemotherapy tumor extent (GTV-T) as study arm and control arm, CTV-N included the positive nodal drainage area for both arms. One to 2 weeks after induction chemotherapy, 45 Gy/30 Fx/19 d TRT was administered concurrently with the third cycle of EP regimen. After that, additional 3 cycles of EP consolidation were administered. Prophylactic cranial irradiation (PCI) was administered to patients with a complete response.Thirty-seven and 40 patients were randomly assigned to study arm and control arm. The local recurrence rates were 32.4% and 28.2% respectively (P = 0.80); the isolated nodal failure (INF) rates were 3.0% and 2.6% respectively (P = 0.91); all INF sites were in the ipsilateral supraclavicular fossa. Medastinal N3 disease was the risk factor for INF (P = 0.02, OR = 14.13, 95% CI: 1.47-136.13). During radiotherapy, grade I, II weight loss was observed in 29.4%, 5.9% and 56.4%, 7.7% patients respectively (P = 0.04). Grade 0-I and II-III late pulmonary injury was developed in 97.1%, 2.9% and 86.4%, 15.4% patients respectively (P = 0.07). Median survival time was 22.1 months and 26.9 months respectively. The 1 to 3-year OS were 77.9%, 44.4%, 37.3% and 75.8%, 56.3%, 41.7% respectively (P = 0.79).The preliminary results of this study indicate that irradiant the post-chemotherapy tumor extent (GTV-T) and positive nodal drainage area did not decrease local control and overall survival while radiation toxicity was reduced. But the current sample size has not met designed requirements, and further investigation is warranted before final conclusions could be drawn.

Project description:PURPOSE:Our previously published findings reported that local consolidative therapy (LCT) with radiotherapy or surgery improved progression-free survival (PFS) and delayed new disease in patients with oligometastatic non-small-cell lung cancer (NSCLC) that did not progress after front-line systemic therapy. Herein, we present the longer-term overall survival (OS) results accompanied by additional secondary end points. PATIENTS AND METHODS:This multicenter, randomized, phase II trial enrolled patients with stage IV NSCLC, three or fewer metastases, and no progression at 3 or more months after front-line systemic therapy. Patients were randomly assigned (1:1) to maintenance therapy or observation (MT/O) or to LCT to all active disease sites. The primary end point was PFS; secondary end points were OS, toxicity, and the appearance of new lesions. All analyses were two sided, and P values less than .10 were deemed significant. RESULTS:The Data Safety and Monitoring Board recommended early trial closure after 49 patients were randomly assigned because of a significant PFS benefit in the LCT arm. With an updated median follow-up time of 38.8 months (range, 28.3 to 61.4 months), the PFS benefit was durable (median, 14.2 months [95% CI, 7.4 to 23.1 months] with LCT v 4.4 months [95% CI, 2.2 to 8.3 months] with MT/O; P = .022). We also found an OS benefit in the LCT arm (median, 41.2 months [95% CI, 18.9 months to not reached] with LCT v 17.0 months [95% CI, 10.1 to 39.8 months] with MT/O; P = .017). No additional grade 3 or greater toxicities were observed. Survival after progression was longer in the LCT group (37.6 months with LCT v 9.4 months with MT/O; P = .034). Of the 20 patients who experienced progression in the MT/O arm, nine received LCT to all lesions after progression, and the median OS was 17 months (95% CI, 7.8 months to not reached). CONCLUSION:In patients with oligometastatic NSCLC that did not progress after front-line systemic therapy, LCT prolonged PFS and OS relative to MT/O.

Project description:ObjectivesOur goal was to evaluate stereotactic ablative radiotherapy (SABR) as a salvage option for isolated recurrence of NSCLC in the lung parenchyma after definitive treatment of stage I to III disease.MethodsPatients who had histologically confirmed, positron emission tomography-staged, isolated NSCLC recurring locally or metastasis in the lung parenchyma (≤3 cm, suitable for SABR) after previous definitive treatment were prospectively enrolled in this trial and treated with volumetric, image-guided SABR to 50 Gy in four fractions. Patients were then followed with computed tomography or positron emission tomography/computed tomography. Primary end points included the pattern of failure after salvage SABR, overall survival (OS), and progression-free survival (PFS).ResultsFifty-nine patients with recurrent disease were treated with salvage SABR. The median age was 70 years (range 45-86 years), and the median follow-up time after salvage SABR was 58.3 months. Re-recurrence after salvage SABR developed in 19 patients (32%). Measuring from the date of salvage SABR, the estimated 5-year rates of local, regional, and distant failure were 5.2%, 10.3%, and 22.4%, respectively; the estimated PFS was 46.2% at 3 years and 41.1% at 5 years; and the OS rates were 63.5% at 3 years and 56.5% at 5 years. A high post-SABR neutrophil-to-lymphocyte ratio was found to predict poor survival. Grade 3 treatment-related adverse events developed in three patients (5%). No patient had a grade 4 or 5 event.ConclusionOur study showed that salvage SABR provides excellent 5-year OS, local control, and PFS rates with minimal toxicity for patients with isolated NSCLC recurrence in the lung parenchyma. These results are striking and comparable to historically reported outcomes of patients with primary early-stage NSCLC treated with definitive SABR. SABR appears to be a very effective and safe salvage option for patients with isolated lung parenchyma recurrent disease after definitive treatment and should be considered along with surgery as a potential first-line option for patients with local lung parenchymal recurrent disease.

Project description:ImportanceCheckpoint inhibitors targeting programmed cell death 1 or its ligand (PD-L1) as monotherapies or in combination with anti-cytotoxic T-lymphocyte-associated antigen 4 have shown clinical activity in patients with metastatic non-small cell lung cancer.ObjectiveTo compare durvalumab, with or without tremelimumab, with chemotherapy as a first-line treatment for patients with metastatic non-small cell lung cancer.Design, setting, and participantsThis open-label, phase 3 randomized clinical trial (MYSTIC) was conducted at 203 cancer treatment centers in 17 countries. Patients with treatment-naive, metastatic non-small cell lung cancer who had no sensitizing EGFR or ALK genetic alterations were randomized to receive treatment with durvalumab, durvalumab plus tremelimumab, or chemotherapy. Data were collected from July 21, 2015, to October 30, 2018.InterventionsPatients were randomized (1:1:1) to receive treatment with durvalumab (20 mg/kg every 4 weeks), durvalumab (20 mg/kg every 4 weeks) plus tremelimumab (1 mg/kg every 4 weeks, up to 4 doses), or platinum-based doublet chemotherapy.Main outcomes and measuresThe primary end points, assessed in patients with ≥25% of tumor cells expressing PD-L1, were overall survival (OS) for durvalumab vs chemotherapy, and OS and progression-free survival (PFS) for durvalumab plus tremelimumab vs chemotherapy. Analysis of blood tumor mutational burden (bTMB) was exploratory.ResultsBetween July 21, 2015, and June 8, 2016, 1118 patients were randomized. Baseline demographic and disease characteristics were balanced between treatment groups. Among 488 patients with ≥25% of tumor cells expressing PD-L1, median OS was 16.3 months (95% CI, 12.2-20.8) with durvalumab vs 12.9 months (95% CI, 10.5-15.0) with chemotherapy (hazard ratio [HR], 0.76; 97.54% CI, 0.56-1.02; P = .04 [nonsignificant]). Median OS was 11.9 months (95% CI, 9.0-17.7) with durvalumab plus tremelimumab (HR vs chemotherapy, 0.85; 98.77% CI, 0.61-1.17; P = .20). Median PFS was 3.9 months (95% CI, 2.8-5.0) with durvalumab plus tremelimumab vs 5.4 months (95% CI, 4.6-5.8) with chemotherapy (HR, 1.05; 99.5% CI, 0.72-1.53; P = .71). Among 809 patients with evaluable bTMB, those with a bTMB ≥20 mutations per megabase showed improved OS for durvalumab plus tremelimumab vs chemotherapy (median OS, 21.9 months [95% CI, 11.4-32.8] vs 10.0 months [95% CI, 8.1-11.7]; HR, 0.49; 95% CI, 0.32-0.74). Treatment-related adverse events of grade 3 or higher occurred in 55 (14.9%) of 369 patients who received treatment with durvalumab, 85 (22.9%) of 371 patients who received treatment with durvalumab plus tremelimumab, and 119 (33.8%) of 352 patients who received treatment with chemotherapy. These adverse events led to death in 2 (0.5%), 6 (1.6%), and 3 (0.9%) patients, respectively.Conclusions and relevanceThe phase 3 MYSTIC study did not meet its primary end points of improved OS with durvalumab vs chemotherapy or improved OS or PFS with durvalumab plus tremelimumab vs chemotherapy in patients with ≥25% of tumor cells expressing PD-L1. Exploratory analyses identified a bTMB threshold of ≥20 mutations per megabase for optimal OS benefit with durvalumab plus tremelimumab.Trial registrationClinicalT rials.gov Identifier: NCT02453282.

Dataset Information

Consolidative Radiotherapy for Limited Metastatic Non-Small-Cell Lung Cancer: A Phase 2 Randomized Clinical Trial.

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Consolidative Radiotherapy for Limited Metastatic Non-Small-Cell Lung Cancer: A Phase 2 Randomized Clinical Trial.

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