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To report early findings from a phase II trial of high-dose radiotherapy (HD-RT) with or without low-dose RT (LD-RT) for metastatic cancer.Eligible patients had metastatic disease that progressed on immunotherapy within 6 months. Patients were given either HD-RT (20-70 Gy total; 3-12.5 Gy/f), or HD-RT + LD-RT (0.5-2 Gy/f up to 1-10 Gy total) to separate lesions, with continued immunotherapy. Radiographic response was assessed per RECIST 1.1 and Immune-Related Response Criteria (irRC). Primary endpoints: (1) 4-month disease control (DCR, complete/partial response [CR/PR] or stable disease [SD]) or an overall response (ORR, CR/PR) at any point in ≥10% of patients, per RECIST 1.1; (2) dose-limiting toxicity within 3 months not exceeding 30%. Secondary endpoint was lesion-specific response.Seventy-four patients (NSCLC, n = 38; melanoma n = 21) were analyzed (39 HD-RT and 35 HD-RT + LD-RT). The median follow-up time was 13.6 months. The primary endpoint was met for 72 evaluable patients, with a 4-month DCR of 42% (47% [16/34] vs. 37% [14/38] in HD-RT + LD-RT vs. HD-RT, P = 0.38), and 19% ORR at any time (26% [9/34] vs. 13% [5/38] in HD-RT + LD-RT vs. HD-RT, P = 0.27). Three patients had toxicity ≥grade 3. LD-RT lesion response (53%) was improved compared to nonirradiated lesions in HD-RT + LD-RT (23%, P = 0.002) and HD-RT (11%, P 0.001). T- and NK cell infiltration was enhanced in lesions treated with LD-RT.HD-RT plus LD-RT safely improved lesion-specific response in patients with immune resistant solid tumors by promoting infiltration of effector immune cells into the tumor microenvironment.

Metastatic cancer is inherently heterogeneous, and patients with metastatic disease can experience vastly different oncologic outcomes depending on several patient- and disease-specific characteristics. Designing trials for such a diverse population is challenging yet necessary to improve treatment outcomes for metastatic-previously thought to be incurable-disease. Here we review core considerations for designing and conducting clinical trials involving radiation therapy and immunotherapy for patients with metastatic cancer.

Findings Overall, 148 patients were included in the pooled analysis, 76 of whom had been assigned pembrolizumab and 72 who had been assigned pembrolizumab plus radiotherapy. Median follow-up for all patients was 33 months (IQR 32?4?33?6). 124 (84%) of 148 patients had non-squamous histological features and 111 (75%) had previously received chemotherapy. Baseline variables did not differ between treatment groups, including PD-L1 status and metastatic disease volume. The most frequently irradiated sites were lung metastases (28 of 72 [39%]), intrathoracic lymph nodes (15 of 72 [21%]), and lung primary disease (12 of 72 [17%]). Best ARR was 19?7% (15 of 76) with pembrolizumab versus 41?7% (30 of 72) with pembrolizumab plus radiotherapy (odds ratio [OR] 2?96, 95% CI 1?42?6?20; p=0?0039), and best ACR was 43?4% (33 of 76) with pembrolizumab versus 65?3% (47 of 72) with pembrolizumab plus radiotherapy (2?51, 1?28?4?91; p=0?0071). Median progression-free survival was 4?4 months (IQR 2?9?5?9) with pembrolizumab alone versus 9?0 months (6?8?11?2) with pembrolizumab plus radiotherapy (hazard ratio [HR] 0?67, 95% CI 0?45?0?99; p=0?045), and median overall survival was 8?7 months (6?4?11?0) with pembrolizumab versus 19?2 months (14?6?23?8) with pembrolizumab plus radiotherapy (0?67, 0?54?0?84; p=0?0004).Methods Inclusion criteria for the PEMBRO-RT and MDACC trials were patients (aged ?18 years) with metastatic nonsmall-cell lung cancer and at least one unirradiated lesion to monitor for out-of-field response. In the PEMBRO-RT trial, patients had previously received chemotherapy, whereas in the MDACC trial, patients could be either previously treated or newly diagnosed. Patients in both trials were immunotherapy-naive. In the PEMBRO-RT trial, patients were randomly assigned (1:1) and stratified by smoking status (

Purpose/objective(s) Retrospective and prospective studies in patients with oligometastatic non-small-cell lung cancer (NSCLC) suggested clinical benefit after complete metastatic ablation (CMA). So far, no studies have addressed the toxicity and efficacy of CMA to oligometastatic lesions in patients that progressed during immune checkpoint inhibitors (ICIs) therapy. Here, we report results of a single arm- radiotherapy (RT) to oligometastatic lesions from our ongoing phase II trial (NCT02710253). Materials/methods This study enrolled patients that progressed within 6 months of ICI therapy and developed oligo-metastases. Treatment intervention allowed for any dose and fractions of RT per the treating physician to all metastatic sites, with irradiation for up to 6 sites. Primary endpoints of this study are time to new lesion development, and disease control rate (DCR) by RECIST 1.1. Secondary endpoints are toxicity, progression-free survival (PFS), overall survival (OS) and absolute lymphocyte counts (ALC). Results Of the 30 patients initially enrolled in this study, 26 patients (N = 21 NSCLC; N = 5 melanoma) were included in the analysis as they had completed imaging follow-up. A total of 64 lesions were irradiated with a mean of 2.5 lesions per patient. Most frequent location of irradiated was lung (n = 45), followed by adrenal (n = 7), liver (n = 4), bone (n = 4) and others (n = 4); 50% of patients received SBRT. At a median follow-up time of 23.0 months (range, 5.0-44.7 months), 12 patients had no new lesions, while 14 patients developed new lesions in lung (50%), bone (25%), brain (21%). Median time to new lesion development was 14.6 months. DCR was 77% (complete response 19%, partial response 19%, stable disease 38%); median PFS was 10.1 months and median OS was not reached. No toxicities greater than grade 2 was observed. Pre-RT ALC is an independent risk factor for time to new lesion development (P = 0.006, HR = 0.1, 95% CI, 0.02-0.51). Patients without new lesion development had significantly higher baseline ALC (P = 0.011) and more ALC after RT at 1 month (P = 0.025), 3 months (P = 0.006), 6 months (P = 0.002) and 12 months (P = 0.045) compared to patients with new lesions. Other factors including age, gender, SBRT, baseline tumor size, performance status and tumor histology did not affect the time to new lesion development. Conclusion In patients with oligometastatic lesions that progressed on ICI, CMA may be a valid treatment option that generates clinical benefits. By eradicating gross sites of disease by converting area sites into in-situ vaccines, T cells are able to access microscopic metastasis. Larger randomized trials are indicated to further define the role of CMA for ICIs resistance.

Introduction Few advancements in treating limited-stage SCLC (LS-SCLC) have been made in decades. We report here a phase 1/2 trial of concurrent chemoradiotherapy (CRT) and pembrolizumab. Methods This single-center, open-label phase 1/2 study recruited adults with LS-SCLC or other neuroendocrine tumors and good performance status (Eastern Cooperative Oncology Group ≤ 2). The primary end point was safety, as assessed by dose-limiting toxicities. Concurrent CRT consisted of etoposide and a platin with 45 Gy radiotherapy (30 twice daily). Prophylactic cranial irradiation (25 Gy, 10 fractions) was given at the physician’s discretion. Pembrolizumab was started concurrently with CRT and continued for up to 16 cycles. The phase 1 portion consisted of a 3 + 3 design. Toxicity was assessed with Common Terminology Criteria for Adverse Events version 4.0. Secondary outcomes were progression-free survival, overall survival, and tumor response as measured by the immune-related response criteria. Results A total of 45 patients were screened, and 40 were enrolled. All completed radiation therapy and received greater than or equal to one cycle of pembrolizumab. A total of 27 (61%) received percutaneous coronary intervention. One dose-limiting toxicity was observed in the phase 1 portion. There were no grade 5 toxicities, but there were three grade 4 events (two neutropenia, one respiratory failure). Pneumonitis rate was 15% (three grade 2 and three grade 3). All 17 esophagitis events (42.5%) were grades 1 to 2. At median follow-up time of 23.1 months, the median progression-free survival time was 19.7 months (95% confidence interval: 8.8‒30.5) and the median overall survival time was 39.5 months (95% confidence interval: 8.0‒71.0). Conclusion Concurrent CRT and pembrolizumab for LS-SCLC was well tolerated and yielded favorable outcomes, providing a basis for randomized studies.

PURPOSE/OBJECTIVE(S) To report updated findings from a prospective phase II trial of salvage high-dose radiotherapy (HD-RT) with or without low-dose RT (LD-RT) for metastatic cancer (NCT02710253). MATERIALS/METHODS Eligible patients had metastatic disease that progressed on immunotherapy within the prior 6 months. Patients were given either HD-RT (20-70Gy total; 3-12.5Gy/fraction), or HD-RT and LD-RT to separate lesions (LD-RT comprised of < 2Gy/fraction up to 10Gy total), with continued immunotherapy. Radiographic response was assessed per RECIST1.1 and Immune-Related Response Criteria (irRC). Primary endpoints were 1) 4-month disease control (complete/partial response [CR/PR] or stable disease [SD]) or an overall response (CR/PR) at any point in ≥10% of patients, and 2) dose-limiting toxicity within 3 months not exceeding 30%. Also, where applicable, biopsies pre- and post- low-dose RT were collected, FFPE slides were prepared and analyzed by Multiplex Immunofluorescence (Multi-IF) microscopy for immune-cell infiltration. RESULTS Seventy-four patients were analyzed (39 in HD-RT group and 35 in HD-RT+LD-RT group), mostly with non-small cell lung cancer (n = 38) or melanoma (n = 21). Patients received immunotherapy for a median of 7.1 months (3.7-10.6 months) before RT, and 95% maintained the same therapy after RT. The median follow-up time was 13.8 months. The site most commonly treated with HD- or LD-RT was lung/mediastinum. The primary endpoint was met for the 72 evaluable patients, with a 4-month overall disease control rate of 42% (RECIST1.1, 47% [16/34] for the HD-RT+LD-RT group and 37% [14/38] for the HD-RT only group). Three (4.2%) patients experienced grade ≥3 toxicity. LD-RT treated lesion response rates (irRC, 53%) was improved compared to nonirradiated lesions in the HD-RT+LD-RT (23%, P = 0.002) and HD-RT only (11%, P < 0.001) group. The median PFS was 7.0 months vs. 5.8 months, while median OS was 15.9 months vs. 10.5 months for the HD-RT+LD-RT group vs. HD-RT only group respectively; however, statistical significance was not reached. Furthermore, the addition of LD-RT did not significantly affect the absolute lymphocyte counts (ALC), with ALC reduction after treatment recorded as 420/μL vs. 340/μL in the HD-RT only vs. HD-RT+LD-RT groups (P = 0.44). The Multi-IF data for 3 analyzed biopsies of LD-RT lesions showed strong correlation between T cell and NK cell infiltration and clinical response rate. Lesion 1 for example (24% SD), had CD56+ NK cell numbers increase from 67 to 1837 n/mm2 post LD-RT. Lesion 2 (-80% PR) had its CD3+CD4+ T cells increase from 287 to 1233 n/mm2 and NK cells increase from 0 to 187 n/mm2; while lesion 3 (-8% SD) showed an increase from 79 to 131 n/mm2 and 3.6 to 7.3 n/mm2 in the T cell and NK cell compartments respectively. CONCLUSION Low-dose RT is an effective and safe way to enhance individual lesion-specific response rates among progressing patients with solid tumors, with the ability to improve the infiltration of effector immune cells into the tumor microenvironment.

BackgroundDespite some successes with checkpoint inhibitors for treating cancer, most patients remain refractory to treatment, possibly due to the inhibitory nature of the tumor stroma that impedes the function and entry of effector cells. We devised a new technique of combining immunotherapy with radiotherapy (XRT), more specifically low-dose XRT, to overcome the stroma and maximize systemic outcomes.MethodsWe bilaterally established 344SQ lung adenocarcinoma tumors in 129Sv/Ev mice. Primary and secondary tumors were irradiated with either high-dose or low-dose of XRT with systemic anti-programmed cell death protein 1 and anti-cytotoxic T-lymphocyte associated protein 4 administration. Survival and tumor growth were monitored for the various groups, and secondary tumors were phenotyped by flow cytometry for immune populations. Tumor growth factor-beta (TGF-β) cytokine levels were assessed locally after low-dose XRT, and specific immune-cell depletion experiments were conducted to identify the major contributors to the observed systemic antitumor effect.ResultsThrough our preclinical and clinical studies, we observed that when tumor burden was high, there was a necessity of combining high-dose XRT to ‘prime’ T cells at the primary tumor site, with low-dose XRT directed to secondary (metastatic) tumors to ‘modulate the stroma’. Low-dose XRT improved the antitumor outcomes of checkpoint inhibitors by favoring M1 macrophage polarization, enhancing natural killer (NK) cell infiltration, and reducing TGF-β levels. Depletion of CD4+T cells and NK cells abrogated the observed antitumor effect.ConclusionOur data extend the benefits of low-dose XRT to reprogram the tumor environment and improve the infiltration and function of effector immune cells into secondary tumors.

9548 Background: In metastatic non-small cell lung cancer (mNSCLC), the clinical trials NCT02492568 and NCT02444741 are the only known randomized comparisons of pembrolizumab alone versus pembrolizumab combined with radiation therapy (RT). When the trials were analyzed individually, some potential benefit was observed in the combination therapy group, but the relatively small sample size of each trial limited the detection of potential differences in response rates and outcomes. Hence, we perform a pooled analysis of these two randomized trials to validate and explore whether RT improves mNSCLC patient responses to immunotherapy. Methods: This was a pooled analysis of two randomized trials (NCT02492568 and NCT02444741) of pembrolizumab with or without RT for mNSCLC. Endpoints included the out-of-field overall response rate (ORR) and disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and subgroup analysis of the different RT schemes. Results: In all, 131 patients were analyzed (n = 66 pembrolizumab; n = 65 pembrolizumab/RT (iRT)). ORR was 21% in the pembrolizumab arm vs. 38% in the iRT arm (p = 0.01); DCR was 53% in the pembrolizumab arm vs. 67% in the iRT arm (p = 0.0009); PFS was 4.4 m vs 8.3 m (p = 0.046); and OS was 9.2 m vs 19.2 m (HR 0.66; p = 0.040). Ablative RT (24Gy/3 fractions and 50Gy/4 fractions) had better ORRs of 48% and 54%, respectively, compared to 18% for non-ablative RT (45Gy/15 fractions) and 20% for pembrolizumab alone (p < 0.05, respectively). Conclusions: The addition of RT to immunotherapy significantly increased the ORR of unirradiated lesions and was additionally associated with significant improvements in PFS and OS. Ablative RT was associated with response rates significantly higher than those of non-ablative RT, possibly due to a detrimental effect of non-ablative RT on ALC. These hypothesis-generating findings require dedicated, large-volume, and randomized studies for corroboration. Clinical trial information: NCT02492568 and NCT02444741 .