Combination Of Stereotactic Body Radiotherapy Research Articles

Stereotactic body radiotherapy (SBRT) combined with transcatheter arterial chemoembolization (TACE) and tyrosine kinase inhibitors (TKIs) versus TACE and TKIs alone for unresectable hepatocellular carcinoma (uHCC) with portal vein tumor thrombus (PVTT): A randomized controlled trial.

4102 Background: TKIs-based systemic therapy is a primary treatment option for uHCC. Clinical studies have established the effectiveness and safety of radiotherapy (RT) in patients with PVTT, who typically have a poor prognosis. Previous research has shown that combining TACE and RT can extend survival in HCC patients with PVTT compared to sorafenib treatment. This study aimed to explore the efficacy and safety of combined local therapy (TACE plus SBRT) and TKIs in HCC patients with PVTT. Methods: This single-center, randomized controlled study enrolled patients aged ≥18 years with HCC and PVTT. Additional eligible criteria included ECOG PS 0-1, Child-Pugh score ≤B7, no extrahepatic metastasis on CT scan, and normal liver volume ≥700cc. Patients were randomly assigned to either the SBRT+TACE+TKIs group (Group A) or the TACE+TKIs group (Group B). SBRT was administered at 35-45 Gy in 5 fractions, 3 fractions per week. TKIs (sorafenib 0.4g bid; donafenib 0.2g bid; or lenvatinib 8mg/12mg qd, depending on body weight) were paused during the perioperative period of TACE (up to 4 times). The primary endpoint was the 6-month progression-free survival (PFS) rate, with secondary endpoints including objective response rate (ORR), overall survival (OS), disease control rate (DCR) and treatment-related adverse events (TRAEs). Treatment response was evaluated using mRECIST. Results: A total of 90 patients with uHCC were enrolled from June 2019 to October 2023 in this trial, with baseline characteristics presented in the Table. As of January 5th 2024, the median follow-up time was 14.5 months [IQR, 2.43-55]. The 6-month PFS rate was significantly higher in Group A (78%) compared to Group B (36%, P=0.0245). Group A also showed prolonged median PFS (9.75 vs. 4.89 months, HR=1.703 [95%CI, 1.045-2.777], P=0.0245) and OS (17.93 vs. 9.61 months, HR=1.869 [95%CI, 1.059-3.266], P=0.017). Improved ORR was observed in the SBRT group (74.4% vs. 40.5%, P=0.0015). DCR was 81.4% in Group A and 66.7% in Group B ( P=0.1211). The most common grade 3/4 TRAEs were hypertension (Group A: 17.8%, Group B: 13.3%, P=0.5608), ALT elevation (Group A: 26.7%, Group B: 22.2%, P=0.6237), and AST elevation (Group A: 22.2%, Group B: 15.6%, P=0.4191). There was one treatment-related death in Group B due to liver failure. Conclusions: In uHCC patients with PVTT, the combination of SBRT and TACE-TKIs showed significant survival benefit without the identification of any severe safety concerns. Clinical trial information: ChiCTR1900025300. [Table: see text]

Abstract CT134: Safety and immunologic impact of neoadjuvant/adjuvant GM-CSF-secreting allogenic pancreatic tumor cell vaccine (GVAX) combined with cyclophosphamide, pembrolizumab, and macrophage-targeting CSF1R inhibitor IMC-CS4 in pancreatic adenocarcinoma

Abstract Background: Strategies are needed to improve effectiveness of immunotherapy in pancreatic ductal adenocarcinoma (PDA). Our recently published study (NCT02648282) showed that increased M1/M2 ratio and decreased PDL1+ M2-like tumor associated macrophages (TAM) in locally advanced PDA is associated with longer overall survival (OS) following combination of stereotactic body radiotherapy, GVAX and anti-PD1 antibody pembrolizumab (Pem). We hypothesized targeting M2-like macrophages, regulated by the colony stimulating factor-1 (CSF1) pathway, would improve outcomes. In this pilot study we investigated the safety and intratumoral immune response of neoadjuvant/adjuvant triplet immunotherapy: GVAX/cyclophosphamide (CY), Pem, and CSF1 receptor blockade (IMC-CS4) in patients with resectable or borderline resectable PDA. Methods: After completing chemotherapy and radiation patients received two 3-week cycles of neoadjuvant triplet immunotherapy. Following surgery, patients received 4 additional cycles followed by booster Pem every 3 weeks and GVAX/CY every 6 months, for one year. Co-primary endpoints were safety, assessed by NCI Common Terminology Criteria for Adverse Events (AEs), and immune response (increased CD8+ T-cell density in surgical specimen as compared to pre-treatment core). Secondary endpoints included disease free survival (DFS), OS, surgical resectability, and pathologic response (PR). Results: Nine patients were enrolled. Two immune related grade 3/4 AEs (diarrhea and rash) were reported. Median DFS was 12.6 months (95% CI: 7.3, NR) and median OS was 20.4 months (95% CI: 17.5, NR). All patients underwent surgery with major PR rate of 78% (defined as <10% residual viable tumor), including one complete PR. Comparing paired biopsies, the study met its primary immunologic endpoint showing 6/8 patients (75%) had a >80% increase of CD8+ T cells; the increase was at least 1.8 times the baseline median absolute deviation following triple therapy (p=0.012). There was a significant increase of Granzyme B+ CD8+ T cells among all patients (p=0.045). No significant change in myeloid cell density, including TAM, was observed, suggesting IMC-CS4 did not deplete macrophages, but potentially reprogrammed them. The 4 patients with greatest drop in CD66b+ granulocyte levels had major PR (grade 0 or 1). Conclusion: The triplet was safe and significantly increased activated CD8+ T cells suggesting the combination can induce an effector T cell response. Decreased granulocyte levels correlated with PR. Citation Format: Arielle Urman, Yingjun Ding, Hao Wang, Richard A. Burkhart, Jin He, Elizabeth M. Jaffee, Amol K. Narang, Dung Le, Daniel A. Laheru, Lei Zheng, Ana De Jesus-Acosta. Safety and immunologic impact of neoadjuvant/adjuvant GM-CSF-secreting allogenic pancreatic tumor cell vaccine (GVAX) combined with cyclophosphamide, pembrolizumab, and macrophage-targeting CSF1R inhibitor IMC-CS4 in pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT134.

Stereotactic Body Radiotherapy Combined With Lenvatinib With or Without PD-1 Inhibitors as Initial Treatment for Unresectable Hepatocellular Carcinoma

PurposeThe aim of this study was to compare the clinical benefit and safety of the triple combination of stereotactic body radiotherapy (SBRT), lenvatinib and programmed death 1 (PD-1) inhibitors with the dual combination of SBRT and lenvatinib in patients with unresectable hepatocellular carcinoma (uHCC). Methods and MaterialsPatients with uHCC who received SBRT in combination with lenvatinib and PD-1 inhibitors or SBRT in combination with lenvatinib alone as first-line treatment from October 2018 to July 2022 were reviewed in this study. The primary endpoints were overall survival (OS), and progression-free survival (PFS). The second endpoints were intra-hepatic PFS (IHPFS), extra-hepatic PFS (EHPFS) and objective remission rate (ORR). In addition, safety profiles were assessed by analyzing treatment-related adverse events (TRAEs) between the two groups to assess safety profiles. ResultsIn total, 214 patients with uHCC who received combination therapy were included in this retrospective study. Among them, 146 patients received triple combination therapy of SBRT, lenvatinib and PD-1 inhibitors (SBRT-L-P group), and 68 patients received dual therapy of SBRT and lenvatinib (SBRT-L group). The median OS times of the two groups were 31.2 months and 17.4 months, respectively (P<0.001). The median PFS time was significantly longer in the SBRT-L-P group than that in SBRT-L group (15.6 months vs. 8.8 months, p<0.001). Additionally, the median IHPFS (17.5 vs. 9.9 months, p<0.001) and EHPFS (20.9 vs. 11.6 months, p<0.001) were significantly longer in the SBRT-L-P group than that in SBRT-L group. The ORR in the SBRT-L-P group was higher than that in the SBRT-L group (63.0 vs. 39.7%, p=0.002). The incidence and severity of TRAEs in the SBRT-L-P group were comparable to those in the SBRT-L group. ConclusionThe use of both lenvatinib and PD-1 inhibitors with SBRT in patients with uHCC was associated with improved overall survival compared to lenvatinib and SBRT alone with a manageable safety profile.

Systematic review and meta-analysis on safety and efficacy of immune checkpoint inhibitors and radiotherapy for advanced pancreatic cancer

Objective: The aim of this study is to assess the safety and efficacy of stereotactic body radiotherapy (SBRT) in combination with immune checkpoint inhibitors (ICIs) in patients with advanced pancreatic cancer. Method: A PRISMA selection protocol was used to identify studies across electronic databases such as; PubMed, Google scholar, Cochrane, Embase, and web of science from inception until November 23, 2022, where data from SBRT studies were compared to data from a combination of SBRT and ICIs for advanced pancreatic cancer. The endpoints recorded after therapy were overall survival (OS), complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), progression-free survival (PFS) and treatment-related adverse effect (TRAE) were collected in each study. Results: The primary endpoint (OS) retrieved from five studies following SBRT disclosed OS at the rate of one year at 44% as compared to the combination studies of SBRT+ICI with 42%. PFS recorded at the rate of 1 year revealed an outcome of 46% following SBRT. In contrast, PFS in the combination studies recorded SBRT+ICI of 86%. The risk of grade &gt;3 TRAE in the SBRT was 21.5% as compared to the combination studies of 75%. This risk of grade&gt;3 TRAE was reduced as compared to any grade in two studies (Heterogeneity: Chi² = 2.78, df = 1 (P = 0.10); I² = 64%). Conclusion: The Combination of SBRT and ICIs demonstrate modest treatment efficiency and acceptable safety profile in patients with advanced pancreatic cancer. However, combination trials are fewer, and further studies are warranted.

Survival Outcome Analysis of Stereotactic Body Radiotherapy and Immunotherapy (SBRT-IO) versus SBRT-Alone in Unresectable Hepatocellular Carcinoma

Introduction: While combination of stereotactic body radiotherapy (SBRT) and immunotherapy are promising, their efficacy and safety have not been compared with SBRT-alone in patients with unresectable hepatocellular carcinoma (HCC). Methods: This retrospective study included 100 patients with nonmetastatic, unresectable HCC in two hospitals. Eligible patients had tumor nodules ≤3 and Child-Pugh liver function score of A5 to B7. Seventy patients received SBRT-alone, and 30 patients underwent combined SBRT and immunotherapy (SBRT-IO). Overall survival (OS), time to progression (TTP), overall response rate (ORR), and toxicity were analyzed. We adjusted for the potential confounding factors using propensity score matching. Results: The median tumor size was 7.3 cm (range, 2.6–18 cm). Twenty-five (25%) of patients had vascular invasion. Before propensity score matching, the 1-year and 3-year OS rate was 89.9% and 59.8% in the SBRT-IO group and 75.7% and 42.3% in SBRT-alone group (p = 0.039). After propensity score matching (1:2), 25 and 50 patients were selected from the SBRT-IO and SBRT-alone group. The 1-year and 3-year OS was 92.0% and 63.9% in the SBRT-IO group versus 74.0% and 43.3% in the SBRT-alone group (p = 0.034). The 1-year and 3-year TTP was better in SBRT-IO group (1-year: 68.9% vs. 58.9% and 3-year: 61.3% vs. 32.5%, p = 0.057). The ORR of 88% (complete response [CR]: 56%, partial response [PR]: 22%) in SBRT-IO arm was significantly better than 50% (CR: 20%, PR: 30%) in the SBRT-alone arm (p = 0.006). Three patients (12%) developed ≥grade 3 immune-related treatment adverse events (n = 2 hepatitis, n = 1 dermatitis) leading to permanent treatment discontinuation. Conclusion: Adding immunotherapy to SBRT resulted in better survival with manageable toxicities. Prospective randomized trial is warranted.

A phase I clinical trial of stereotactic body radiotherapy with atezolizumab and bevacizumab in advanced hepatocellular carcinoma.

TPS626 Background: Systemic therapy with atezolizumab and bevacizumab (atezo/bev) has improved outcomes for advanced HCC, but results in objective responses in fewer than 30% of patients. Stereotactic body radiotherapy (SBRT) is currently used for small HCC tumors that do not require systemic therapy but has also been shown in a number of clinical trials of other solid tumors to enhance the anti-cancer immune response. Of particular interest, our prior experience with SBRT in a 17Gy fraction has demonstrated the ability to restore sensitivity to immunotherapy in advanced solid tumors, even those previously refractory to immunotherapy. We hypothesize that repeated high dose fractions of radiation will act as an immune booster and will improve on outcomes of patients with advanced HCC. Since the combination of SBRT and atezo/bev has not yet been tested prospectively in patients with HCC, and because bevacizumab is a known radiosensitizer, we are conducting a phase I trial to evaluate the safety of repeated SBRT doses. Methods: This is a single-site phase I clinical trial utilizing a Rolling 6 design to determine the safety of 1, 2, or 3 doses of SBRT fractions in combination with atezo/bev. Up to 18 total patients will be enrolled (n=6 per cohort). Patients must be naïve to systemic therapy with Child-Pugh A or B liver function, at least one lesion amenable to radiation, and a measurable lesion that will not receive radiation. Patients with uncontrolled ascites or hepatic encephalopathy are excluded. Atezo/bev is administered at the standard doses every 21 days. SBRT will start 1 week after the first infusion of this combination. Patients will receive 1, 2, or 3 17Gy fractions of SBRT at 4-week intervals (cohorts 2 and 3 only). Patients will undergo serial collections of circulating cell-free DNA (ccfDNA), methylated DNA, and peripheral blood mononuclear cells to investigate the application of these markers as a predictor of response. Following completion of SBRT, patients will continue with atezo/bev until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint is the proportion of patients experiencing dose-limiting toxicities (grade 3 or higher radiation-related toxicities graded by the Common Terminology Criteria for Adverse Events, Version 5). Secondary endpoints are overall survival, progression-free survival, objective response rate, duration of response, and toxicity rates. Enrollment began 9/2022 and complete accrual is expected by June 2024. NCT05488522. Clinical trial information: NCT05488522 .

Stereotactic Body Radiotherapy for Kidney Cancer: Ready for Prime Time?

The standard treatment for renal cell carcinoma (RCC) is surgery. However, a number of patients will not be candidates for surgical treatment or will reject this therapeutic approach. Therefore, alternative approaches are required. Historically, radiotherapy has been considered an ineffective treatment for RCC due to the radioresistance of renal tumour cells to conventional fractionation and the increased rate of toxicity. Stereotactic body radiotherapy (SBRT) is a radiotherapy technique that provides a non-invasive ablative treatment with remarkable rates of local control in both primary tumours and metastases in several locations, with a low associated morbidity due to the highly conformal dose and the use of image-guided techniques. Current evidence shows that a higher dose per fraction, achieving a higher biological effective dose, can overcome the radioresistance of RCC cells. Therefore, SBRT, as well as the combination of SBRT and new emerging immune therapies, has a potential role in the local treatment of primary RCC and oligometastatic RCC patients.

Chancen und Grenzen der stereotaktisch fraktionierten Hochpräzisionsbestrahlung beim nichtkleinzelligen Lungenkarzinom im Stadium I/II

BackgroundFractionated stereotactic body radiotherapy (SBRT) can achieve excellent tumor control with good toxicity profiles and maintained quality of life through non-invasive application of ablative radiation dose in patients with early stage non-small-cell lung cancer (ES-NSCLC).Materials and methodsThe current standard and challenges of SBRT for patients with ES-NSCLC are presented. Recommendations from guidelines and literature are also discussed.ResultsFor inoperable patients, SBRT is considered the standard of care and is superior to conventionally fractionated RT and radiofrequency ablation (RFA) in survival data. For operable patients, resection remains the standard, even if studies show good local control rates, toxicity profiles, and quality of life for SBRT. Only risk-adapted fractionation schemes should be used in patients with central ES-NSCLC; in patients with interstitial lung disease (ILD), increased risk of toxicity must be weighed against the indication. Another challenge is to improve systemic control and survival, which is addressed by combining SBRT with checkpoint inhibitors.ConclusionsThe innovative technique of extracranial SBRT has undergone exorbitant developments in recent years and represents an established treatment alternative to surgery and RFA that is already recommended for inoperable patients with ES-NSCLC and is to be considered for operable patients. Challenges in the use of SBRT are treatment of centrally localized tumors, patients suffering from pulmonary diseases and the combination of SBRT with systemic therapy, which is the subject of current studies.

A phase II study of stereotactic body radiotherapy (SBRT) combined with sintilimab in patients with recurrent or oligometastatic hepatocellular carcinoma (HCC).

4071 Background: SBRT is an emerging treatment option for oligometastatic cancer disease. Preclinical studies have shown the synergistic effects between the radiotherapy and immunotherapy. Early clinical data also suggested that immunotherapy might augment the local effects of radiotherapy and decrease metastatic recurrence. This study aimed to evaluate the efficacy and safety of SBRT combined with sintilimab (a PD-1 antibody) in patients with recurrent or oligometastatic HCC. Methods: In this single arm, phase II study (NCT03857815), eligibility criteria included Pts with recurrent or oligometastatic HCC (defined as ≤5 metastatic/recurrent lesions), Child-Pugh class A, ECOG PS ≤ 1. Pts received sintilimab 200 mg IV Q3W for up to 12 months, progressive disease, unacceptable toxicity, or withdrawal. SBRT to all lesions was started at cycle 1 day 1. Primary endpoint was progression free survival (PFS) per RECIST 1.1. Secondary endpoints included safety, objective response rate (ORR), disease control rate (DCR) and overall survival (OS). Results: At data cutoff (Dec 28th, 2021), 25 pts with 32 lesions were treated with SBRT + Sintilimab. SBRT was delivered at a median dose of 54 Gy (range 48-60) in 6 fractions (range 6-10) and the median follow-up time was 16.9 months (range 3.9-32.1). In those 25 evaluable pts, median age was 64 years (range 37-77), 24 (96%) were male, 24 (96%) were HBV+, 6 (24%) had extrahepatic metastasis, most pts had prior ≥2 local therapies. The confirmed ORR was 96% (24/25) according to RECIST 1.1 with 18pts CR and 6pts PR. 6-mo and 12-mo PFS rate was 100% and 70% (95%CI, 52.3%-93.6%), respectively.12-mo local control rate was 100%. Median PFS and OS was still not mature. Treatment-related adverse events (TRAEs) occurred in 14 pts (56%). Most common TRAEs were rash (16%), platelet count decreased (12%), myositis (8%). Grade 3 TRAEs (myositis) occurred in 1pt (4%). There were no grade 4-5 TRAEs. TRAEs led to discontinuation in 6 pts (24%). SAE were myocarditis (1pt Grade1), viral hepatitis (1pt Grade 3, treatment-independent) and upper gastrointestinal haemorrhage (1pt Grade 3, PD related). Conclusions: The combination of SBRT with Sintilimab was tolerable and showed an encouraging ORR of 96% in pts with recurrent or oligometastatic HCC. Longer follow up is required to further evaluate the efficacy and safety. Clinical trial information: NCT03857815.

Management of Patients with Metastatic Bladder Cancer in the Real-World Setting from the Multidisciplinary Team: Current Opinion of the SOGUG Multidisciplinary Working Group.

Simple SummaryThis report presents clinically relevant advances in the management of metastatic bladder cancer, which have been the focus of discussion of expert members of the Spanish Oncology Genitourinary (SOGUG) Multidisciplinary Working Group in the framework of the Genitourinary Alliance project (12GU) designed as a space for the integration of novel information in the care of bladder cancer patients. The present study is focused on different aspects regarding integration of immunotherapy especially in the patient unfit for platinum-based chemotherapy, PD-L1 assays and samples to be evaluated, role of imaging techniques in preoperative staging or re-staging, definition and treatment approach of oligometastatic disease, and rescue strategies in responders. Involvement of a dedicated multidisciplinary team in the care of patients with mBC is crucial to improve outcome.Based on the discussion of current state of research of relevant topics of metastatic bladder cancer (mBC) among a group of experts of a Spanish Oncology Genitourinary (SOGUG) Working Group, a set of recommendations were proposed to overcome the challenges posed by the management of mBC in clinical practice. First-line options in unfit patients for cisplatin are chemotherapy with carboplatin and immunotherapy in PD-L1 positive patients. FDG-PET/CT may be a useful imaging technique in the initial staging or re-staging. In patients with oligometastatic disease, it is important to consider not only the number of metastatic lesions, but also the tumor biology and the clinical course. The combination of stereotactic body radiotherapy and immunotherapy with anti-PD-L1 monoclonal antibodies is under investigation and could improve the results of systemic treatment in patient with oligometastatic disease. Rescue treatment with curative intent could be considered in patients with oligometastatic disease after complete response on FDG-PET/CT. Metastatic disease should be evaluated using the same imaging modality over the course of the disease from diagnosis until rescue treatment. For improving the outcome of patients with mBC, the involvement of a dedicated multidisciplinary team, including urologists, pathologists, oncologists, radiologists and other specialists is of outmost importance in the daily care of these patients.

Safety and Efficacy of PD-1/PD-L1 inhibitors combined with radiotherapy in patients with non-small-cell lung cancer: a systematic review and meta-analysis.

BackgroundA combination of programmed cell death protein‐1 (PD‐1)/programmed cell death ligand‐1 (PD‐L1) inhibitors and radiotherapy (RT) is increasingly being used to treat non‐small‐cell lung cancer (NSCLC). However, the safety and efficacy of this approach remains controversial. We performed a systematic review and meta‐analysis to summarize the related research.MethodsWe searched the China Biology Medicine, EMBASE, Cochrane Library, and PubMed databases for all the relevant studies. The Stata software, version 12.0 was used for the meta‐analysis.ResultsThe study included 20 clinical trials that enrolled 2027 patients with NSCLC. Compared with non‐combination therapy, combination therapy using PD‐1/PD‐L1 inhibitors and RT was associated with prolonged overall survival (OS) (1‐year OS: odds ratio [OR] 1.77, 95% confidence interval [CI] 1.35–2.33, p = 0.000; 2‐year OS: OR 1.77, 95% CI 1.35–2.33, p = 0.000) and progression‐free survival (PFS) (0.5‐year PFS: OR 1.83, 95% CI 1.13–2.98, p = 0.014; 1‐year PFS: OR 2.09, 95% CI 1.29–3.38, p = 0.003; 2‐year PFS: OR 2.47, 95% CI 1.13–5.37, p = 0.023). Combination therapy also improved the objective response rate (OR 2.76, 95% CI 1.06–7.19, p = 0.038) and disease control rate (OR 1.80, 95% CI 1.21–2.68, p = 0.004). This meta‐analysis showed that compared with non‐combination therapy, combination therapy using PD‐1/PD‐L1 inhibitors and RT did not increase the serious adverse event rates (≥grade 3); however, this approach increased the rate of grade 1–2 immune‐related or radiation pneumonitis. Subgroup analyses revealed that the sequence of PD‐1/PD‐L1 inhibitors followed RT outperformed in which concurrent PD‐1/PD‐L1 inhibitor and RT followed PD‐1/PD‐L1 inhibitor. Combination of stereotactic body RT or stereotactic radiosurgery with PD‐1/PD‐L1 inhibitors may be more effective than a combination of conventional RT with PD‐1/PD‐L1 inhibitors in patients with advanced NSCLC.ConclusionCombination therapy using PD‐1/PD‐L1 inhibitors and RT may improve OS, PFS, and tumor response rates without an increase in serious adverse events in patients with advanced NSCLC. However, combination therapy was shown to increase the incidence of mild pneumonitis.

Combination with Stereotactic Body Radiotherapy Offers a Promising Strategy to Overcome Resistance to Immunotherapy in Advanced Renal Cell Cancer.

Immunotherapy for renal cell cancer (RCC) has witnessed several developments for more than two decades. Checkpoint inhibitors, including anti-CTLA-4 and anti-PD-1/PD-L1 blockers, have changed the treatment landscape for patients with advanced RCC in the past 3 years. Despite these advances, more than 55% RCC patients become resistant to different immunotherapies without other treatment combination. Among various attempts at overcoming resistance to immunotherapy, stereotactic body radiotherapy (SBRT) has been found to potentiate the activity of immunotherapy agents through several potential mechanisms, including normalization of microvessels to alleviate tumor hypoxia, improvement in efficient delivery of drugs, abundant neoantigen exposure, and recruitment of antitumor immune cells to alter the immunosuppressive tumor microenvironment. Preclinical studies and clinical case reports have predicted that the combination of SBRT, an immunotherapy, may lead to remarkable results. This review aims to provide the biological basis for the feasibility of combining SBRT to overcome immunotherapy resistance and to review the currently available clinical evidence of this combination therapy in patients with advanced RCC.

Final Results of a Phase II Prospective Trial Evaluating the Combination of Stereotactic Body Radiotherapy (SBRT) with Concurrent Pembrolizumab in Patients with Metastatic Non-Small Cell Lung Cancer (NSCLC)

Final Results of a Phase II Prospective Trial Evaluating the Combination of Stereotactic Body Radiotherapy (SBRT) with Concurrent Pembrolizumab in Patients with Metastatic Non-Small Cell Lung Cancer (NSCLC)

A phase Ib study of pembrolizumab (Pem) in combination with stereotactic body radiotherapy (SBRT) for resectable liver metastatic MSS colorectal cancer (CRC): A postoperative safety analysis.

e15047 Background: Adjunctive therapies are essential to enhance the effect of anti-PD1 therapies for the treatment of microsatellite stable (MSS) colorectal cancer. SBRT is utilized to treat liver metastatic CRC, causing an increase in immunogenic intra-tumoral and intra-lymphatic antigen release and a rapid influx of responding immune cells. We hypothesize that radiation enhances the immunogenicity of MSS CRC and potentiates the effectiveness of PD-1 blockade. This phase Ib study examines the safety and efficacy of the sequential combination of SBRT and Pem in patients for whom the goal is to resect all sites of known disease. Methods: Key eligibility criteria include MSS CRC with liver-confined metastatic disease with the therapeutic goal of resection of all radiographic disease with one operation. Subjects must be a candidate for SBRT to 1-3 liver metastases. Prior surgery and systemic chemotherapy are allowed. Subjects receive sequential SBRT and cycle 1 of Pem prior to operative management. Postoperatively, patients complete cycles 2-9 of Pem followed by scheduled surveillance with imaging every 12 weeks. The primary objectives are to determine the safety/tolerability of this regimen and the recurrence rate at 1 year following clearance of metastatic disease. Secondary objectives include time to recurrence, DFS, and OS. Results: 10 patients (median age 61.5 [range 39-69]) have been enrolled and completed the intended neoadjuvant therapy, operative management and at least 4 adjuvant cycles of Pem. All patients had received prior FOLFOX. SBRT median dose was 50 Gy (40-60 Gy) to a single lesion targeted in all patients. Mean gross tumor size targeted was 19.1cc (2.3-80.4). Any-grade post-operative AEs (&gt;20%) attributable to Pem include diarrhea (30%), hyperbilirubinemia (20%%), and leukopenia (20%). Post-operative AEs included one case of biliary tract injury and biloma, not related to immunotherapy. No grade 3/4 immunotherapy AEs have occurred. Conclusions: The combination of SBRT with Pem and surgical resection is well tolerated with no signal of increased immunotherapy-related toxicity in the post-operative setting. Clinical trial information: NCT02837263.

Abstract P2-09-06: Safety and efficacy of stereotactic body radiotherapy and Pembrolizumab in advanced breast cancer patients with 1 to 5 metastases

Abstract Background Pre-clinical studies have demonstrated that stereotactic body radiotherapy (SBRT) induces immunogenic cell death and tumor antigen release promoting anti-tumor immunity. We hypothesized that the efficacy of SBRT could be improved with the addition of PD-1 blockade in advanced breast cancer (BC) patients with oligometastatic disease. Methods Advanced BC patients with 1 – 5 metastatic sites of disease received SBRT at a dose of 20Gy in 1 fraction to at least 1 metastasis followed by pembrolizumab 200mg IV (within 5 days of SBRT), once every 3 weeks for a total of 8 cycles. The primary endpoint was safety of the combination. The secondary endpoints were response using RECIST 1.1 and PERCIST 1.0 using 18F-Flurodeoxyglucose (FDG)- positron emission tomography (PET) scans as well as local progression-free survival and distant progression-free survival (d-PFS). Correlatives included deep sequencing of the T cell receptor (TCR) CDR3 regions of archival metastatic tumor material and in peripheral blood as well as evaluation of systemic markers of immune activation. Results 15 patients were enrolled between March 2016 and Nov 2017. The number of patients with 1, 2, 4 and 5 metastases treated with SBRT was 9 (60%), 3 (20%), 2 (13%) and 1 (7%), respectively. There were 3 (20%) TNBC, 2 (13%) HER2+ and 10 (67%) ER+/HER2- (Luminal) BC patients. Five (33%) patients experienced Grade 3 or higher Aes. Immune related Aes were reported in 10 (67%) patients, the most common being rash (n=4), thyroid (n=3) and pneumonitis (n=3) with pembrolizumab delayed in 3 (20%) patients and discontinued in 2 (13%) patients. Nine (60%) patients had a complete response or partial response according to RECIST 1.1 criteria and 13 (86%) patients had a complete metabolic response (CMR) or partial metabolic response (PMR) according to PERCIST 1.0 at the 3-month FDG-PET scan. At time of reporting (median follow-up 15 months; range 9-26 months) no deaths or local progression have been observed. Five patients (33%) progressed distantly at 3, 8, 8, 12 and 18 months: 2 of 3 (66%) TNBC, 2 of 10 (20%) Luminal and 1 of 2 (50%) HER2+. Estimated dPFS at 9 months was 80% (95% CI [62% – 100%]). Three patients have reached the 2-year mark without progression (all Luminal). In a patient who remained progression free at 24 months, TCR profiling showed that TCR sequences in a pre-treatment metastatic tumor biopsy were found in peripheral blood and became elevated after combination treatment, along with the emergence of new TCR sequences not seen in the tumor sample. Markers of increased CD8+ and CD4+ T cell activation using flow cytometry of peripheral blood lymphocytes were observed. This data suggests that the treatment induced peripheral expansion of tumor-specific T cells in this responding patient. Further correlatives are pending. Conclusion The combination of SBRT and 6 months of pembrolizumab in advanced breast cancer patients with 1-5 metastases showed an acceptable toxicity profile and promising clinical benefit especially in Luminal BC patients. Evidence of peripheral anti-tumor T cell responses was observed in a patient who remains progression free at 24 months. The potential synergy between these treatment modalities requires further study. Citation Format: David SP, Savas P, Neeson PJ, Luen SJ, Foroudi F, Siva S, Loi S. Safety and efficacy of stereotactic body radiotherapy and Pembrolizumab in advanced breast cancer patients with 1 to 5 metastases [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-09-06.

Feasibility of stereotactic radiotherapy for lung lesions and conventional radiotherapy for nodal areas in primary lung malignancies

BackgroundCombined stereotactic body radiotherapy (SBRT) for lung lesions and conventional radiotherapy (CRT) for nodal areas may be more effective than CRT alone in patients with locally advanced lung cancer.MethodsThis study included 21 patients with small primary lung tumors distant from the regional nodal areas. The SBRT dose was 40–60 Gy in 4 fractions. CRT doses were 66 Gy in 30 fractions for non-small cell lung cancer and 52.5 Gy in 25 fractions for small cell lung cancer.ResultsThe median follow-up duration was 12 months, and the median survival was 13 months. The 1 year overall survival, local recurrence-free survival, and distant metastasis-free survival rates were 60.5, 84.8, and 62.1%, respectively. Two patients experienced in-field local recurrence combined with out-field regional recurrence and/or distant failure. The major recurrence pattern was distant failure (crude incidence, 43%). Three patients aged ≥79 years experienced grade ≥ 3 acute radiation pneumonitis, and one also had idiopathic interstitial pneumonia.ConclusionThe combination of SBRT for the lung lesion and CRT for the nodal region seems to be effective and safe for lung malignancies. However, patients older in age and/or with underlying pulmonary disease require stricter lung dose constraints.

Final results of a phase I prospective trial evaluating the combination of stereotactic body radiotherapy (SBRT) with concurrent pembrolizumab in patients with metastatic non-small cell lung cancer (NSCLC) or melanoma.

9099Background: We report final Phase I results of a Phase I/II prospective trial assessing safety and tolerability of SBRT and concurrent pembrolizumab. Methods: Eligible patients had metastatic N...

MP64-16 HYPOFRACTIONATED STEREOTACTIC RADIOTHERAPY INCREASES BOTH TUMOR-INFILTRATING LYMPHOCYTES AND SUPPRESSIVE IMMUNE CELLS IN PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology II1 Apr 2018MP64-16 HYPOFRACTIONATED STEREOTACTIC RADIOTHERAPY INCREASES BOTH TUMOR-INFILTRATING LYMPHOCYTES AND SUPPRESSIVE IMMUNE CELLS IN PROSTATE CANCER Lin Lin, Nathan Kane, Naoko Kobayashi, Siliva Diaz-Perez, Rajan Kulkarni, Nicholas Nichols, and Robert Reiter Lin LinLin Lin More articles by this author , Nathan KaneNathan Kane More articles by this author , Naoko KobayashiNaoko Kobayashi More articles by this author , Siliva Diaz-PerezSiliva Diaz-Perez More articles by this author , Rajan KulkarniRajan Kulkarni More articles by this author , Nicholas NicholsNicholas Nichols More articles by this author , and Robert ReiterRobert Reiter More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.2061AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Extremely hypofractionated stereotactic body radiotherapy (SBRT) is a technique for delivering radiotherapy (RT) to prostate cancer that is growing in use due to improved convenience as compared to conventional radiotherapy and equivalent efficacy results. It is hypothesized that SBRT may enhance or suppress tumor reactive immunity. The goal of this study is to assess both the anti-tumor and immunosuppressive effects induced by SBRT in prostate cancer patients and experimental models, and ultimately, to test if a combination of SBRT with targeted immune therapy can achieve a superior antitumor effect. METHODS Twelve patients are recruited in our Phase I feasibility trial (NCT02830165) of hypofractionated SBRT followed by radical prostatectomy in high-risk localized prostate cancer. Pre-SBRT biopsies, post-SBRT prostatectomies, and sequential blood samples are collected to assess local radiation-induced tumor immunity and the development of systemic immune response. Syngeneic murine allograft prostate cancer models are used to study the dynamic change of tumor-infiltrating lymphocyte (TIL), T regulatory cell (Treg), myeloid-derived suppressive cell (MDSC), and circulating T memory cell. These immune cell populations from human prostates and experimental models are evaluated using flow cytometry. RESULTS Results from the first patients treated suggest that SBRT increased the density of TILs within the resected prostate tumor two-weeks after treatment, and the majority of the post-SBRT TILs were CD8+ T cells. Co-clinical syngeneic murine prostate cancer models demonstrated a drastic increase in tumor-infiltrating MDSCs immediately after a single RT dose and then a gradual rise of TILs. Besides local effects, irradiation of primary tumors also increased the fractions of MDSCs and Tregs in non-irradiated synchronous tumors, suggesting that hypofractionated SBRT induced a systemic immune response. CONCLUSIONS In prostate cancer patients, hypofractionated SBRT may enhance CD8 T cell infiltration weeks after treatment. In murine prostate cancer models, RT induces an early rise of tumor-infiltrating MDSCs, a gradual increase of TILs, and a systemic immune response in non-irradiated tumors. The expansion of immunosuppressive cell populations induced by SBRT allows us to further explore the effectiveness of SBRT in combination with targeted immune therapies in prostate cancer. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e856 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Lin Lin More articles by this author Nathan Kane More articles by this author Naoko Kobayashi More articles by this author Siliva Diaz-Perez More articles by this author Rajan Kulkarni More articles by this author Nicholas Nichols More articles by this author Robert Reiter More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Comparison of Late Urinary Symptoms Following SBRT and SBRT with IMRT Supplementation for Prostate Cancer

Background: Prostate cancer survivors commonly experience late-onset lower urinary tract symptoms following radiotherapy. We aimed to compare lower urinary tract symptoms in patients treated with stereotactic body radiotherapy (SBRT) to those treated with a combination of lower dose SBRT and supplemental intensity-modulated radiotherapy (SBRT + IMRT). Methods: Subjects with localized prostate carcinoma scheduled to receive SBRT or a combination of SBRT and IMRT were enrolled and followed for up to 2 years after treatment completion. Participants treated with SBRT received 35-36.25 Gy in 5 fractions, while those treated with SBRT + IMRT received 19.5 Gy of SBRT in 3 fractions followed by 45-50.4 Gy of IMRT in 25-28 fractions. Urinary symptoms were measured using the American Urological Association (AUA) Symptom Score. Results: Two hundred patients received SBRT (52% intermediate risk, 37.5% low risk according to D'Amico classification) and 145 patients received SBRT + IMRT (61.4% high risk, 35.2% intermediate risk). Both groups experienced a transient spike in urinary symptoms 1 month after treatment. More severe late urinary flare (increase in AUA scores ≥ 5 points from baseline to 1 year after treatment completion and an AUA score ≥ 15 at 1 year after treatment) was experienced by patients who received SBRT compared to those treated with SBRT + IMRT. Conclusion: Participants who received SBRT and supplemental IMRT experienced less severe late urinary flare 1 year after treatment compared to those who received higher dose SBRT alone. This information can be used by clinicians to provide patients with anticipatory counseling to mitigate any psychological burden that comes with unanticipated late urinary toxicities.

P3.02c-048 A Phase I/II Trial Evaluating the Combination of Stereotactic Body Radiotherapy and Pembrolizumab in Metastatic NSCLC: Topic: IT

Immune checkpoint inhibitors are taking on a growing role in the treatment of patients with metastatic NSCLC. Pre-clinical evidence suggests that radiotherapy may increase the frequency, or enhance the strength of the host anti-cancer immune response. We report the preliminary results of an ongoing phase I/II trial combining stereotactic body radiotherapy (SBRT) and the anti-PD-1 antibody pembrolizumab in patients with metastatic NSCLC. Eligible patients are those with metastatic NSCLC who have received no prior immune-directed therapy, and have at least 2 sites of measurable disease as per RECIST 1.1. PD-L1 expression is not required for study entry. All patients are treated with pembrolizumab at 200 mg every 3 weeks until development of progressive disease by immune-related RECIST criteria (irPD). After irPD, patients receive SBRT to a single site of disease and continue pembrolizumab. The primary endpoint is safety and tolerability. Secondary endpoints include the pre- and post-SBRT overall response rate. 27 patients with advanced NSCLC have enrolled and started trial therapy. The overall response rate (irPR and irCR) to the initial course of pembrolizumab is 35%. To date, 13 patients have had irPD: 5 were not eligible for SBRT and stopped study treatment (2 developed new brain metastases, 3 had decline in PS), and 8 patients received SBRT to a single site of disease (6 thoracic, 1 adrenal, 1 vertebral) and continued pembrolizumab. 5 of these patients are evaluable for post-SBRT response: 1 patient had confirmed irPD, 4 have irSD and continue pembrolizumab post-SBRT at a median duration of 3 months (range 1 to 5 months). 2 of the 4 patients with irSD have had > 20% decrease in the sum of diameters of their unirradiated targets, since SBRT. Regarding adverse events, in the pre-SBRT phase 6 of 27 patients (22%) developed grade 3 treatment-related toxicity (2 colitis, hepatitis, pneumonitis, hypothyroidism, conjunctivitis). In the SBRT and post-SBRT phases, there have been no grade 2 or greater treatment-related events. The addition of SBRT to pembrolizumab has not resulted in an increase in treatment-related toxicity. Several patients who had serially confirmed irPD to pembrolizumab monotherapy underwent SBRT and now have irSD, with some evidence of tumor regression. Updated results will be presented.