Concurrent Immunotherapy Research Articles

A Matched Comparison of Early Toxicity in p16+ Oropharynx Cancer Treated With Definitive Chemoradiation With or Without Nivolumab

To compare acute toxicity and quality of life (QOL) outcomes up to 3 months post chemoradiotherapy (CRT) versus CRT with nivolumab (iCRT) in locally advanced p16+ oropharyngeal cancer (OPC).Matched cohorts with AJCC 8 stage III p16+ OPC patients treated at a single institution on two prospective protocols were compared: 1) CRT (Carboplatin + Paclitaxel) to 70 Gy with concurrent and 3 months of adjuvant nivolumab (iCRT) 2) CRT (Carboplatin or Cisplatin) to 70-80 Gy. 30 CRT patients were matched 2:1 to 15 iCRT patients according to primary site and tumor volume. In both groups, we compared the following clinical variables during and within 3 months of RT: physician graded mucositis, ED visits/hospitalizations, treatment interruptions, opioids requirements, and need for IV hydration or feeding tube (FT). The iCRT patients reported weekly Common Terminology Criteria for Adverse Events (CTCAE) during RT. Videofluoroscopy (VFSS) and validated QOL patient reported outcomes (PROs) were completed at baseline and 3 months. PROs were scored for minimal clinically important difference (MCID) changes. Student t-tests and chi-square were used to compare groups.Clinical characteristics were balanced in mean age (P = 0.065), tumor volume (P = .74), base of tongue vs tonsil site (P = .88). Current smoking and pack year history were higher in the CRT patients (P = 0.003). iCRT patients had significantly higher rates of grade 3+ mucositis (87 vs 17%, P < 0.001), persistent opioid use at 3mo post-RT (69 vs 17%, P = 0.002), and missed chemotherapy doses (47 vs 13%, P = 0.04). No patient had any RT interruption. Non-significantly increased endpoints in iCRT patients included ED visits (53 vs 23%, P = 0.09), hospitalizations (40 vs 20%, P = .28), FT use (53 vs 33%, P = .33) and need for IV hydration during therapy (80% vs 47%, P = 0.07). From the 10 iCRT and 30 CRT patients who had complete PROs, iCRT patients reported significant MCID changes at 3 months in global QOL (80% vs 20%, P = 0.002), pain (90 vs 40%, P = 0.02) and sticky saliva (100% vs 57, P = 0.03), while changes in taste (90% vs 60%, P = .17) and swallow function (90% vs 50%, P = 0.06) were non-significantly worse in iCRT patients. In addition, from the 8 iCRT and 27 CRT who had complete VFSS scored by SLP at the time of this interim evaluation, there were increased aspiration events in the iCRT from baseline to 3 months (63 vs 44%, P = 0.06). Finally, weekly PROs during RT in iCRT patients revealed severe taste changes (78%), severe mouth sores (54%), and severe dry mouth (62%) by week 3.Despite increased smoking history and RT boost, CRT patients exhibited fewer acute toxicities compared to iCRT patients. iCRT patients reported severe taste changes, mucositis, and xerostomia early in treatment. As many trials are currently ongoing to establish the oncologic benefit of concurrent immunotherapy, attention must be paid to acute and late toxicities as well as their impact on QOL in order to define their therapeutic utility.

P40.04 CNS Adverse Events and Survival in Patients with NSCLC Brain Metastases Treated With Concurrent Radiation and Immunotherapy

Immune checkpoint inhibitors (ICIs) are an essential component of metastatic non-small cell lung cancer (NSCLC) treatment. Metastatic NSCLC patients frequently develop brain metastases requiring treatment with CNS radiation therapy (CNS-RT). Prospective data on safety and outcomes with overlapping immunotherapy and CNS-RT is lacking. Retrospective studies have reported safety in this population with no increased risk of radiographic events of hemorrhage or radionecrosis. We completed a retrospective review to evaluate rates of clinically significant CNS adverse events (CNS-AEs) and OS in those receiving CNS-RT with and without concurrent ICI use.

OS03.3.A Characterization of long-term metabolic changes of irradiated brain metastases using serial dynamic FET PET imaging

Abstract BACKGROUND In the present study, we characterized the long-term metabolic changes of brain metastases irradiated with stereotactic radiosurgery (SRS) by sequential dynamic PET imaging using the radiolabeled amino acid O-(2-[18F]-fluoroethyl)-L-tyrosine (FET). We hypothesized that this approach is of considerable clinical value to diagnose delayed radiation-induced changes. MATERIAL AND METHODS From 2010–2021, we retrospectively identified patients with brain metastases from solid extracranial primary tumors who (i) were treated with SRS with or without concurrent immunotherapy using checkpoint inhibitors, (ii) had equivocal or progressive MRI findings after SRS, and (iii) subsequently underwent at least two additional dynamic FET PET scans during follow-up for long-term evaluation. Mean tumor-to-brain ratios (TBR) and the dynamic FET PET parameter time-to-peak were obtained. Diagnostic performances were calculated using receiver operating characteristic curve analyses. Diagnoses were confirmed histologically or clinicoradiologically. RESULTS We identified 36 patients with 98 FET PET scans (median number, 3; range, 2–6). Concurrent to SRS, 8 patients (22%) were treated with checkpoint inhibitors. Following SRS, suspicious MRI findings occurred after a median time of 11 months (range, 2–64 months). Subsequently, FET PET scans were acquired over a median period of 13 months (range, 5–60 months). The overall median follow-up time was 26 months (range, 8–101 months). Twenty-one patients (58%) had delayed radiation-induced changes. TBRs calculated from the last available FET PET scan showed the highest accuracy (92%) to identify delayed radiation-induced changes (threshold, 1.95; P&amp;lt;0.001). CONCLUSION FET PET has a high diagnostic accuracy for characterizing the long-term changes of irradiated brain metastases.

Effects of exercise and anti-PD-1 on the tumour microenvironment

Immune checkpoint inhibition is highly effective in treating a subset of patients with certain cancers, such as malignant melanoma. However, a large proportion of patients will experience treatment resistance, and other tumour types, such as breast cancer, have thus far proven largely refractory to immune checkpoint inhibitors as single agents. Exercise has been associated with improved cancer patient survival, has known immune-modulatory effects, may improve anti-tumour immunity and may normalise tumour blood vessels. Therefore, we hypothesised that post-implant exercise would boost the effect of concurrent immunotherapy by enhancing anti-tumour immune responses and improving tumour blood flow. To investigate this, mice with EO771 breast tumours or B16-F10 melanomas received anti-PD-1, an isotype control antibody or no treatment. Mice were randomised to exercise (voluntary wheel running) or no exercise at tumour implant. Exercise reduced the number of CD8+T cells in EO771 (p = 0.0011) but not B16-F10 tumours (p = 0.312), and reduced the percentage of CD8+T cells within the total T cell population in both tumour types (B16-F10: p = 0.0389; EO771: p = 0.0015). In contrast, the combination of exercise and anti-PD-1 increased the percentage of CD8+T cells in EO771 (p = 0.0339) but not B16-F10 tumours. Taken together, our results show that exercise and anti-PD-1 induce changes in the tumour immune microenvironment which are dependant on tumour type.

Radiation therapy for vaginal and perirectal lesions in recurrent ovarian cancer

<h3>Objectives:</h3> The role for radiation therapy (RT) to treat ovarian cancer (OC) patients with locally recurrent vaginal/perirectal lesions remains unclear, though we hypothesize that these patients may be salvaged locally and gain long-term survival benefit. We aimed to describe our institutional outcomes using vaginal brachytherapy±intensity modulated radiation therapy (IMRT) to treat this population and report our in-field control rate, RT-related toxicities, post-RT chemotherapy-free interval (CFI), RT-related toxicities, progression-free survival (PFS), and overall survival (OS). We also studied the prognostic impact of platinum status immediately prior to RT. <h3>Methods:</h3> This is a single institution retrospective case series of 17 recurrent OC patients treated with brachytherapy±IMRT for vaginal and/or perirectal recurrences between January 2006 and November 2019. Intent of RT (palliative or definitive) was determined collaboratively by the treating gynecologic and radiation oncologists. PFS and OS were defined from date of RT completion to either progression or death/last follow-up, respectively. <h3>Results:</h3> This was a heavily pre-treated cohort (median 3 prior lines of chemotherapy, range 1-9), with a median follow-up of 28.4 months (range 4.5-166.4) after RT completion (Figure 1). Most patients had high-grade serous histology (9 of 17) with the remainder of patients even distributed between low-grade serous, clear cell, mixed, and carcinosarcoma. Eleven patients were treated with definitive intent, including 4 with isolated vaginal/perirectal disease. Three patients received concurrent chemotherapy or immunotherapy and RT. Four (23.5%) patients had in-field failures at 2.3, 10.9, 23.2, and 25.7 months post-RT, all of whom had been treated with definitive intent. The 9 patients who were platinum-sensitive prior to RT had similar median PFS (8.1 vs. 10.4 months, log-rank p=0.91), but longer OS (53.9 vs 16.5 months, log-rank p=0.03) compared to their platinum-resistant counterparts. Excluding patients with low-grade histology or who were treated with palliative RT, the median CFI was 12.6 months (range 1.3-31.7). When including all patients, the two patients with the longest CFI post-RT included a <i>BRCA2</i> mutation carrier with an isolated vaginal recurrence and a patient with a <i>MLH1</i> somatic mutation treated with concurrent RT and pembrolizumab. RT was well tolerated with 2 (12%) experiencing grade 3/4 gastrointestinal/genitourinary toxicities. <h3>Conclusions:</h3> RT to treat locally recurrent vaginal and perirectal lesions in heavily pre-treated OC patients is safe and may effectively provide locoregional control.

OC-0408 Higher-dose radiotherapy for metastatic spinal cord compression: First results of a phase II trial

Purpose or Objective To evaluate the outcomes after high-precison RT (preferably VMAT) with increased doses (EQD2 for tumors >40 Gy) when compared to 10x3 Gy (EQD2=32.5 Gy) for metastatic spinal cord compression (MSCC) in patients with favorable survival prognoses. Materials and Methods Since 08/2019, 29 (of 65) patients (9 female, 20 male) with motor deficits due to MSCC and a favorable survival prognosis according to a validated score have been included in a phase II trial (RAMSES-01). Median age is 68 (48-90) years, and most common tumor types are prostate cancer (n=10), breast cancer (n=7) and myeloma (n=6). RT regimens include 18x2.333 Gy (EQD2=43.2 Gy, n=10), 15x2.633 Gy (41.6 Gy, n=17;fewer fractions due to Covid-19 pandemic) and 12x2.663 Gy + 3x2.333 Gy (40.5 Gy, n=2;due to concurrent immunotherapy). Primary endpoint is local progression-free survival (LPFS=no progression of motor deficits during RT and no in-field recurrence following RT). Secondary goals include effect on motor function [improvement, overall response (OR) = at least no further progression] and sensory deficits, pain relief, overall survival (OS) and toxicity. Follow-up (FU) is performed until death or for 12 months. Results Three patients are currenty under treatment, one patient died after 14 Gy. Thus, 25 patients are evaluable for LPFS and response. LPFS is 100% at the end of RT (currently n=25), and at 1 month (n=21), 3 months (n=16), 6 months (n=9), 9 months (n=5) and 12 months (n=3) following RT. Considering best response during FU, OR and improvement rates are 100% and 60%, respectively. Sensory function normalized in 5 of the 9 patients (55.6%) with pre-RT sensory dysfunction. Of 21 patients with pain (median score 8, range 4-10), 18 (86%) achieved pain relief [complete in 7 patients (33%)]. OS-rates at 6 and 12 months are 71% and 71%, respectively. Six patients died (3 sepsis, 2 pneumonia, 1 tumor progression);death was not related to RT. RT-related grade 3 toxicity occurred in 2/25 (8%) patients (1 esophagitis, 1 diarrhea). Conclusion First results of high-precision RT with increased doses for MSCC in patients with favorable survival prognoses appear very promising with high response and LPFS rates and very few grade 3 toxicities. Updated information will be presented at the meeting.

Engineered extracellular vesicles for concurrent Anti-PDL1 immunotherapy and chemotherapy

Immune checkpoint inhibitors (ICI) targeting PD-1/PD-L1 have been approved for the treatment of a variety of cancers. However, the efficacy of antibody-based ICIs could be further improved by mitigating anti-drug antibodies, proteolytic cleavage, and on-target off-tumor toxicity. One strategy for accomplishing this is through the use of extracellular vesicles (EVs), cell derived submicron vesicles with many unique properties. We constructed an engineered MDA-MB-231 cell line for harvesting EVs. This was accomplished by overexpressing a high-affinity variant human PD-1 protein (havPD-1), while simultaneously knocking out intrinsic PD-L1 and beta-2 microglobulin. The engineered havPD-1 EVs reduced PD-L1 overexpressing cancer cell proliferation and induced cellular apoptosis. Moreover, the EVs were shown to efficiently block PD-L1 mediated T cell suppression. Meanwhile antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity were not observed. The havPD-1 EVs treatment resulted in robust anti-tumor activity in both preventative co-implantation and therapeutic xenograft tumor models reconstituted with human T cells. The efficacy of the havPD-1 EVs was shown to be comparable to clinical anti-PD1 monoclonal antibodies. Additionally, loading the havPD-1 EVs with a potent PARP inhibitor was shown to further augment treatment efficacy. In brief, the engineered universal EVs harboring havPD-1 proteins can be used for cancer concurrent immunotherapy and chemotherapy.

JS2-3 Current status of concurrent radiotherapy and immunotherapy

JS2-3 Current status of concurrent radiotherapy and immunotherapy

#50: Cytomegalovirus Retinitis Among Pediatric Hematopoietic Stem Cell and Solid Organ Transplantation Recipients: A Contemporary Review

Abstract Background Cytomegalovirus infection can cause significant morbidity and mortality after transplantation. Cytomegalovirus retinitis (CMVR) can be a major complication of tissue invasive CMV disease in transplant recipients. There are little data regarding the contemporary incidence and outcomes of CMVR among pediatric transplant recipients. Methods We performed a retrospective cohort analysis of allogeneic hematopoietic (allo-HCT) and solid organ transplant (SOT) recipients who received medical care at Nationwide Children’s Hospital (NCH) from 1/1/10–11/30/20 and had a diagnosis of CMVR to describe the incidence, timing post-transplant, ocular manifestations, management, and outcomes. Basic demographic and clinical data, pre-transplant donor/recipient CMV serostatus, and post-transplant CMV infection data were collected. Graft-specific CMV surveillance and prophylaxis strategies were performed according to NCH hospital guidelines. During the study period, quantitative plasma CMV PCR assays included copies/mL (2010–2013) and WHO international standard IU/mL (2013–2020). Results During the 10-year study period, 347 patients underwent allo-HCT (N=214) or SOT (N=133; heart N=46, liver N=36, kidney N= 52; 1 patient had concomitant kidney and liver transplantation); median age was 8.6 years [range 0.1–25.9] and 198 (56.5%) were male. In total, 98 patients had CMV DNAemia post-transplant, and CMVR was diagnosed in 3 (HCT=2, SOT=1), for an overall CMVR incidence of 0.86% among all transplant recipients and occurring in 3% of patients with CMV DNAemia. No CMVR was diagnosed in patients without CMV DNAemia. An ophthalmologic examination was performed in 58 (59%) of patients with any DNAemia compared with 67 (27%) of patients without DNAemia. CMVR was diagnosed on funduscopic examination a median of 183 days [range 34–512] post-transplant based on visual symptomatology (N=2) or by routine eye screening prompted by DNAemia (N=1). CMV DNAemia at the time of CMVR was 1,463 copies/mL, 3,000, and 14,204 IU/mL; all patients had prolonged (&amp;gt;3 months) CMV detection before CMVR. One SOT recipient had concomitant pathology confirming CMV gastrointestinal tract disease. Two of the 3 CMVR cases occurred in the setting of genotypic UL94 CMV resistance mutations (A594V, H520Q)(Figure 1). Two patients were already receiving CMV antiviral therapy (maribavir N=1; valganciclovir=1) at the time of CMVR diagnosis. After the CMVR diagnosis, all patients were prescribed systemic foscarnet. Adjunctive therapies included concurrent intravitreal antiviral therapy (ganciclovir N=1; foscarnet N=1) and adoptive immunotherapy with CMV antiviral specific T-cells (N=1, HCT). Improvement of ocular symptoms occurred in 2 patients at 15 and 20 days after starting targeted CMV antiviral therapy; one patient developed permanently impaired vision. Conclusion CMVR remains as an important complication in transplant recipients. Although CMVR incidence was low in our cohort of transplant recipients, it occurred most frequently in cases of CMV resistance, prolonged DNAemia, and led to permanent visual impairment in 1 of 3 patients. The development of resistant CMV may have a role in the occurrence, progression, and severity of CMVR. Additional pediatric-specific data are needed to better characterize CMVR and inform optimal prevention strategies.

Narrative review of immune checkpoint inhibitors and radiation therapy for brain metastases.

Radiation therapy plays a key role in the management of intracranial metastatic disease. Historically, systemic therapy was able to address extracranial disease but not cross the blood-brain barrier and radiation therapy and surgery were the only mechanisms to treat intracranial metastases. There are now several examples of contemporary systemic therapies with central nervous system efficacy in some patients. With such improvements in systemic therapies, patients are living longer and the optimal management of brain metastases is becoming an increasingly important clinical priority. However, the role of radiation therapy remains critical in treating brain metastases. The concurrent use of new systemic therapies with radiation brings about novel and significant questions regarding potential synergy between these therapies in the brain in regard to both oncologic efficacy and toxicity. One important systemic therapy to consider is immune checkpoint inhibitors. These drugs are now at the forefront of management of many malignancies and have changed the landscape of treatment for many common cancers, particularly those with a predilection for brain metastases. In this review we will examine the existing data on the efficacy and toxicity of concurrent radiation therapy and immunotherapy for brain metastases and explore potential mechanisms underlying the published clinical observations.

77TiP From liquid biopsy to cure: Using CtDNA detection of minimal residual disease to identify patients for curative therapy after non-small cell lung cancer (NSCLC) resection

Background: For resectable Stage IA2 to IIB (T1b-T3N0) NSCLC, the current practice is surgery followed by observation for Stage IA disease. Adjuvant platinum-based doublet chemotherapy is offered to patients (pts) with stage IB disease with high-risk pathological and radiological features and is recommended for those with Stage II NSCLC. In pts with resected lung cancer, post-operative ctDNA predicts and precedes radiographic recurrences. The survival benefit seen with 1st-line chemo-immunotherapy (chemo-IO) for advanced NSCLC provided the rationale to launch this trial offering concurrent immunotherapy with adjuvant chemo to selected pts.

Locally advanced non-small-cell lung cancer (NSCLC): The potential role of concurrent immunotherapy and radiotherapy

Locally advanced non-small-cell lung cancer (NSCLC): The potential role of concurrent immunotherapy and radiotherapy

Gamma Knife Radiosurgery for Brain Metastases in Non-Small Cell Lung Cancer Patients Treated with Immunotherapy or Targeted Therapy.

Simple SummaryIn non-small cell lung cancer patients with brain metastases, combined Gamma Knife radiosurgery and immunotherapy or targeted therapy showed an increase in overall survival. The combination of Gamma Knife radiosurgery and immunotherapy or targeted therapy did not increase complications related to radiosurgery. Therefore, the combined treatment seems to be a safe and powerful treatment option for non-small cell lung cancer patients with brain metastases.The combination of Gamma Knife radiosurgery (GKRS) and systemic immunotherapy (IT) or targeted therapy (TT) is a novel treatment method for brain metastases (BMs) in non-small cell lung cancer (NSCLC). To elucidate the safety and efficacy of concomitant IT or TT on the outcome after GKRS, 496 NSCLC patients with BMs, who were treated with GKRS were retrospectively reviewed. The median time between the initial lung cancer diagnosis and the diagnosis of brain metastases was one month. The survival after the initial BM diagnosis was significantly longer than the survival predicted by prognostic BM scores. After the first Gamma Knife radiosurgery treatment (GKRS1), the estimated median survival was 9.9 months (95% CI = 8.3–11.4). Patients with concurrent IT or TT presented with a significantly longer survival after GKRS1 than patients without IT or TT (p < 0.001). These significant differences in the survival were also apparent among the four treatment groups and remained significant after adjustment for Karnofsky performance status scale (KPS), recursive partitioning analysis (RPA) class, sex, and multiple BMs. About half of all our patients (46%) developed new distant BMs after GKRS1. Of note, no statistically significant differences in the occurrence of radiation reaction, radiation necrosis, or intralesional hemorrhage in association with IT or TT at or after GKRS1 were observed. In NSCLC-BM patients, the concomitant use of GKRS and IT or TT showed an increase in overall survival without increased complications related to GKRS. Therefore, the combined treatment with GKRS and IT or TT seems to be a safe and powerful treatment option and emphasizes the role of radiosurgery in modern BM treatment.

The promising role of radiotherapy in the treatment of advanced or metastatic renal cell carcinoma: a narrative review.

Traditionally, renal cell carcinoma (RCC) has been regarded to be “radioresistant”. Conventional fractionated radiation (CFRT) has played a limited role in RCC as a palliative treatment to relieve pain and bleeding. Succeed to the rapid development of precise radiotherapy techniques, realizing safe delivery of high-dose radiotherapy, an increasing amount of convincing data suggests that the delivery of high-dose-per-fraction radiation through stereotactic radiosurgery (SRS) or stereotactic body radiation therapy (SBRT), also known as stereotactic ablative radiotherapy (SABR) can help to overcome resistance to radiotherapy. Herein, we summarized and analyzed the data from randomized controlled trials, retrospective and prospective studies, and meta-analyses relating to the treatment of advanced and metastatic RCC (mRCC) with CFRT, SBRT, or SBRT combined with systemic therapy. CFRT has a limited effect on local control (LC) of advanced RCC and mRCC, but it is a major palliative treatment which could obviously relieve pain caused by cancer. SBRT and SRS have the significant advantage of being able to precisely deliver a high dose of radiation to the target tissues. SBRT could cause a higher LC for advanced and metastatic RCC and could be used as an alternative to surgery for patients with oligometastatic RCC. The combination of SBRT with systemic therapy, such as targeted therapy or immunotherapy, is safe and tolerable. Concurrent immunotherapy and SBRT is a promising treatment strategy for patients with advanced or metastatic RCC. However, research on radiotherapy combined with systemic therapy is still limited and further studies to explore this treatment for RCC are urgently needed.

PO-1226: Safety and outcomes of concurrent immunotherapy and radiation therapy for melanoma brain metastases

PO-1226: Safety and outcomes of concurrent immunotherapy and radiation therapy for melanoma brain metastases

Quantitative Volumetric Tumor Response And Toxicity Outcomes In Patients Treated With Combination Stereotactic Radiosurgery (SRS) And Immunotherapy For Melanoma Brain Metastases

Stereotactic radiosurgery (SRS) confers excellent local control for melanoma brain metastases (MBM). Factors impacting the rate of volumetric regression in the follow-up period, including the nature and timing of systemic therapy, are poorly understood. This study examines the impact of systemic therapy on MRI volumetric tumor response over time of melanoma brain metastases following SRS. A retrospective analysis was performed of patients who received single-fraction Cobalt-based SRS for MBM from January 2016 to June 2019. Predictive factors relating to SRS dose, volume and systemic therapy treatment factors such type (CTLA-4, PD-1 and/or BRAF/MEK inhibitors) and timing were collected. Treatment volume of each lesion was delineated on a T1-weighted Gadolinium contrast enhanced MRI at baseline and follow-up. Cubic spline interpolation was used to impute missing data across time intervals. The primary outcome was relative volumetric change in T1-contrast enhancement at 3, 6, 9, 12- and 15-months relative to baseline. A repeated measures ANOVA was used to assess for differences in mean volumetric change between intervals. A linear mixed multivariate regression analysis was performed to assess the relationship between explanatory variables and volumetric change with a two-tailed significance of α = 0.05. 101 patients with 425 MBM were treated with SRS. Median follow-up was 29.2 months (IQR 19.7-39.8). Median dose, baseline volume and lesion diameter were 20Gy (IQR 18-20), 0.24cc (IQR 0.06-1.02) and 7.7mm (IQR 4.8-12.4). 53% of patients were BRAF mutant. 65% had failed BRAF inhibitors at time of SRS. 34% of patients received BRAF inhibitors concurrently (± 48 hours). 77% of patients received concurrent CTLA-4/PD-1 immunotherapy (2 weeks prior-4 weeks post-SRS). Median interpolated lesion size at 3, 6, 9, 12 and 15-month was 73.6%, 55.4%, 49.7%, 54.2% and 42.5% of baseline respectively. There was a statistically significant decrease in lesion size in the 0-3 and 3-6 month interval (p<0.001). Lesion regression stabilized after 6-months. 89.7% of treated lesions had durable local control on MRI at last follow-up. Patients receiving concurrent immunotherapy had a significantly greater regression in tumor volume at 3-months (37% superior [95% CI 6-68.1%, p = 0.02] and 6-months (48% superior [95% CI 7.4-89.5%, p = 0.02] compared to those commencing >4 weeks post SRS however lesion regression velocity was comparable by 9- and 12-months. A 1mm increase in maximal lesion diameter was associated with a 1.5% (95% CI 0.04-2.9, p = 0.04) and 2% (95% CI 0.4-3.7%, p = 0.016) greater reduction in volume at 3- and 6-months. 5% of patients experienced symptomatic radionecrosis (RN). 19% had non-RT grade 3 or higher toxicity. This study demonstrates a significantly greater volumetric regression with concurrent immunotherapy and SRS in MBM in the initial 6 months post SRS. Combined modality treatment offers excellent local control with low RN specific toxicity.

Concurrent Immunotherapy and Stereotactic Radiosurgery for Patients with Melanoma Brain Metastases is not Associated with Increased Risk of Brain Radionecrosis

Concurrent Immunotherapy and Stereotactic Radiosurgery for Patients with Melanoma Brain Metastases is not Associated with Increased Risk of Brain Radionecrosis

Optimal Management of Radiation Pneumonitis: Preliminary Findings of an International Delphi Consensus Study

Radiation pneumonitis (RP) is a dose-limiting toxicity for patients undergoing radiotherapy (RT) and systemic therapy for lung cancer; however, the optimal practice for diagnosis, management and follow-up remains unclear. We sought to establish expert consensus recommendations for RP management. Following literature review on RP, 9 open-ended questions related to knowledge, risk-reduction, diagnosis and treatment were generated for this first round of a consensus-building Delphi process. International leaders in multidisciplinary thoracic oncology were invited to participate (n = 31). Key statements regarding RP diagnosis and management were generated from responses to produce statements for Round 2. Participants will be solicited regarding agreement/disagreement with statements using a 5-point Likert scale. Subsequent rounds will seek consensus in areas that remain unresolved. For Round 1, a 74% response rate (n = 23; 12 radiation oncologists, 5 clinical oncologists, 6 respirologists) was achieved. Eighty-three percent of respondents were not aware of any guidelines for management of RP and 17% used local guidelines or expert review articles. Clinical history, exam and lab criteria (13 respondents) and imaging (15 respondents) were cited as used for diagnosis, and RTOG (9 respondents) and CTCAE grading (14 respondents) for assessment. Radiation-specific factors predictive of RP included irradiated lung volume (especially V20), dose, RT technique and location. The majority of clinical and radiation oncologists used motion management, image guidance and IMRT planning to achieve dosimetric constraints and minimize normal lung dose. Systemic therapy-related RP predictive factors included adjuvant or concurrent chemotherapy, immunotherapy (IO), and use of other pulmonotoxic medications. Patient-related predictive factors included lung function, autoimmune disease, age, performance status and smoking status. Majority of clinicians use risk stratification of patients in order to mitigate RP. Respondents uniformly agreed that steroid therapy is the mainstay of treatment for moderate to severe RP, with variability in the dosing and tapers used. A multidisciplinary management approach was favored by all, including radiation and medical oncologists, respirologists, thoracic radiologists and/or infectious disease or rheumatology specialists if indicated. The majority believe that IO will add complexity in identifying RP. Regarding additional measures to prevent RP in IO patients, respondents were split, with 50% taking additional measures and 50% not, though majority favored monitoring by oncologists during IO cycles and counseling patients on increased RP risk. Responses from international thoracic oncology experts highlight areas lacking consensus in the diagnosis and management of RP. These data will inform the next round of Delphi questions, with an aim of reaching consensus on this common issue.

Effects of Concurrent Stereotactic Radiosurgery and Immunotherapy on Intracranial Progression for Brain Metastases

Effects of Concurrent Stereotactic Radiosurgery and Immunotherapy on Intracranial Progression for Brain Metastases

Phase II Trial of Low-Dose Radiation for Metastases Progressing on Immunotherapy

To report initial response rates from an ongoing prospective phase II trial of salvage high-dose and low-dose radiation with concurrent immunotherapy for patients with disease progression on immunotherapy alone (NCT02710253). Eligible patients had progressive disease (PD) (metastases from any primary) during treatment with an immunotherapy agent. Based on disease burden and safety, patients were given both high-dose and low-dose irradiation, each to one or more unique lesions. High-dose radiation regimen ranged from 20 Gy in 5 fx to 70 Gy in 6 fx; low-dose was 4 to 8 Gy in 4-6 fx. Concurrent with radiation, patients received the immunotherapy they had previously progressed on (most often pembrolizumab, followed by atezolizumab, nivolumab, or ipilimumab with nivolumab). Radiographic response was assessed per the Immune-related Response Criteria. Baseline characteristics were analyzed for association with response via linear regression testing. At this analysis, 15 patients with 27 lesions treated with low-dose radiotherapy were evaluable. At a median follow-up time of 9 months, no low-dose treatment-related toxicity was noted. Primary tumors were non-small cell lung cancer (5), melanoma (4), head and neck (4), and thyroid (2). Lesions that received low-dose radiation were in the lung (12), lymph nodes (11), spleen (2), peritoneum (1), and liver (1). The average best response of lesions treated with low-dose radiation (at a median 5 months’ follow-up) was a 51% decrease in size; the combined complete and partial response rate (CR+PR) was 63%, and the clinical response rate [CR+PR+stable disease (SD)] was 96%. Responses were sustained, with an average 41% size reduction at last follow-up. Lesion response rates were CR 18.5%, PR 44.5%, SD 18.5%, and PD 18.5%. Patients with a confirmed CR or PR had a median duration of response of 6 months at last follow-up. The average decrease in overall systemic tumor burden was 45% at best response and 34% at last follow-up. In terms of systemic responses, 7 patients (47%) had a PR; an additional 5 patients (33%) had SD. Of the 3 patients with continuing progression at last follow-up, control of irradiated lesions (SD, PR, or CR) was achieved in 2. No significant differences in response rates were noted by primary cancer type, lesion location, immunotherapy agent, or low-dose regimen. Use of high-dose and low-dose radiation for disease that progressed on immunotherapy led to systemic responses outside the high-dose-treated lesions. Low-dose radiation represents a novel and potentially safe approach that should be tested further in clinical trials.