Concurrent Immunotherapy Research Articles

PO-1075 Results of Concurrent SBRT and Immunotherapy in Recurrent and Metastatic Head and Neck Cancer

PO-1075 Results of Concurrent SBRT and Immunotherapy in Recurrent and Metastatic Head and Neck Cancer

115P Concurrent versus sequential immune checkpoint inhibition in stage III NSCLC patients treated with chemoradiation

Maintenance treatment with durvalumab after completion of chemoradiotherapy (CRT) in PD-L1-positive patients with inoperable stage III NSCLC is the international standard therapy. Treatment intensification with concurrent immunotherapy is controversial discussed. In this prospective study, we evaluated the role of concurrent versus sequential immunotherapy in patients receiving platinum-based CRT for stage III NSCLC.

Stereotactic radiosurgery for melanoma brain metastases: Concurrent immune checkpoint inhibitor therapy associated with superior clinicoradiological response outcomes.

Introduction/purposeThis study assessed long‐term clinical and radiological outcomes following treatment with combination stereotactic radiosurgery (SRS) and immunotherapy (IT) for melanoma brain metastases (BM).MethodsA retrospective review was performed in a contemporary cohort of patients with melanoma BM at a single tertiary institution receiving Gamma Knife® SRS for melanoma BM. Multivariate Cox proportional‐hazards modelling was performed with a P <0.05 for significance.Results101 patients (435 melanoma BM) were treated with SRS between January‐2015 and June‐2019. 68.3% of patients received IT within 4 weeks of SRS (concurrent) and 31.7% received SRS alone or non‐concurrently with IT. Overall, BM local control rate was 87.1% after SRS. Median progression free survival was 8.7 months. Median follow‐up was 29.2 months. On multivariate analysis (MVA), patients receiving concurrent SRS‐IT maintained a higher chance of achieving a complete (CR) or partial response (PR) [HR 2.6 (95% CI: 1.2–5.5, P = 0.012)] and a reduced likelihood of progression of disease (PD) [HR 0.52 (95% CI: 0.16–0.60), P = 0.048]. Any increase in BM volume on the initial MRI 3 months after SRS predicted a lower likelihood of achieving long‐term CR or PR on MVA accounting for concurrent IT, BRAF status and dexamethasone use [HR = 0.048 (95% CI: 0.007–0.345, P = 0.0026)]. Stratified volumetric change demonstrated a sequential relationship with outcomes on Kaplan–Meier analysis.ConclusionConcurrent SRS‐IT has favourable clinical and radiological outcomes with respect to CR, PR and a reduced likelihood of PD. Changes in BM volume on the initial MRI 3 months after SRS were predictive of long‐term outcomes for treatment response.

Neoadjuvant immunotherapy in microsatellite stability or mismatch repair proficient colorectal cancer

Immunotherapy has become an important treatment option for microsatellite instability-high (MSI-H) and mismatch repair deficient (dMMR) colorectal cancer. From late-line to first-line treatment, and even in neoadjuvant setting for early stage colorectal cancer, promising efficacy was observed with immunotherapy. In microsatellite stability (MSS) or mismatch repair proficient (pMMR) colorectal cancer, the researches of neoadjuvant immunotherapy have been conducted constantly. This paper focuses on the recent researches and progress of neoadjuvant immunotherapy for MSS or pMMR colorectal cancer. Neoadjuvant immunotherapy alone led to a good pathological response in a subset of patients. Studies of induction or consolidation immunotherapy before or after neoadjuvant chemoradiotherapy or concurrent immunotherapy during radiotherapy showed higher pathological complete remission (pCR) rates as compared to standard chemoradiotherapy. Studies on sequential dual immunotherapy after radiochemotherapy and targeted therapy combined with neoadjuvant immunotherapy are ongoing. At present, most of these are pilot studies with small sample size. More researches and long-term follow-up are needed to prove the efficacy of neoadjuvant immunotherapy in MSS or pMMR colorectal cancer.

A phase I/II trial of concurrent immunotherapy with chemoradiation in locally advanced larynx cancer.

ObjectivesCisplatin‐based chemoradiation is an established organ‐preserving strategy for locally advanced laryngeal cancer, but long‐term survival remains suboptimal. Immunotherapy has been studied in the metastatic and unresectable recurrent settings. However, additional data are needed to assess its role in organ preservation for locally advanced laryngeal cancer.MethodsThis trial was an open‐label, single‐arm, multi‐institutional study with a Phase I run‐in portion followed by a planned Phase II component, which closed early due to low accrual. Study patients had Stage III or IV (T2–3; N0–3; M0) laryngeal squamous cell carcinoma and were candidates for larynx preservation. Pembrolizumab was given 2–3 weeks prior to chemoradiation and then, q21 days concurrently with high‐dose cisplatin and radiation prescribed to a total dose of 70 Gy. The primary endpoint of the trial was organ‐preservation rate (OPR) at 18 months.ResultsA total of nine patients were enrolled with a median follow‐up of 30.1 months. No patient required laryngectomy, resulting in 100% OPR at 18 months. The 12‐month overall survival (OS) rate was 77.8% and the median duration of OS was not reached. All acute Grade 4 (n = 3) toxicities occurred in a single patient with poorly controlled diabetes at baseline. One patient had late Grade 4 laryngeal edema requiring tracheostomy 8 months after chemoradiation, which self‐resolved.ConclusionUCCI‐HN‐15‐02 demonstrated the safety of the addition of immunotherapy to definitive chemoradiation and the patient outcomes suggest the potential for improving long‐term survival while minimizing negative impact from treatment. While results from this trial were promising, a randomized study with a larger number of patients and longer follow‐up is warranted to verify this treatment approach prior to wider adoption. NCT #: NCT02759575.Level of evidence: 2b

Long-term control of melanoma adrenal metastasis treated with radiotherapy.

Melanoma remains a large global burden with a significant proportion of patients succumbing to metastatic disease. The adrenal gland is a common area for metastasis with surgical treatment as the main modality. Radiotherapy is less utilised in this setting with uncertainty over deliverability and efficacy. Here, we present the details and outcomes of 20 patients treated with radiotherapy, with or without systemic therapy, for melanoma adrenal metastasis in a single institute. Twenty patients were identified from radiation treatment and medical records from between 2015 and 2019 at our institution. Three patients had bilateral radiotherapy treatments and therefore 23 adrenal lesions were analysed. Demographics, indications for treatment, radiotherapy methodology and outcomes were recorded. Outcomes were based on serial 18F FDG PET/computerized tomography scans reporting using the PERCIST criteria. The most common indication for radiotherapy was oligo-progressive disease (70%) followed by symptom palliation. Eight (35%) of the treatments were delivered by stereotactic ablative body radiotherapy. Twelve (60%) patients had concurrent immunotherapy. Twenty of twenty-three (87%) adrenal lesions had an initial response to treatment with 12 (60%) maintaining local control until death or end of follow-up. Median adrenal-specific progression-free survival was 13 months. Four patients (17%) required salvage adrenalectomy. Symptom palliation was achieved in the majority of patients for which it was indicated and there were no grade three toxicities. The median time from radiotherapy to change of immunotherapy treatment was 4 months. Radiotherapy for melanoma adrenal metastasis is effective and deliverable. With the majority of patients achieving a palliative and clinically relevant durable response, adrenalectomy can be reserved as a salvage option.

A single-arm, multicenter, phase II clinical study of tislelizumab plus albumin-bound paclitaxel/cisplatin as neoadjuvant therapy for borderline resectable esophageal squamous cell carcinoma.

BackgroundEsophageal cancer responds poorly to conventional radiotherapy, chemotherapy, and/or surgery. Immunotherapy works by boosting the body’s immune system, and preoperative immunotherapy combined with chemotherapy may increase the survival rate of patients with esophageal cancer. Here we further explore immunotherapy’s role in treating borderline resectable (BR) esophageal squamous cell carcinoma (ESCC) by combining immunotherapy with chemotherapy.MethodsIn this multicenter, randomized controlled study of preoperative immunotherapy plus chemotherapy for BR ESCC, immunotherapy plus chemotherapy [i.e., tislelizumab plus albumin-bound paclitaxel (ABP)/cisplatin] will be given according to the inclusion and exclusion criteria. Patients are to be observed and recorded for various indicators, the follow-up visits are standardized, and a database is to be established for the statistical analysis, with an attempt to clarify the value of preoperative immunotherapy plus chemotherapy in improving the survival of patients with BR ESCC. The primary endpoints are disease-free survival (DFS), major pathologic response (MPR), and pathologic complete response (pCR). The secondary endpoints include the objective response rate (ORR) and overall survival (OS) in subjects with PD-L1 expression levels of <1%, ≥1%, ≥20%, and ≥50%.DiscussionThe role of preoperative concurrent immunotherapy plus chemotherapy in improving the survival rates of patients with BR ESCC will be explored in this study. Given that the 5-year survival rate of BR ESCC is 10%, we hope that a reasonable immunotherapy plus chemotherapy regimen with higher efficacy and lower toxicity will further increase the pCR.Trial RegistrationChinese Clinical Trial Registry Identifier: ChiCTR2100051514.

Local control outcomes for combination of stereotactic radiosurgery and immunotherapy for non-small cell lung cancer brain metastases.

Previous series have demonstrated CNS activity for immune checkpoint inhibitors, yet no prior data exists regarding whether this activity can improve outcomes of stereotactic radiosurgery. In this single institution retrospective series, the clinical outcomes of 80 consecutive lung cancer patients treated with concurrent immune checkpoint inhibitors and stereotactic radiosurgery were compared to 235 in the historical control cohort in which patients were treated prior to immune checkpoint inhibition being standard upfront therapy. Overall survival was estimated using the Kaplan Meier method. Cumulative incidence of local progression was estimated using a competing risk model. Median overall survival time was improved in patients receiving upfront immunotherapy compared to the historical control group (40months vs 8months, p < 0.001). Factors affected overall survival include concurrent immunotherapy (HR 0.23, p < 0.0001) and KPS (HR 0.97, p = 0.0001). Cumulative incidence of local failure in the historical control group was 10% at 1year, compared to 1.1% at 1year in the concurrent immunotherapy group (p = 0.025). Factors affected local control included use of concurrent immunotherapy (HR 0.09, p = 0.012), and lowest margin dose delivered to a metastasis (HR 0.8, p = 0.0018). Local control and overall survival were both improved in patients receiving concurrent immune checkpoint inhibitors with radiosurgery compared to historical controls. While these data remain to be validated, they suggest that brain metastasis patients may benefit from concurrent use of immunotherapy with SRS.

Safety and efficacy of immunotherapy in combination with epigenetic therapy in an esophageal adenocarcinoma model.

335 Background: There is a critical need to develop effective therapeutic approaches for patients with esophageal cancer, a leading cause of cancer mortality. Recently, immune checkpoint blockade (ICB) has demonstrated modest survival benefit in gastroesophageal cancer patients. Epigenetic therapies, including DNA methyltransferases (DNMT) and histone deacetylases (HDACs), have shown to enhance tumor immune recognition by directly upregulating antigen presentation and by activation of type-1 interferon response triggered by cytoplasmic double-stranded RNA, a phenomenon known as viral mimicry. In other cancer models, epigenetic therapy has shown early promise by enhancing the effectiveness of ICB via addictive antiproliferative effects, enhanced immune activation and reversal of T cell exhaustion towards a memory-effector T-cell phenotypes. Methods: Esophagojejunostomy was performed to induce gastroduodenojejunal reflux in rats, leading to development of EAC. At 32 weeks postop, animals were randomized into eight treatment and control groups: placebo ± radiation, epigenetic treatment ± radiation, immunotherapy treatment ± radiation, and concurrent epigenetic and immunotherapy ± radiation. Animals underwent three 14 day cycles of epigenetic treatment or placebo. Each cycle consisted of one week of DNMT treatment or placebo at a dose of 0.5mg/kg, followed by one week of HDAC treatment or placebo at a dose of 2mg/kg. Animals received one 3mg/kg dose of PD1 inhibitor or placebo on day 12 of each cycle. Safety and efficacy were evaluated via objective health assessments, change in tumor volume, immunofluorescent labeling and RT-PCR. Results: Seventy of 74 randomized animals reached study end-point with no significant differences in mortality observed across groups (p = 0.556). There were no significant differences in observed health scores or weights between all groups (p = 0.431 and p = 0.882, respectively). Pre to posttreatment, mean MRI tumor volume increased by 263.1% and 90.9% in the placebo and the placebo plus radiation groups, respectively. The largest tumor reduction was observed in the concurrent treatment groups, 84.5% and 61.8% with and without radiation, respectively. Additionally, independent epigenetic and immunotherapy treatments with or without radiation also exhibited decrease in tumor volume, but to a lesser extent than the concurrent regimens (p = 0.005). Immunofluorescent labeling demonstrated a significant increase in CD3+ CD8+ T cells in all treatment groups compared to placebo (p = &lt; 0.001). Gene expression displayed upregulation of CD206 (p = 0.002), TNFα (p = &lt; 0.001), and Arg1 (p = &lt; 0.001) in treatment arms compared to placebo. Conclusions: This study establishes addictive antitumor efficacy and enhanced immune sensitization for a concurrently sequenced treatment, combining epigenetic therapy and radiation with immunotherapy, to treat EAC.

Senescence induction dictates response to chemo- and immunotherapy in preclinical models of ovarian cancer

High-grade serous ovarian carcinoma (HGSOC) is a cancer with dismal prognosis due to the limited effectiveness of existing chemo- and immunotherapies. To elucidate mechanisms mediating sensitivity or resistance to these therapies, we developed a fast and flexible autochthonous mouse model based on somatic introduction of HGSOC-associated genetic alterations into the ovary of immunocompetent mice using tissue electroporation. Tumors arising in these mice recapitulate the metastatic patterns and histological, molecular, and treatment response features of the human disease. By leveraging these models, we show that the ability to undergo senescence underlies the clinically observed increase in sensitivity of homologous recombination (HR)-deficient HGSOC tumors to platinum-based chemotherapy. Further, cGas/STING-mediated activation of a restricted senescence-associated secretory phenotype (SASP) was sufficient to induce immune infiltration and sensitize HR-deficient tumors to immune checkpoint blockade. In sum, our study identifies senescence propensity as a predictor of therapy response and defines a limited SASP profile that appears sufficient to confer added vulnerability to concurrent immunotherapy and, more broadly, provides a blueprint for the implementation of electroporation-based mouse models to reveal mechanisms of oncogenesis and therapy response in HGSOC.

Systemic and Radiation Therapy Approaches for Locally Advanced Non-Small-Cell Lung Cancer.

The treatment for locally advanced non-small-cell lung cancer has changed dramatically over the past several years, with consolidative immunotherapy after concurrent chemoradiation becoming the new standard of care. Five-year survival outcomes have substantially improved with this approach. Despite these advances, further improvements are needed as the majority of patients ultimately develop progression of disease. The next-generation immunotherapy trials are currently being conducted that include approaches such as concurrent immunotherapy and addition of other therapeutic agents in the concurrent and consolidative settings. Specific unmet needs continue to exist for patients who develop disease progression after concurrent chemoradiation and immunotherapy, as well as defining the best treatment for patients with driver mutations. Future directions also include refinement of radiation techniques to reduce toxicities as much as possible, as well as the use of circulating tumor DNA in the surveillance setting. The current scientific landscape shows promising approaches that may further improve outcomes for patients with locally advanced non-small-cell lung cancer.

Microenvironment-driven intratumoral heterogeneity in head and neck cancers: clinical challenges and opportunities for precision medicine.

Squamous cell carcinoma of the head and neck (SCCHN) is among the most prevalent cancer types worldwide. Despite multimodal therapeutic approaches that include surgical resection, radiation therapy or concurrent chemoradiation, targeted therapy and immunotherapy, SCCHN is still associated with a poor prognosis for patients with locally advanced or recurrent/metastatic (R/M) diseases. Although next-generation sequencing data from thousands of SCCHN patients have provided a comprehensive landscape of the somatic genomic alterations in this disease, genomic-based precision medicine is not implemented yet in routine clinical use since no satisfactory genetic biomarker has been identified for diagnosis, patient outcome prediction and selection of tailored therapeutic options. The lack of significant improvement in SCCHN patient survival over the last decades stresses the need for reliable predictive biomarkers and new therapeutic strategies for personalized clinical management of SCCHN patients. Targeting the SCCHN-associated microenvironment or the interaction of the latter with cancer cells may represent such paradigm shift in the development of new strategies to treat SCCHN patients, as exemplified by the recent implementation of immune checkpoint inhibitors to improve clinical outcomes by increasing anti-tumor immune responses in SCCHN patients. Several clinical trials are in progress in SCCHN patients to evaluate the activity of monoclonal antibodies and small-molecule inhibitors targeting the tumor microenvironment (TME) at different treatment settings, including combinations with adjuvant surgery, radiation therapy and chemotherapy. This review describes the current knowledge about the influence of the TME on intratumoral heterogeneity and clinical relapse in human SCCHN patients. More precisely, the role of hypoxia as well as the presence of non-cancer cells (e.g. cancer-associated fibroblasts and immune cells) on therapy response of SCCHN cells is highlighted. We also discuss relevant (pre)clinical models that may help integrate the microenvironment-tumor cell interplay in translational research studies for SCCHN. Finally, this review explores potential therapeutic strategies that may exploit the crosstalk between TME and SCCHN cells in order to implement fundamental changes in the tumor treatment paradigm of patients with locally advanced or R/M SCCHN.

Clinical Correlates of Rhinovirus Infection in Preschool Asthma

Asthma is a common chronic disease of childhood in developed countries causing significant burden on public health. Rhinovirus is one of the most commonly identified triggers for wheezing episodes in preschool-aged children. In this study, researchers identified characteristics of children with preschool asthma associated with susceptibility to rhinovirus infections. The authors also investigated whether rhinovirus infections were associated with a more acute clinical course of asthma exacerbation and if rhinovirus infections were associated with a more compromised 12-month asthma course.A total of 130 children aged 4 to 6 years and who have a gestational age of at least 36 weeks. They had to have a diagnosis of mild-to-moderate persistent asthma by using Global Initiative for Asthma (GINA) criteria within the last 2 years. Patients were recruited from 5 centers in Europe. Subjects had to be asymptomatic for at least 4 to 6 weeks at baseline. Exclusion criteria included severe persistent asthma, concurrent immunotherapy treatment, and nonatopic chronic disease.A standardized questionnaire on symptoms of asthma, rhinitis, eczema, infections, immunizations, environmental factors, and family history was completed at study entry. Baseline blood tests and nasopharyngeal swab samples were obtained. Daily medication and symptom diary was recorded. Subjects had 6-month follow-up visits for 2 years to review symptoms of asthma and rhinitis and collect nasopharyngeal samples. Guardians contacted the study center if subjects developed signs of a respiratory tract infection, had an exacerbation of asthma, had a noted decrease in forced expiratory volume in 1 second of >15% or peak flow of >30%, or had increase in symptom scores on diary of ≥4. A clinic visit was then scheduled to obtain a nasopharyngeal sample to identify respiratory pathogens.Among 130 study subjects, 62% were boys, 55% had aeroallergen sensitization, 38% had active atopic dermatitis, and 38% had vitamin D supplementation. A total of 59% had mild persistent asthma, 25% intermittent asthma, and 83% had peak expiratory flows in the normal range. Of 571 visits, 54% were positive for any virus, and rhinovirus was detected in 39% of visits. Patient characteristics were only assessed with rhinovirus because of the low number of other respiratory viruses. The use of supplemental vitamin D was inversely associated with rhinovirus infection (P < .05). Rhinovirus was associated with more acute illness, including prolonged runny nose, severe night cough, and more sleep disturbance (all P < .05). Rhinovirus infection was also analyzed for its impact on asthma activity for the following year. Rhinovirus infection was associated with an increase in asthma activity, with more night awakenings and more days of exercise triggered symptoms (P < .05). Increased rhinitis activity was also noted in the 12-months follow-up.Rhinovirus infection has both acute and long-term impact on preschool asthma stability. Vitamin D supplementation appears to modify rhinovirus infection and may have a protective effect against infection.Rhinovirus infection has been a well-known trigger for asthma exacerbation, and the findings in this study are not surprising. Increasing asthma severity was noted for acute rhinovirus infection as well as for the 12-month period after rhinovirus infection. If vitamin D supplementation is truly protective against rhinovirus infection, than it may also have an impact on long-term control of childhood asthma. Controlled trials are required to confirm this prospective observation.

NIMG-06. 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. PATIENTS 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). CONCLUSIONS FET PET has a high diagnostic accuracy for characterizing the long-term changes of irradiated brain metastases.

Loco-Regional Control and Survival Outcomes After Combined Stereotactic Radiation Therapy and Immune Checkpoint Inhibitors for Brain Metastases From Non-Small Cell Lung Cancer

Over the past decade, improvements in the management of advanced non-small-cell lung cancer (NSCLC) through immunotherapy (IT) with PD-1 pathway inhibitors have been significant, with a major improvement in progression-free survival (PFS) and overall survival (OS). Nevertheless, brain metastases (BM) remain frequent at the time of diagnosis (10%) or during the disease (40%). Stereotactic radiation therapy (SRT) has demonstrated its interest in patients with BM from NSCLC, allowing a clear decrease in neurological toxicity compared to that induced by whole brain RT, without loss of OS. The purpose of this study was to analyze locoregional control (LRC), OS, and neurological toxicity in patients with BM from NSCLC treated with IT and SRT and propose the best possible therapeutic sequence between these two treatments.We retrospectively analyzed NSCLC patients' data with BM treated with IT and SRT within six months between 2015 and 2019. The treated lesions were categorized into the following three groups: "SRT before IT,'' "concurrent SRT and IT," and "SRT after IT.'' "Concurrent" was defined as IT within one month of SRT. Regional progression was defined as the progression or apparition of a BM outside an irradiated area. Regional progression-free interval (R-PFI), OS, and local progression-free interval (L-PFI) were estimated using Kaplan-Meier method and compared using the log-rank test.Fifty-one patients with 84 BM received SRT and IT. The patients were mostly men (60.8%) and WHO 1 (56.9%). For SRT, most lesions were treated with either 15 to 21 Gy in a single fraction (56.0%); or with 18 to 27 Gy in three fractions (41.8%). For IT, patients were treated with Nivolumab (47.1%), Pembrolizumab (33.3%), Durvalumab (15.7%), or Atezolizumab (3.9%) for a median duration of 4.9 months. Among lesions, 76 (90.5%) were intact, and eight (9.5%) were previously resected. The median follow-up from SRT was 22.5 months (2.7-47.3). Six- months and 1-year R-PFI in "SRT before IT" group, "concurrent SRT and IT" group, and "SRT after IT" group were 24.1% and 24.1% vs 56.3% and 49.6% vs 41.0% and 34,2% respectively, (P = 0.094). Although no significant difference has been observed in R-PFI, there was a trend in better regional control of BM from NSCLC in the ''concurrent SRT and IT" group. One-year OS was 67.5% vs 70.2% vs 69.2%, respectively (P = 0.44). One- year L-PFI was 70.1% vs 78.9% vs 77.8%, respectively (P = 0.79). There was no difference in toxicity between the three groups regarding radionecrosis or acute neurological toxicity.Regional control of BM from NSCLC seems to be better in the ''concurrent SRT and IT" group without an increase in acute neurological toxicity or radionecrosis rate. These results may lead to prospective studies on larger cohorts.J. Porte: None. C. Saint Martin: None. T. Frederic Moreau: None. M. Massiani: None. E. Jadaud: None. J. Otz: None. P. Verrelle: None. N. Girard: None. G. Crehange: None. A. Beddok: None.

Concurrent Immunotherapy With Chemoradiation for Definitive Management of Locally Advanced Laryngeal Cancer: A Prospective Trial

<h3>Purpose/Objective(s)</h3> Cisplatin-based chemoradiation is an established organ-preserving strategy for locally advanced laryngeal squamous cell carcinoma, but long-term survival remains suboptimal, warranting an improved approach. Immunotherapy has been studied in the metastatic and unresectable recurrent setting, but additional data are needed to assess its role in definitive therapy. The study hypothesis was that the use of immunotherapy in conjunction with chemoradiation would be safe and result in improved laryngectomy-free survival (LFS) compared to standard of care chemoradiation. <h3>Materials/Methods</h3> This trial was an open-label, single-arm, prospective, multi-institutional study. The study included a Phase I run-in portion to assess safety in the first 6 enrolled patients and a planned subsequent Phase II component. Due to slow accrual, the study was closed after enrollment of 9 patients and the data were allowed to mature. The primary endpoint of the Phase II portion was LFS at 18 months. Study patients had Stage III or IV (T1-3; N0-3; M0) laryngeal squamous cell carcinoma and were candidates for larynx preservation. Pembrolizumab was given as a 200 mg flat dose 3 weeks prior to the start of chemoradiation and was then given q21 days until the completion of chemoradiation. Cisplatin was given at a dose of 100 mg/m² q21 days during radiation with allowed dose modifications for toxicities. Radiation was prescribed to a total dose of 70 Gy in 35 daily fractions using IMRT with an elective nodal dose of 56-63 Gy. <h3>Results</h3> A total of 9 patients with a median age of 54 were enrolled from 2017 to 2019. The median follow-up time was 30.1 months. None of the enrolled patients required laryngectomy, resulting in 100% LFS at 18 months for evaluable patients. The 18-month overall survival (OS) rate was 66.7%; of the 3 patient deaths, 2 were due to co-morbid conditions (diabetes, peripheral arterial disease) rather than malignancy. The remaining 6 patients were alive at the time of last follow-up and the median duration of OS was not reached. There were 27 Grade 3 toxicities, with 2 attributable to pembrolizumab. Nearly all Grade 4 (n = 4) and Grade 5 (n = 1) toxicities occurred in a single patient with poorly-controlled diabetes; the Grade 5 toxicity was due to diabetic ketoacidosis. One patient had late Grade 4 laryngeal edema requiring tracheostomy 8 months after chemoradiation; the edema has since resolved and the tracheostomy was reversed. <h3>Conclusion</h3> The use of concurrent pembrolizumab with chemoradiation for locally advanced larynx cancer resulted in high LFS. Most toxicities were attributable to chemoradiation and the majority of Grade 4 and 5 toxicities occurred in a patient with poorly-controlled diabetes. A case of late Grade 4 laryngeal edema could have been related to immunotherapy. Future studies with concurrent immunotherapy with chemoradiation should account for this possibility.

PD-L1 Expression Level of Primary Tumor as a Predictor of Local Control and Symptomatic Radiation Necrosis in Patients With Brain Metastases Undergoing SRS/fSRT With Concurrent Immunotherapy

PD-L1 is often overexpressed in the tumor microenvironment to dampen host immune response and allow tumor proliferation. Radiation works partially through the immune system, but the correlation between PD-L1 expression in primary tumors and oncologic outcomes for metastatic lesions treated with SRS with concurrent immunotherapy (ICI) is unknown. We seek to evaluate the association of PD-L1 expression level of the primary tumor in patients undergoing SRS/fSRT with local control and symptomatic radiation necrosis.A total of 282 patients with 616 metastatic brain lesions which were treated with SRS or fSRT from 2014-2020 were retrospectively reviewed at a single institution. PD-L1 expression level in the primary tumor was available for 43 patients with 147 metastatic brain lesions, of whom 33 patients with 103 lesions received concurrent ICI. Concurrent ICI was defined as having received ICI within 3 months before, during, or after SRS. PD-L1 expression was categorized as negative (PDn) (< 1%), or positive (PDp) (≥1% - 100%). Patients were excluded if a one month post-treatment MRI was not available or if > 15 lesions were treated. The lesion level endpoint of local failure (LF) and symptomatic radiation necrosis (RN) were analyzed using Kaplan Meyer method with salvage WBRT used as a censoring event. Univariate and multivariate analysis were performed with competing risk adjustment.One-hundred and four lesions (range 1-10) from 33 unique patients were included in the analysis. Ten patients with PDn primary tumors with 31 lesions and 23 patients with PDp primary tumors with 73 lesions were analyzed. After competing risk adjustment, the LF rate at 12 months were rare for both patient cohorts: PDn vs PDp was 3.5% and 1.5% (P = 0.99), respectively. For RN, the event rate at 12 months for PDn vs PDp was 4% vs 14% (HR 0.648; 95% CI 0.05-9.03; P = 0.747). On MVA for local control, factors such as metastasis size (< 2cm vs ≥2 cm; P = 0.181), histology (NSCLC vs other; P = 0.997), or lesion location (supratentorial vs other; P = 0.392) were not found to have a statistically significant association. On MVA for RN, only metastasis size reached statistical significance (HR 32.8; 95% CI 3.56-301.81; P < 0.002).Patients receiving concurrent ICI and SRS for management of brain metastases have an excellent local control, irrespective of PD-L1 status. PD-L1 positive patients may be at an increased risk for RN. These findings require further evaluation in a larger patient cohort.G.S. Alexander: None. B.Savla: None. L.J. Berg: None. K. Sun: None. J.S.Remick: None. E.S. Kowalski: None. S. Chen: None. N.Lamichhane: None. W.F. Regine: None. M.V. Mishra: Employee; Orthofix. Research Grant; ASTRO, Keep Punching. Advisory Board; Patient Centers Outcomes Research Institute (PCORI. Travel Expenses; Patient Centers Outcomes Research Institute (PCORI.

Concurrent Immunotherapy With Stereotactic Radiation for Brain Metastases is Not Associated With Increased Rates of Radionecrosis

Early concerns were raised about higher rates of radionecrosis (RN) with concurrent use of immune checkpoint inhibition (ICI) and stereotactic radiotherapy (SRT) for brain metastases (BM). We sought to clarify if this same concern translated to linear accelerator-based SRT for BM.We retrospectively reviewed cases of SRT delivered at a single institution for BM (2004-2019). In total, 251 patients and 723 courses of treatment were analyzed on a per-treatment basis for any grade RN. RN was graded by CTCAE v5 and defined as an enlarging lesion after SRT that resolved spontaneously, resolved with steroids, or was surgically resected and found to have no viable tumor. Differences were assessed with Chi-squared, Kaplan-Meier, and univariable/multivariable Cox regression analyses with candidate variables including timing of ICI with SRT (neoadjuvant, concurrent defined as within 3 months, or adjuvant), primary histology, and symptomatic vs not at time of BM diagnosis, among others.In total, 251 patients received SRT for BM: 53 without ICI, 58 neoadjuvant ICI, 102 concurrent ICI, and 38 adjuvant ICI. Median follow up for the surviving patients who received any ICI was 24.0 months (IQR 7.6-41.4) and not different from those without ICI at 26.8 months (IQR 8.8-45.6) (P = 0.22) with 38% of patients alive at last follow up. Analyzed by timing of ICI at the patient level, those not receiving ICI were more likely to have a diagnosis of breast or other cancers as compared to melanoma, lung, and kidney primaries that were more common with ICI (P < 0.01). This is likely due to the longer historical use of ICI in these malignancies. The overall rates of Grade 1-3 RN were 4.0%, 4.6%, and 2.2% (no Grade 4+ events). Median time to RN was 11.4 months (IQR 6.0-22.5). Analyzed by timing of ICI on a per-treatment basis, there was no difference among rates of any grade RN for no (13.5%), neoadjuvant (9.8%), concurrent (8.5%), and adjuvant ICI (14.1%) (P = 0.052). On univariable analysis, primary histology, performance status, SRT fractionation, and metastasis diameter were significantly associated with time to RN (all P < 0.05). Time to RN did not vary among treatment courses with neoadjuvant, concurrent, adjuvant, or no ICI (P = 0.72). On multivariable analysis, once histology and SRT fractionation were included, only a performance status of ECOG 0 (HR 0.43 CI 0.23-0.81) and increasing diameter (HR 1.58 CI 1.24-2.03) remained significant (both P < 0.01).In this large single-institution study of linear accelerator-based SRT, consistent with previous reports, we found that lesion diameter positively correlated with risk of RN. However, there was not an increased risk of RN in patients who received ICI. On subset analysis, there was no association of RN with ICI timing - including with concurrent administration. These data suggest that linear accelerator-based SRT is safe to combine with ICI.S.G. Allen: Employee; University of Michigan Mott Children's Hospital. J.J. Waninger: None. S.R. Birer: None. S. Journey: None. J. Skvarce: None. D.R. Wahl: Research Grant; Agios Inc, Innocrin Inc, American Cancer Society, NIH. Stock Options; Lycera Inc. Advisory Board Member; Agios Inc. T.S. Lawrence: None. J.A. Hayman: Research Grant; Blue Cross Blue Shield of Michigan. M.M. Kim: Research Grant; Blue Earth Diagnostics.; Red Journal. Site PI of ongoing CCTG CE.7, N0577, A071801, and NCI 9979 trials; NCTN (Alliance, NRG, CCTG) and ETCTN.M. Green: None.

Head and Neck Stereotactic Body Radiation Therapy Re-Irradiation for Patients With Carotid or Skin Involvement Ineligible for RTOG 3507

Patients with recurrent head and neck squamous cell carcinoma (HNSCC) who present with carotid encasement (CE) > 180˚, skin involvement and/or require bolus are not eligible for SBRT per RTOG 3507. The objective of this study was to characterize our institutional experience of SBRT for patients ineligible for RTOG 3507.Patients with recurrent HNSCC treated with SBRT from 2010-2020 with a history of prior radiation were extracted from an IRB approved database. Patients were evaluated based on CE > 180˚ or ≤180˚ and if there was skin involvement and/or use of bolus. The primary outcome was incidence of treatment related carotid bleeding event (CBE) and skin toxicity after SBRT in the absence of disease.Thirty-one patients were treated with SBRT to 37 sites with a median follow up of 8 months (mo) (range 2-47). The median time from prior radiation to SBRT was 13 mo (range 2-257). SBRT fractionation included 35 Gy (13%), 40 Gy (57%), and 45 Gy (30%) in 5 fractions. SBRT was delivered every other day (76%) or 2 fractions (24%) per week. Concurrent immunotherapy was given in 11% and cetuximab in 8%. A total of 30% (N = 11) of sites treated exhibited CE > 180˚ and 70% (N = 26) ≤180˚. There were no CBE related to SBRT, however 18% (N = 2) of patients with CE > 180˚ experienced fatal CBE related to progressive disease at 2.3 mo and 7.6 mo from SBRT. The risk of CBE was potentially related to CE > 180˚ (P = 0.08). Skin involvement and/or use of bolus was present in 43% (N = 16) of sites treated and absent in 57% (N = 21). The rate of treatment related skin toxicity was 19% (N = 3) and only occurred in those with pre-SBRT skin involvement and/or use of bolus. The cumulative incidence of treatment related skin toxicity at 3 mo and 6 mo was 13% (95% CI 1.9-33.6) and 27% (95% CI 4.0-58.8), respectively. Of the 3 treatment related skin toxicities there was one each of grade 2, 3, and 5. Grade 5 toxicity was related to untreated SBRT wound infection as the patient transitioned to hospice. The risk of treatment related skin toxicity was possibly related to pre-SBRT skin involvement and/or use of bolus (P = 0.007). Of the 13 sites with pre-SBRT skin involvement, 31% (N = 4) completely resolved, 54% (N = 7) had residual ulceration attributed to disease, and 15% (N = 2) had ulceration related to SBRT toxicity. The cumulative incidence of local failure at site of SBRT at 3 mo and 6 mo was 13% (95% CI 4-27.3) and 38% (95% CI 20.5-55.9), respectively. The median time of local and regional recurrence free survival were 7 and 5.5 mo, respectively. Median OS was 8 mo and the estimated 1-year OS was 25% (95% CI 9.9-40.9).The risk of toxicity following SBRT for patients with > 180˚ CE, skin involvement and/or use of bolus appears to be largely related to persistent or recurrent disease. There were no CBE related to SBRT in the absence of disease and 31% of patients with pre-SBRT skin involvement exhibited complete healing after SBRT. Consideration of SBRT may still be beneficial for such patients with appropriate counselling.

Quantitate Image Responses in High Risk p16+ Oropharyngeal Cancer Patients Treated With Definitive ChemoRT and Concurrent Nivolumab Compared to ChemoRT Alone

Biomarkers of immunotherapy response are increasingly important in oropharyngeal cancer with the rapid expansion of treatment in the R/M population and many ongoing upfront trials. CPS score is the most commonly used method to quantify immune infiltration and predict response to immunotherapy, although limited by its static nature and sampling error. Previous studies show that pre-RT to mid-treatment changes in MRI-derived blood volume (BV) and apparent diffusion coefficient (ADC) as well as FDG-PET derived metabolic tumor volume (MTV) and total lesion glycolysis (TLG) serve as imaging markers for pattern failure of HNC treated by CRT. The goal of this study is to evaluate changes in image metrics during concurrent immunotherapy and CRT compared to those from CRT.MRI and FDG-PET scans were acquired pre- and mid-treatment (fx 10) from 75 patients with high risk p16+ OPSCC (AJCC stage 3 or "matted nodes") who were treated with definitive concurrent CRT on 2 prospective institutional trials. The patients included: 1) the first 15 patients treated with definitive CRT 70Gy/concurrent carboplatin/taxol and concurrent nivolumab (iCRT) and 2) 60 patients treated with 70-80Gy/concurrent weekly cisplatin/carboplatin (CRT). Changes in quantitative image metrics from pre- to mid-treatment of primary tumors and individual lymph nodes were evaluated: gross tumor volume (GTV), MTV at 50% max SUV, TLG, mean SUV, mean BV and ADC between the two treatment groups using unpaired t test.Clinical characteristics and baseline quantitative image metrics were similar between CRT and iCRT groups, except the iCRT group had a lower BV value of primary tumors and a greater MTV of nodal tumors than CRT group (P = 0.05). However, at mid-treatment, iCRT patients had: 1) significantly greater increases in mean BV and ADC of primary tumors than CRT patients (49% vs. 23% and 21% vs. 12%, P < 0.007 and 0.03, respectively); but 2) less decreases in MTV, TLG and mean SUV of primary tumors than CRT patients, for which 11% of the TLG decrease was significantly different from 43% decrease of CRT group (P < 0.05); and 3) 12% decrease in mean SUV of nodal tumors that was significantly less than 25% in CRT group (P < 0.0001). With a mean follow-up of 11 months in the iCRT group, there has been only 1 DM in a patient with persistent low BV in the primary tumor, consistent with our previous findings in CRT patients.This analysis suggests that high risk p16+ OPSCC patients treated with iCRT had larger increases in BV and ADC and a smaller decrease in TLG in primary tumors mid-treatment compared to CRT group. Increases in BV and ADC have been identified to be associated with improved tumor control by previous studies of CRT. The minimal reduction of FDG metrics of iCRT group may be due to inflammatory response to anti-PD1. These findings warrant further investigation as predictive biomarkers for iCRT response to treatment.