A Prospective Study Assessing the Efficacy and Toxicity of Stereotactic Body Radiation Therapy for Oligometastatic Bone Metastases.

Purpose: Stereotactic body radiation therapy (SBRT) is a promising treatment for oligometastatic disease in bone because of its delivery of high dose to target tissue and minimal dose to surrounding tissue. The purpose of this study is to assess the efficacy and toxicity of this treatment in patients with previously unirradiated oligometastatic bony disease. Methods and Materials: In this prospective phase II trial, patients with oligometastatic bone disease, defined as ≤3 active sites of disease, were treated with SBRT at Brigham and Women's Hospital/Dana Farber Cancer Center and Beth Israel Deaconess Medical Center between December 2016 and May 2019. SBRT dose and fractionation regimen were not protocol mandated. Local progression-free survival, progression-free survival, prostatic specific antigen progression, and overall survival were reported. Treatment-related toxicity was also reported. Results: A total of 98 patients and 126 lesions arising from various tumor histologies were included in this study. The median age of patients enrolled was 72.8 years (80.6% male, 19.4% female). Median follow-up was 26.7 months. The most common histology was prostate cancer (68.4%, 67/98). The most common dose prescriptions were 27/30 Gy in 3 fractions (27.0%, 34/126), 30 Gy in 5 fractions (16.7%, 21/126), or 30/35 Gy in 5 fractions (16.7%, 21/126). Multiple doses per treatment regimen reflect dose painting employing the lower dose to the clinical target volume and higher dose to the gross tumor volume. Four patients (4.1%, 4/98) experienced local progression at 1 site for each patient (3.2%, 4/126). Among the entire cohort, 2-year local progression-free survival (including death without local progression) was 84.8%, 2-year progression-free survival (including deaths as well as local, distant, and prostatic specific antigen progression) was 47.5%, and 2-year overall survival was 87.3%. Twenty-six patients (26.5%, 26/98) developed treatment-related toxicities. Conclusions: Our study supports existing literature in showing that SBRT is effective and tolerable in patients with oligometastatic bone disease. Larger phase III trials are necessary and reasonable to determine long-term efficacy and toxicities.

Tissue-resident memory and circulating T cells are early responders to pre-surgical cancer immunotherapy.

Neoadjuvant immune checkpoint blockade has shown promising clinical activity. Here, we characterized early kinetics in tumor-infiltrating and circulating immune cells in oral cancer patients treated with neoadjuvant anti-PD-1 or anti-PD-1/CTLA-4 in a clinical trial (NCT02919683). Tumor-infiltrating CD8 T cells that clonally expanded during immunotherapy expressed elevated tissue-resident memory and cytotoxicity programs, which were already active prior to therapy, supporting the capacity for rapid response. Systematic target discovery revealed that treatment-expanded tumor T cell clones in responding patients recognized several self-antigens, including the cancer-specific antigen MAGEA1. Treatment also induced a systemic immune response characterized by expansion of activated T cells enriched for tumor-infiltrating T cell clonotypes, including both pre-existing and emergent clonotypes undetectable prior to therapy. The frequency of activated blood CD8 T cells, notably pre-treatment PD-1-positive KLRG1-negative T cells, was strongly associated with intra-tumoral pathological response. These results demonstrate how neoadjuvant checkpoint blockade induces local and systemic tumor immunity.

Retrospective Review of Outcomes After Radiation Therapy for Oligoprogressive Disease on Immune Checkpoint Blockade.

PURPOSE: We retrospectively evaluated outcomes after radiation therapy for patients with oligoprogression on immune checkpoint inhibitors (ICI). METHODS AND MATERIALS: We identified patients irradiated to ≤5 progressive lesions while receiving ICI between 2010 and 2020. We excluded patients whose systemic therapy was switched after radiation but before progression. We evaluated predictors of local control (LC), progression-free survival (PFS) and overall survival (OS). RESULTS: We screened 1423 patients and identified 120 who were eligible; the most common histologies were lung cancer (n = 59) and melanoma (n = 36). The median number of oligoprogressive lesions was 1. For the median LC of irradiated oligoprogressive lesions, PFS and OS were not reached at 6.41 (4.67-7.66) and 29.80 (22.54-43.33) months, respectively. Tumor histology, radiated site, or radiation modality were not associated with LC, PFS, or OS. Local response to radiation (P < .0001) and radiation of newly developed lesions (P = .02) were associated with LC. Predictors of PFS on univariate and multivariate analyses were best response to radiation (P = .006) and high programmed death ligand 1 tumor proportion score (P = .02). On multivariate analyses, OS was associated with cumulative oligoprogressive lesion volumes (P = .02) and duration of ICI before oligoprogression (P = .03). CONCLUSIONS: Promising outcomes were observed among patients irradiated for oligoprogression on ICI, especially those with a favorable local response, high tumor programmed death ligand 1 expression, and those receiving ICI for longer periods before oligoprogression. These data can help identify patients well suited for radiation therapy versus those who should switch systemic treatment.

Association between radiation dose to organs at risk and acute patient reported outcome during radiation treatment for head and neck cancers.

BACKGROUND: Associations between patient-reported outcomes and dose to organs at risk (OARs) may promote management and guide future investigations. METHODS: We retrospectively evaluated PROs and OAR dose in head and neck (H&N) cancer. RESULTS: In 169 patients, we identified weak associations between: "Difficulty swallowing/chewing" and increased mean RT dose to the oral cavity, larynx, pharyngeal constrictor muscles (PCM) and contralateral parotid; "choking/coughing" and larynx mean dose; "problems with mucus in mouth and throat" and oral cavity, contralateral parotid mean dose and parotid V30, contralateral submandibular gland and PCM mean dose; "difficulty with voice/speech" and oral cavity, contralateral parotid, contralateral submandibular gland and larynx mean dose; and "dry mouth" and ipsilateral submandibular gland, oral cavity and PCM mean dose. CONCLUSION: We identified weak associations between PRO and dose to OARs-these data can guide on treatment management, patient counseling, and serve as a baseline for future investigations.

Dosimetric Modeling of Lymphopenia in Patients With Metastatic Cancer Receiving Palliative Radiation and PD-1 Immune Checkpoint Inhibitors.

PURPOSE: Radiation therapy (RT)-associated lymphopenia may adversely affect treatment outcomes, particularly in the era of immunotherapy. We sought to determine dosimetric factors correlated with lymphopenia after palliative RT in a cohort of patients with advanced cancer treated with anti-PD-1 immune checkpoint inhibitors. METHODS AND MATERIALS: We included patients with metastatic lung cancer, melanoma, or renal cell carcinoma who were treated with either pembrolizumab or nivolumab and received palliative RT to an extracranial site. Baseline and nadir absolute lymphocyte counts (ALCs) within 6 weeks of RT were recorded. Dosimetric factors were extracted from the corresponding dose-volume histograms and also used to model the dose to circulating lymphocytes via a whole-body blood flow model that simulates the spatiotemporal distribution of blood particles in major organs during RT. RESULTS: We analyzed 55 patients who underwent 80 total courses of palliative RT; most (94%) were treated with 3-dimensional conformal RT. Doses to the whole body, bone, and large blood vessels (LBVs) were negatively correlated with the ALC nadir, with the strongest correlations seen at V15 (rs, -0.38, -0.43, and -0.37, and P = .0004, .0001, and .0008, respectively). Doses to other organs were not significantly correlated with the ALC nadir. The modeled dose to circulating lymphocytes was also negatively correlated with the ALC nadir and percent ALC change (for D2%, rs, -0.31 and -0.44, and P = .005 and .0001, respectively). Grade ≥3 lymphopenia was associated with LBV V15 (odds ratio [OR], 1.16; 95% CI, 1.07-1.26; P < .001), bone V15 (OR, 1.04; 95% CI, 1.01-1.08; P = .03), body V15 (OR, 1.003; 95% CI, 1.001-1.006; P = .008), and modeled lymphocyte dose (OR, 1.45; 95% CI, 1.16-1.82; P < .001). CONCLUSIONS: The RT dose to the whole body, bone, and LBVs and the modeled dose to circulating lymphocytes were correlated with lymphopenia in patients treated with palliative RT and anti-PD-1 immune checkpoint inhibitors. These findings may inform future radiation planning in this setting.

Durvalumab plus tremelimumab alone or in combination with low-dose or hypofractionated radiotherapy in metastatic non-small-cell lung cancer refractory to previous PD(L)-1 therapy: an open-label, multicentre, randomised, phase 2 trial.

BACKGROUND: Patients with non-small-cell lung cancer (NSCLC) that is resistant to PD-1 and PD-L1 (PD[L]-1)-targeted therapy have poor outcomes. Studies suggest that radiotherapy could enhance antitumour immunity. Therefore, we investigated the potential benefit of PD-L1 (durvalumab) and CTLA-4 (tremelimumab) inhibition alone or combined with radiotherapy. METHODS: This open-label, multicentre, randomised, phase 2 trial was done by the National Cancer Institute Experimental Therapeutics Clinical Trials Network at 18 US sites. Patients aged 18 years or older with metastatic NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, and progression during previous PD(L)-1 therapy were eligible. They were randomly assigned (1:1:1) in a web-based system by the study statistician using a permuted block scheme (block sizes of three or six) without stratification to receive either durvalumab (1500 mg intravenously every 4 weeks for a maximum of 13 cycles) plus tremelimumab (75 mg intravenously every 4 weeks for a maximum of four cycles) alone or with low-dose (0·5 Gy delivered twice per day, repeated for 2 days during each of the first four cycles of therapy) or hypofractionated radiotherapy (24 Gy total delivered over three 8-Gy fractions during the first cycle only), 1 week after initial durvalumab-tremelimumab administration. Study treatment was continued until 1 year or until progression. The primary endpoint was overall response rate (best locally assessed confirmed response of a partial or complete response) and, along with safety, was analysed in patients who received at least one dose of study therapy. The trial is registered with ClinicalTrials.gov, NCT02888743, and is now complete. FINDINGS: Between Aug 24, 2017, and March 29, 2019, 90 patients were enrolled and randomly assigned, of whom 78 (26 per group) were treated. This trial was stopped due to futility assessed in an interim analysis. At a median follow-up of 12·4 months (IQR 7·8-15·1), there were no differences in overall response rates between the durvalumab-tremelimumab alone group (three [11·5%, 90% CI 1·2-21·8] of 26 patients) and the low-dose radiotherapy group (two [7·7%, 0·0-16·3] of 26 patients; p=0·64) or the hypofractionated radiotherapy group (three [11·5%, 1·2-21·8] of 26 patients; p=0·99). The most common grade 3-4 adverse events were dyspnoea (two [8%] in the durvalumab-tremelimumab alone group; three [12%] in the low-dose radiotherapy group; and three [12%] in the hypofractionated radiotherapy group) and hyponatraemia (one [4%] in the durvalumab-tremelimumab alone group vs two [8%] in the low-dose radiotherapy group vs three [12%] in the hypofractionated radiotherapy group). Treatment-related serious adverse events occurred in one (4%) patient in the durvalumab-tremelimumab alone group (maculopapular rash), five (19%) patients in the low-dose radiotherapy group (abdominal pain, diarrhoea, dyspnoea, hypokalemia, and respiratory failure), and four (15%) patients in the hypofractionated group (adrenal insufficiency, colitis, diarrhoea, and hyponatremia). In the low-dose radiotherapy group, there was one death from respiratory failure potentially related to study therapy. INTERPRETATION: Radiotherapy did not increase responses to combined PD-L1 plus CTLA-4 inhibition in patients with NSCLC resistant to PD(L)-1 therapy. However, PD-L1 plus CTLA-4 therapy could be a treatment option for some patients. Future studies should refine predictive biomarkers in this setting. FUNDING: The US National Institutes of Health and the Dana-Farber Cancer Institute.

Use of Fluoro-[18F]-Deoxy-2-D-Glucose Positron Emission Tomography/Computed Tomography to Predict Immunotherapy Treatment Response in Patients With Squamous Cell Oral Cavity Cancers.

IMPORTANCE: Neoadjuvant immunotherapy is a novel approach with the potential to improve outcomes for patients with oral cavity squamous cell cancer (OCSCC). Adverse events of varying severity are reported with immunotherapy, and a biomarker to predict response would be clinically useful to avoid toxic effects in those unlikely to benefit. OBJECTIVE: To correlate changes on fluoro-[18F]-deoxy-2-D-glucose positron emission tomography/computed tomography (FDG-PET/CT) scans with primary tumor pathologic response and immunologic biomarkers in patients with OCSCC receiving neoadjuvant immunotherapy. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective analysis of serial FDG-PET/CT scans obtained prospectively as part of a phase 2 open-label randomized clinical trial investigating neoadjuvant immunotherapy in patients with untreated OCSCC between 2016 and 2019. Included were a total of 29 patients from a single academic medical center with untreated OCSCC (≥T2, or clinically node positive) randomized 1:1 to receive neoadjuvant therapy with single agent nivolumab or combination nivolumab and ipilimumab followed by surgery and standard of care adjuvant therapy. INTERVENTIONS: The interventions in this study were FDG-PET/CT scans before (T0) and after (T1) preoperative immunotherapy. MAIN OUTCOMES AND MEASURES: Data collected from FDG-PET/CT scans included maximum standardized uptake value (SUVmax) of primary OCSCC and cervical lymph nodes (LNs) at T0 and T1 and new LN uptake and uptake consistent with radiologic immune-related adverse events (irAEs) at T1. Primary OCSCC pathologic response reported as percentages of viable vs nonviable tumor. The number of CD8+ cells/mm2 was determined in the primary tumor biopsy specimen and at surgery. RESULTS: There was no correlation between pathologic response and change in SUVmax in the primary OCSCC between T0 and T1. Out of 27 total participants, 13 had newly FDG-avid ipsilateral LNs at T1, most negative on pathology. A total of 9 had radiologic irAEs, most commonly sarcoid-like LN (7 of 27). No correlations were found between primary OCSCC SUVmax at T0 and CD8+ T-cell number in the primary tumor biopsy, and no correlations were found between primary OCSCC SUVmax at T1 and CD8+ T-cell number in the primary tumor at surgery. CONCLUSIONS AND RELEVANCE: There were no correlations between changes in FDG uptake after neoadjuvant immunotherapy and pathologic primary tumor response. Importantly, newly FDG-avid ipsilateral LNs following neoadjuvant immunotherapy were commonly observed but did not represent progressive disease or indicate pathologically disease positive nodes in most cases. These findings argue against altering surgical plans in this setting and suggest that the role of FDG-PET/CT may be limited as an early imaging biomarker for predicting pathologic response to preoperative immunotherapy for OCSCC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02919683.