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In the following brief report, we highlight the advances in the neuro-oncology space from the ASCO 2022 Annual Meeting. We put into context the phase 2 and 3 trials and how these may alter the standard of care going forward. In addition, we highlight some other earlier work that will lead to future and potentially practice-changing trials.

Over 500 clinical trials are investigating combination radiotherapy and immune checkpoint blockade (ICB) as cancer treatments; however, the majority of trials have found no positive interaction. Here we perform a comprehensive molecular analysis of a randomized phase I clinical trial of patients with non-small cell lung cancer (NSCLC) treated with concurrent or sequential ablative radiotherapy and ICB. We show that concurrent treatment is superior to sequential treatment in augmenting local and distant tumor responses and in improving overall survival in a subset of patients with immunologically cold, highly aneuploid tumors, but not in those with less aneuploid tumors. In addition, radiotherapy alone decreases intratumoral cytotoxic T cell and adaptive immune signatures, whereas radiotherapy and ICB upregulates key immune pathways. Our findings challenge the prevailing paradigm that local ablative radiotherapy beneficially stimulates the immune response. We propose the use of tumor aneuploidy as a biomarker and therapeutic target in personalizing treatment approaches for patients with NSCLC treated with radiotherapy and ICB.

Thoracic stereotactic body radiation therapy (SBRT) is associated with high rates of local control but carries a risk of pneumonitis. Immunotherapy is a standard treatment for patients with metastatic disease but can also cause pneumonitis. To evaluate the feasibility and safety of thoracic SBRT with systemic immunotherapy, clinical outcomes of patients treated with immune checkpoint blockade (ICB) and SBRT on prospective trials were reviewed.Three consecutive phase 1 trials of combination SBRT and ICB conducted between 2016 to 2020 for widely metastatic solid tumors were reviewed. The protocols mandated adherence to NRG BR001/BR002 organs at risk constraints, resulting in100% coverage of some target volumes. ICB was administered either sequentially (within 7 days after completion of SBRT) or concurrently (before or at the start of SBRT), depending on protocol. End points included pneumonitis, dose-volume constraints, local failure, and overall survival. The cumulative incidence estimator and Kaplan-Meier method were used.In the study, 123 patients met eligibility with 311 metastases irradiated. The most common histologies included non-small cell lung cancer (33%) and colorectal cancer (12%). Median follow-up was 12 months. The overall rate of grade 3+ pneumonitis was 8.1%; 1-year local failure was 3.6%. Established dosimetric parameters were significantly associated with the development of pneumonitis (P.05). In most patients, the lungs were not challenged with high doses of radiation, defined as receiving ≥75% of the maximum for a given lung dose-volume constraint. Patients who were challenged were not found to have a significantly higher risk of pneumonitis.In the largest series of thoracic SBRT and immunotherapy, local control was excellent with acceptable toxicity and support the conclusion that established dose-volume constraints for the lung are safe. However, these results highlight the potential value in reporting of organs at risk being challenged with doses approaching protocol specified limits.

Purpose:CD137 agonism and CSF1R blockade augment stereotactic body radiotherapy (SBRT) and anti-programmed death-1 in preclinical models. We evaluated the safety and efficacy of SBRT with nivolumab+urelumab (CD137 agonist) or nivolumab+cabiralizumab (CSF1R inhibitor).Patients and Methods:This phase I clinical trial enrolled patients with advanced solid tumors that had progressed on standard therapies. SBRT was delivered to 1–4 metastases with nivolumab+urelumab or nivolumab+cabiralizumab given concurrently and following SBRT. Dose-limiting toxicity (DLT) was the primary endpoint with anatomic location-specific SBRT doses deemed safe if ≤33% DLT frequency was observed. Secondary endpoints included RECISTv1.1 response, progression-free survival (PFS), overall survival (OS), and molecular correlative studies.Results:Sixty patients were enrolled, and median follow-up for living patients is 13.8 months. Of these, 23 (38%) received SBRT+nivolumab+urelumab and 37 (62%) received SBRT+nivolumab+cabiralizumab. Seven patients (12%) experienced a DLT (n = 3 grade 3, n = 4 grade 4) in the following anatomic cohorts: abdominal/pelvic (3/17, 18%), liver (1/13, 8%), central lung (2/14, 14%), and peripheral lung (1/12, 8%). Of 41 patients radiographically evaluable for best overall response including 55 radiated and 23 unirradiated RECIST target lesions, 2 had complete responses (5%), 7 had partial responses (17%), 12 had stable disease (29%), and 20 had progression (49%). Median estimated PFS and OS are 3.0 months [95% confidence interval (CI), 2.9–4.8] and 17.0 months (95% CI, 6.8–undetermined), respectively. No patients with elevated pre-SBRT serum IL8 experienced a response.Conclusions:SBRT to ≤4 sites with nivolumab+urelumab or nivolumab+cabiralizumab for treating advanced solid tumors is feasible with acceptable toxicity and modest antitumor activity.See related commentary by Rodriguez-Ruiz et al., p. 5443

Table S1 shows the included solid tumor histologies for enrolled patients. Table S2 shows at least possibly treatment-related grade 2 or greater adverse events among patients remaining on study for at least 3 months. Table S3 shows all adverse events among patients remaining on study for at least 3 months. Table S4 shows the proportion of patients receiving stereotactic body radiation therapy to all RECIST target lesions and all clinically or radiographically apparent metastases by response category.

Supplemental Methods, Figures, and Tables

Purpose:Multisite stereotactic body radiotherapy followed by pembrolizumab (SBRT+P) has demonstrated safety in advanced solid tumors (ASTs). However, no studies have examined the relationships between irradiated tumor response, SBRT-induced tumor gene expression, and overall survival (OS).Patients and Methods:Patients with AST received SBRT (30–50 Gy in 3–5 fractions) to two to four metastases followed by pembrolizumab (200 mg i.v. every 3 weeks). SBRT was prescribed to a maximum tumor volume of 65 mL. Small metastases received the complete prescribed coverage (complete-Rx), while larger metastases received partial coverage (partial-Rx). Treated metastasis control (TMC) was defined as a lack of progression for an irradiated metastasis. Landmark analysis was used to assess the relationship between TMC and OS. Thirty-five biopsies were obtained from 24 patients: 19 pre-SBRT and 16 post-SBRT (11 matched) prior to pembrolizumab and were analyzed via RNA microarray.Results:Sixty-eight patients (139 metastases) were enrolled with a median follow-up of 10.4 months. One-year TMC was 89.5% with no difference between complete-Rx or partial-Rx. On multivariable analysis, TMC was independently associated with a reduced risk for death (HR, 0.36; 95% confidence interval, 0.17–0.75; P = 0.006). SBRT increased expression of innate and adaptive immune genes and concomitantly decreased expression of cell cycle and DNA repair genes in the irradiated tumors. Elevated post-SBRT expression of DNASE1 correlated with increased expression of cytolytic T-cell genes and irradiated tumor response.Conclusions:In the context of SBRT+P, TMC independently correlates with OS. SBRT impacts intratumoral immune gene expression associated with TMC. Randomized trials are needed to validate these findings.

Stereotactic radiosurgery (SRS) is a standard of care for many patients with brain metastases. To optimize post-SRS surveillance, this study aimed to validate a previously published nomogram predicting post-SRS intracranial progression (IP). We identified consecutive patients completing an initial course of SRS across two institutions between July 2017 and December 2020. Patients were classified as low- or high-risk for post-SRS IP per a previously published nomogram. Overall survival (OS) and freedom from IP (FFIP) were assessed via the Kaplan–Meier method. Assessment of parameters impacting FFIP was performed with univariable and multivariable Cox proportional hazard models. Among 890 patients, median follow-up was 9.8 months (95% CI 9.1–11.2 months). In total, 47% had NSCLC primary tumors, and 47% had oligometastatic disease (defined as ≤5 metastastic foci) at the time of SRS. Per the IP nomogram, 53% of patients were deemed high-risk. For low- and high-risk patients, median FFIP was 13.9 months (95% CI 11.1–17.1 months) and 7.6 months (95% CI 6.4–9.3 months), respectively, and FFIP was superior in low-risk patients (p < 0.0001). This large multisite BM cohort supports the use of an IP nomogram as a quick and simple means of stratifying patients into low- and high-risk groups for post-SRS IP.

Oligometastatic breast cancer is typically defined as the presence of 1-5 metastases and represents an intermediate state between locally advanced and widely metastatic disease. Oligometastatic cancer appears have a molecular signature that is distinct from widely metastatic disease and is associated with a superior prognosis. Due to its more limited capacity for widespread progression, oligometastatic disease could potentially benefit from aggressive ablative therapy to known sites of disease. The phase II SABR-COMET trial enrolled patients with oligometastatic disease of multiple histologies and randomized them to HIGRT vs. standard of care, finding a notable survival advantage in favor of HIGRT. There are many ongoing trials exploring the role of HIGRT for the treatment of oligometastatic breast cancer. Future studies may identify optimal candidates for ablative therapy by molecular signature; current clinically-based selection criteria include longer disease-free interval from diagnosis to metastasis (2 years), fewer metastases, and fewer involved organs.

299 Background: Recently, an MMAI prognostic biomarker, ArteraAI Prostate, was trained and validated in localized prostate cancer to more accurately risk stratify patients for multiple endpoints compared to NCCN risk groups (Esteva et al., 2022). Prognostication within an NCCN risk group remains clinically important given the multiple treatment decisions required within each risk group (e.g., radiotherapy dose or hormone therapy use). Herein, we validated the MMAI biomarker in high-risk prostate cancer where an increasing number of therapeutic decisions is required. Methods: This study leveraged histopathology image and clinical data from patients with at least one high-risk feature (HRF; cT3-cT4, Gleason 8-10, PSA > 20 ng/mL, primary Gleason pattern 5) from six NRG/RTOG phase III randomized trials (n=1,088). Patients from two trials not part of the initial MMAI biomarker training/validation (RTOG 0521 [n=344] and 9902 [n=318]) and the MMAI validation cohort (RTOG 9202, 9408, 9413, and 9910 [n=426]) were included. Fine-Gray, cumulative incidence, and time dependent area under the curve (tdAUC) analyses were performed for time to distant metastasis (DM) and prostate cancer-specific mortality (PCSM) for standard clinicopathologic variables (age, PSA, Gleason score, T-stage, number of HRFs) and the MMAI model, as a continuous score (per standard deviation increase) and categorically by quartile. Death from other causes were treated as competing risks. Results: The analyzed cohort had a median follow-up of 10.4 years. Median PSA was 21 ng/mL, 60% had Gleason 8-10 disease, 37% had cT3-T4 disease, and 20% were African American. On univariable analysis, the MMAI model was significantly associated with DM (subdistribution hazard ratio [sHR] 2.05, 95% CI 1.74-2.43, p

Background: Radiation therapy has immune-modulating effects resulting from apoptosis of tumor cells and DNA damage. The downstream generation of cytosolic DNA activates the cyclic GMP-AMP Synthase (cGAS)-STimulator of INterferon Gene (STING) signaling axis in both tumor and nearby immune cells, leading to increased induction of type I interferon (IFN-I) and other immune stimulating molecules. TAK-676 is a novel synthetic STING agonist being investigated (+/- pembrolizumab) in an ongoing first-in-human phase 1 study (NCT04420884). TAK-676 is a potent modulator of the innate immune system and leads to downstream activation of the adaptive immune system to produce antitumor responses in preclinical studies. In contrast to intratumorally injected STING agonists, TAK-676 is optimally designed for reduced serum degradation and enhanced permeability, allowing systemic IV delivery and access to tumor sites and lymphatics. The addition of TAK-676 following radiation therapy may enhance the immune response by increasing the STING-mediated IFN-I release and further stimulate T cell-mediated antitumor immunity, particularly in combination with anti-PD-1/PD-L1 therapies. Impaired IFN signaling has been linked to checkpoint inhibitor (CPI) resistance. Preclinical studies show that addition of a STING agonist may reverse the mechanisms of resistance in tumors with prior exposure to CPIs. This phase 1 trial was designed to investigate the safety and preliminary antitumor activity of TAK-676 + pembrolizumab following radiation therapy (NCT04879849). Methods: Patients aged ≥18 years with advanced NSCLC, TNBC, or SCCHN who have progressed on CPIs with ≥2 lesions, one of which can be targeted with radiation, are being enrolled. Patients receive 8 Gy x 3 fractions of image-guided radiation therapy followed by (after a minimum of 40 hours) IV pembrolizumab 200 mg on day 1 plus escalating doses of IV TAK-676 on days 1, 8, and 15 of a 21-day cycle. TAK-676 dose escalation is guided by the Bayesian Optimal Interval design. Patients receive TAK-676 + pembrolizumab until disease progression, intolerance, or withdrawal of consent. Once pharmacologically active dose levels of TAK-676 have been observed, paired biopsies will be collected in patients with a safely accessible lesion outside the radiation field at screening and between days 15 and 21 of cycle 1. The primary objective is to determine the safety and tolerability of TAK-676 + pembrolizumab following radiation therapy; secondary objectives are to determine the recommended phase 2 dose of TAK-676 + pembrolizumab following radiation therapy, and to assess preliminary antitumor activity both locally (in the radiation field) and systemically (non-radiated lesions). As of January 2022, nearly 10% of the planned patients have been enrolled. Citation Format: Benjamin Cooper, Steven J. Chmura, Jason J. Luke, Stephen L. Shiao, Reva K. Basho, Wade T. Iams, David B. Page, Cong Li, Richard C. Gregory, Michael H. Shaw, Kristin H. Horn, John P. Gibbs, Vicky A. Appleman, Allison J. Berger, Adnan O. Abu-Yousif, Neil B. Lineberry, Kate F. Stumpo, Aymen Elfiky, Naamit K. Gerber. Phase 1 study of TAK-676 + pembrolizumab following radiation therapy in patients with advanced non-small-cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), or squamous-cell carcinoma of the head and neck (SCCHN) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT243.

TPS2698 Background: The cyclic GMP-AMP Synthase (cGAS)–STimulator of INterferon Genes (STING) pathway is an important modulator of the innate immune system via induction of type I interferon (IFN-I). Cytosolic DNA generated as a result of tumor cell death following radiation therapy has been demonstrated to activate the cGAS-STING signaling axis resulting in antitumor immunogenicity. TAK-676 is a novel, synthetic STING agonist and it has been shown in preclinical studies to potently modulate the innate immune system and subsequently activate the adaptive immune system to produce antitumor responses. TAK-676 is designed for prolonged half-life in serum and enhanced tissue permeability compared with other STING agonists designed for intratumoral injection, allowing for systemic IV delivery with access to tumor sites and lymphatic tissue. IFN signaling impairment has been linked to checkpoint inhibitor (CPI) resistance in tumors. Treatment with TAK-676 after radiation therapy has the potential to stimulate T cell-mediated antitumor immunity via STING-mediated IFN-I release, particularly when used with anti-PD-1/PD-L1 therapies. Preclinical data support the addition of STING agonists to reverse resistance in tumors with prior exposure to CPIs. TAK-676 is being investigated (+/- pembrolizumab) in an ongoing first-in-human phase 1 study (NCT04420884). Here, we describe another phase 1 trial to investigate the safety and preliminary antitumor activity of TAK-676 plus pembrolizumab following radiation therapy in pts with advanced or metastatic NSCLC, TNBC, or SCCHN (NCT04879849). Methods: Adult pts with progressive disease (PD) following CPI treatment and who have ≥2 lesions, 1 of which can be targeted with radiation, are being enrolled. Pts receive 8 Gy x 3 fractions of image-guided radiation followed (after ≥40 hours) by IV pembrolizumab 200 mg on day 1 plus escalating doses of IV TAK-676 on days 1, 8, and 15 of a 21-day cycle. TAK-676 dose escalation is guided by the Bayesian optimal interval design. Pts receive TAK-676 plus pembrolizumab until PD, intolerance to treatment, or withdrawal. Pts enrolled at TAK-676 dose levels shown to have pharmacodynamic activity, and who have a safely accessible lesion outside the radiation field, will have paired biopsies collected at screening and between days 15 and 21 of cycle 1. The primary objective is to determine the safety and tolerability of TAK-676 plus pembrolizumab following radiation therapy; secondary objectives are to establish the recommended phase 2 dose of TAK-676 plus pembrolizumab following radiation therapy, and to assess preliminary antitumor activity both locally (within the radiation field) and systemically (non-radiated lesions). As of February 2022, we have enrolled ̃10% of the planned pts. Clinical trial information: NCT04879849.

1007 Background: Prospective and retrospective studies of patients (pts) with oligometastatic (OM) disease have supported that metastases (mets) directed treatment (MDT) with SBRT or SR in addition to standard of care systemic therapy (SOC ST) can improve progression-free (PFS) and overall survival (OS) compared with SOC ST alone. However, randomized evidence in oligometastatic breast cancer (OMBC) are lacking. NRG-BR002, a randomized Phase IIR/III trial, sought to determine the efficacy of SOC ST + MDT (SBRT or SR) as first line treatment of OMBC. Methods: OMBC pts with ≤ 4 extracranial mets on standard imaging with controlled primary disease were eligible if on first line SOC ST for ≤ 12 months without progression. Pts were randomized (1:1) to ARM 1 – SOC ST (mainly chemotherapy, endocrine therapy, anti-HER2) or ARM 2 – SOC ST with MDT of all mets. Stratification included mets number (1 vs > 1), ER/PR and Her2 status, and chemotherapy use. Phase IIR targeted sample size was 128 total/116 eligible pts, for 92% power and 1-sided significance level = 0.15 to determine if adding MDT shows a signal for improved PFS (hazard ratio [HR] = 0.55, corresponding to median PFS (mPFS) from 10.5 to 19 months), in order to continue to the full phase III trial for OS. PFS and OS were estimated by Kaplan-Meier and arms compared with log-rank. Results: 125 of the 129 pts randomized were eligible (ARM 1 = 65, ARM 2 = 60). Key characteristics included median age 54, 79% ER+ or PR+/HER2-, 13% HER2+, 8% triple negative. 60% had 1 metastasis and 20% presented synchronously with primary disease. Following randomization, systemic therapy was delivered to 95% in ARM 1 and 93% in ARM 2; ablation: SBRT 93%, SR 2%, and 5% none. The median follow-up was 30 mo. The mPFS (70% CI) in ARM 1 was 23 mo (18, 29) and 19.5 mo (17, 36) in ARM 2; 24 and 36-mo PFS (70% CI) for ARM 1 were 45.7% (38.9, 52.5) and 32.8% (26.0, 39.5) compared with 46.8 (39.2, 54.3) and 38.1 (29.7, 46.6) in ARM 2; HR (70% CI): 0.92 (0.71, 1.17); and 1-sided log-rank p = 0.36. As PFS did not show signal, OS reporting is included: median OS was not reached in either arm; 36-mo OS (95% CI) in ARM 1 71.8% (58.9, 84.7) and ARM 2 68.9% (55.1, 82.6; 2-sided log-rank p = 0.54). Analysis of first failure showed new mets outside index area (Arm 1) /RT field (Arm 2) developed similarly in both arms at 40%. There were fewer new mets inside treated/index area for Arm 2 6.7% vs ARM 1 29.2%, respectively. There were no grade 5 treatment-related adverse events (AEs), 1 grade 4 AE in ARM 1, and 9.7% and 5.3% grade 3 AEs in ARMS 1 and 2, respectively. Circulating tumor cell counts (0 vs ≥1) at baseline were similar in both arms and were not prognostic HR (95% CI): 1.04 (0.54, 2.02). Conclusions: The addition of MDT to SOC ST did not show signal for improved PFS, nor OS difference in patients with OMBC. The trial will not proceed to the Phase III component. Clinical trial information: NCT02364557.