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Background The limited availability of proton beam therapy (PBT) requires individual treatment selection strategies that can be based on normal tissue complication probability (NTCP) models. We developed and externally validated NTCP models for common late side-effects following PBT in brain tumour patients to optimise patients’ quality of life. Methods Cohorts from three PBT centres (216 patients) were investigated for several physician-rated endpoints at 12 and 24 months after PBT: alopecia, dry eye syndrome, fatigue, headache, hearing and memory impairment, and optic neuropathy. Dose-volume parameters of associated normal tissues and clinical factors were used for logistic regression modelling in a development cohort. Statistically significant parameters showing high area under the receiver operating characteristic curve (AUC) values in internal cross-validation were externally validated. In addition, analyses of the pooled cohorts and of time-dependent generalised estimating equations including all patient data were performed. Results In the validation study, mild alopecia was related to high dose parameters to the skin [e.g. the dose to 2% of the volume (D2%)] at 12 and 24 months after PBT. Mild hearing impairment at 24 months after PBT was associated with the mean dose to the ipsilateral cochlea. Additionally, the pooled analyses revealed dose–response relations between memory impairment and intermediate to high doses to the remaining brain as well as D2% of the hippocampi. Mild fatigue at 24 months after PBT was associated with D2% to the brainstem as well as with concurrent chemotherapy. Moreover, in generalised estimating equations analysis, dry eye syndrome was associated with the mean dose to the ipsilateral lacrimal gland. Conclusion We developed and in part validated NTCP models for several common late side-effects following PBT in brain tumour patients. Validation studies are required for further confirmation.

Cranial irradiation results in cognitive decline, which is hypothesized to be partially attributable to hippocampal injury and stem cell loss. Recent advances allow for targeted reduction of radiation dose to the hippocampi while maintaining adequate dose coverage to the brain parenchyma and additional increasing dose to brain metastases, a approach called hippocampal avoidance whole brain radiation therapy with a simultaneous integrated boost (HA-WBRT + SIB.) We review our early clinical experience with HA-WBRT + SIB. We evaluated treatments and clinical outcomes for patients treated with HA-WBRT + SIB between 2014 and 2018. A total of 32 patients (median age, 63.5 years, range 45.3–78.8 years) completed HA-WBRT + SIB. Median follow-up for patients alive at the time of analysis was 11.3 months. The most common histology was non-small cell lung cancer (n = 22). Most patients (n = 25) were prescribed with WBRT dose of 30 Gy with SIB to 37.5 Gy in 15 fractions. Volumetric modulated arc therapy reduced treatment time (p

Circulating tumor DNA (ctDNA) sequencing guides therapy decisions but has been studied mostly in small cohorts without sufficient follow-up to determine its influence on overall survival. We prospectively followed an international cohort of 1,127 patients with non-small-cell lung cancer and ctDNA-guided therapy. ctDNA detection was associated with shorter survival (hazard ratio (HR), 2.05; 95% confidence interval (CI), 1.74-2.42; P 0.001) independently of clinicopathologic features and metabolic tumor volume. Among the 722 (64%) patients with detectable ctDNA, 255 (23%) matched to targeted therapy by ctDNA sequencing had longer survival than those not treated with targeted therapy (HR, 0.63; 95% CI, 0.52-0.76; P 0.001). Genomic alterations in ctDNA not detected by time-matched tissue sequencing were found in 25% of the patients. These ctDNA-only alterations disproportionately featured subclonal drivers of resistance, including RICTOR and PIK3CA alterations, and were associated with short survival. Minimally invasive ctDNA profiling can identify heterogeneous drivers not captured in tissue sequencing and expand community access to life-prolonging therapy.

OBJECTIVES: Liquid biopsy for plasma circulating tumor DNA (ctDNA) next-generation sequencing (NGS) can detect ALK fusions, though data on clinical utility of this technology in the real world is limited. MATERIALS AND METHODS: Patients with lung cancer without known oncogenic drivers or who had acquired resistance to therapy (n = 736) underwent prospective plasma ctDNA NGS. A subset of this cohort (n = 497) also had tissue NGS. We evaluated ALK fusion detection, turnaround time (TAT), plasma and tissue concordance, matching to therapy, and treatment response. RESULTS: ctDNA identified an ALK fusion in 21 patients (3%) with a variety of breakpoints and fusion partners, including EML4, CLTC, and PON1, a novel ALK fusion partner. TAT for ctDNA NGS was shorter than tissue NGS (10 vs. 20 days; p

8540 Background: The standard of care for patients with inoperable early stage or locally advanced NSCLC is definitive stereotactic body radiotherapy (SBRT) or conventional radiation therapy (RT) with systemic therapy. Circulating tumor DNA (ctDNA) testing can be used for the assessment of MRD and predict risk of recurrence. Few studies have prospectively evaluated MRD detection and ctDNA dynamics specifically among patients with early or locally advanced NSCLC receiving definitive RT. Methods: In a prospective clinical cohort of patients with stage I-III NSCLC (n = 17), serial plasma samples (n = 70) were collected before and after SBRT as well as before, during, and after conventional RT with or without concurrent systemic therapy and adjuvant durvalumab. Patients were followed-up for a median of 29 months (range: 4 to 54 months) with the last serial plasma collected at a median of 5 months from completion of RT (range: 1 – 26 months). A personalized, tumor-informed multiplex PCR assay (Signatera™ bespoke mPCR NGS assay) was used for the detection and quantification of ctDNA and tracked 16 tumor variants among 16 patients and 15 tumor variants in one patient. This study evaluated the prognostic value of ctDNA, correlating MRD status with clinical outcomes, in addition to ctDNA clearance kinetics during RT. Results: Among 17 patients with early-stage and locally advanced NSCLC, baseline ctDNA was detected in 82% of patients (14/17). Clinical progression was confirmed radiographically for 53% (9/17). All events of clinical progression were detectable by ctDNA (sensitivity 100%, 0.63 – 1.0), with a median lead-time of 5.5 months for MRD detection compared to radiographic disease progression. Durable ctDNA clearance was observed in 29% (5/17) of patients, all of whom then remained recurrence-free until the end of follow-up (median 12 months; specificity 100%, 95% CI 0.6 – 1.0). Transient ctDNA clearance was observed in 3 patients, and recurrent ctDNA was detected before or at the time of disease progression in all 3. ctDNA status after treatment at a single time point and longitudinally were highly predictive of disease recurrence (p < 0.0001). Conclusions: ctDNA detection is feasible for patients with stage I-III NSCLC undergoing definitive chemoradiation. and can serve as a powerful predictive biomarker for disease recurrence. High baseline detection rate is essential for feasibility of a ctDNA-based MRD assay. Residual detectable ctDNA represents a powerful predictive tool to identify patients who might benefit from intensification of adjuvant therapy following definitive RT.

Circulating cell-free DNA (cfDNA) from blood plasma of cancer patients can be used to interrogate somatic tumor alterations non-invasively or when adequate tissue is unavailable. We have developed and clinically implemented MSK-ACCESS (Analysis of Circulating cfDNA to Evaluate Somatic Status), an NGS assay for detection of very low frequency somatic alterations in select exons and introns of 129 genes. Analytical validation demonstrated 92% sensitivity in de-novo mutation calling down to 0.5% allele frequency and 99% for a priori mutation profiling. To evaluate the performance and utility of MSK-ACCESS, we report results from the first 681 prospective blood samples (617 patients) that underwent clinical analysis to guide patient management. Somatic mutations, copy number, and/or structural variants were detected in 73% of the samples, and 56% of these circulating-tumor DNA (ctDNA) positive samples had clinically actionable alterations. The utilization of matched white blood cell sequencing allowed retention of somatic alterations while filtering out over 10,000 germline and clonal hematopoiesis variants, thereby greatly enhancing the specificity of the assay. Taken together, our experience illustrates the importance of analyzing a matched normal sample when interpreting cfDNA results and highlights the potential of cfDNA profiling to guide treatment selection, monitor treatment response, and identify mechanisms of treatment resistance.

Background: There is compelling rationale to use bridging radiotherapy (BRT) between leukapheresis and chimeric antigen receptor T-cell infusion for cytoreduction and palliation of relapsed/refractory B cell malignancies. There is also preclinical evidence suggesting possible immune synergy with the combination of BRT and CAR T. Existing BRT series are small and generally focused on diffuse large B-cell lymphoma (DLBCL). We report a large cohort of RT-bridged patients including early experience with BRT for non-DLBCL histologies. Methods: We analyzed 43 patients with DLBCL (n=35), mantle cell lymphoma (MCL; n=6), and Burkitt's lymphoma (BL; n=2). All received RT for any intent within 1 month prior to leukapheresis up until CAR T infusion. PET response was evaluated by Lugano criteria within the BRT treatment field ("in field"), outside of the BRT field ("out of field") and overall at 5 time points: pre-BRT, pre-CAR T infusion, and day +30 (n=41), +90 (n=30), and +180 (n=19). Survival analysis was per Kaplan-Meier and clincodemographic associations with survival were assessed by Cox univariate proportional hazards. Results: Patients received axicabtagene (n=20, 48%), tisagenlecleucel (n=11, 26%), lisocabtagene (n=8, 19%), brexucabtagene (n=2, 5%), and an experimental CAR T product (n=1, 2%). Overall, patients had a median of 3 prior therapies (range 1-9). Prior to BRT, most (74%) had advanced stage III/IV relapsed/refractory disease and 17 (40%) had bulky (>7.5 cm) lesions. There was heterogeneity in BRT-treatment parameters; most commonly treated sites were head/neck (n=10), pelvis/groin (n=8), and abdomen (n=7). Median BRT dose was 30 Gy (range 4-54), with 20 Gy in 5 fractions as the most common regimen (n=12). 18 (42%) received BRT to all sites of PET avid disease ("comprehensive BRT"). 16 (37%) patients also received systemic bridging therapy, including concurrently (n=10) with BRT. With a short 14d median time to restaging PET, in field overall response rate (ORR) post BRT was 82% (complete response, CR; n=9, 27% or partial response, PR; n=18, 55%) [Figure 1]. Reflective of the population referred for bridging, 21 (64%) had out of field progression post BRT and pre-CAR T. Post-CAR T, 2 patients (5%) had grade 3 cytokine release syndrome, 4 (9%) had grade 3 neurotoxicity, and no severe toxicity within the BRT field was noted. Following CAR T, ORR was 72% (CR: n=25, 60%; PR: n=5, 12%). Median post CAR T follow-up was 9 mos (range 1-40), with 44% (n=19) of patients having no evidence of disease, 44% (n=19) deceased, and 12% (n=5) alive with disease at last contact. 33 (77%) patients never progressed within the BRT field. Of the 27 (63%) patients who relapsed, 10 were CD19- and 9 (33%) had disease in the BRT field at first progression. In DLBCL patients, progression free survival (PFS) was 83%, 60%, and 51% and overall survival (OS) was 100%, 89% and 69%, respectively at Day +30, +90, and +180. Univariate analysis showed that pre-BRT ECOG performance status ≥2 (HR: 12.0, p Conclusion: BRT has broad utility for aggressive B-cell malignancies and is associated with excellent pre-CAR T local control and no serious toxicity within the irradiated sites. Most patients had durable post-CAR T local control. Prospective studies are planned to clarify outcomes and evaluate mechanistic synergies. Future studies are needed to define optimal patient characteristics for systemic vs. radiotherapy bridging and elucidate the best BRT strategy for maximizing local control and potential immune augmentation. Figure 1 Figure 1. Disclosures Palomba: Kite: Consultancy; Novartis: Consultancy; Notch: Honoraria, Other: Stock; Seres: Honoraria, Other: Stock, Patents & Royalties, Research Funding; Lygenesis: Honoraria; PCYC: Consultancy; BeiGene: Consultancy; Pluto: Honoraria; Wolters Kluwer: Patents & Royalties; Juno: Patents & Royalties; Ceramedix: Honoraria; Magenta: Honoraria; Priothera: Honoraria; Nektar: Honoraria; WindMIL: Honoraria; Rheos: Honoraria. Shouval: Medexus: Consultancy. Batlevi: Regeneron: Current holder of individual stocks in a privately-held company; Viatris: Current holder of individual stocks in a privately-held company; TouchIME: Honoraria; BMS: Current holder of individual stocks in a privately-held company; Moderna: Current holder of individual stocks in a privately-held company; Pfizer: Current holder of individual stocks in a privately-held company; Medscape: Honoraria; TG Therapeutics: Consultancy; Seattle Genetics: Consultancy; Life Sciences: Consultancy; Kite Pharma: Consultancy; Dava Oncology: Honoraria; Karyopharm: Consultancy; Juno/Celgene: Consultancy; Bayer: Research Funding; Memorial Sloan Kettering Cancer Center: Current Employment; ADC Therapeutics: Consultancy; GLG Pharma: Consultancy; Xynomic: Research Funding; Roche/Genentech: Research Funding; Novartis: Research Funding; Epizyme: Research Funding; Janssen: Research Funding; Autolus: Research Funding. Brentjens: BMS: Consultancy, Patents & Royalties, Research Funding; Gracell Biotechnologies, Inc: Consultancy, Ended employment in the past 24 months; sanofi: Patents & Royalties; Caribou: Patents & Royalties. Dahi: Kite / Gilead: Membership on an entity's Board of Directors or advisory committees. Giralt: JENSENN: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; PFIZER: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; AMGEN: Membership on an entity's Board of Directors or advisory committees; JAZZ: Membership on an entity's Board of Directors or advisory committees; SANOFI: Membership on an entity's Board of Directors or advisory committees; CELGENE: Membership on an entity's Board of Directors or advisory committees; Actinnum: Membership on an entity's Board of Directors or advisory committees. Park: Kura Oncology: Consultancy; Intellia: Consultancy; Autolus: Consultancy; Artiva: Consultancy; Novartis: Consultancy; Amgen: Consultancy; PrecisionBio: Consultancy; Curocel: Consultancy; Affyimmune: Consultancy; BMS: Consultancy; Minerva: Consultancy; Servier: Consultancy; Kite Pharma: Consultancy; Innate Pharma: Consultancy. Scordo: i3 Health: Other: Speaker; Kite - A Gilead Company: Membership on an entity's Board of Directors or advisory committees; Omeros Corporation: Consultancy; Angiocrine Bioscience: Consultancy, Research Funding; McKinsey & Company: Consultancy. Sauter: Gamida Cell: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Precision Biosciences: Consultancy; Kite/Gilead: Consultancy; Genmab: Consultancy; GSK: Consultancy; Bristol-Myers Squibb: Research Funding; Spectrum Pharmaceuticals: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding. Shah: Janssen: Research Funding; Amgen: Research Funding. Perales: NexImmune: Honoraria; Kite/Gilead: Honoraria, Other; Karyopharm: Honoraria; Bristol-Myers Squibb: Honoraria; Cidara: Honoraria; Incyte: Honoraria, Other; Equilium: Honoraria; Celgene: Honoraria; MorphoSys: Honoraria; Medigene: Honoraria; Omeros: Honoraria; Novartis: Honoraria, Other; Nektar Therapeutics: Honoraria, Other; Miltenyi Biotec: Honoraria, Other; Merck: Honoraria; Sellas Life Sciences: Honoraria; Servier: Honoraria; Takeda: Honoraria.

Background: Patients with diffuse large B cell lymphoma (DLBCL) who do not achieve a complete response (CR) following CD19-targeted Chimeric Antigen Receptor T cell (CAR T) therapy are less likely to obtain durable benefit. Greater tumor burden pre-CAR T has been shown to predict lower CR rate and shorter survival. Recently, patterns of failure studies have identified baseline lesion characteristics including size, SUV, and extranodal location as associated with increased risk of post-CAR T failure. It is not yet known how bridging radiotherapy (BRT) prior to CAR T can alter subsequent patterns of failure. Methods: We reviewed DLBCL patients treated from 2017 to 2021 with BRT for any intent in the period from 30d pre-leukapheresis to CAR T infusion. Comprehensive BRT fields were defined as no avidity above liver mean outside of the BRT field. Bulky disease was defined as a max diameter of ≥7.5cm in any dimension. PET response was evaluated by Lugano criteria. Pattern of failure analysis was performed to identify failure sites as pre-existing (present pre-CAR T) vs. new and as in-field, marginal, or distant with respect to BRT. Marginal was defined as failure outside of the area receiving prescription dose but within 1cm of BRT field edge. One patient with a cutaneous target was excluded from size-based analyses. Significance was assessed by Fisher's exact test or T-test. Results: Thirty-five patients were identified with a median age of 66. Most were advanced stage (74%) at BRT with a median of 3 prior lines of systemic therapy. Twelve (35%) had bulky disease at any site pre-BRT (median max diameter 5.9 cm; range 1.1 - 24) with highest overall SUV median 19.8 (range 3.4 - 47); 83% (n=29) had ≥1 extranodal site (bone: n=13; CNS: n=4). Most common BRT sites were head/neck (n=10), pelvis (n=6), and extremity (n=5). BRT targeted the largest lesion in 85% (median 5.8 cm; 32% bulky) and the site of highest SUV in 81% (median 18.7); 49% (n=17) of targets were extranodal. BRT fields were comprehensive in 39%; median radiation treatment volume was 751cc (range 18 - 5856). Twenty-four patients (63%) received ≥30 Gy (median 30 Gy; range 20 - 54). Systemic therapy was given during the bridging period to 31% (n=11). Patients received axicabtagene (n=20), tisagenlecleucel (n=11), lisocabtagene (n=3), or experimental CAR T (n=1). On PET after BRT and pre-infusion (median 12d from BRT), 85% (n=23) had achieved partial response (PR) or better in-field (CR: n=7) though 63% had kinetically active disease with out-of-field progression (PD) and 19% (n=5) had marginal PD. Despite short interval restaging, there was a significant reduction in patients with bulky disease after BRT both within the irradiated field (p=0.007) and at any site (p=0.01). (Fig 1a) A median 81% SUV reduction in the irradiated site was noted with a significant decrease in max SUV in both the irradiated (p Conclusion: BRT significantly reduced the number of patients with bulky disease at any site at time of CAR T and significantly reduced the overall highest lesional SUV. Marginal failure rates of 19% and 23% at interim scan post-BRT and after CAR T, respectively in conjunction with the pattern of post CAR T failure predominantly in pre-existing sites, may suggest a need for more generous fields when a BRT approach is used in this population with rapidly proliferating disease. Further work and larger sample sizes are needed to evaluate the impact of dose on local control in bulky lesions as well as to investigate whether comprehensive BRT affects outcomes or patterns of failure. Figure 1 Figure 1. Disclosures Palomba: Juno: Patents & Royalties; Notch: Honoraria, Other: Stock; Novartis: Consultancy; Kite: Consultancy; PCYC: Consultancy; Wolters Kluwer: Patents & Royalties; Seres: Honoraria, Other: Stock, Patents & Royalties, Research Funding; Magenta: Honoraria; Ceramedix: Honoraria; WindMIL: Honoraria; Nektar: Honoraria; Rheos: Honoraria; Priothera: Honoraria; BeiGene: Consultancy; Lygenesis: Honoraria; Pluto: Honoraria. Shouval: Medexus: Consultancy. Batlevi: Kite Pharma: Consultancy; Viatris: Current holder of individual stocks in a privately-held company; Dava Oncology: Honoraria; TG Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Regeneron: Current holder of individual stocks in a privately-held company; TouchIME: Honoraria; Juno/Celgene: Consultancy; Medscape: Honoraria; BMS: Current holder of individual stocks in a privately-held company; Seattle Genetics: Consultancy; Life Sciences: Consultancy; Pfizer: Current holder of individual stocks in a privately-held company; Karyopharm: Consultancy; Moderna: Current holder of individual stocks in a privately-held company; Memorial Sloan Kettering Cancer Center: Current Employment; Bayer: Research Funding; GLG Pharma: Consultancy; Xynomic: Research Funding; Roche/Genentech: Research Funding; Novartis: Research Funding; Epizyme: Research Funding; Janssen: Research Funding; Autolus: Research Funding. Brentjens: Gracell Biotechnologies, Inc: Consultancy, Ended employment in the past 24 months; BMS: Consultancy, Patents & Royalties, Research Funding; sanofi: Patents & Royalties; Caribou: Patents & Royalties. Dahi: Kite / Gilead: Membership on an entity's Board of Directors or advisory committees. Giralt: JAZZ: Membership on an entity's Board of Directors or advisory committees; AMGEN: Membership on an entity's Board of Directors or advisory committees; JENSENN: Membership on an entity's Board of Directors or advisory committees; PFIZER: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; SANOFI: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; CELGENE: Membership on an entity's Board of Directors or advisory committees; Actinnum: Membership on an entity's Board of Directors or advisory committees. Park: BMS: Consultancy; Kite Pharma: Consultancy; Innate Pharma: Consultancy; Novartis: Consultancy; Minerva: Consultancy; Servier: Consultancy; Kura Oncology: Consultancy; PrecisionBio: Consultancy; Amgen: Consultancy; Intellia: Consultancy; Artiva: Consultancy; Curocel: Consultancy; Autolus: Consultancy; Affyimmune: Consultancy. Scordo: Angiocrine Bioscience: Consultancy, Research Funding; Kite - A Gilead Company: Membership on an entity's Board of Directors or advisory committees; i3 Health: Other: Speaker; Omeros Corporation: Consultancy; McKinsey & Company: Consultancy. Sauter: Bristol-Myers Squibb: Research Funding; GSK: Consultancy; Gamida Cell: Consultancy; Precision Biosciences: Consultancy; Kite/Gilead: Consultancy; Celgene: Consultancy, Research Funding; Genmab: Consultancy; Novartis: Consultancy; Spectrum Pharmaceuticals: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding. Shah: Amgen: Research Funding; Janssen Pharmaceutica: Research Funding. Perales: Merck: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Cidara: Honoraria; Miltenyi Biotec: Honoraria, Other; Kite/Gilead: Honoraria, Other; Equilium: Honoraria; Incyte: Honoraria, Other; Medigene: Honoraria; Karyopharm: Honoraria; Takeda: Honoraria; Servier: Honoraria; NexImmune: Honoraria; Novartis: Honoraria, Other; Nektar Therapeutics: Honoraria, Other; Sellas Life Sciences: Honoraria; Omeros: Honoraria; MorphoSys: Honoraria.

Ionization radiation induces DNA damage, most importantly the double-strand DNA break which is difficult to repair and may be lethal to the cell. The sensitivity of cancer cells to radiation is dependent on many factors including capacity to detect and repair DNA damage (termed the DNA-damage response), tumor hypoxia, cell cycle distribution, and radiation dose and fractionation. Inherited deficiencies in the DNA-damage response are associated with profound cancer predispositions, reflecting the essential role of DNA repair on organismal function. Radiosensitizing drugs improve the efficacy of radiation therapy. For example, the addition of temozolomide to radiation therapy for glioblastoma patients with O-6-methylguanine-DNA methyltransferase (MGMT) epigenetic silencing improves survival compared to radiation therapy alone. Early toxicity following radiation therapy is reversible and occurs due to depletion of cells in highly proliferative tissues, while late toxicity is permanent and occurs due to fibrosis and loss of organ function. Ionizing radiation can cause genomic instability and acquisition of a mutator phenotype through damage to genes critical for DNA repair, making cells less likely to repair additional oncogenic mutations. As a result, radiation therapy is associated with risk of secondary malignancy. Radiation therapy most commonly utilizes photons, which are high-energy X-rays. Photons collide with orbital electrons to produce reactive oxygen species which are highly volatile and damage nearby DNA. Proton radiation therapy utilizes hydrogen atoms stripped of their electrons. Compared to photons, the depth-dose characteristics of protons allow for decreased radiation dose to normal tissues adjacent to the tumor. As a result, protons offer the potential to reduce early and late toxicity, including risk of secondary malignancy.

Background Although slow growing, head and neck paragangliomas (HNPG) can cause significant morbidity. We evaluated the efficacy of proton therapy in the management of HNPG. Methods Retrospective review of an institutional proton therapy experience of treating patients between 1997 and 2016; 37 patients and 40 tumors were included. Results Proton therapy was delivered to a median of 50.4 Gy(RBE) (range: 45-68). Having a genetic/family predisposition for HNPG was associated with multifocal tumors (P = .02) and younger diagnosis age (P = .02). Twenty-six (70%) patients had symptom improvement posttreatment, and 65% of treated tumors showed ≥20% volumetric shrinkage. The 5-year recurrence-free and overall survival rates were both 97%. Grade 2 to grade 3 toxicities (54%) included subjective hearing impairment (19%), middle ear inflammation (14%), and dry mouth (8%). There were no grade 4-5 toxicities. Conclusions Patients with HNPGs can be effectively and safely treated with proton therapy with excellent tumor control, successful volumetric tumor reduction, and symptomatic improvement.

9009 Background: The effectiveness of circulating tumor DNA (ctDNA) at matching patients to life prolonging therapy has been studied mostly in small cohorts with limited follow up. The prognostic value of ctDNA alterations, particularly those absent on tissue, is also unclear. To address these questions, we studied survival outcomes in a prospective cohort of patients (N = 1002) with non-small cell lung cancer (NSCLC). Methods: Adults with metastatic or recurrent NSCLC were eligible if they had no known driver mutation or a known driver with progression following targeted therapy. Patients were enrolled at Memorial Sloan Kettering Cancer Center (New York, NY) starting October 21, 2016; analysis here is from a snapshot November 1, 2020. All patients had ctDNA sequenced via the Resolution ctDx Lung platform. To reduce inclusion of incidental germline mutations, we excluded non-functionally significant mutations with an allele frequency 35-65% that were present in gnomAD. Patients could also receive, at their provider’s discretion, tissue sequencing with MSK-IMPACT, which filters germline and clonal hematopoietic (CH) mutations with matched white blood cell sequencing. We performed survival analyses using Cox proportional hazards models from time of diagnosis of advanced disease to death, left truncating at time of study entry. Results: Of 1002 patients, 348 (35%) were treated with targeted therapy; in 181 of these (52%) the targetable alteration was detected in ctDNA. Patients treated with targeted therapy had prolonged survival whether matched by tissue-based methods (HR 0.39, 95%CI 0.30-0.51) or ctDNA (HR 0.47, 95%CI 0.37-0.61). These benefits persisted across multiple subgroups. ctDNA alterations themselves were associated with worse survival (HR 2.2, 95%CI 1.8-2.8), in a manner that scaled with allele fraction and burden. Of 401 patients with time-matched tissue sampling, 62 (15%) had ctDNA alterations that were absent on IMPACT (“unique” ctDNA alterations). Three such patients had unique ctDNA EGFR T790M mutations leading to changes in therapy. However, unique ctDNA alterations were generally associated with worse survival than no ctDNA alterations (HR 2.5, 95%CI 1.7-3.7) and even tissue-matched ctDNA alterations (HR 1.7, 95%CI 1.1-2.4). Of 98 unique ctDNA mutations, 48 (49%) were detectable in tissue at subthreshold levels, 12 (12%) were filtered by IMPACT as CH or germline, and 38 mutations (39%) were absent even at subthreshold levels. ctDNA alteration burden correlated with radiographic disease extent. In multivariate models with radiographic disease extent and other clinical variables, ctDNA alterations were the strongest independent predictor of worse survival. Conclusions: Our results show that ctDNA may match patients to life-prolonging targeted therapy and have prognostic importance. ctDNA may provide data about a patient’s cancer missed by spatially restricted tissue sequencing. Clinical trial information: NCT01775072.

Background: KRAS is the most common oncogene in lung cancer, but has historically been considered undruggable. The recent development of mutant-selective KRAS G12C inhibitors has for the first time created potential therapeutic opportunities for this unmet need. Simultaneously, circulating tumor DNA (ctDNA) is increasingly being used to detect targetable oncogenes in patients with metastatic lung cancers. There is limited data regarding the utility of plasma ctDNA in specifically identifying KRAS G12C mutations. Methods: Plasma was collected from 599 patients with lung cancer seen at Memorial Sloan Kettering Cancer Center between 10/2016 and 1/2019. ctDNA sequencing was performed using the ctDX-Lung Assay (Resolution Bioscience; Kirkland, WA). Tissue DNA sequencing was carried out using the MSK-IMPACT assay. Results: Mutations in KRAS (KRAS+) were detected in 129 patients (21.5%). Of patients with KRAS+ lung cancers, 116 had metastatic disease at the time of plasma testing. Plasma testing was carried out within 90 days of metastatic diagnosis in 92 of the 116 metastatic KRAS+ patients (79.3%), of whom 66 patients had both plasma and tissue sequencing available for comparison. 59 of the 66 patients (89.4%) had not had systemic treatment at the time of plasma testing. Average turn-around-time (TAT) for ctDNA testing in this cohort of 66 patients was 10 days, while average TAT for tissue sequencing was 22 days. ctDNA detected a KRAS mutation in 48 of the 66 patients (72.7%). A G12C mutation was found in the tissue and/or blood from 29 patients (43.9%), while 37 patients (56.1%) had other KRAS mutations. In one patient with a G12C mutation detected on plasma testing, no KRAS mutation or other known oncogenic drivers were found on tissue testing, though with limited tumor cells in the tissue sample. 75.6% of the patients with G12C mutations had KRAS detectable in the plasma, as compared to 70.3% of patients with other KRAS mutations (p=0.6). Within the cohort of patients with paired tissue and plasma testing, at a median follow-up of 202 days post-metastatic diagnosis, survival was longer in those patients without detectable KRAS in the plasma as compared to those patients with detectable plasma KRAS (log rank (Mantel-Cox), p Conclusion: Plasma testing was able to rapidly detect KRAS G12C mutations in the majority of patients with this alteration, which may guide G12C inhibitor therapy. In our cohort, patients that shed KRAS mutant DNA into the plasma had shorter survival. Citation Format: Yonina R. Murciano-Goroff, Kathryn C. Arbour, Michael D. Offin, Hai-Yan Y. Tu, Emily S. Lebow, Tristan S. Shaffer, Caterina Bertucci, Syed A. Hosseini, Kavita Garg, Lee P. Lim, Mark Li, Jason C. Chang, Jorge S. Reis-Filho, Pedram Razavi, James M. Isbell, Gregory J. Riely, David M. Hyman, Piro Lito, Bob T. Li. The utility of plasma ctDNA for detection of KRAS G12C and other mutations in lung cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 709.

Background: KRAS is the most common oncogene in lung cancers, but despite decades of intense research, there are no FDA-approved drugs targeting these cancers. Recent recognition that KRAS G12C harbors a binding pocket near the mutant cysteine residue has enabled the development of a new class of allele-specific inhibitors that are currently in early-phase trials. However, the mutational landscape and clinical characteristics of KRAS G12C mutant lung cancers are not well understood. The clinical use of plasma circulating tumor DNA (ctDNA) provides an opportunity to characterize this disease. Methods: Plasma was collected from 636 patients seen at Memorial Sloan Kettering Cancer Center between 11/2016 and 5/2019. ctDNA was extracted and analyzed using the validated 23-gene ctDx-Lung assay (Resolution Bioscience; Kirkland, WA). Categorical comparisons were carried out using Fisher’s exact test. Results: 95 NSCLC patients were identified as having alterations in KRAS based on ctDNA analysis, of whom 93.7% were metastatic at the time of plasma testing. 81.8% and 80.6% of G12C and non-G12C patients were systemic treatment naive at the time of testing, respectively. 33 patients had KRAS G12C mutations (34.7%), and 62 had other KRAS mutations (65.3%), including mutations in G12D in 24 patients, G12V in 9 patients, Q61H in 5, G12A in 8, G12S in 7, G13C in 3, G13D in 2, G13V and G12F in one patient each, as well as both Q61L and G13C in 2 patients. 60.6% of KRAS G12C patients and 53.2% of KRAS non-G12C were female. 97% of patients with G12C mutations were former smokers as compared to 77.4% in the non-G12C group (p=0.02). Of patients with stage IV adenocarcinoma with plasma KRAS detection, 9 of 25 patients with G12C were alive at the time of data analysis (36%), while 28 of 53 (52.8%) patients with KRAS non-G12C disease were alive (p =0.23; days from metastatic diagnosis to data analysis: G12C patients: 113-608, median: 396.0; non-G12C patients: 79-2248, median: 427.5). For patients with KRAS G12C mutations, co-alterations were found in TP53 (n=12, 36.4%), as well as SNVs in ROS1 (n=2), and in ALK (n=1). In patients with non-G12C KRAS detected on plasma, co-alterations were found in TP53 (n=26, 41.9%), and PIK3CA (n=3), with additional concurrent alterations in RTKs, including one patient with EGFR K714N, one with EGFR L858R, one patient with an FGFR1 amplification, and one each with an FGFR1 and FGFR3 mutation. Alterations were also detected in MET R988C (n=1) and a MET exon 14 splice variation, with SNVs in RET (n=2), as well as in ALK, ROS1, and AKT1, with a MET as well as a RICTOR amplification in one patient each. Conclusion: Patients with KRAS G12C mutations detected on plasma analysis were more likely to be smokers. Our data support the need for further analysis of co-alterations both in plasma and on tissue sequencing to aid the development of therapies for patients with KRAS mutations as well as to advance research on combinations of G12C inhibitors with other pathway inhibitors. Citation Format: Yonina R. Murciano-Goroff, Emily S. Lebow, Hai-Yan Tu, Mark Li, Lee P. Lim, Kathryn C. Arbour, William Travis, David B. Solit, Marc Ladanyi, David R. Jones, Charles M. Rudin, Andres Martinez, Mackenzie L. Myers, Alexander Makhnin, Pedram Razavi, Michael D. Offin, James W. Isbell, Gregory J. Riely, David M. Hyman, Piro Lito, Bob T. Li. Characterizing KRAS G12C and other mutations in plasma ctDNA from patients with lung cancer [abstract]. In: Proceedings of the AACR Special Conference on Advancing Precision Medicine Drug Development: Incorporation of Real-World Data and Other Novel Strategies; Jan 9-12, 2020; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_1):Abstract nr 12.

Introduction: Circulating cell-free DNA (cfDNA) is a source of tumor-derived DNA to interrogate somatic alterations when tissue is not available or of insufficient quantity for analysis. At MSKCC, we have developed and validated MSK-ACCESS (Analysis of Circulating cfDNA to Evaluate Somatic Status), a targeted next-generation sequencing assay that can detect ultra-low frequency somatic variants in select exons and introns of 129 genes. MSK-ACCESS can identify mutations, copy number alterations, gene fusions, and MSI status in plasma and was recently approved by the NYS-DOH for clinical testing. Here, we present the results of the validation study and our clinical experience with MSK-ACCESS since June 2019. Methods: Target regions from 129 genes were selected to maximize coverage of actionable, oncogenic, and hotspot mutations based on the first 25,000 tumors sequenced using MSK-IMPACT, our institutional clinical sequencing assay. Plasma cfDNA and buffy-coat DNA were extracted from whole blood collected in cell-stabilizing tubes (STRECK BCT cell-free DNA tube). Unique molecular indexes were introduced during DNA library construction, allowing for error suppression from consensus reads collapsed by Marianas, an in-house-developed algorithm. These consensus reads enable variant calling at low allelic frequency (AF) based on a 10−6 background error rate. Results: Analytical validation of MSK-ACCESS demonstrated 93% accuracy (n=100 variants), 99% precision (n=153 variants), and 100% sensitivity based on an assay limit of detection of 0.5% AF (n=19 variants). Variants were detected down to 0.1% AF. To date, 240 clinical cfDNA and matched normal DNA pairs have been sequenced, analyzed for somatic alterations, and clinically reported to guide patient management. Most clinical cases were from lung (55%) or prostate (13%) cancers and submitted for diagnostic purposes (71%). Median raw coverage was 18,367X, and median consensus coverage was 1411X. Mutations were detected in 180 (75%) samples with a median variant AF of 1.8% (0.02% - 95%). Comparison of concurrent commercial plasma testing results to MSK-ACCESS revealed multiple variants that were of clonal hematopoiesis or germline origin incorrectly reported as somatic variants. In the lung cohort, 48 patients had tissue testing with MSK-IMPACT; among 32 patients with a driver alteration detected by MSK-ACCESS, 91% had the identical driver alteration reported by MSK-IMPACT. Additionally, MSK-ACCESS identified a MET exon 14 alteration in one lung cancer patient that led to protocol enrollment and partial response. Conclusions: Liquid biopsy testing using MSK-ACCESS reliably detected clinically actionable mutations, reducing the need for multiple biopsies. These results also illustrate the importance of analyzing a matched normal sample when interpreting cfDNA results and highlight the potential of using cfDNA analysis to guide treatment selection, assess for treatment response, and identify mechanisms of treatment resistance. This abstract is also being presented as Poster A20. Citation Format: A. Rose Brannon, Gowtham Jayakumaran, Monica Diosdado, Yu Hu, Anna Razumova, Fanli Meng, Emily Lebow, Juber Patel, Ian Johnson, Preethi Srinivasan, Maysun Hasan, Jenna-marie Dix, Aijazuddin Syed, Brian Houck-Loomis, Bob T. Li, Charles Rudin, David Solit, Marc Ladanyi, Maria Arcila, Dana Tsui, Ahmet Zehir, Michael Berger, Ryma Benayed. Validation and clinical implementation of MSK-ACCESS, an ultra-deep sequencing assay for noninvasive somatic mutation profiling [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr PR08.

3529 Background: Circulating cell-free DNA (cfDNA) next-generation sequencing (NGS) is a promising strategy for non-invasive molecular profiling of cancers. MSK-ACCESS (Analysis of Circulating cfDNA to Evaluate Somatic Status) is a hybridization-capture targeted NGS assay that detects somatic variants in select exons of 129 genes with matched white blood cell sequencing. We present the initial clinical experience with MSK-ACCESS among patients with advanced non-small cell lung cancer (NSCLC). Methods: Patients with stage IV NSCLC underwent prospective MSK-ACCESS testing at initial diagnosis or progression of disease on targeted therapy between June 2019 and January 2020. A subset of patients had matched tissue-based NGS testing with the MSK-IMPACT 468 gene assay. We assessed oncogenic driver detection, turnaround time, plasma-tissue concordance, and matching to therapy. National Comprehensive-Cancer Network designated driver alterations were included in evaluation of tissue-plasma concordance (EGFR, ALK, KRAS, MET, RET, BRAF, HER2, ROS1, NTRK). Turnaround time was compared by a two-sided Wilcoxon signed-rank test. Results: A total of 201 patients with NSCLC had MSK-ACCESS testing at initial diagnosis (n = 79) or following progression of disease (n = 122). The median turn-around-time from plasma collection to MSK-ACCESS report was 16 days (range: 9 – 36 days) compared to 19 days from lab receipt of tissue to report (range: 12 – 57) for MSK-IMPACT (p < 0.001). Among patients with a driver detected on MSK-ACCESS, 100% (92/92) had an identical driver detected on MSK-IMPACT. Among patients with a driver detected on MSK-IMPACT, 75% (92/123) had an identical driver detected on MSK-ACCESS. This rate was similar among patients who were treatment-naive (74%; 64/86) and had disease progression (76%, 28/37) at the time of MSK-ACCESS. MSK-ACCESS identified driver alterations that directly guided first-line targeted therapy (n = 18) with response in all patients with available radiographic follow-up (n = 10), including a patient without confirmatory tissue testing. MSK-ACCESS identified resistance alterations among patients with disease progression including EGFR T790M, EGFR C797S, ROS1 G2032R, as well as a BRAF fusion. Conclusions: MSK-ACCESS successfully identified driver alterations with high concordance to tissue-based testing, directly guided patients to therapy with clinical responses, and detected known and novel resistance mechanisms. This assay warrants further clinical development to guide and facilitate precision oncology.

9067 Background: Small cell lung cancer (SCLC) is an aggressive disease, characterized by inevitable chemotherapy resistance and rapid progression. We hypothesized that circulating tumor DNA (ctDNA) analysis can rapidly identify sensitivity to platinum-based therapy. Methods: Patients with SCLC at Memorial Sloan Kettering Cancer Center underwent serial plasma collections, including prior to the start of treatment and prior to Cycle 2 Day 1 of therapy (C2D1). Tumor mutations were identified from pre-treatment biopsies by MSK-IMPACT and/or pre-treatment plasma by CAncer Personalized Profiling by deep Sequencing (CAPP-Seq). Median variant allele fraction (VAF) of all mutations was monitored on subsequent blood draws using CAPP-Seq. Progression free survival (PFS) was measured from the time of first pre-treatment blood draw. Results: Plasma was collected from 19 patients treated with carboplatin and etoposide, including three who received concurrent atezolizumab. Seven were female, and mean age was 64.5 years. ctDNA was detected in 17 patients (89%), including in the two patients in our series with limited stage disease. The most common mutations were in TP53 and RB1 in 14 and 6 patients, respectively. Fourteen patients had available plasma at C2D1. At baseline prior to treatment, median VAF did not differ significantly between radiologic responders and non-responders (9.4% versus 30.3%, p = 0.35). After one cycle of chemotherapy, the VAF percent decrease was significantly more in responders versus non-responders (-96.9% versus -10.3%, p < 0.001). Median VAF was therefore significantly lower by C2D1 in patients who responded compared to non-responders (0.51% versus 27.2%, p = 0.02). Those who ultimately responded to therapy all had a > 2 fold decrease in VAF by C2D1. With a median follow-up of 180 days, PFS was significantly longer in patients with > 2 fold decrease in VAF by C2D1 (6.4 versus 1.9 months, log rank p < 0.001). Conclusions: A 2-fold decrease in plasma VAF by C2D1 predicted platinum-sensitivity in SCLC and was associated with longer PFS. ctDNA may permit early assessment of benefit and expedite alternative treatment options for those without significant decrease in median VAF after one cycle of therapy.