CTIM-15. FIRST-IN-HUMAN PHASE 1 STUDY OF CD200 ACTIVATION RECEPTOR-LIGAND (CD200AR-L) AND ALLOGENEIC TUMOR LYSATE VACCINE IMMUNOTHERAPY FOR RECURRENT GLIOBLASTOMA: INITIAL RESULTS FROM AN ONGOING CLINICAL TRIAL

BACKGROUND Poor efficacy and adverse events limit the use of immunotherapy in the treatment of glioblastoma. CD200AR-L, a novel immunotherapy targeting multiple checkpoints with a single peptide inhibitory ligand, activates the immune system by downregulating CD200-inhibitory receptor, PD-1/PD-L1, and CTLA-4. METHODS Single-center, first-in-human, dose-escalation phase 1 clinical trial (NCT04642937) utilizing a 3 + 3 design initiated accrual in 12/2020 at dose level-1; CD200AR-L 3.75micrograms/kg/dose administered on days 1 and 2 by intradermal injection after topical imiquimod. On day 2, a fixed dose of an allogeneic vaccine is also injected intradermally. Induction Phase consists of this injection series weekly for 4 weeks with monitoring for dose-limiting toxicity through day 28. RESULTS Between 12/2020 to 3/2021, 6 patients were enrolled on dose level-1; aged 37-65 years, 4 men, all with KPS >/= 80, and 3 patients on daily dexamethasone (4mg (n=2), 2mg (n=1)). Five were at first recurrence, 1 at second and 5 had cancers MGMT-promoter unmethylated. All completed the 4 weeks of induction. One dose-limiting toxicity of a grade-III encephalopathy was observed. Non-dose-limiting grade-III toxicities included, lymphopenia (n=1) and immunotherapy-related intracranial edema (IrICE) (n=2). IrICE symptoms were temporarily mitigated with ‘bevacizumab rescue protocol.’ No patients had local injection site reactions. Three patients are off study for radiographic disease progression confirmed on pathology (n=1) and radiographic disease progression with progressive neurological decline (n=2). Completed investigational hematologic immune monitoring for 4/6 patients revealed, that between weeks 2 and 4 post-vaccination, evidence of immune stimulation with an increase in CD4/8 T-cells, natural killer, and natural killer T-cells. There was also a reduction in immunosuppressants noted by a decrease in PD-1/PD-L1 and CTLA-4 expression on CD4/8 T-cells, CD14, CD11c, and myeloid-derived suppressor cells. CONCLUSION Initial dosing of CD200AR-L was well tolerated with early positive signal of immunological effect. Enrollment continues, now at dose level-2; CD200AR-L at 5micrograms/kg/dose.

Pathologic and radiographic responses in a window of opportunity for durvalumab plus metformin trial for squamous cell carcinoma of the head and neck (HNSCC).

6068 Background: Durvalumab is a human monoclonal IgG1 antibody directed against programmed death-ligand 1 (PD-L1). PD-1/PD-L1 immune checkpoint inhibition (ICI) shows promise in HNSCC, but durable responses have been seen in only a fraction of patients. Metformin, a biguanide oral anti-hyperglycemic, has shown promise in altering immunity within the tumor microenvironment (TME) towards a stronger anti-tumor distribution of immune cells. We aimed to investigate the combined effect of metformin and durvalumab in patients with HNSCC. Methods: This was a single-center prospective phase 1, window of opportunity clinical trial in which previously untreated patients with any stage resectable HNSCC were randomized 3:1 to durvalumab + metformin (Arm A) or durvalumab alone (Arm B) during a four-week period between diagnosis and surgical resection. Six patients were included in a safety lead-in of durvalumab and metformin and an additional 32 patients were randomized. The primary endpoint was immune cell polarization. Here we report pathologic and radiographic effect. Pathologic effect was graded independently by two pathologists. Radiographic effect was evaluated using the immune-related Response Criteria (irRC). Results: Thirty-eight patients were enrolled (29 Arm A, 9 Arm B). Three patients withdrew consent prior to intervention (2 Arm A, 1 Arm B) and were excluded from analysis. AJCC 8th edition staging was as follows: Stage I (n = 21), Stage II (n = 2), Stage III (n = 3), Stage IVa (n = 6), Stage IVb (n = 3). Primary tumor sites included the oropharynx (n = 20, all p16+), oral cavity (n = 11), larynx (n = 2), maxillary sinus (n = 1), and unknown (n = 1). Pathologic effect was observed in 55% (18/33) of evaluable patients: 60% in Arm A vs 37.5% in Arm B (p = 0.418). 40% of patients with involved lymph nodes had discordance of pathologic effect at the primary site versus lymph node. Radiographic response based on irRC among 30 evaluable patients included 1 CR, 1 PR, 24 SD, and 4 PD. There was a significant correlation between pathologic effect and radiographic disease control, defined as CR, PR, and SD (p = 0.021), but no correlation when looking only at radiographic responders (p = 0.925). No patients experienced Grade 3–4 treatment or immune-related adverse events or a delay in surgery due to trial participation. All patients remained resectable. Conclusions: Our data demonstrate that the study intervention was well-tolerated in HNSCC patients. There was a trend towards an increased proportion of pathologic responders in the group receiving metformin. Additional studies targeting the TME are needed to further elucidate whether synergistic effects between metformin and durvalumab were seen in this patient cohort. Clinical trial information: NCT03618654.

Overall survival with circulating tumor DNA-guided therapy in advanced non-small cell lung cancer.

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.

P111 Cross-sectional imaging is highly sensitive in detecting endoscopic post-operative recurrence in Crohn’s disease patients

Background Postoperative Crohn’s disease (CD) surveillance relies on endoscopic monitoring. The role of cross-sectional imaging in post-operative CD surveillance is less clear. We aimed to evaluate radiographic characteristics, endoscopic concordance, and the predictive ability of imaging for postoperative recurrence (POR). Methods Multi-institution retrospective cohort study of adult CD patients who underwent ileocolonic resection (ICR) between 2009–2020. Patients with a CT or MR enterography within 90 days of a postoperative surveillance colonoscopy were included. Imaging studies were interpreted by blinded expert CD radiologists. Endoscopic activity was assessed by Rutgeerts’ scoring (POR ≥ i2b). Patients were categorized by presence of endoscopic POR (E+ or E-) or radiographic disease activity (R+ or R-) and grouped by endoscopic and radiographic concordance. Results 201 CD patients (57.7% female, mean age 31 years, 81.2% stricturing CD, 17.9% >1 prior ICR, 22.5%) with paired colonoscopy and imaging were included. Median time from ICR to paired endoscopy was 23.2 months. Imaging was highly sensitive for detecting POR (84.2%), but poorly specific (32.8%). The plurality (41.8%, N=84) were discordant E-/R+, 32.8% concordant positive (E+/R+), 20.4% concordant negative (E-/R-), and 5% discordant E+/R-. In patients with endoscopic POR, imaging detected intestinal wall thickening (86.8%; p=0.004) and hyper-enhancement (84.2%; p=0.003) at higher rates and corresponded with endoscopic severity (Figure 1). Multiple correspondence analysis showed association between severe endoscopic (i3/i4) disease and advanced radiographic disease. The majority (58.3 %) of E+/R- patients (N=12) had a Rutgeerts’ score of i2b. Majority of E-/R+ (N=84) had minimal/mild radiographic disease (81%). Differences in characteristics between the E-/R+ and E+/R+ was most pronounced in length of disease >10 cm (26.1%, 45.3%). Subsequent colonoscopies were performed in 74 E-/R+ (i0=28, i1=12, i2a=34) and 35 E-/R- (i0=20, i1=9, i2a=6) patients with 18 E-/R+ (24.3%; i0=8, i1=3, i2a=7) and 4 E-/R- (11.4%; i0=1, i1=2, i2a=1) patients developing POR (p=0.09). However, survival analysis between E-/R+ and E-/R- showed no difference to time to subsequent POR (p=0.24) (Figure 2). Imaging features at time of paired negative endoscopy did not predict subsequent endoscopic POR. Conclusion Cross-sectional imaging is highly sensitive to detect endoscopic POR; advanced radiographic disease correlates with increased endoscopic severity. Patients with no endoscopic recurrence in the presence of radiographic activity may require increased surveillance, though larger study cohorts are needed. Imaging compliments, but should not supplant, endoscopic POR surveillance paradigms.