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PURPOSE Preclinical cancer models harboring CCNE1 amplification were more sensitive to adavosertib treatment, a WEE1 kinase inhibitor, than models without amplification. Thus, we conducted this phase II study to assess the antitumor activity of adavosertib in patients with CCNE1-amplified, advanced refractory solid tumors. PATIENTS AND METHODS Patients aged ≥ 18 years with measurable disease and refractory solid tumors harboring CCNE1 amplification, an Eastern Cooperative Oncology Group performance status of 0-1, and adequate organ function were studied. Patients received 300 mg of adavosertib once daily on days 1 through 5 and 8 through 12 of a 21-day cycle. The trial followed Bayesian optimal phase II design. The primary end point was objective response rate (ORR). RESULTS Thirty patients were enrolled. The median follow-up duration was 9.9 months. Eight patients had partial responses (PRs), and three had stable disease (SD) ≥ 6 months, with an ORR of 27% (95% CI, 12 to 46), a SD ≥ 6 months/PR rate of 37% (95% CI, 20 to 56), a median progression-free survival duration of 4.1 months (95% CI, 1.8 to 6.4), and a median overall survival duration of 9.9 months (95% CI, 4.8 to 15). Fourteen patients with epithelial ovarian cancer showed an ORR of 36% (95% CI, 13 to 65) and SD ≥ 6 months/PR of 57% (95% CI, 29 to 82), a median progression-free survival duration of 6.3 months (95% CI, 2.4 to 10.2), and a median overall survival duration of 14.9 months (95% CI, 8.9 to 20.9). Common treatment-related toxicities were GI, hematologic toxicities, and fatigue. CONCLUSION Adavosertib monotherapy demonstrates a manageable toxicity profile and promising clinical activity in refractory solid tumors harboring CCNE1 amplification, especially in epithelial ovarian cancer. Further study of adavosertib, alone or in combination with other therapeutic agents, in CCNE1-amplified epithelial ovarian cancer is warranted.

PURPOSEPatients with relapsed or refractory T-cell acute lymphoblastic leukemia (r/r T-ALL) have few options and poor prognosis. The aim was to assess donor-derived anti-CD7 chimeric antigen receptor (CAR) T-cell safety and efficacy in patients with r/r T-ALL.METHODSIn this single-center, phase I trial, we administered anti-CD7 CAR T cells, manufactured from either previous stem-cell transplantation donors or new donors, to patients with r/r T-ALL, in single infusions at doses of 5 × 105or 1 × 106(±30%) cells per kilogram of body weight. The primary end point was safety with efficacy secondary.RESULTSTwenty participants received infusions. Adverse events including cytokine release syndrome grade 1-2 occurred in 90% (n = 18) and grade 3-4 in 10% (n = 2), cytopenia grade 3-4 in 100% (n = 20), neurotoxicity grade 1-2 in 15% (n = 3), graft-versus-host disease grade 1-2 in 60% (n = 12), and viral activation grade 1-2 in 20% (n = 4). All adverse events were reversible, except in one patient who died through pulmonary hemorrhage related to fungal pneumonia, which occurred at 5.5 months, postinfusion. Ninety percent (n = 18) achieved complete remission with seven patients proceeding to stem-cell transplantation. At a median follow-up of 6.3 months (range, 4.0-9.2), 15 remained in remission. CAR T cells were still detectable in five of five patients assessed in month 6, postinfusion. Although patients' CD7-positive normal T cells were depleted, CD7-negative T cells expanded and likely alleviated treatment-related T-cell immunodeficiency.CONCLUSIONAmong 20 patients with r/r T-ALL enrolled in this trial, donor-derived CD7 CAR T cells exhibited efficient expansion and achieved a high complete remission rate with manageable safety profile. A multicenter, phase II trial of donor-derived CD7 CAR T cells is in progress ( NCT04689659 ).

138 Background: Anlotinib is an oral multi-target tyrosine kinase inhibitor, mainly targeting VEGFR1-3, FGFR 1-4, PDGFR a/b and c-kit. Previous trial had demonstrated that anlotinib monotherapy was effective and safe in advanced colorectal cancer. ALTER-C002 trial is an open-label, single-arm, phase II study, aimed to evaluate the efficacy and safety of anlotinib plus CAPEOX as first-line therapy in patients with RAS/ BRAF wild-type unresectable metastatic colorectal cancer (mCRC). Preliminary results demonstrated significant antitumor activity and manageable toxicity. Here we reported the updated results at the data cutoff of August 19, 2022. Methods: RAS/BRAF wild-type unresectable mCRC patients with no prior systemic treatment received anlotinib (12 mg p.o. qd, d1-d14, q3w), capecitabine (850 mg/m2 p.o., bid, d1-d14, q3w) and oxaliplatin (130 mg/m2 i.v., d1, q3w) for 6 cycles followed by anlotinib and capecitabine as maintenance therapy until disease progression. Tumor response was assessed every 6 weeks according to RECIST v1.1 by investigator. The primary endpoint was ORR, and secondary endpoints included safety, DCR, DOR and PFS. Results: From Nov 2019 to February 2021, 30 eligible patients were enrolled, of whom, median age was 60y (range, 32-72y), 26 (86.7%) had left colon or rectal cancer, and 25 (83.3%) had liver metastases. The ORR was 76.7% (95% CI, 57.7-90.1%) with 2 patient achieved a complete response (CR); DCR was 93.3% (95% CI, 77.9-99.2%). At the data cutoff date, the median DOR was 7.9 months (95% CI, 4.3–11.4) and the median DOT was 8.38 months (95%CI, 5.9-10.9). The median OS has not reached yet, the 24-month OS rate was 72.8% (95%CI, 50.7-86.3%) and the 30-month OS rate was 58.3% (95%CI:25.5-80.8%). Grade 3-4 treatment-emergent adverse events (TEAEs) occurred in 25 (83.3%) patients; the most common grade 3 or 4 TEAEs ( > 10%) were hypertension (50%, 15/30 pts), neutropenia (26.7%, 8/30 pts) and diarrhea (13.3%, 4/30 pts). No grade 5 treatment-related events occurred. Conclusions: Anlotinib combined with CAPEOX exhibited promising ORR in the first-line treatment of mCRC compared to those of previous treatment. A longer follow-up is needed for a more complete assessment, and we launched a phase III, multicenter, open-label trial to assess the efficacy of this regimen comprehensively. Clinical trial information: NCT04080843 .

LBA4011 Background: Pancreatic cancer is one of the most lethal malignancies diagnosed at an advanced stage, and current treatment regimens are ineffective, with only 6-8 months of median overall survival (mOS). The present study aims to assess the clinical efficacy and safety of nimotuzumab (anti-EGFR humanized monoclonal antibody) combined with gemcitabine in K-Ras wild-type patients with locally advanced or metastatic pancreatic cancer. Methods: Patients with locally advanced or metastatic pancreatic cancer were randomized to receive nimotuzumab (400 mg, every one week) followed by gemcitabine (1000 mg/m2 on days 1, 8, and 15, every four weeks), or placebo plus gemcitabine until progression or unacceptable toxicity. The primary endpoint was overall survival (OS), and secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. Use restricted mean survival time (RMST)-Log function to analyze the survival benefits when the proportional hazards assumption is untrue. Results: A total of 92 Chinese patients were randomly assigned to the nimotuzumab- gemcitabine (n = 46) or placebo-gemcitabine group (n = 46). In the full analysis set (FAS, n = 82), the mOS was significantly longer in the nimotuzumab-gemcitabine group (10.9 vs. 8.5 months, p = 0.025 by RMST-Log test, hazard ratio [HR], 0.50, 95% Confidence Interval [CI], 0.06 to 0.94). The one-year survival rate was 43.6% in the nimotuzumab-gemicitabine group vs. 26.8% in the placebo-gemicitabine group, and 13.9% vs. 2.7% at three years. Subgroup analyses showed more survival benefit in patients without treatment of biliary obstruction (11.9 vs. 8.5 months, HR = 0.54, 95%CI 0.33-0.88, p = 0.037) and no surgical history (15.8 vs. 6.0 months, HR = 0.40, 95%CI 0.19-0.84). The median progression-free survival (mPFS) was 4.2 months in the nimotuzumab-gemicitabine group, as compared with 3.6 months in the placebo-gemicitabine group (HR = 0.56; 95% CI, 0.12 to 0.99; p = 0.013 ); Patients without treatment of biliary obstruction had significantly longer PFS (5.5 vs. 3.4 months; p = 0.008 ). No statistical difference in the ORR between the two groups ( p > 0.05). Nimotuzumab was safe and the incidence of adverse events in the nimotuzumab-gemicitabine group is similar to placbo-gemicitabine group. The most common grade 3 TRAEs in Nim-Gem group were neutropenia (11.1%), leukopenia (8.9%) and thrombocytopenia (6.7%). No grade 4 TRAEs. Conclusions: Nimotuzumab combined with gemcitabine increases OS and PFS in patients with K-Ras wild-type locally advanced or metastatic pancreatic cancer, particularly for those without treatment of biliary obstruction. The safety profile of nimotuzumab is similar to placebo. Clinical trial information: 02395016.

9519 Background: In a pilot phase II trial, we investigated the use of neoadjuvant immunotherapy to induce a pathologic response in patients with stage III/IV (M0) cutaneous squamous cell carcinoma of the head and neck (CSCC-HN). Here, we report the long-term outcomes according to pathologic response. Methods: Patients with newly diagnosed or recurrent stage III/IV (M0) (AJCC 8th Ed) CSCC-HN were treated with 2 doses of cemiplimab 350 mg intravenously every 3 weeks prior to surgery. The primary endpoint was overall response rate (ORR) per RECIST v1.1. Secondary endpoints included safety, pathologic response, disease-free and overall survival. Results: Of 20 patients enrolled, 7 (35%) had recurrent disease and 12 (60%) were stage IV on presentation. Neoadjuvant immunotherapy was generally well-tolerated and there were no surgical delays. Adverse events (AEs) were observed in 7 (35%) patients; 1 (5%) grade 3 diarrhea, 6 (30%) ≤ grade 2 AEs. ORR by RECIST was 30%. However, 85% (17/20) achieved a pathologic response (≤50% viable tumor), with pathologic complete response (pCR) in 11 (55%), major pathologic response (MPR, ≤10% viable tumor) in 4 (20%) and pathologic partial response (pPR, >10% and ≤50% viable tumor) in 2 (10%). Patients with a pCR did not receive planned radiotherapy after surgery. Patients who did not have a pathologic response (> 50% viable tumor) either progressed and died (1, 5%) or developed recurrence (2, 10%) despite surgery and adjuvant radiation or chemoradiation. At a median follow up of 34.5 months (range: 7.7-42.7), none of the patients who achieved a pathologic response have recurred. Conclusions: Consistent with other cancer types, pathologic response to neoadjuvant immunotherapy is durable in patients with advanced, resectable CSCC-HN. Adjuvant radiation therapy may be spared in patients who achieve a pCR and warrants further investigation. Clinical trial information: NCT03565783.

2536 Background: TIL therapy has been used extensively in metastatic melanoma patients for many years, now with ongoing efforts to commercialize treatment. The efficacy of TIL outside of melanoma is largely unknown thus we designed and implemented a trial using TIL manufactured at a single academic center for treatment refractory metastatic colorectal (CRC), pancreas (PDAC) and ovarian (OVA) cancers. Methods: Patients with CRC, PDAC and OVA refractory to standard therapies with ECOG PS 0-1 and normal organ function were eligible for TIL harvest. Ex vivo TIL expansion and manufacturing was conducted at the MD Anderson TIL lab under conditions that included IL2 and 41BB stimulation (using urelumab). All patients received a lymphodepletion regimen consisting of cyclophosphamide 60mg/kg days -7 and -6 and fludarabine 25mg/m2 days -5 through day -1, followed by infusion of pooled ex-vivo expanded TIL. Patients received up to 6 doses of high dose IL-2 (600,000 IU/kg) after TIL infusion. The primary endpoint was evaluation of the objective response rate (ORR) using RECIST 1.1 criteria with secondary endpoints including disease control rate, duration of response, PFS, OS and safety. Results: A total of 17 patients underwent TIL harvest and 16 were treated on protocol; including 8 CRC, 5 PDAC and 3 OVA. Median age was 57.5 (range 33-70) and 50% were females. Median number of lines of prior therapy was 2 (range 1-8). Median number of TIL infused was 76 X 109 (range 20.3 x 109-150 x 109). Median doses of cyclophosphamide and fludarabine administered were 2 (range, 2-2) and 3 (range, 1-5), respectively. Median doses of IL-2 administered was 6 (range, 1-6). There were no responders. Best response included prolonged SD in a patient with PDAC lasting until 18 months. Grade 3 or higher toxicities attributable to therapy was seen in 14 subjects (87.5%; 95% CI: 61.7 – 98.4) with the majority of toxicities representing expected pancytopenia from lymphodepletion. Infusion product analysis showed the presence of effector memory cells with high expression of CD39 irrespective of tumor type. Early on-treatment biopsy of PDAC patient with prolonged SD showed presence of proliferating (KI67+) CD4+ and CD8+ TIL. Conclusions: Generation of TIL at a single academic center for CRC, PDAC and OVA is feasible and treatment is associated with no new safety signals. For these tumor types, further research is required to identify host factors associated with resistance to TIL therapy and optimize manufacturing processes to create more effective TIL cell therapy. Clinical trial information: NCT03610490.

3563 Background: The prognosis of metastatic colorectal cancer (mCRC) patients with RAS gene mutation and microsatellite stable (MSS) is poor. MSS patients account for 95% of CRC and have a low response rate to immunotherapy. Previous studies have reported that chemotherapy and anti-angiogenesis therapy can promote immunotherapy response. This study aims to assess the safety and antitumor activity of sintilimab (IBI308) combined with CapeOx and bevacizumab in the first-line treatment of patients with RAS-mutant and MSS mCRC. Methods: This is an open-label, single-arm, phase II trial. Eligible patients were aged 18 to 75 years with histologically confirmed unresectable metastatic colorectal adenocarcinoma by multidisciplinary team, and had RAS gene mutation and confirmed MSS status. All patients received treatment with sintilimab (200 mg, day 1) plus bevacizumab (7.5mg/kg, day 1) and oxaliplatin (135 mg/m2, day 1) and capecitabine (1g/m2, bid, day 1-14) of each 21-day cycle. The primary endpoint included objective response rate (ORR) evaluated via RECIST 1.1 criteria and adverse events according to CTCAE 5.0. Secondary endpoint was progression-free survival (PFS). Results: 25 patients were enrolled and received at least two cycle treatment. At baseline, median age was 60 years (range 45-74), 72% of patients were male, ECOG PS 0/1 was 100%, 60% had liver metastases (mets), and the primary tumor site was right-sided colon in 36.0% and left-side colorectum in 64.0%. 25 patients completed at least one efficacy evaluation. 2 (8.0%) patients showed complete response (CR), 19 (76.0%) patients had a partial response (PR) and 4 (16.0%) had stable disease (SD). Patients with liver or lung mets had a higher ORR (93.3% and 100%, respectively) compared to the overall ORR (84.0%). Disease control rate (DCR) reached 100%. Median PFS has not yet reached. No grade 5 adverse events occurred. The most common treatment-related adverse events (TRAEs) in all grades were anemia (19/25, 76.0%), peripheral neurotoxicity (6/25, 24.0%) and neutropenia (17/25, 68.0%). The most frequent grade 3/4 TRAEs were neutropenia (3/25, 12.0%), elevated aspartate transaminase (1/25, 4.0%), elevated alanine transaminase (1/25, 4.0%) and elevated bilirubin (1/25, 4.0%). Conclusions: Combination treatment with sintilimab (IBI308) plus CapeOx and bevacizumab demonstrated a high ORR (84.0%; 93.3% in patients with liver mets, and 100% in patients with lung mets) and a manageable safety profile in RAS-mutant and MSS mCRC. Clinical trial information: NCT05171660. [Table: see text]

1588 Background: Emerging clinical studies report correlation of time-of-day infusion (TOI) to immunotherapy outcomes and the intricate interplay of the human circadian rhythm and cancer and immunotherapy exposure. Preclinical and clinical studies have shown cancer chronotherapy to play important role in transcriptional rhythmicity of oncogenic process. We evaluated the association of TOI and immunotherapy outcomes in a large cohort to determine impact of TOI on overall survival (OS) and progression free survival (PFS). Methods: We reviewed charts of patients with solid tumors who received immunotherapy, specifically anti programmed cell death protein 1 (PD1) and anti-programmed death-ligand 1 (PD-L1) agents at MD Anderson Cancer Center. Infusion times were divided into two hours cohorts from 8am-8pm and one overnight cohort from 8pm-8am. Accelerated failure time models were used to model OS (log-normal distribution) and PFS (Weibull distribution) with relation to TOI after adjusting for factors such as age, gender, tumor type and prednisone > 10mg daily use within 1 month of immunotherapy initiation to minimize confounding factors. Results: Of 6151 patients with advanced tumors, 4441 patients received immunotherapy therapy after adjusting for minimum 140 patients in each tumor cohort from 10/15/2016 until 10/15/2021. Tumor types included advanced lung cancer (31.4%), melanoma (28.7%), renal (14.4%), breast (7.6%), colon (6.2%), liver cancer (3.9%) and head and neck (H&N) cancers (2.8%). Median age was 63 (15-99) with 58% males and 42% female. 1894 (43%) patients received investigational agents and 2547 (57%) received standard of care therapies. Mechanism of action of various agents: anti PD1, anti-PDL1, TGF-βRII and anti-PDL1, anti-PD-1 with OX40+ T Cell activation, PD-1 / PD-L1 bispecific antibody, PD-L1 dependent 4-1BB agonist and anti PD-1 and CTLA-4 activity. Among all patients, median OS was 26.4 months while median PFS was 4.8 months. Preponderance of immunotherapy TOI occurred between 12-2pm and 2-4pm in all patients. Patients receiving overnight TOI with lung, renal and breast cancer demonstrated significantly (p < 0.05) poorer OS compared to TOI (10am-4pm) whereas in melanoma, significantly lower OS was seen with overnight, 8-10am and 6-8pm compared to 10am-4pm TOIs. Among H&N cancer patients, early TOI (8-10am) was associated with significantly lower OS compared to afternoon TOI (12pm-4pm). PFS trends were less distinct than for OS but showed a slighted inverted tendency towards lower PFS following daytime TOI. Conclusions: In this large cohort of patients treated with immunotherapy, clinically significant association of TOI with overall survival is seen. These intriguing findings warrant prospective validation in a future randomized trial to harness the role of chronomodulation of cancer therapies for improving outcomes.

3591 Background: Raltitrexed-based chemotherapy regimen is one of the common regimens for the treatment of metastatic colorectal cancer (mCRC). This prospective observational real-world study aimed to evaluate the safety and effectiveness of raltitrexed administered to Chinese patients with mCRC in real life setting. Methods: This is a prospective, multicenter, real-world study. Prospectively registered Patients received second-line treatment of raltitrexed plus irinotecan combined with or without target therapy until progression disease or unacceptable toxicity. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), quality of life (QOL) and safety. Totally,1000 patients were required for primary point testing. Results: Between May 2018 and December 2021,a total of 1039 patients from 57 centers were screened for enrollment,among which 271 patients were treated with raltitrexed plus irinotecan, 753 patients accepted target therapy (bevacizumab or cetuximab) additionally, and 15 patients combined with other drugs. Overall mPFS was 6.8 months (95%CI: 6.5-7.1),ORR was 20.2%, and DCR was 85.7%; The ORR of combined with or without target therapy were 21.6% and 16.2% ( p = 0.038),respectively, the DCR were 88.2% and 79.0% ( p < 0.001). The mPFS of combined without or with target therapy were 5.2 months (95% CI: 4.7 to 5.7) and 7.3 months respectively (95% CI: 7.0-7.7) [HR = 0.67, 95% CI 0.56̃0.80, p < 0.001], The mPFS of combined with bevacizumab or cetuximab were 7.4 months (95% CI: 7.0 -7.8) and 6.8 months (95% CI: 5.9-7.7) [HR = 1.15, 95% CI 0.88̃1.51, p = 0.3]. mOS has not yet reached. Majority of treatment-related adverse events (TEAEs) were grade I or II. The most common grade III or IV TRAEs reported by 116 patients (11.2%) were aspartate aminotransferase increased (4.0%), alanine aminotransferase increased (3.7%), neutrocytopenia (2.7%), glutamyltransferase increased (2.5%), leukocytopenia (1.1%). Conclusions: The real-world study confirmd that raltitrexed was an effective and safe regimen for the second-line treatment in Chinese patients with mCRC, especially combined with target therapy additionally, which was aligned with previous trials. Clinical trial information: ChiCTR1800016185.

4126 Background: Surufatinib is a small-molecule inhibitor of VEGFR1, 2, & 3, FGFR1, and CSF-1R. Surufatinib demonstrated prolonged PFS and tolerable safety in two phase 3 studies in advanced neuroendocrine tumors (NETs) of pancreatic (SANET-p; NCT02589821) and extrapancreatic (SANET-ep; NCT02588170) origin (Xu, 2020 Lancet Oncology). Detailed outcomes on safety from these 2 studies are reported here as a pooled analysis. Methods: Data is pooled from SANET-p and SANET-ep studies which have similar designs including a 2:1 randomization of surufatinib to placebo in patients ≥18 years with advanced, well differentiated NETs, progressing on or after ≤2 prior therapies. Surufatinib 300 mg or placebo, was administered once daily until disease progression or unacceptable toxicity. Safety outcomes for each pooled treatment group are reported as treatment-emergent adverse events (TEAE) assessed by NCI-CTC 4.03. Patients were included if they had received study treatment during the double-blinded phase of the studies. Results: As of 30th June 2020, 396 patients were assigned to the surufatinib (n = 263) and placebo (n = 133) groups. Median treatment duration was longer with surufatinib 7.4 months (range 0.1–41.4) compared with placebo 4.6 months (range 0.1–39.9). 29% of patients reached more than 12 months of treatment with surufatinib group compared to 11% with placebo. The mean relative dose intensity was 87.56% in the surufatinib group and 97.01% in the placebo group. Most common TEAEs (surufatinib vs placebo) were proteinuria 68.8% vs 54.9%, hypertension 68.4% vs 27.1%, and diarrhea 49% vs 22.6%. Most common grade ≥3 TEAE were hypertension 38.8% vs 13.5%, proteinuria 14.8% vs 0.8% and hypertriglyceridaemia 5.3% vs 0%. Deaths due to TEAEs were comparable between groups 2.7% vs 2.3%. TEAEs led to dose reductions in 43.0% vs 6.8% of patients and dose interruptions in 47.1% vs 29.3% of patients. The majority of patients (83.3% vs 93.2%) were managed without discontinuation because of TEAE. Median onset of proteinuria and hypertension were < 1 month in both groups. Median (range) onset was 0.95 months (0.16–30.36) vs 0.95 months (0.23–16.95) for proteinuria and 0.49 months (0.03–31.18) vs 0.89 months (0.03–14.75) for hypertension. Among patients with hypertension, 59% (n = 111) vs 28% (n = 11) received antihypertensive medication. Conclusions: Surufatinib was generally well tolerated in this pooled analysis and the safety profile was consistent with its previously reported data. The monitoring and management of hypertension and proteinuria are important for patients receiving surufatinib. Clinical trial information: NCT02589821; NCT02588170. [Table: see text]

5522 Background: Neoadjuvant chemotherapy has demonstrated limited activity in low-grade serous carcinomas (LGSOC) of the ovary, fallopian tube, and peritoneum, with objective response rate of 11% and complete gross resection (CGR) rate of 38% at the time of interval cytoreductive surgery (ICS). LGSOC has many similarities to hormone receptor positive (HR+) breast cancer, including clinical benefit from endocrine therapies in the recurrent and maintenance settings. Based on the activity of antiestrogen plus CDK4/6 inhibitor combination therapy in HR+ breast cancer, we conducted a phase II pilot study to assess the clinical benefit of neoadjuvant treatment with fulvestrant and abemaciclib for women with advanced LGSOC. Methods: Women with unresectable, untreated stage III or IV LGSOC of the ovary, fallopian tube or peritoneum were eligible. Patients received fulvestrant (500 mg IM on day 1 and 15 of the first 28-day cycle, followed by day 1 of subsequent cycles) and abemaciclib 150 mg orally BID. Pre/perimenopausal patients also received goserelin 10.8 mg subcutaneously every 12 weeks for ovarian suppression. Patients continued treatment until deemed resectable by the treating surgeon with imaging re-assessment every 8 weeks using RECIST 1.1. Following ICS, patients receive 4 cycles of adjuvant fulvestrant and abemaciclib and then transition to maintenance letrozole. Patients with progressive disease (PD) were removed from study and received standard of care chemotherapy. Primary endpoint is clinical benefit rate (CBR). Results: Fifteen patients were enrolled and evaluable. At data cutoff date (January 20, 2022), 7 of 15 patients (47%) had partial response (PR) (one patient with radiologic PR had a pathologic complete response at ICS), 5 of 15 (33%) had stable disease (SD), and 3 of 15 (20%) had progressive disease (PD), resulting in a CBR of 80%. Of the 7 patients with PR, 3 have had ICS with CGR, 3 have not yet had ICS, and 1 underwent resection of supraclavicular disease with small volume residual disease in the chest. Of the 5 patients with SD, one underwent ICS with CGR, and two have been on treatment for 8 and 16 weeks with reduction in measurable disease but not yet deemed to be candidates for surgery. Four of the 5 patients (80%) who had ICS, had CGR. Median time on study prior to surgery was 24 weeks. Adverse events (grade 3 or 4) possibly related to abemaciclib occurred in 2 patients (13.3%) and included acute kidney injury (6.7%) and neutropenia (6.7%). Conclusions: Neoadjuvant treatment with fulvestrant and abemaciclib was tolerable and demonstrated unprecedented response and CGR rates in this pilot study. These results compare favorably to published outcomes of neoadjuvant chemotherapy in LGSOC. Further studies are planned to explore this new treatment option in a larger study population. Clinical trial information: NCT03531645.

e24002 Background: Illness beliefs are important determinants of self-management behaviors (SMBs). Spousal or informal caregiver involvement improves clinical outcomes in non-cancer survivors with chronic diseases. However, very little is known about the influence that caregivers have on comorbid disease SMBs in cancer survivors. In this study, we aim to understand and identify concordance in illness beliefs and perceptions between caregivers and prostate cancer survivors and to determine their impact on hypertension (HTN) SMBs. Methods: Survivors and their caregivers completed surveys assessing their beliefs and perceptions and SMBs regarding survivors’ HTN. Both survivors and caregivers answered the Brief Illness Perception Questionnaire (BIPQ) to assess beliefs and perceptions of survivors’ HTN. The BIPQ score is a sum of eight questions with a higher sum score indicating a more threatening view of the illness. Survivors reported adherence to SMBs using the Medication Adherence Report Scale (MARS) and Hypertension Self-Care Activity Level Effects (HSCALE). MARS scores >4.5 were considered adherent. The HSCALE isdivided into five sub-scores – diet, physical activity, smoking behavior, weight management and alcohol intake and each was score was dichotomized. Cohen’s Kappa statistic assessed concordance between survivor and caregiver dyad responses to the BIPQ. Logistic regression assessed associations between survivor and caregiver BIPQ scores and odds of SMB adherence. Results: This analysis included 55 dyads. Mean age of survivors was 70.4 years ± 9.6; 12 (22%) were Black, 36 (65%) were White, 2 (4%) were Asian and 3 (5%) were other race. Mean age of caregivers was 64.4 years ± 10.5, 9 (16%) self-identified as Black, 35 (64%) White, 2 (4%) Asian and 3 (5%) other race. Survivors and caregivers had fair agreements about how much HTN affected survivors’ lives (k = 0.147, p = 0.008), how concerned survivors are about their HTN k = 0.130, p = 0.014), and HTN’s emotional impact on survivors (k = 0.185, p = 0.002). However, survivor-caregiver concordance about HTN had no significant impact on survivors’ SMBs. In contrast, caregivers’ beliefs about HTN was associated with survivors’ SMB such that a 1-point increase in caregiver’s BIPQ score was associated with 8% increase in the odds of survivors’ self-reported weight adherence (p = 0.0314). Survivors’ HTN beliefs were not associated with adherence to SMBs. Conclusions: Caregivers have a significant influence on prostate cancer survivors’ adherence to weight-related SMB, demonstrating that it is important to also educate caregivers who support cancer survivors with chronic comorbidities. Future analysis will include a larger cohort to better understand the interrelationship between caregivers’ illness beliefs and survivors’ SMBs and may help clinicians better direct interventions to improve survivorship outcomes.

3110 Background: IBI351(GFH925) is an irreversibly covalent inhibitor of KRASG12C. In this first-in-human dose-escalation study, we report the preliminary safety and anti-tumor activity of IBI351 (GFH925) in patients (pts) with advanced solid tumors harboring the KRAS p.G12C mutation. Methods: Pts with locally advanced, recurrent or metastatic solid tumors with KRASG12C mutation for whom standard therapy had failed were enrolled. Phase I dose escalation had an accelerated titration design for dose level 250mg QD and a BOIN design with 450/700/900mg QD. The primary end points were safety and tolerabilityThe secondary end points were pharmacokinetics (PK) and anti-tumor activity of IBI351(GFH925) monotherapy per RECIST v1.1. Results: As of Feb 07 2022, 15 pts (13 men, 2 women; median age: 62 yrs, range: 48–74 yrs) were enrolled, among whom 12 had non-small cell lung cancer (NSCLC), and 3 had colorectal cancer (CRC). 4 pts had ≥3 prior lines of treatment (tx). Median tx duration was 66.5 ds (range: 21–98 ds). No dose-limiting toxicity (DLT) or any ≥grade 3 treatment-related adverse events were observed in any dose cohorts. A total of 12 patients (80.0%) had treatment-related adverse events (grade 1, n = 6; grade 2, n = 6). By investigator-assessment, tumor response was evaluated in 9 pts (4 with ≥2 assessments); 6 pts had not reached their first assessment. 2 pts had PR (1 NSCLC at wks 12, 450mg, tx ongoing; 1 CRC at wks 6, 700mg, tx ongoing), 4 pts (NSCLC) had SD, and 3 pts had PD (1 NSCLC at wks 12, 2 CRC at wks 6). As data cut-off date, 11 pts were continuing to receive IBI351 (GFH925). Conclusions: IBI351(GFH925) was well-tolerated without unanticipated adverse events across all doses explored in pts with advanced solid tumors harboring the KRAS p.G12C mutation. The data also demonstrated the preliminary efficacy signal of IBI351 (GFH925) in previously treated advanced NSCLC and CRC. Clinical trial information: NCT05005234.

3577 Background: Dual blockade of immune checkpoint and angiogenesis is an effective strategy for multiple cancers. We initiated an open-label, multicenter phase II basket study to evaluate the antitumor activity and safety of camrelizumab (an anti-PD-1 antibody) plus famitinib (a receptor tyrosine kinase inhibitor) in patients (pts) with advanced solid tumors. Herein, we report the results from the metastatic colorectal cancer (mCRC) cohort. Methods: Pts with histologically confirmed mCRC, who had received previous irinotecan, oxaliplatin, and fluoropyrimidine combination chemotherapy, and progressed after ≥ 2 lines of systemic treatment were enrolled to receive camrelizumab (200 mg i.v. every 3 weeks) and famitinib (20 mg orally once daily). Primary endpoint was objective response rate (ORR) per RECIST version 1.1. Results: Between Jul 10, 2020, and Jul 12, 2021, of all the 44 mCRC pts enrolled, 14 (31.8%) pts had colon cancer (CC) and 30 (68.2%) pts had rectal cancer (RC). As of Nov 30, 2021, the median time from enrollment to data cutoff was 10.6 months (range, 4.7-16.7). The ORR was 13.6% (95% CI, 5.2-27.4) and the DCR was 45.5% (95% CI, 30.4-61.2) in all mCRC pts. Of them, no pts with CC achieved response; six pts with RC achieved PR, with the ORR of 20.0% (95% CI, 7.7-38.6) and the DCR of 46.7% (95% CI, 28.3-65.7). Pts with RC showed a median duration of response (DoR) of 7.1 months (95% CI, 2.3-not reached [NR]). The median overall survival (OS) was 15.2 months (95% CI, 7.2-NR) in pts with RC. Of all 44 mCRC pts, 28 (63.6%) had grade 3 or higher treatment related adverse events (TRAEs), mainly hypertension (25.0%), proteinuria (18.2%), decreased platelet count (11.4%), decreased neutrophil count (11.4%) and palmar-plantar erythrodysaesthesia syndrome (11.4%). Three (6.8%) pts discontinued any study treatment due to TRAEs. No grade 5 TRAE was reported. Conclusions: Camrelizumab plus famitinib appeared to show encouraging antitumor activity in pts with mCRC, especially in those with RC, and the safety profile of this combination regimen seemed to be manageable and consistent with single agent alone. Clinical trial information: NCT04346381. [Table: see text]

e14556 Background: TIS is an anti-programmed cell death protein-1 antibody engineered to minimize binding to FcγR on macrophages to abrogate antibody-dependent phagocytosis. Primary results from this single-arm, multicenter, open-label, Phase 2 study evaluating TIS in pts with MSI-H/dMMR solid tumors, showed a clinically meaningful improvement in the objective response rate (ORR) for this patient population. Here we report results from the updated analysis (NCT03736889). Methods: Eligible adult pts with previously treated, locally advanced, unresectable/metastatic histologically confirmed MSI-H/dMMR solid tumors with ≥ 1 measurable lesion (RECIST v1.1) and an Eastern Cooperative Oncology Group performance status of ≤ 1 were enrolled. Pts received TIS 200 mg intravenously every 3 weeks until disease progression, unacceptable toxicity, or withdrawal. The efficacy analysis set were all pts who received any dose of TIS with measurable disease per independent review committee (IRC) at baseline. The primary endpoint was IRC-assessed ORR (RECIST v1.1). Secondary endpoints included duration of response (DoR), time to response (TTR), disease control rate (DCR), progression-free survival (PFS) (all IRC-assessed [RECIST v1.1]), overall survival (OS), and safety. Programmed death ligand 1 (PD-L1) immunohistochemistry assay (Ventana SP263) was applied retrospectively. Results: Between Sep 2018–Jul 2021, 80 pts were enrolled (median age 53 years; range 19–81 years) and 75 were included in the efficacy analysis set. In this updated efficacy analysis set, at a median follow-up of 15.2 months, ORRIRC was 46.7% (n = 35; 95% CI 35.1, 58.6) in all tumor types (1-sided p < 0.0001), including 5 complete responses (CR) and 30 partial responses (PR). ORRIRC was 39.1% (n = 18; 95% CI 25.1, 54.6) in colorectal cancer (CRC) pts (N = 46), 55.6% (n = 5; 95% CI 21.2, 86.3) in G/GEJC pts (N = 9), and 60.0% (n = 12; 95% CI 36.1, 80.9) in other pts (N = 20). Of the pts who responded (n = 35), one patient had disease progression. Median DoR was not reached, median TTRIRC was 11.9 weeks (range 8.4–98.9) and DCR was 72.0% (95% CI 60.4, 81.8). Median PFSIRC was not reached (95% CI 7.5, not estimable [NE]). Median OS (safety analysis set) was not reached (95% CI 28.7, NE). No clear association was observed between PD-L1 expression and clinical efficacy. Treatment-emergent adverse events (TEAEs) ≥ Grade 3 occurred in 48.8% (n = 39) of pts. The most common ≥ Grade 3 TEAE was anemia, 10.0% (n = 8). Immune-mediated TEAEs ≥ Grade 3 were 8.8% (n = 7). Conclusions: With a longer follow up time, TIS demonstrated clinically meaningful improvement in ORR in pts with MSI-H or dMMR solid tumors. TIS was generally well tolerated, with no new safety signals. These data support TIS as a new treatment option for this patient population. Clinical trial information: NCT03736889.

TPS3638 Background: Refractory RAS mutated MSS mCRC represents a critical unmet need with minimal response to immune checkpoint blockade (ICB). Preclinical CRC models reveal that KRAS mutations activate the CXCR2 axis promoting an immunosuppressive tumor microenvironment (TME). This occurs via KRAS repression of interferon regulatory factor 2 (IRF2) resulting in upregulation of CXCL3 chemokines, which bind CXCR2 and recruit myeloid-derived suppressor cells (MDSC; Liao et al, Cancer Cell 2019; Grover et al, Cancer Discovery, 2022). SX-682 is a novel oral small-molecule inhibitor of the CXCR1/2 chemokine receptors involved in MDSC-recruitment to the TME. This proof-of-concept study investigates whether de novo immunotherapy resistance in MSS RAS mutated mCRC can be overcome by treatment with a small molecule CXCR1/2 antagonist in combination with anti-PD-1 therapy. Methods: STOPTRAFFIC-1 (NCT04599140, enrolling) is a phase I/II, open-label, dose-escalation/dose expansion study of SX-682 in combination with nivolumab to evaluate safety and clinical activity for patients (pts) with refractory RAS ( KRAS and NRAS) mutated MSS mCRC. Key eligibility criteria: patients (pts) with MSS mCRC with measurable disease, progression or intolerance to at least 2 prior lines of standard therapy, and ECOG 0 or 1. Pts will receive SX-682 (5 dose levels: 25 mg, 50 mg, 100mg, 200mg, or 400 mg by mouth twice daily) administered in an 8-week cycle with intravenous nivolumab (480 mg) on days 1 and 29 of each cycle. Adverse events are assessed according to CTCAE v5.0. Response assessments (per RECIST) occur every 8 weeks. In dose escalation, pts enter a 3-week monotherapy safety run-in of SX-682 followed by 3-week combination with nivolumab for a six-week dose-limiting toxicity (DLT) period. Cohorts 1-4 have been completed without DLT. Enrollment to cohort 5 began in January 2022. Following determination of maximum tolerated dose (MTD), dose expansion design is a Simon's optimal two-stage design. Efficacy will be assessed in the first 15 pts with a requirement of at least 2 responses in order to enroll 14 additional pts (N=29) in the second stage. Pre- and on-treatment tissue biopsies will be collected in the expansion phase. The primary objectives are to determine the safety profile of SX-682 alone and in combination with nivolumab, including the MTD, recommended phase 2 dose, and the DLT. The secondary objectives include overall response rate, progression-free survival, overall survival, and pharmacokinetic profiles of SX-682. Translational analyses include correlations of clinical outcomes with genomic and immune biomarkers from paired tissue and plasma samples. Clinical trial information: NCT04599140.

3111 Background: Ongoing trials are exploring ATR inhibitors (ATRi) in genomically selected contexts. However, myelosuppression, particularly anemia, has limited the therapeutic window of this class of drugs. We sought to discover clinical biomarkers predicting severe hematological toxicity from ATRi. Methods: We retrospectively analyzed clinical parameters and peripheral blood cell indices retrieved from complete blood count (CBC) reports of patients (pts) pre- and during treatment with an oral ATRi on phase I/II trials at our center. Pts received ATRi monotherapy or in combination with a PD1 inhibitor (PD1i) or a PARP inhibitor (ATRi+PARPi) in dose-escalation and expansion cohorts, which included ATRi at potentially toxic doses. Results: 37553 indices from 2209 CBC reports of 141 pts treated with an ATRi from 10/2017 to 1/2022 were analyzed. 132 (93.6%) pts received ATRi +/- PD1i; 9 (6.4%) pts received ATRi+PARPi. The incidences of ≥ grade (G) 3 anemia, neutropenia and thrombocytopenia were 47.5%, 31.9% and 11.4%. 73/141 (51.8%) pts received red cell transfusion. Baseline risk factors predicting ≥G3 anemia on univariate analysis included: lower median (med) hematocrit (Hct) (hazard ratio (HR) (95% confidence interval) = 3.05 (1.82, 5.13) ≤med vs > med; p < 0.0001), hemoglobin (Hb) (HR = 2.74 (1.64,4.57) ≤med vs > med; p = 0.0001), mean corpuscular Hb concentration (HR = 1.85 (1.11,3.10) ≤med vs > med; p = 0.019); and higher median immature reticulocyte fraction (HR = 0.43 (0.25,0.71) ≤med vs > med; p = 0.0012), reticulocyte count (ct) (HR = 0.59 (0.35,0.97) ≤med vs > med; p = 0.037) and red cell distribution width (RDW) (HR = 0.54 (0.33,0.88) ≤med vs > med; p = 0.015). On multivariate analysis, lower median Hct (HR = 3.76 (2.15, 6.6) ≤med vs > med; p < 0.0001), higher immature granulocyte ct (HR = 1.71 (1.30, 2.25) per 1 fold increase; p = 0.0001), higher RDW (HR = 7.83 (1.70, 36.03) per 1 fold increase; p = 0.0082) and higher ATRi starting dose (HR = 1.40 (1.05, 1.86) per 1 fold increase; p = 0.022) significantly predicted ≥G3 anemia risk. Baseline risk factors for ≥G3 neutropenia on univariate analysis included: lower median absolute neutrophil ct (ANC) (HR = 2.26 (1.18, 4.33) ≤med vs > med; p = 0.015) or white blood cell ct (WBC) (HR = 2.73 (1.40, 5.33) ≤med vs > med; p = 0.0032). On multivariate analysis, lower median WBC (HR = 2.85 (1.45, 5.59) ≤med vs > med; p = 0.0024) was associated with higher risk of neutropenia, while ATRi+PARPi increased risk of neutropenia (ANC < 0.75) (HR = 4.15 (1.40, 12.3); p = 0.01) and thrombocytopenia (HR = 3.90 (1.47, 10.4); p = 0.0064). Conclusions: ≥G3 anemia was frequent in pts receiving ATRi. At baseline, lower median Hct and higher RDW predict severe anemia, while lower WBC predicts neutropenia from ATRi. ATRi+PARPi has increased risk of neutropenia and thrombocytopenia vs ATRi +/- PD1i. These indices may inform patient selection and CBC monitoring for future ATRi trials.

2569 Background: Tislelizumab is an anti-programmed cell death protein 1 antibody engineered to minimize binding to FcγR on macrophages to abrogate antibody-dependent phagocytosis. In early phase clinical studies, tislelizumab monotherapy was generally well tolerated and had antitumor activity in patients (pts) with solid tumors, including microsatellite instability-high (MSI-H) or mismatch-repair-deficient (dMMR) solid tumors such as colorectal cancer (CRC). Methods: This single-arm, multicenter, open-label, phase 2 study evaluated the efficacy and safety of tislelizumab monotherapy in adult Chinese pts with previously treated, locally advanced, unresectable or metastatic histologically confirmed MSI-H/dMMR solid tumors by central lab. Pts received tislelizumab 200 mg intravenously every 3 weeks until disease progression, unacceptable toxicity, or withdrawal. Radiological imaging was performed at 9 weeks then every 6 weeks for the first year of therapy and every 12 weeks thereafter. The primary efficacy analysis set was all pts who received any dose of tislelizumab with measurable disease per independent review committee (IRC) at baseline. The primary endpoint was IRC-assessed overall response rate (ORR; RECIST v1.1). Secondary endpoints included duration of response (DoR) and disease control rate. Using a binomial exact test, the null hypothesis of ORR=10% (historical rate) was rejected if 1-sided p≤0.025. Results: Between Sep 2018-Aug 2020, 80 pts were enrolled (median age 53 years; range 19-81 years) and 74 were included in the primary efficacy analysis set. At median study follow-up of 11.78 months, ORR by IRC was 45.9% (n=34/74; 95% CI 34.3, 57.9) in all tumor types (1-sided p

e13579 Background: Many trial designs with futility or toxicity monitoring require that accrual halt to wait for currently enrolled patients to complete their assessment window. However, logistics often prevent this. In these cases, the performance of those designs might be compromised. This study examines the performance of 2 popular designs when enrollment is not halted at interim. Methods: Simulations were run to examine the effect of continuous enrollment on the operating characteristics (OCs) of a Simon’s 2-stage design for futility monitoring and a design using Bayesian posterior probabilities for toxicity monitoring. Both sets of 10,000 simulations examined the OCs when accrual rate was 0.5, 1.5, 3 and 5 patients/month with an assessment window of 30, 60 and 180 days. Results: The first scenario examined the OCs of a Simon design with 12 patients in the first stage and 21 at the end of the second stage. Regardless of accrual rate, the expected number of patients (EN0) increased and probability of early termination (PET0) decreased under the null hypothesis. Rate of change increased as assessment window increased. EN0 was 16 and PET0 was 54% when halting enrollment between stages. With continuous enrollment, EN0 ranged from 16-19, 17-21, and 18-21 patients for the 30-, 90- and 180-day assessment windows. PET0 ranged from 54%-50% with a 30-day assessment window. It halved to 24% with 3 patients/month enrolled and a 90-day window. PET0 was essentially 0 with a 180-day window and an enrollment of 3 patients/month. OCs for toxicity monitoring were examined for the early stopping rule Pr(toxicity rate > 0.3 | data) > 0.85 with toxicity rate ̃ beta(1, 1) with a maximum sample size of 20 and cohort size of 5. Expected number of patients (EN) increased and probability of early termination (PET) decreased as accrual rate increased, with rate of change increasing as assessment window increased. When the true probability of toxicity was 50% and enrollment halted between cohorts, EN was 10 patients and PET was 78%. EN was 17 and PET 54% with an assessment window of 30 days and 5 patients were enrolled per month. With a 90-day assessment window and 3 patients/month enrolled, EN was 16 and PET 59%. EN was 20 and PET was 12% with a 180-day assessment window and 3 patients were enrolled per month. Similar results were noted for cohorts of size 10 and a maximum number of 40 patients. Conclusions: The performance of designs that require halting enrollment while waiting for results of an interim analysis can be compromised by continuous accrual when assessment windows are lengthy and the accrual is fast. In these circumstances, consideration should be given to designs, such as Bayesian multiple imputation for delayed outcomes (Cai et al Stat Med 2014) and TOP2 (Lin et al JNCI 2019), that do not require accrual halt to make real-time interim analysis in the presence of pending patients, which protects patients from excessive toxicity or a futile intervention.

TPS2067 Background: Resection (R) followed by single or multi-fraction stereotactic radiosurgery (SRT) of brain metastases lowers resection bed recurrence compared to R alone. Nevertheless, for larger (>2.5cm) brain metastasis, 12-month recurrence rates after R+SRT can exceed 20–30%. Aiming to improve outcomes, a permanently implanted collagen tile brachytherapy device (GammaTile or GT, GT Medical Technologies, Tempe, AZ) utilizing Cs-131 seeds embedded within a bioresorbable collagen tile was developed and is described as Surgically Targeted Radiation Therapy (STaRT) to distinguish it from external beam radiation therapy. It is hypothesized that immediate adjuvant radiotherapy (RT) and/or RT dose intensification could improve outcomes. The device is FDA-cleared for this indication and early commercial use is demonstrating favorable safety and efficacy outcomes. STaRT allows rapid dose delivery of radiation therapy directly to the tumor bed with predictable dosimetry immediately at the time of resection, and an intense but localized radiation treatment, which may confer a reduced risk for radiation necrosis compared to other therapies. The device is easily placed with minimal additional operative time and limited staff radiation exposure. It is hypothesized that R+ STaRT will increase the surgical bed recurrence-free survival, while reducing the impact on functional and neurocognitive status compared to R+SRT. Methods: Multicenter, randomized, comparison trial of patients with resectable, previously untreated “index” brain metastases measuring ≥2.5–5 cm, and 0–3 other tumors, will be preoperatively randomized 1:1 to undergo either R+ SRT or R+STaRT to the index lesion; unresected tumors in both groups will receive SRT. Planned sample size is 180 from 13 sites. Enrollment will open in Q1. Primary endpoint is surgical bed-recurrence free survival. Secondary endpoints include overall survival, quality of life (Functional Assessment of Cancer Therapy-Brain, Linear Analog Self-Assessment), neurocognition (Hopkins Verbal Learning Test, Trail Making Tests, Controlled Oral Word Association), functional status (Karnofsky Performance Scale, Barthel-ADL), and adverse events. Follow-up will be at 1,3,6,9, and 12 months, then every 6 months through 24 months. This will be the first randomized trial comparing R+SRT versus R+STaRT delivered by Cs-131 sources in permanently implanted resorbable collagen tile carriers. Primary and secondary outcome measures will be captured to elucidate the potential risks and benefits of these two differing post-operative RT delivery methods in the setting of newly diagnosed metastatic brain tumors. Clinical trial information: NCT04365374.

e15564 Background: Antiangiogenic therapy plus chemotherapy is one of the standard treatments in mCRC. Anlotinib, an oral small multi-targeted tyrosine kinase inhibitor targeting VEGFR 1/2/3, FGFR 1-4, PDGFR α/β and c-kit, has demonstrated prolonged PFS in refractory mCRC. This trial was conducted to evaluate the efficacy and safety of anlotinib combined with CAPEOX as first-line treatment for unresectable RAS/BRAF wild-type mCRC. Methods: Patients aged 18-75, with RAS/BRAF wild-type unresectable mCRC, without prior systemic treatment and ECOG status ≤ 1were enrolled in 3 hospitals in Zhejiang, China. Enrolled patients received capecitabine (850 mg/m2 p.o., bid, on day 1-14 every 3 weeks), oxaliplatin (130 mg/m2 i.v., on day 1 every 3 weeks) and anlotinib (12 mg p.o. qd, on day1-14 every 3 weeks) as inducing therapy. After 6 cycles of combined therapy, patients who achieve complete response (CR)/ partial response (PR)/ stable disease (SD) would receive capecitabine and anlotinib as maintenance therapy until tumor progression. The primary endpoint is objective response rate (ORR); secondary endpoints included safety, disease control rate (DCR) and progression-free survival (PFS). Results: From November, 2019 to February, 2021, 31 patients had been enrolled. 1 patient was excluded for refused treatment. By now, 27 patients received at least 2 cycles of treatment and were available for efficacy evaluation: 22 patients had partial response (PR), 5 patients had stable disease (SD). The ORR was 81.5% (95% CI: 61.9–93.7%), and DCR was 100% (95% CI: 87.2–100%).1 patient received radical surgery after 6 cycles of treatment. The median PFS has not been reached yet. The most common grade≥3 AEs included hypertension (45.2%), neutropenia (25.8%) and diarrhea (12.9%). No treatment-related deaths occurred. Conclusions: The combination of anlotinib and CAPEOX showed promising antitumor activity and manageable toxicity in unresectable RAS/BRAF wild-type mCRC. Furthermore, we are launching a phase 3, multicenter, double-blind trial to further assess the efficacy of this regimen. Clinical trial information: NCT04080843. [Table: see text]

e14547 Background: MSB2311 is a novel humanized PD-L1 antibody with a unique pH-dependent antigen binding property that enables intra-tumor recycling and potentiates tumor penetration. Methods: Patients with metastatic solid tumors or selected lymphoma progressed on or after standard treatments were enrolled in this phase I study. In dose escalation part, MSB2311 was given at dose levels of 3, 10, and 20 mg/kg intravenously every 3 weeks. At the dose expansion part, patients with enriched biomarker expression, including EBV+, PD-L1+ (TPS≥50%), MSI-High or TMB-High (≥10muts/Mb), were dosed at 20mg/kg Q3W or 10mg/kg Q2W. Primary objectives are to evaluate the safety and tolerability and to identify MTD and RP2D. Secondary objectives include the assessment of pharmacokinetic parameter, immunogenicity, and preliminary anti-cancer activity per RECIST1.1. Results: As of data cutoff by Aug 31, 2020, 33 Chinese patients had been treated, including 27 heavily pre-treated solid tumor patients and 6 lymphoma patients. No dose limiting toxicity was reported and MTD has not been reached. The most common AEs (>20%) included: anemia, hypothyroidism, aspartate aminotransferase elevated, proteinuria, weight loss. 13 patients (39.4%) experienced grade 3 AEs, and 6 patients (18.2%) experienced SAEs. No treatment related grade 4 or 5 event was reported. Of the 17 efficacy evaluable solid tumor patients with biomarker selection, 6 achieved confirmed partial response with 35% ORR: 2/8 (25%) at 10 mg/kg Q2W and 4/9 (44%) at 20 mg/kg Q3W. Additionally, one patient achieved sustained iPR via iRECIST. 4 out of 7 responding patients (including one iPR) achieved tumor shrinkage of more than 50%, 3 of them got durable response (≥24 weeks).1 out of 6 lymphoma patients achieved PR. Conclusions: MSB2311 demonstrated a manageable safety profile and promising preliminary antitumor activity in patients with advanced solid tumors and selected lymphomas. Clinical trial information: NCT04272944.

5505 Background: Wee1 phosphorylates and inhibits cyclin-dependent kinases 1 and 2 and is involved in regulation of the intra-S and G2/M cell cycle checkpoint arrest for premitotic DNA repair. The Wee1 inhibitor, adavosertib, has demonstrated activity alone and in combination with olaparib in PARP inhibitor (PARPi)-resistant preclinical models. We sought to evaluate efficacy of adavosertib (A) with or without olaparib (O) in a phase II noncomparative study of recurrent PARPi-resistant ovarian cancer. Methods: Women with recurrent ovarian, fallopian tube or primary peritoneal cancer with documented progressive disease on a PARPi were eligible. All patients (pts) had measurable disease and adequate end organ function. On the A arm, pts received A 300mg PO daily on days 1-5 and 8-12 of a 21-day cycle. On the A/O arm, pts received A 150mg PO BID on days 1-3 and 8-10 and O 200mg PO BID on days 1-21 of a 21-day cycle. Primary endpoint was objective response per RECIST 1.1 and was assessed every 2 cycles. Clinical benefit rate (CBR) was defined as proportion of pts with objective response or stable disease > 16 weeks. Progression free survival (PFS) was assessed using the Kaplan Meier method and calculated from date of treatment initiation to earliest date of progression, death, or last visit. Results: 116 pts were screened with 80 pts enrolled and randomized (A: n=39, A/O: n=41). Median age was 60 years (range 36-76) and the majority of pts had platinum resistant disease (64%) and high grade serous histology (98%). Pts received a median of 4 prior therapies (range 1-11) and 48% had germline or somatic BRCA mutations. There were 35 pts evaluable for response in each arm. Table demonstrates efficacy data. On the A arm, Grade 3/4 toxicities occurred in 51% of pts, most commonly neutropenia (13%), thrombocytopenia (10%), and diarrhea (8%). 28 (72%) pts required at least one dose interruption and 20 (51%) required dose reduction. On the A/O arm, Grade 3/4 toxicities occurred in 76% of pts, most commonly thrombocytopenia (20%), neutropenia (15%), diarrhea (12%), fatigue (12%), and anemia (10%). 36 (88%) of pts required at least one dose interruption, 29 (71%) required dose reduction, and 4 (10%) did not restart due to toxicity. Conclusions: A given alone and in combination with O demonstrated efficacy in pts with PARPi-resistant ovarian cancer. Although grade 3 and 4 toxicities were observed on both arms, these were generally manageable with supportive care, dose interruptions and dose reductions as needed. Additional translational analyses are ongoing to clarify which pts received clinical benefit. Clinical trial information: NCT03579316. [Table: see text]

e15554 Background: HER2 is an emerging treatment target for colorectal cancer (CRC). Previous phase 2 trials have demonstrated the promising antitumor activity of dual HER2 inhibition with trastuzumab plus lapatinib or pertuzumab in HER2-positive metastatic CRC. Pyrotinib, a novel irreversible HER2/EGFR dual tyrosine kinase inhibitor, has been approved for breast cancer in 2018 in China. The antitumor effect of pyrotinib was also shown in other solid tumors, such as lung cancer and gastric cancer. The randomized phase 3 PHOEBE trial proved that the efficacy of pyrotinib was better than lapatinib when in combination with capecitabine in HER2-positive local relapsed or metastatic breast cancer. We reported preliminary results of pyrotinib plus trastuzumab in patients with HER2-positive advanced CRC from an ongoing multicenter phase 2 trial (NCT04380012). Methods: Patients with confirmed recurrent/metastatic CRC, HER2-positive disease, and ECOG performance status 0-2, received oral pyrotinib 400 mg once a day plus intravenous trastuzumab 8 mg/kg loading dose followed by 6 mg/kg once every 3 weeks. The primary endpoint was objective response rate (ORR), as assessed according to the Response Evaluation Criteria In Solid Tumors version 1.1. The data cutoff date was December 24, 2020. Results: From December 2019 to November 2020, a total of 11 patients were enrolled. The median age was 57 (range, 44-70) years and 73% (8/11) of patients were male. The number of prior therapy lines was 0, 1, and ≥2 in 1 (9%), 2 (18%), and 8 (73%) patients, respectively. One (9%) patient only showed HER2 overexpression, 7 (64%) showed HER2 amplification and overexpression, and 3 (27%) showed HER2 mutation and overexpression. The detection of co-mutations showed that 5 (45%) patients had KRAS mutations, 1 (9%) had NRAS mutation, and none had BRAF mutation. Three patients achieved partial response, with an ORR of 27% (3/11) in the total population, 50% (3/6) in KRAS wild-type patients, and 60% (3/5) in patients with wild type of both KRAS and NRAS, respectively. The disease control rate was 45% (5/11). The most common (occurring in at least 2 patients) grade ≥3 adverse event was diarrhea (73% [8/11]). Dose interruption owing to diarrhea occurred in 7 (64%) patients, and 5 (45%) patients reduced the dose to 320 mg due to diarrhea. No treatment-related death was observed. Conclusions: Pyrotinib combined with trastuzumab showed promising ORR with acceptable safety in patients with HER2-positive advanced CRC, suggesting a potential treatment option, especially in those without co-mutations. Clinical trial information: NCT04380012.

2595 Background: Infection with human papillomavirus (HPV) types 16 or 18 drives oncogenesis for the majority of patients (pts) with cervical, anal, and some penile cancers via viral oncoproteins E6 and E7. While anti-PD1/PD-L1 antibodies have activity in pts with HPV-associated cancers, the majority do not derive benefit from these agents as monotherapy. MEDI0457, a therapeutic DNA vaccine containing plasmids for E6 and E7 oncogenes for HPV-16/18 and IL-12 adjuvant, has been shown to be safe and to provoke an immune response against the expressed antigens. We tested MEDI0457 with the anti-PD-L1 antibody durvalumab for pts with recurrent or metastatic HPV-associated cancers with the goal of improving anti-tumor activity. Methods: Pts with HPV-16/18 cervical cancer or rare (anal, penile, vaginal, or vulvar) HPV- associated cancers that were recurrent and/or metastatic following standard therapies were eligible. No prior immunotherapy was allowed. Pts received 7 mg of MEDI0457 intramuscularly (weeks 1, 3, 7, 12, and every 8 weeks thereafter) and durvalumab 1500 mg intravenously every 4 weeks starting at week 4. The primary endpoint was best overall response according to RECIST 1.1. Adverse events (AE) were assessed using CTCAE v4.03. A Simon two-stage phase 2 trial (Ho: p

TPS2072 Background: The majority of recurrent CNS tumors lack effective systemic therapy options following surgical resection and adjuvant radiotherapy. ONC201, the founding member of the imipridone class of small molecules, has induced durable tumor regressions in patients with diffuse midline glioma, H3 K27M-mutant (DMG H3K27M). ONC206, the second imipridone to enter clinical development, is a DRD2 antagonist and ClpP agonist that exhibits differentiated receptor pharmacology and gene expression profiles in tumors relative to ONC201. The compound is orally bioavailable, penetrates the blood-brain barrier, and exhibits anti-cancer efficacy without toxicity in several preclinical cancer models with pronounced efficacy in myc-overexpressing CNS tumors. Methods: A first-in-human, open label, dose escalation, and food effect Phase I study of oral ONC206 (NCT04541082) is currently enrolling. Patients must be 18 years or older and diagnosed with a recurrent, primary CNS neoplasm. Eligible diseases include recurrent glioblastoma, WHO Grade 2 and 3 infiltrating glial neoplasms, DMG H3K27M, ependymoma, medulloblastoma, malignant meningiomas, and other rare primary CNS neoplasms. Dose escalation, initially with weekly dosing, will follow a standard 3+3 design. After the MTD is established, a food effect cohort will enroll with a balanced, single-dose, two-arm, two-period, crossover design. The primary endpoint is to determine DLT during the first 28-day cycle. Secondary endpoints will include objective response rate by RANO criteria, overall and progression-free survival, and disease control rate. Exploratory biomarker analyses based on preclinical correlations with efficacy will include DRD2, DRD2 dimer, ClpP, DRD5, c-myc, and n-myc expression. Clinical trial information: NCT04541082.

TPS365 Background: Sitra is a spectrum-selective receptor tyrosine kinase inhibitor (TKI) that targets TAM receptors (TYRO3, AXL, MERTK), VEGFR2, c-Kit, and c-MET. Sitra has shown antitumor activity in accRCC, and reduces type 2 tumor-associated macrophages, regulatory T-cells and myeloid-derived suppressor cells and enhances T cell–mediated antitumor immune responses. The combination of sitra with anti-PD1 immune checkpoint inhibitors (ICIs), such as nivo, has an acceptable safety profile and demonstrates efficacy across multiple tumor types, including accRCC (Msaouel et al. J Clin Oncol, 2020, abstr 612). Ipi enhances the efficacy of nivo through distinct but complementary pathways to those targeted by sitra. We hypothesize that the triple combination of sitra + nivo + ipi will lead to more potent antitumor responses. This study is designed to determine the optimal dose of sitra when combined with nivo + ipi, and assess the safety as well as the preliminary efficacy of this combination in accRCC, and potentially other cancers, that have shown favorable responses to nivo + ipi. Methods: This phase I/Ib study (NCT04518046) is evaluating sitra + nivo + ipi in frontline advanced or metastatic ccRCC or other solid malignancies. The primary endpoint of the trial is safety and tolerability of this regimen. Secondary endpoints include: objective response rate (RECIST 1.1), duration of response, progression-free survival, overall survival, and pharmacokinetic measurements. The phase I dose escalation portion of the trial will enroll approximately 30 pts with intermediate- or poor-risk accRCC by International Metastatic RCC Database Consortium (IMDC) criteria, who will receive escalating doses of sitra (starting dose 35 mg orally QD) following the Time-to-Event Bayesian Optimal Interval (TITE-BOIN) design (Yuan et al. Clin Cancer Res, 2018), combined with nivo 3 mg/kg and ipi 1 mg/kg (NIVO3/IPI1) every 3 weeks (wks) for up to 4 doses, followed by maintenance nivo (240 mg every 2 wks or 480 mg every 4 wks). The phase Ib dose expansion cohorts will be initiated following identification of the recommended dose of sitra in combination with NIVO3/IPI1 and will enroll up to 31 pts for each of 2 cohorts: pts with intermediate-/poor-risk accRCC (Cohort A) and pts with favorable-risk accRCC (Cohort B). Pts will receive study treatment until disease progression, unacceptable adverse events, or pt withdrawal of consent. Future dose expansion cohorts may be added to include other solid tumors in which favorable activity has been previously demonstrated with nivo + ipi, such as metastatic urothelial carcinoma, melanoma, non–small-cell lung cancer, hepatocellular carcinoma, and colorectal cancer. The study is currently enrolling at 1 US site and additional sites may be added at dose expansion. At the time of the abstract submission, 3 pts have been enrolled. Clinical trial information: NCT04518046 .

75 Background: Anlotinib is an oral small molecule multi-target tyrosine kinase inhibitor that is designed to primarily inhibit VEGFR1/2/3, FGFR1-4, PDGFR α/β and c-Kit, with a broad spectrum of inhibitory effects on tumor angiogenesis and growth. In a previous trial, Anlotinib had been demonstrated to be safe and efficacious in advanced colorectal cancer after failure of recommended treatment. We aimed to evaluate the efficacy and safety of Anlotinib combined with CAPEOX as first-line treatment for unresectable RAS and BRAF wild-type metastatic colorectal cancer (mCRC). Methods: ALTER-C-002 is a single-arm phase II clinical trial. A total of 30 patients with RAS/BRAF wild-type unresectable mCRC, aged 18-75, without prior systemic treatment and ECOG performance score ≤ 1 will be prospectively included. Patients received Capecitabine (850 mg/m2, p.o., on day 1-14 every 3 weeks), Oxaliplatin (130 mg/m2, i.v., every 3 weeks) and Anlotinib (12 mg, p.o., 2 weeks on/1 week off). After 6 cycles of inducing therapy, patients will receive Capecitabine and Anlotinib as maintenance therapy until tumor progression. Primary endpoint was objective response rate (ORR); secondary endpoints included safety, disease control rate (DCR) and progression-free survival (PFS). Results: As of Sep.15th, 2020, 19 patients had been enrolled. 12 of 19 patients were evaluable for antitumor activity: 10 patients had partial response, 2 patients had stable disease. The ORR was 83.3% (95% CI: 51.6–97.9%), and DCR was 100% (95% CI: 73.5–108.1%). 9 patients (47.4%) developed grade Ⅲ adverse events with 1 (5.3%) grade Ⅳ AE. The grade Ⅲ AEs included hypertension (n = 8), diarrhea (n = 3), hypertriglyceridemia (n = 2), leukopenia and neutropenia (n = 3), alanine aminotransferase increase (n = 1), intestinal obstruction (n = 1), nausea and vomiting (n = 1), and grade Ⅳ AE was blood bilirubin increase. 1 patient received emergent surgery for relieving intestinal obstruction after 14 days of Anlotinib treatment discontinuation. No extra bleeding or wound healing risk were observed during the perioperative period. No treatment-related deaths occurred. Conclusions: The combination of Anlotinib and CAPEOX displayed promising antitumor activity and manageable toxicity in unresectable RAS and BRAF wild-type mCRC, which should be merited further evaluation in randomized studies. Clinical trial information: NCT04080843.

TPS4115 Background: Previous studies showed that high dose vitamin C especially when administered intravenously might have anti-cancer effect. A recent preclinical study found that human colorectal cancer cells harboring KRAS or BRAF mutations are selectively killed by high dose vitamin C. Our phase I dose-escalation and expansion study has shown that high dose (up to 1.5g/kg) intravenous vitamin C with FOLFOX or FOLFIRI is well tolerated in patients with colorectal or gastric cancer. This trial is a randomized, multicenter, phase Ⅲ study of high dose vitamin C infusion combined with FOLFOX +/- bevacizumab versus FOLFOX +/- bevacizumab as first-line therapy in patients with advanced colorectal cancer. Methods: This study has enrolled patients with histologically confirmed metastatic adenocarcinoma of colorectum, normal G6PD status and no prior treatment for metastatic disease. 432 patients are randomized 1:1 into one of two groups. Patients in the control group are treated with mFOLFOX6 (oxaliplatin 85 mg/m² d1 concurrent with leucovorin 400 mg/m², followed by bolus 5FU 400 mg/m² d1, followed by infusional 5FU 2400 mg/m² over 46 hours) with or without bevacizumab (5mg/kg, d1) every 2 weeks. Patients in the experimental group are treated with vitamin C intravenously (1.5g/kg/day, d1-3) in combination with mFOLFOX6 with or without bevacizumab every 2 weeks. Randomization is stratified by the location of primary site (left-sided or right-sided) and treatment with bevacizumab (with or without). The primary endpoint is progression free survival (assessed by investigator per RECIST v1.1). Secondary endpoints are overall survival, response rate, assessment of treatment-related adverse events, progression free survival and overall survival in RAS or BRAF mutant patients. Genome, microbiome and metabolome are also assessed. Clinical trial information: NCT02969681 .

6578 Background: Given the expected excellent prognosis of low-risk oropharyngeal squamous cell carcinoma (OPSCC), consideration of long-term toxicity and functional outcomes has become increasingly important. Activity monitors (e.g. FITBIT) are imperfect but have been shown to have reasonable validity in healthy adults. Here we aimed to test the feasibility of using medical grade longitudinal digital activity monitoring to better define objective functional outcomes after treatment of low-risk OPSCC. Methods: This prospective, observational parallel cohort study included patients with previously untreated stage I-III (AJCC 7) OPSCC eligible for standard of care single-modality treatment with either Intensity-Modulated Proton Therapy (IMPT) or TransOral Robotic Surgery (TORS). Objective Actigraph accelerometer data (Actigraph, Pensacola, FL) were collected continuously for 1 week at baseline, 3, 6 and 12 months after treatment along with subjective patient-reported outcome (PRO) measures. Results: Forty-four patients (34M, 10F) enrolled with median age 59 years (range: 42-78). Baseline, 3 and 6 month activity data were available for 40 patients (91%): 16 IMPT and 24 TORS. There was a significant decrease in mean percent of day performing moderate to vigorous physical activity (MVPA) (-0.78, 0.021) mean number of steps/minute (-1.1, p = 0.035), and mean kcals/day (-115.9, p < 0.001) from baseline to 3 months after treatment for the overall cohort. A significant decrease in mean kcals/day (-82.2, p = 0.004) persisted for the overall cohort at 6 months with no significant difference between groups. Conclusions: Longitudinal digital activity monitoring is feasible before and after treatment of low-risk OPSCC. This approach may offer objective functional endpoints for future de-escalation trials. Similar short-term decreases in objective activity measurements were observed after IMPT and TORS. Long-term (12 month) activity data and correlations to subjective PRO measures will be available at the time of presentation. Clinical trial information: 02663583 .

TPS2576 Background: Blockade of the dopamine receptor D2 (DRD2) has emerged as a therapeutic target in neuro-oncology. ONC201, a first-generation imipridone that antagonizes DRD2, has demonstrated clinical activity in Diffuse Midline Gliomas, H3K27M-mutant (DMGs). Treatment options beyond surgical resection and radiation therapy are limited for most recurrent and rare primary CNS neoplasms. DRD2 blockade holds promise as a therapeutic target in multiple primary CNS cancers. ONC206 is a next generation imipridone and a chemical analog of ONC201 that possesses favorable drug properties such as oral bioavailability, robust stability, and blood-brain barrier penetrance. ONC206 exhibits enhanced allosteric inhibition of DRD2 and nanomolar affinity/potency as a DRD2 antagonist with complete antagonism and specificity for DRD2. ONC206 demonstrated broad spectrum anti-cancer efficacy in vitro across most solid tumor types tested in a panel of > 1000 human cancer cell lines with nervous system tumors emerging as most responsive. In addition to its broad-spectrum activity in vitro, ONC206 efficacy has been demonstrated in xenograft mouse models. Methods: This is an open label, dose escalation, and food effect Phase I study of ONC206at the National Cancer Institute, Neuro-Oncology Branch. Adult patients 18 years and older with recurrent, primary CNS neoplasms will initially be accrued to the dose escalation portion of the study and evaluated for toxicity. Eligible diseases include recurrent glioblastoma, WHO Grade 2 and 3 infiltrating glial neoplasms, and rare primary CNS neoplasms in the NCI-CONNECT program: DMGs, ependymomas, medulloblastomas, and other rare CNS tumor types. The primary endpoint is to determine DLT during the first cycle (28 days). Dose escalation will proceed according to a standard 3+3 design. Both once weekly and more frequent dosing of ONC206 will be explored in the dose escalation scheme. After the MTD is established, food effect will be determined in a dedicated cohort using a balanced, single-dose, two-arm, two-period crossover design. Secondary endpoints will include objective response rate by RANO criteria, overall and progression-free survival, and disease control rate. Exploratory analysis of DRD2 and DRD5 expression, DRD2 dimerization, expression of MYC and N-MYC in tumor tissue in relation to clinical outcomes will also be performed.

4613 Background: In the phase 3 study (SANET-ep, NCT02588170), surufatinib significantly prolonged progression free survival compared with placebo in patients with progressive, well-differentiated advanced extrapancreatic neuroendocrine tumors (epNETs) (ESMO 2019 Abs. LBA76). Here, we report the results of health-related quality-of-life (HRQoL) from this study. Methods: Eligible patients were randomized in a 2:1 ratio to receive surufatinib or placebo, 300 mg, orally, once daily, until disease progression or intolerable adverse events. Patient-reported outcome questionnaires, including the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and the QLQ-G.I.NET-21, were collected at baseline, Day 15 of the first cycle (28 Days/cycle), and Day 1 of every cycle thereafter and at discontinuation. Time until definitive deterioration (TUDD) was defined as time from randomization to deterioration of 10 points in domain score compared with baseline score (without subsequent observations of deterioration of less than 10 point or any improvement as compared to baseline score), or death due to any cause. TUDD and mean change from baseline based on a longitudinal repeated measures analysis of each domain were analyzed retrospectively. Significance testing was at two-sided 0.05 without adjustment for multiplicity. Results: Of 198 pts randomized (surufatinib n = 129; placebo n = 69), 197 (99.5%) patients completed HRQoL questionnaires at baseline. The questionnaire compliance rate was >90% for most on-treatment assessments. The TUDD was significantly longer in the surufatinib arm versus the placebo arm in the dyspnea domain (hazard ratio [HR] 0.52, p = 0.0103) and social function scale (HR 0.58, p = 0.0222), while the TUDD of diarrhea was significantly shorter in the surufatinib arm compared to placebo (HR 2.68, p = 0.0074). There was no significant difference of TUDD in the remaining domains of QLQ-C30 and G.I.NET-21. There was also no significant difference of the mean change of scores from baseline by repeated measures in the domains between the two arms except diarrhea (increase of 14.0 points [95% CI 9.6, 18.4] in the surufatinib arm versus 2.1 points [95% CI -4.1, 8.4] in the placebo arm, p = 0.0007). Conclusions: Treatment with surufatinib resulted in superior efficacy, acceptable toxicity, while generally maintaining HRQoL, which support surufatinib as a treatment option in this patient population that was previously treated with available therapies for epNETs. Clinical trial information: NCT02588170 .

8003 Background: Dose-adjusted (DA) EPOCH-R is a frontline treatment for aggressive B-cell lymphomas. Bcl-2 is associated with chemoresistance due to BCL2 gene rearrangement or protein overexpression in lymphomas and is antagonized by BH3 mimetic venetoclax (ven). We conducted a phase I study combining ven with DA-EPOCH-R in aggressive B-cell lymphomas. Methods: This phase 1 study used Bayesian optimal interval design with dose expansion. Eligible patients (pts) were 18 years with newly diagnosed diffuse large B-cell (DLBCL), primary mediastinal, and high grade B-cell lymphoma (HGBCL) with double hit (DHL) or not otherwise specified (NOS). Ven was dosed at 400 mg (DL1), 600 mg (DL2), and 800 mg (DL3) daily for 10 days with 6 cycles of DA-EPOCH-R. A subsequent cohort received ven 600 mg daily for 5 days (DL2B). Toxicities were graded by CTCAE v4.0 and response assessed by Lugano criteria. Dose limiting toxicity (DLT) period was cycle 1 and primarily included grade (gr) ≥3 neutropenia on cycle 2 day 1, gr ≥4 febrile neutropenia/thrombocytopenia, and gr ≥3 nausea, vomiting, diarrhea despite supportive care. Results: 30 pts enrolled with median age 64 (24-79), and 50% female. Ann Arbor stage was III-IV in 23. IPI was high risk in > 50%. Diagnosis was DHL (15), DLBCL NOS (13), and HGBCL NOS (2). 18 had MYC and 14 had BCL2 rearrangements. Bcl-2 was expressed ≥50% by IHC in 21/26 with data. There were no DLTs in DL1 (3 pts) or DL2 (9 pts). 1/6 had DLT in DL3 (gr 4 thrombocytopenia). Ven dose reductions occurred in subsequent cycles in 4 (2 in DL2; 2 in DL3). Of 18 in DL1-3, EPOCH was escalated above level 1 in 1 and de-escalated below level 1 in 7. Because of delays and ven dose reductions in DL2-3 due in part to cytopenias, infections and GI toxicities, we accrued DL2B. In DL2B, 0/12 pts had DLTs or ven dose reductions. EPOCH was escalated above level 1 in 4 and de-escalated below level 1 in 3. 1 died of sepsis during cycle 3. Most common gr 3-4 toxicities across all dose levels were cytopenias; febrile neutropenia occurred in 57%. Most common non-hematologic toxicities of all grades were hypocalcemia, nausea, diarrhea, hypokalemia and fatigue. ORR (N = 30) ITT was 97% with 27 (90%) complete and 2 (7%) partial responses; 1 was not evaluable. Follow up is ongoing. Of 15 DHL, ORR and CRR were 93% and 80%. Conclusions: We identified ven 600 mg for 5 days per cycle as RP2D with DA-EPOCH-R. DL2B was well tolerated and required no ven dose reductions. Further efficacy and safety is being evaluated in Alliance 51701, DA-EPOCH-R/R-CHOP in DH/double expressor lymphomas, using the dosing regimen defined by this study. Clinical trial information: NCT03036904 .

e15674 Background: In the last decade, genomics has been increasingly used for therapeutic management of cancer. In precision oncology, genes that can be directly or indirectly targeted with therapeutic agents are considered “actionable”. However, not all alterations affect gene function and alterations in tumor suppressor genes are especially challenging to interpret. The objective of this study was to determine frequency of trial enrollment in patients with “actionable” tumor suppressor alterations and determine whether this varied by genotype and tumor type. Methods: A single-institution retrospective review was performed on patients with metastatic, advanced, or recurrent solid tumors perceived to likely benefit from genomic profiling. Between 1/2015 and 1/2020, the top 5 tumor suppressor alterations CDKN2A, BRCA1/2, PTEN, ATM and NF1 were considered most common “actionable” tumor suppressor genes among patients reviewed by MD Anderson Precision Oncology Decision Support system. Once literature-based or inferred actionability of the tumor-suppressor alteration was determined, a clinical record review was performed to assess an institution-specific annotation detailing trial availability. This annotation matches somatic genomic alteration based on therapeutic significance and availability of matched investigative therapy based on available literature at the time. From here, patient demographics and trial enrollment was extracted from the electronic medical record. Results: 424 patients were categorized as having actionable alterations that had a trial available for enrollment based on genomic characteristics. Of these, 61 patients (14%) enrolled in a matched trial. Primary reasons for non-enrollment for a specific alteration were: enrollment in non-targeted therapeutic trial (39%), treatment with another stand of care therapy (32%), or enrollment in another genomically matched trial targeting another genomic alteration (14%). There was variability in enrollment by disease type approaching statistical significance (p = 0.073). CDKN2A alterations were the most common while BRCA1/2 had the highest rate of matched enrollment (39.5%). Conclusions: In this cohort of patients, the presence of an actionable tumor-suppressor alteration was associated with trial enrollment varying by genotype. Further work is needed to determine the impact of decision support on trial enrollment as well as strategies to increase actionability by building genomically-driven combination therapy trials.

e16001 Background: The FRESCO phase 3 trial demonstrated a significant survival benefit with fruquintinib vs. placebo in the third-line or later therapy of mCRC patients. CEA levels are widely used in conjunction with imaging to monitor response to systemic therapy in patients with mCRC. Herein, we undertook post-hoc analyses of FRESCO patient data to investigate the early changes in CEA during treatment, as well as potential relationships with efficacy parameters. Methods: Patients were included if baseline CEA was abnormal according to local lab reference range. Serum CEA levels were measured at baseline and Day 1 of each cycle (except for Cycle 1). Early CEA change was analyzed at first radiological evaluation (C3D1, Week 8), CEA response was defined as ≥ 50% decrease from baseline, and CEA progression was defined as ≥ 100% increase from baseline. Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier method; hazard ratio (HR) was estimated through Cox proportional hazards model; p-value was generated from log rank test. Results: 88.4% (245/277) and 94.9% (130/137) of patients had an abnormal baseline CEA in the fruquintinib group and placebo group, respectively. Median baseline CEA values were similar between treatment groups. After 2 cycles of treatment, the proportion of patients had CEA response was significantly higher in the fruquintinib group than placebo group (30.0% vs. 1.3%, p < 0.001). In the fruquintinib group, patients with early CEA response (n = 63) had longer median OS (12.8 vs. 7.8 months, HR = 0.45, p < 0.001) and median PFS (5.6 vs. 3.7 months, HR = 0.49, p < 0.001) than patients without (n = 147). 66.7% (140/210) of patients in fruquintinib group had stable disease (SD), and fruquintinib in those patients with concomitant CEA response exhibited a significantly greater OS benefit than with CEA progression (14.4 vs. 8.7 months, HR = 0.38, p = 0.004). Conclusions: Fruquintinib increased early CEA response. CEA response at first radiological evaluation after cycle 2 could be considered as a predictor for better OS and PFS. Among patients with SD at first evaluation, those with CEA response seems benefit more from fruquintinib. Clinical trial information: NCT02314819 .

2559 Background: Neoadjuvant pembrolizumab improved outcome of patients with recurrent Glioblastoma (GBM) in two early phase clinical trials. However, several large phase II/III studies in patients with newly diagnosed and recurrent GBM failed to demonstrate a therapeutic benefit of anti-PD-1 therapy. Therefore, identification of biomarkers of response is crucial for appropriate patient selection and further clinical development of anti-PD-1 therapy. We reported the outcome of our window-of-opportunity clinical trial of neoadjuvant pembrolizumab in 15 patients with recurrent GBM, demonstrating rare CD8+ T cells and abundant of CD68+ macrophages in GBM tissue after 3 weeks of anti-PD-1 treatment (NCT02337686). In the current study, we compared tumor infiltrating lymphocyte (TIL) and PD-L1 scores, known biomarkers of response to anti-PD-1 therapy in other cancers, in pre-trial vs. on-trial tumor tissue and associated these markers with survival. Methods: We determined TIL score (morphological assessment of the presence or absence of TILs, 0-3) and PD-L1 H score (defined as [1*1+ %]+[2*2+ %]+[3*3+ %], 0-200) and correlated these with survival. The Wilcoxon signed rank test was used to compare levels of PD-L1 H or TIL scores between pre-trial and on-trial specimens. The Cox proportional hazards models were used to assess associations between correlative markers and progression free survival or overall survival (OS). Results: The on-trial TIL level (median: 3) was significantly higher than the pre-trial TIL level (median: 1) (p = 0.031). However the difference between pre-trial and on-trial PD-L1 levels was not statistically significant (p > 0.9). Patients whose on-trial PD-L1 H score was ≥ 3 trended toward a longer OS than those with a PD-L1 H score < 3 (HR [95% CI] = 0.225 [0.043, 1.183]) (p = 0.0782). Conclusions: Although GBM tissue lacks abundant T cells, treatment with pembrolizumab increases trafficking of T cells to the tumor microenvironment, which is necessary but not sufficient to induce an effector T-cell response. Elevated PD-L1 expression may be a biomarker of response to anti-PD1 therapy in GBM, which needs confirmation in larger studies. Further genomic, transcriptomic, and methylation profiling of the pre-trial and on-trial tissues is ongoing. Clinical trial information: NCT02337686 .

3021 Background: KN035 is a novel fusion protein of humanized anti-PD-L1 single domain antibody and human IgG1 Fc formulated for subcutaneous injection. This open-label phase II study evaluated the safety and antitumor activity of KN035 in patients with advanced microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) cancer. Methods: The study included patients aged ≥18 years with previously treated MSI-H/dMMR colorectal cancer (CRC) or other advanced solid tumors. MSI-H/dMMR status was assessed centrally for CRC and gastric cancer (GC) and locally for other tumors. KN035 was administered at 150 mg once weekly until progression, unacceptable toxicity, or withdrawal. Tumor assessments were every 8 weeks. The primary endpoint was the objective response rate per RECIST v1.1 by independent radiology review. The primary efficacy population (PEP) included patients with CRC who failed fluoropyrimidine (F), oxaliplatin (O), and irinotecan (I) plus those with advanced GC who had failed at least one prior systemic treatment. This was a planned interim analysis performed after the first 50 patients in the PEP had at least two on-study tumor assessments (PEPi). Results: As of December 17, 2019, 103 patients with MSI-H/dMMR advanced cancers were enrolled at 25 centers in China. The PEPi included 39 patients with CRC and 11 with GC, with a median follow-up of 7.5 months. The overall population included 65 patients with CRC (24 had prior therapy with F and O or I), 18 with GC, and 20 with other tumors, with a median follow-up of 6.7 months. The confirmed objective response rate was 30% (95% CI: 17.9%, 44.6%) in the PEPi, 54.2% (95% CI: 32.8%, 74.4%) in the CRC patients who had prior therapy with F and O or I, and 34.0% (95% CI: 24.9%, 44.0%) in the overall population. Of patients who had an objective response at the interim analysis, 80% of those in the PEPi, 84.6% of CRC patients who had prior therapy with F and O or I, and 85.7% of those in the overall population were still responding at the time of data cutoff. Median progression-free survival was 6.6 months in both the PEPi and the overall population. Median overall survival was not reached in either population. Fourteen (13.6%) patients had grade 3–4 treatment-related adverse events. No grade 5 treatment-related adverse events, pneumonitis, or colitis were reported. Local injection-site reactions, all grade 1 or 2, were reported in nine patients. Conclusions: Envafolimab demonstrated durable anti-tumor activity with a manageable safety profile in patients with previously treated advanced MSI-H/dMMR cancer. Clinical trial information: NCT03667170 .

612 Background: Sitra is a receptor tyrosine kinase (RTK) inhibitor targeting TAM receptors (Tyro3, Axl, MerTK), split family receptors (VEGFR2 and c-Kit) and c-Met. Inhibition of these RTKs has direct biological activity against aCCRCC and can also enhance immunotherapy with nivo by reducing immunosuppressive regulatory T-cells, myeloid derived suppressor cells, and type 2 tumor-associated macrophages. We therefore hypothesized that the addition of sitra to nivo will produce higher clinical activity than nivo alone. Methods: The objective of this phase I/II trial is to evaluate the safety and efficacy of sitra + nivo in pts with aCCRCC that progressed on up to two prior VEGF-targeted therapies. Eligibility criteria were similar to those used for CheckMate 025. The late-onset Bayesian EffTox design is used to account for potential late-onset immune-related toxicities, and allow optimal dose-finding of sitra from four dose levels (60, 80, 120, 150 mg/day) continuously based on both efficacy and toxicity. Additional objectives include estimation of survival times and correlative biomarkers. Results: A total of 38 pts have enrolled as of 22 October 2019 with 34 pts evaluable for response at ≥12 weeks. Tumor reductions have been noted in 28/34 pts (82.3%) with objective responses demonstrated in 13/34 pts (ORR = 38.2%), median progression-free survival of 10.5 months (95% CI 7.6 – 13.5), and 23/34 pts (67.6%) achieving disease control ≥ 6 months. Toxicities requiring dose-reduction of sitra within 12 weeks from treatment initiation have been noted in 14/34 pts (41.2%). The most common treatment-related adverse events include fatigue, diarrhea, palmar-plantar erythrodysesthesia, hypertension, and elevated lipase. There was one nivo-related Grade 5 event (myasthenia gravis). Updated dose-finding, safety and efficacy data will be presented. Conclusions: The combination of sitra + nivo has not demonstrated unexpected safety signals and produces higher objective responses and longer disease control compared with what is historically expected with nivo alone in pts with aCCRCC that progressed on prior VEGF-targeted therapy. Clinical trial information: NCT03015740.

2031 Background: Therapies targeting multiple survival pathways simultaneously may be more effective for high-grade gliomas, a disease highly resistant to treatment. Our preclinical studies have shown potent anti-glioma effects of TG02 and synergy with temozolomide (TMZ) through modulation of transcription and cellular metabolism. A phase I/II trial was launched to test the combination of TG02 and TMZ in recurrent malignant gliomas and herein we report the phase I results. Methods: Adults with recurrent high-grade astrocytoma, KPS ≥ 60, normal organ function, ≤ 2 prior relapses were enrolled. The primary endpoint was dose limiting toxicity (DLT) from the start of the combined treatment to 4 weeks after in each arm. Bayesian optimal interval (BOIN) design was employed to determine the maximum tolerated dose (MTD) with the target DLT rate of 35% and the toxicity profile of the combination of TG02 (starting dose 200mg orally on days 1, 12, 15, and 26) and TMZ, either as a dose-dense (DD; 125mg/m2/d, 7on/7off, Arm 1) or metronomic (MN; 50mg/m2/d, Arm 2) dosing schedule on a 28-day cycle. Results: Forty patients were enrolled; 38 were evaluable; 70% male; overall median age 50.7; median KPS 90. Of 18 evaluable patients in Arm 1 (DD TMZ), at TG02 dose level 200mg, 1/6 had a DLT: Gr3 diarrhea. At TG02 dose level 250mg, 3/12 had DLTs: Gr4 neutropenia for over 5 days, Gr3 elevated ALT, and Gr3 fatigue. Of 20 evaluable patients in Arm 2 (MN TMZ), at TG02 dose level 200mg, 1/6 had a DLT: recurrent Gr3 neutropenia. At TG02 dose level 250mg, 5/12 had a DLT: Gr3 elevated ALT, Gr3 fatigue, and Gr4 neutropenia. At TG02 dose level 300mg,1 out of 2 had a DLT: Gr4 febrile neutropenia, Gr4 elevated ALT, Gr4 elevated AST, which resulted in hospitalization. Therefore, the TG02 dose level of 250mg was declared as the MTD in both Arm 1 and Arm 2. Conclusions: The combination of TG02 at the MTD of 250mg with DD or MN TMZ has a tolerable toxicity profile. Cohort expansion continues at the MTD in both arms to conduct pharmacokinetics and pharmacogenetics to better elucidate the toxicity profile. Objective responses have been observed, suggesting activity of this regimen and supporting continued investigation with the phase II randomized component. Clinical trial information: NCT02942264.

e15012 Background: In phase 3 FRESCO trial, fruquintinib demonstrated a statistically significant and clinically meaningful overall survival benefit in Chinese metastatic colorectal cancer (mCRC) patients. As a known adverse effect of vascular endothelial growth factor receptor (VEGFR) inhibitors, hand-foot skin reaction (HFSR) was commonly reported as a drug-related adverse event (AE) in fruquintinib group. This retrospective analysis explored whether HFSR in fruquintinib group is associated with survival benefit in FRESCO. Methods: This analysis used a subpopulation of intent-to-treat population who at least completed one cycle and entered cycle two of fruquintinib treatment. Patients randomized to receive fruquintinib 5 mg/day during the first 3 weeks of each 4-week cycle were divided into subgroups based on whether they reported HFSR. Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier method. Hazard ratio (HR) was estimated through Cox proportional hazards model. P-value was generated from log-rank test. Results: Among a total of 255 fruquintinib-treated patients who at least completed one cycle and entered cycle two, 52% (n = 133) reported HFSR of any grade. The median time-to-onset of HFSR (any grade) was 21 days and approximate 75% patients reported HFSR after cycle two treatment completion. The baseline characteristics were well balanced between HFSR reported and non-reported subgroups. Patients who reported HFSR showed both OS and PFS benefit with statistical significant difference comparing with HFSR non-reported patients in fruquintinib group. Fruquintinib significantly decreased 43% death risk in HFSR reported patients and prolonged the median OS to 11.14 months in comparison with HFSR non-reported patients (median: 11.24 vs 7.54 months; HR = 0.57, 95% CI: 0.42-0.78; p < 0.001). Similarly, Patients reported HFSR had a significantly longer PFS than those who did not reported HFSR in the fruquintinib group (median: 5.49 vs 3.48 months; HR = 0.70, 95% CI: 0.54-0.91; p = 0.008). Conclusions: This post-hoc analysis indicates that patients who had HFSR had a greater survival benefit from fruquintinib in Chinese mCRC patients. Clinical trial information: NCT02314819 .

3045 Background: The gut microbiota is closely associated with the progression of colorectal neoplasia. While most metagenomics studies utilized fecal samples, circulating bacteria DNA in colorectal adenocarcinoma (ADC) or adenoma (ADM) patients remain unexplored. This study aimed to characterize microbiota DNA in plasma samples and build a machine-learning model for ADC and ADM early detection. Methods: In this proof-of-concept study, we performed whole genome sequencing (~30X) of plasma samples from 25 ADC patients, 10 ADM patients, and 22 healthy controls (HC). Significant biomarkers were identified in the discovery cohort (12 ADC and 11 HC) and built into a random-forest model which was tested in the validation cohort (13 ADC and 11 HC). These biomarkers were further examined in ADM and tested for abundance difference with ADC and HP. Results: In the discovery cohort, 111 species had increased relative abundance in ADC compared to HC and 165 species had decreased relative abundance. Alteration in several species such as Flavobacterium and Ruminococcus torques were consistent with previously published results in faecal and gut microbiome samples. The random forest-recursive feature elimination model selected 28 significant species from the discovery cohort (mean AUC = 0.98, repeated 2-fold cross-validation) and yielded an AUC of 1 in the validation cohort. Interestingly, most biomarker species in ADM patients, with abundance intermediate between ADC and HC, were distinguished from HC. To further test the clinical utility of this model, sequencing data were randomly down-sampled to 1X and the model performance remained robust (AUC = 1) at distinguishing ADC and ADM from HC. Conclusions: This study is the first effort to characterize circulating bacteria DNA in patients with ADC and ADM. Our findings revealed significant difference in relative abundance of several bacterial species between ADC, ADM and HC. A predictive model constructed with selected microbial features accurately distinguished ADC and ADM from HC. Circulating bacteria biomarkers represent potential non-invasive tools for early diagnosis of colorectal neoplasia.

TPS2650 Background: Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) has a long history of efficacy in metastatic melanoma, and is being increasingly considered across other solid tumors. Preclinical data generated at MD Anderson Cancer Center has demonstrated the ability to grow TIL from a variety of tumor types including various types of sarcomas, ovarian and pancreas cancers. We are testing the efficacy of TIL across multiple tumor types using two different manufacturing protocols. Methods: We are conducting two ongoing investigator initiated basket TIL therapy trials. The first (NCT03449108) includes cohorts with poorly differentiated soft tissue and bone sarcomas, osteosarcoma, and platinum resistant ovarian cancer. The TIL product used in this trial is an investigational cell product (LN-145, Iovance Biotherapeutics, Inc.). The second trial (NCT03610490) includes cohorts of osteosarcoma, platinum resistant ovarian cancer, and pancreatic cancer (who have progressed on, or received maximal benefit from, front-line therapy). For this trial, TIL are manufactured at MD Anderson Cancer Center using a protocol that includes the use of urelumab (an agonistic anti-CD137 antibody) combined with T cell receptor activation during TIL expansion. In both trials eligible subjects undergo tumor harvest using a surgical excisional biopsy of the tumor for TIL manufacturing, receive a modified cyclophosphamide and fludarabaine lymphodepletion regimen and up to six doses of IL-2 (600,000 IU/kg) following TIL infusion. No intervening therapy is allowed between tumor harvest and initiation of lymphodepletion. The primary endpoint for each cohort is ORR as assessed by investigators using RECIST 1.1 criteria. The Simon’s two stage design is used to monitor the efficacy of each cohort independently. In the first stage, 10 patients will be treated per cohort. If there is no confirmed response in these 10 evaluable patients, the cohort will be terminated. If the cohort moves forward to Stage II, an additional 8 patients will be treated leading to a total of 18 patients. Three or more responders out of 18 treated patients for the cohort will be considered clinically relevant to justify further investigation. Enrollment is ongoing in all cohorts in both trials. An accrual update will be provided at the annual meeting. Clinical trial information: NCT03449108, NCT03610490.

2556 Background: Epidemiology of NPC is characterized by a unique geographic distribution, with China having one of the highest incidence rates of NPC worldwide. Tislelizumab is an investigational monoclonal antibody with high affinity and specificity for PD-1. Tislelizumab was engineered to minimize binding to FcɤR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. Previous reports from this phase 1/2 study (CTR20160872) have shown that single-agent tislelizumab was generally well tolerated and demonstrated preliminary antitumor activity in Chinese patients (pts) with advanced solid tumors. In the dose-verification part of this study, the recommended dose was established as 200 mg IV Q3W. Here we present preliminary results from the NPC cohort of this study. Methods: Chinese pts with advanced or metastatic, histologically or cytologically confirmed WHO type II-III NPC were enrolled in the indication-expansion phase of this study. Enrolled pts received tislelizumab 200 mg IV Q3W until unacceptable toxicity, consent withdrawal, or no evidence of continued clinical benefit. Antitumor activity (per RECIST v1.1) and safety/tolerability (per NCI-CTCAE v4.03) were assessed. Results: As of 11 May 2018, 20 NPC pts (median age 49 yr [range 35–61]) were enrolled. Most pts were male (85%) and non-smokers (65%). All pts received prior radiotherapy; 19 pts (95%) received ≥1 line of systemic treatment and the median number of prior lines of systemic treatment was 2 (range 0–10). At the cut-off date, 15 pts remain on treatment and the median study follow-up was 5.5 mo (range 0.46–9.0). Of 15 response-evaluable pts, 3 achieved a confirmed partial response (PR) and 9 achieved stable disease; 1 patient had an unconfirmed PR. Seven patients experienced ≥1 treatment-related AE (TRAE); hypothyroidism (n = 3) was the only TRAE that occurred in ≥2 pts. No grade ≥3 TRAEs or serious AEs were reported. Furthermore, no AEs led to either treatment interruption or discontinuation. Conclusions: Tislelizumab was generally well tolerated and demonstrated antitumor activity in previously treated pts with advanced NPC. Clinical trial information: CTR20160872.

2008Background: A Phase III study failed to demonstrate a therapeutic benefit of anti-PD-1 therapy in recurrent GBM. This study was initiated to ascertain tumor immune modulatory properties of pemb...

3537Background: Patients with mCRC are typically offered chemotherapy and might also receive target therapy-drugs targeting VEGF or EGFR. In phase 3 FRESCO trial, fruquintinib demonstrated a statis...

e13518Background: Mismatch repair deficiency (dMMR) assessed by microsatellite instability (MSI) or immunohistochemistry (IHC) is a feature of Lynch syndrome, a major hereditary colorectal cancer (...

4045Background: Gastric cancer (GC) is one of the most common tumors in China. The ToGA study has shown trastuzumab in combination with fluoropyrimidine plus cisplatin prolonged overall survival (O...

2014Background: Hypermutator genotype (HMGen) is seen in glioblastoma (GB) and lower-grade gliomas. It may be induced by temozolomide (TMZ) and leads to TMZ resistance. We describe demographics, mu...