Updated Outcomes Research Articles

Updated Outcomes in Adult Philadelphia-Positive Acute Lymphoblastic Leukemia Patients Using Tyrosine Kinase Inhibitors Combined with the Modified University of Southern California (USC ALL) Regimen without Peg-Asparaginase in the Era of Novel Agents

Introduction: Prior to the introduction of tyrosine kinase inhibitors (TKIs), the presence of BCR-ABL1 conferred a poor prognosis in patients with acute lymphoblastic leukemia (ALL). We published our analysis in 2017 comparing the survival of Ph-Positive (Ph+) and Ph-negative ALL patients during the period when TKIs were universally available in the United States for Ph+ ALL using a Surveillance, Epidemiology, and End Results (SEER) Database analysis, but despite using TKIs, we have continued to remain reliant on cytotoxic chemotherapy and allogenic hematopoietic stem cell transplant (allo-HSCT) to achieve the best long-term outcomes. However, with the introduction of more potent TKIs and other novel agents, and better methods for monitoring minimal residual disease (MRD), the best approach is yet to be determined. In this study we present updated data from our institution with incorporation of TKIs in our modified USC ALL pediatric-based regimen without PEG. Methods This retrospective, single institution chart review included adults aged 18 with newly diagnosed Ph+ ALL between 2016 and 2020. Primary objectives were Overall survival (OS) and event-free survival (EFS) at 3 years and secondary objectives were rates of complete remission/complete remission with incomplete recovery (CR/CRi), minimal residual disease (MRD) by flow cytometry and presence of BCR-ABL1 fusion transcript by real time polymerase chain reaction. Descriptive statistics of patients were reported and evaluated using Fisher's exact test. OS and EFS were reported through Kaplan Meier curves and Log-rank tests. Two-sided p value ≤0.05 considered significant. RESULTS: 25 Ph+ ALL patients were reviewed. Median age at diagnosis was 43.5 years with 44% males and 56% females in this study. Median BMI was 31.9 kg/ m2. Most patients were Hispanic at 84%, 12% White and 4% Asian.43.5% had hepatic steatosis and 4% had CNS disease pre-induction. After induction 1, 80% of patients achieved CR/CRi, 4% were refractory, and 50% were MRD negative by flow, with 24% of patients with undetectable BCR-ABL1 by PCR. After induction 2, 90.5% had achieved CR/CRi, none were refractory and 56.3% were MRD negative by flow with 32% of patients with undetectable BCR-ABL1 PCR. 48% of patients received blinatumomab for MRD flow positivity with a median of 3 cycles, none received inotuzumab. 44.4% underwent allo-HSCT, none were sent for CAR-T. Of note, 64% of patients received Dasatinib only, 0.04% received imatinib and 32% received at least 2 TKIs. Overall, 12% had known relapse, none were refractory, and 12.5% died. The 3y OS was 89.4%, 3y EFS and DFS was at 77%. When stratified by blinatumomab use, 3y OS was 87.5% vs 91.7% (p=0.49), 3y DFS was 80.2% vs 76.4% and 3y EFS was 80.2% vs 76.4% (p=0.8). When survival was stratified by transplant status, 3y OS with allo-HSCT was 100% vs 76.9% (p=0.048), 3y EFS/DFS with allo-HSCT was 100% vs 50.1% (p=0.033) (Fig 1-2). CONCLUSIONS: The use of the modified USC ALL regimen without PEG for the treatment of newly diagnosed Ph+ ALL combined with TKI continued to lead to a high 3-year OS at 89.4% and 3-year EFS and DFS at 77%. All patients received TKI, half of the patients received blinatumomab and received allo-HSCT which led to high OS, EFS and DFS even without PEG. This was statistically significant in those who were able to undergo allo-HSCT (3y OS/EFS/DFS 100% vs 76.9% OS/50.1% EFS/DFS) (p=0.033-0.048). This study further highlights the importance of allo-HSCT in Ph+ ALL patients who received TKI without PEG. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Mosunetuzumab Monotherapy Continues to Demonstrate Promising Efficacy and Durable Complete Responses in Elderly/Unfit Patients with Previously Untreated Diffuse Large B-Cell Lymphoma

Background: Elderly/unfit patients (pts) with diffuse large B-cell lymphoma (DLBCL) who are unable to tolerate standard first-line (1L) chemoimmunotherapy (CIT) due to age or pre-existing comorbidities, often receive no treatment, reduced-dose R-CHOP, or therapies such as R-CVP or R-bendamustine. Less toxic, efficacious alternatives to full-dose CIT are needed. Mosunetuzumab (Mosun) is a CD20xCD3 T-cell engaging bispecific monoclonal antibody that redirects T cells to eliminate malignant B cells. Mosun monotherapy has shown durable complete responses in pts with relapsed/refractory DLBCL in an ongoing Phase I study (Budde et al. JCO 2022). Early data from a Phase I/II, multicenter study (NCT03677154) in elderly/unfit pts with previously untreated DLBCL, showed promising efficacy with durable responses and manageable safety with 1L Mosun monotherapy (Olszewski et al. EHA 2021). Here, we report updated efficacy and safety outcomes with at least 1 year of follow-up after the end of treatment (EOT). Methods: Eligible pts were aged ≥80 years, or 60-79 years with ≥1 activity of daily living (ADL) or instrumental ADL impaired, or reduced cardiac, renal, or liver function precluding the use of full-dose CIT. Pre-phase prednisone with or without vincristine was allowed. Pts received Cycle (C) 1 step-up dosing with IV Mosun on Days (D) 1 (1mg), 8 (2mg) and 15 (13.5 or 30mg) and 13.5mg or 30mg Mosun on D1 of each subsequent 21-day cycle (1/2/13.5mg and 1/2/30mg). Pts with a complete response (CR) stopped Mosun after 8 cycles; pts with a partial response (PR) or stable disease (SD) could continue Mosun up to 17 cycles. Primary endpoints included objective response and CR rates (assessed by PET-CT). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were assessed by ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019). Tumor biomarkers were assessed by immunohistochemistry. Pts enrolled in two safety-evaluation cohorts received Mosun 1/2/13.5mg or 1/2/30mg, and pts in the expansion phase received Mosun 1/2/30mg (enrollment completed July 2021). Here, we report combined data for the two doses. Results: As of June 01, 2022, 54 pts had received Mosun (13.5mg, n=8; 30mg, n=46) and all were efficacy evaluable. Median age was 83 years (range: 65-100), 33 (61%) pts were female, 35 (65%) had an ECOG PS 0-1, 30 (56%) had Ann Arbor Stage III-IV, and 44 (81%) had an International Prognostic Index score ≥2. Median number of cycles received was eight (range: 1-16); three pts in PR continued treatment after C8. Median follow-up was 23.3 months (range: 0‒36). Best overall response rates (ORR) and CR rates were 56% (30/54) and 43% (23/54), respectively. Responses following EOT (primary response assessment timepoint) in both dosing cohorts combined were: ORR, 43% (23/54); CR, 35% (19/54); PR, 7% (4/54); SD, 2% (1/54); progressive disease, 33% (18/54). Median duration of CR was 15.8 months (95% CI: 8.5-not estimable); of 23 pts who achieved a CR (at any timepoint), CR was maintained in 11 pts for >12 months (Figure). The 12-month progression-free survival rate was 39% (95% CI: 25.8-52.8). No new safety signals were observed; 98% of pts had ≥1 adverse event (AE); 48% had a grade (gr) 3/4 AE. An AE leading to treatment discontinuation was reported in one patient (renal failure; not related to Mosun). Fatal AEs occurred in three pts; one death from natural causes and two due to COVID-19 pneumonia (none considered Mosun-related). Common (>10%) treatment-emergent AEs were rash (31%), CRS (26%), and fatigue (26%). Ten pts had gr 1 CRS and four had gr 2. No gr 3+ CRS and no new CRS were reported since the previous cut-off. Neutropenia was reported in 15% of pts (gr 2, 2%; gr 3/4, 13%), and gr 3 febrile neutropenia was reported in one patient. Median duration of neutropenia was 12 days (range: 7‒28). Serious infections were reported in 22% of pts (gr 3, 17%; gr 5, 4% [all due to COVID-19 pneumonia]). No ICANS related to Mosun were reported. Exploratory biomarker analyses of tumor composition revealed increased levels of CD8+ T cells at baseline in responders vs non-responders. Conclusions: Mosun monotherapy continued to demonstrate promising efficacy with durable responses and a manageable safety profile. These data support a potential future role for Mosun in elderly/unfit pts with previously untreated DLBCL and may help to identify pts whose tumors respond to treatment with bispecific antibody monotherapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Outcome of Tandem CD19/CD20 CAR Therapy with 3-Year Follow-up in R/R B-NHL

Background: Tandem CD19/CD20 CAR T cells, which got two scFvs connected to a single molecule with different antigen specificities simultaneously, not just showed broad antigen coverage, yet additionally had robust antitumour activity in vitro. The best overall response rate was 78% with 70% achieving a CR. Here, we report updated clinical outcomes from this trial. Methods: 87 patients with R/R B-NHL after ≥ 2 lines of therapy (including an anti-CD20 mAb plus an alkylating agent) recruited between 2017.05 and 2020.01, which underwent leukapheresis and conditioning chemotherapy followed by a Tandem CD19/CD20 CAR T cells at doses of 0.5 - 8×106/kg of body weight. The updated follow-up analysis was mainly in median PFS, median OS, and median EFS. Besides, survival status of patients after CAR T failure were also observed in the follow-up data. Results: Up to 2022.5.10, the median follow-up time was 38.3 months, 40 patients (45.98%) still keep ongoing response, and the median PFS was 33.17 months, with 49.52% of 3-year PFS rate; the median EFS was 27.6 months, with 47.51% of 3-year EFS rate. The median OS was not reached, with 68.6% of 3-year OS rate. Nonrelapse mortality was 4.4%. Among 39 patients (44.83%) experienced PD after tandem CD19/CD20 CAR T infusion, best response was 54% CR and 10% partial response (PR); 36% were primary refractory, the median PFS was 6.03 months, and the median OS was 25.2 months. Survival data were statistically analysed for patients after CAR T failure, the median follow-up was 26.77 months , and the median OS was 16.37 months. Conclusions: With 3-year follow-up, Tandem CD19/CD20 CAR T cells demonstrated substantial and continued benefits in patients with r/r B-NHL. High CR rates lead to sustained remission and durability, with a long-term median PFS and high percentage of patients in ongoing response at data cutoff, maintained a manageable safety profile, with no new safety signals. For the patients failure after tandem CD19/CD20 CAR T treatment, other anti-tumor regimens, such as bispecific antibodies, target drugs, immunomodulator, secondary CAR T, radiotherapy and so on, could also appeared to attain efficacy outcomes to improve these patient's survival. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Updated Results from a Phase I/II Study of Duvelisib and Venetoclax in Patients with Relapsed or Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) or Richter's Syndrome (RS)

Background While venetoclax (VEN) in combination with rituximab is an effective combination for patients (pts) with R/R CLL, it requires 2 years (yrs) of treatment (tx) and intravenous infusions. Duvelisib (DUV) is an oral PI3K-δ/γ inhibitor (PI3Ki) approved for R/R CLL/SLL after 2 prior therapies, and preclinical data support the potential for synergy both in CLL (Patel et al., 2017) and in RS PDX models (Iannello et al., 2019). This ongoing phase I/II study is investigating an all-oral, MRD-guided, time-limited regimen of DUV + VEN. Here, we report updated outcomes, now with nearly 2 yrs median follow-up. Methods In this ongoing investigator-sponsored trial (NCT03534323), primary endpoints were DLTs, MTD, RP2D (phase 1) and best CR rate (phase 2). Key eligibility criteria for CLL pts: requiring tx by iwCLL criteria, ≥1 prior tx but no prior DUV or VEN, ECOG PS ≤2. For RS pts there was no restriction on # of prior tx, though no VEN was allowed within 1 yr. Pts receive a maximum of 12 cycles of combination DUV + VEN. Tx begins with a 7-day lead-in of DUV 25mg BID, and VEN initiation occurs on day 8. In phase 1, VEN was started at 10mg or 20mg inpatient (inpt) with weekly ramp-up outpatient (outpt) to 50mg, and then to a maximum dose of 100mg, 200mg, or 400mg using a 3+3 design. In phase 2, VEN is initiated at 10mg (outpt) or 20mg (inpt) with weekly ramp-up to 400mg daily. Pts with RS can undergo accelerated VEN ramp-up to 400mg over 5 days (inpt). After 12 cycles, pts with undetectable bone marrow MRD (BM-uMRD) can discontinue tx, with an option to reinitiate VEN at progression, and pts with detectable MRD continue VEN. Assessments: toxicities by CTCAE v5, efficacy by 2008 iwCLL criteria, MRD by central 8-color flow (10-4 sensitivity). Research funding and DUV were provided by Secura Bio. Results As of July 13, 2022, 43 pts were enrolled (n=35 CLL and n=8 RS). Median age: 69 yrs (range 50-79); 70% male. 70% unmutated IGHV. In all patients, 42% were TP53-aberrant (del(17p) or TP53 mut); 9% del(11q); 33% complex karyotype (≥ 3 abnormalities); 23% NOTCH1 mut. Median prior tx: 2 (range 1-6). 42% with prior BTKi tx (all ibrutinib). The RP2D of VEN in combination with DUV was 400mg daily. In the total population of 43 pts, all-grade all-causality heme tox included: neutropenia (64%; 57% Gr3/4), thrombocytopenia (43%; 19% Gr3/4), anemia (33%, 5% Gr3). Notable non-heme tox ≥ 20% included: diarrhea (40%; 7% Gr 3), nausea (40%, 2% Gr3), fatigue (40%, all Gr1/2), hypertension (36%, 7% Gr3), increased alkaline phosphatase (36%, all Gr1/2), headache (26%, all Gr1/2), increased AST/ALT (24%; 7% Gr3), and cough (26%, all Gr1/2). Other notable SAEs ≥ 5%: increased bilirubin (12%, 5% Gr3/4), severe infection (9% Gr3, 1 pt with Gr5 COVID-19 pneumonia). 3 pts had laboratory evidence of tumor lysis syndrome (TLS); 1 pt had clinical TLS with acute kidney injury after the 20 mg VEN dose during ramp-up that fully resolved, and the pt successfully resumed VEN monotherapy. One pt developed a Gr4 gastric perforation while on high-dose steroids to manage diarrhea and discontinued study tx. One pt with RS had Gr5 hepatic failure in the setting of biopsy-proven RS liver involvement. The median number of cycles was 13 (range 1-44). The best ORR in the pts with CLL (n=35) was 69% (43% CR/CRi, 26% PR; Figure 1A). 31% of pts with CLL achieved PB-uMRD and 31% BM-uMRD (Figure 1A). 9/35 pts (26%) achieved CR/CRi with BM-uMRD after 1 year of DUV+VEN and electively discontinued therapy in remission, including 4 pts with del(17p). In the pts with RS (n=8), 3 achieved a CR and 1 achieved a PR. In the 16 CLL pts with TP53-aberrancy, the best ORR was 50% (CR 44%, PR 6%). In 15 CLL pts with prior BTKi tx, the best ORR was 53% (CR/CRi 40%, PR 13%). Eleven pts remain on tx. Reasons for tx discontinuation include: achievement of BM-uMRD (n=12 CLL), electively moving on to allogeneic transplant (n=2 CLL, n=1 RS), PD (n=3 CLL, n=6 RS), unacceptable tox (n=4 CLL, n=1 RS), death due to COVID-19 pneumonia (n=1 CLL). The 2-year PFS for pts with CLL was 78% (95% CI: 63-96; Figure 1B) and the 2-year OS was 90% (95% CI: 80-100). Conclusion A time-limited, all oral regimen DUV + VEN is active in R/R CLL and RS, including in high-risk pts post-BTKi. Immune-mediated and infectious toxicities were observed, but were manageable for most patients. Our data support continued exploration of DUV + VEN in pts with R/R CLL and RS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Updated Outcomes of the University of Southern California (USC) ALL Frontline Regimen (based on CCG-1882) after Protocol Modification in the Era of Novel Agents in Ph-Negative ALL Patients

INTRODUCTION: Pediatric inspired regimens in adolescent young adults and adults have improved outcomes in acute lymphoblastic leukemia (ALL). CALGB 10403 was prospectively tested in patients 17-39 years and achieved a 3-year event free survival of 59%. In 2007, we reported outcomes after incorporating peg-asparaginase (PEG) dosed at 2000mg/m in induction for patients aged 17- 55 years. This was well tolerated and achieved a complete remission (CR) rate of 96%. In 2014, we reported experience with the use of multiple doses of PEG (CCG-1882) for newly diagnosed ALL adult patients achieving a 7-year overall survival (OS) of 51%. Since then, the USC ALL regimen consisting of 2 induction phases, was further modified with a goal of maintaining good outcomes and improving compliance and toxicities. Fractionated doses of cytarabine were changed to a single dose, the methotrexate dose of 1g/ m2 (2.5 g/m2 if T cell) given D1,15 in intensification phases was changed to 3g/ m2 (B and T cell) given in single doses, and consolidation was increased to six cycles allowing for PEG holidays. Moreover, the approval and incorporation of novel agents such as blinatumomab and inotuzumab also changed outcomes in ALL. Therefore, this study reports an update of outcomes since further modification of the USC ALL pediatric-based regimen in the era of novel agents. METHODS: This is a retrospective review which included adults aged 18 years with newly diagnosed Philadelphia negative ALL (2016-2020) treated at the USC/Norris Comprehensive Cancer Center and the Los Angeles County Hospital (LAC). Primary objectives were over-all survival (OS), event-free survival (EFS), disease-free survival (DFS) at 3 years. Secondary outcomes were complete remission/complete remission with incomplete recovery (CR/CRi) and minimal residual disease (MRD) by flow cytometry rates. OS, DFS, EFS were reported through Kaplan Meier curves and Log-rank tests. Two-sided p value ≤0.05 was significant. RESULTS: 121 patients with Ph-negative ALL were reviewed (49.6% Ph-negative B-ALL, 23.9% Ph-like B-ALL, 0.8% B cell lymphoblastic leukemia (LBL), 9.1% T cell ALL, 4.1% T cell LBL, 4.1% early T-cell, 5.8% mixed phenotype acute leukemia (MPAL). Median age at diagnosis was 39.3 years. There were 71.9% Hispanic, 15.7% White, 9.9% Asian, 2.5% African Americans. 57.9% males, 42.1% females. In terms of risk stratification, the majority were unfavorable at 54.6% and 37.8% unknown. Median BMI was 29.6 kg/ m2. 52.5% had hepatic steatosis and 5% had CNS disease pre-induction. 68.7% received PEG during induction 1, and 67.9% during induction 2. Post-induction 1, 83.5% patients achieved CR/Cri with 49% MRD negativity by flow. Post-induction 2, 75% achieved CR/Cri with 57.1% MRD negativity by flow. 26.4% received blinatumomab but not allo-HSCT. 20% received blinatumomab and underwent allo-HSCT. 34.7% received blinatumomab for MRD flow positivity, median 2 cycles, only 5.8% received inotuzumab, 35.5% underwent allogenic stem cell transplant. 28.9% and 9.1% had any relapse and refractory disease, respectively. Mortality rate was at 14.9%. 3y OS was at 80.7%, 3y EFS at 54.3% and 3y DFS 61.3%. When stratified by MRD flow negativity after induction 1 and 2, 3y OS was 83.7% vs 91.1% (p=0.55), 3y DFS was 68% vs 64.1%(p=0.98) and 3y EFS was 68% vs 59.5% (p=0.84). When stratified by blinatumomab use, 3y OS 72.5% vs 85.1% (p=0.15), 3y EFS was 31.6% vs 67.5% (p=0.001), 3y DFS was 40.1% vs 73.1% (p=0.001) (Fig 1-2). Use of PEG resulted in grade 3/4 toxicities including hypersensitivity (4.1%), transaminitis (21.5%), pancreatitis (5.4%), hypertriglyceridemia (49.5%), hypofibrinogenemia (45.5%), hyperbilirubinemia (21.5%) and thrombosis (16.5%). CONCLUSIONS: The modified pediatric-based USC ALL induction regimen using PEG maintained a high 3y OS at 85.3% and appreciable 3y EFS at 54.3% and 3y DFS at 61.3%, with tolerable toxicities in an era of novel agents like blinatumomab. This compares favorably with the original USC ALL regimen, CALGB 10407 and GRAALL 2005. Of note, 3y EFS and 3y DFS were significantly lower in those who underwent blinatumomab since these patients were MRD flow positive and lacked deeper remissions, but 3y OS (72.5%) remained high regardless, even though 26.4% who received blinatumomab were not able to go for allo-HSCT. This suggests the beneficial effect of blinatumomab. Further follow-up is necessary to provide a more robust and mature survival data. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Patterns of Failure after Stereotactic Radiosurgery vs. Whole Brain Radiotherapy for Resected Brain Metastases: Central Imaging Review of the N107C/CEC.3 (Alliance) Phase III Clinical Trial

<h3>Purpose/Objective(s)</h3> Whole brain radiotherapy (WBRT) has historically been the main instrument to decrease intracranial progression after resection of brain metastases. The previously reported NCCTG N107C/CEC.3 (Alliance) randomized phase III clinical trial of WBRT vs. stereotactic radiosurgery (SRS) demonstrated that overall survival did not significantly differ between arms, while SRS was associated with less cognitive decline than WBRT. However, the initial analysis also showed that local tumor bed control (LC) was significantly worse with SRS than WBRT, with an unexpectedly low 12-month LC rate of 60.5% in patients receiving post-operative SRS. To further investigate LC, a central imaging review was performed. <h3>Materials/Methods</h3> In N107C/CEC.3, 194 patients were randomized to SRS (n=98) or WBRT (n=96). SRS dose was dependent on resection cavity volume and ranged from 12 Gy to 20 Gy all in a single fraction, and WBRT dose was 30 Gy in 10 fractions or 37.5 Gy in 15 fractions. For this analysis, patients with local failure (LF) or leptomeningeal failure that had imaging available were centrally reviewed by two radiation oncologists to verify pattern of failure. Patient and treatment characteristics were assessed for association with updated outcomes after central review using Cox proportional hazards, Pearson's chi-square, or Kruskal-Wallis tests. <h3>Results</h3> Seventy-three patients with LF or leptomeningeal failure determined by their local site were centrally reviewed. After adding patients with no LF or leptomeningeal failure, 185 (95% of total enrolled) patients were included in this analysis as 9 patients with LF did not have imaging available for central review. Of 59 patients initially determined to have LF, 20 were determined on central review to be free of LF. Accordingly, after central review post-operative SRS was no longer associated with significantly lower rates of LC than WBRT (79.2% vs. 86.5% 12-month LC, respectively, p=0.099). After central review, the interrelated variables of tumor diameter, target volume, and prescription dose were associated with risk of LF. Patients with resection cavities > 3 cm had higher rates of LF than those with smaller cavities (23.5% vs. 12.6% 12-month LF rate, respectively; p=0.010). Larger target volume was associated with increased risk of LF (HR: 1.05, 95% CI: 1.01 – 1.09, p=0.008), while higher prescription dose was associated with lower risk of LF (HR: 0.81, 95% CI: 0.67 – 0.96, p=0.018). <h3>Conclusion</h3> In contrast to the initial report, after central review SRS was not associated with significantly higher rates of LF than WBRT. Patients with larger surgical cavities had higher rates of LF, though it is unclear whether this is related to cavity size, biology, or radiation dose. Randomized data comparing single to multifraction SRS in larger surgical cavities is awaited.

GDC launches consultation on updated learning outcomes and behaviour expectations in dental education

GDC launches consultation on updated learning outcomes and behaviour expectations in dental education

Open abdominal aortic repair in the current era has more complications for occlusive disease than for aneurysm repair

BackgroundEndovascular intervention has become the first-line treatment of patients with abdominal aortic aneurysms (AAAs) or aortoiliac occlusive disease (AIOD). However, open abdominal aortic repair remains a valuable treatment option for patients who are younger, those with unfavorable anatomy, and patients for whom endovascular intervention has failed. The cohort of patients undergoing open repair has become highly selected; nevertheless, updated outcomes or patient selection recommendations have been unavailable. In the present study, we explored and compared the characteristics and postoperative outcomes of patients who had undergone open abdominal aortic repair from 2009 to 2018. MethodsPatients who had undergone open AAA (n = 9481) or AIOD (n = 9257) repair were collected from the National Surgical Quality Improvement Program database. The primary outcome was the 30-day mortality. The secondary outcomes included 30-day return to the operating room, total operative time, total hospital stay, and postoperative complications. Unmatched and matched differences between the two groups and changes over time were analyzed. Univariate and multivariate regression analyses were conducted to assess the risk factors predicting for 30-day mortality. ResultsAfter propensity matching (n = 4980), those in the AIOD group had had a higher 30-day mortality rate (5.1% vs 4.1%; P = .021), a higher incidence of wound complications (7.4% vs 5.1%; P<.0001) and an increased 30-day return to the operating room (14.2% vs 9.1%; P < .0001). More open AIOD cases (P = .02) and fewer open AAA cases (P = .04) had been treated in the second half of the decade than in the first. The factors associated with an increased odds of 30-day mortality included advanced age, American Society of Anesthesiologists score ≥III, functional dependence, blood transfusion <72 hours before surgery, weight loss in previous 6 months, and a history of chronic obstructive pulmonary disease. ConclusionsFrom 2009 to 2018, the number of open AAA repairs decreased and the proportion of open abdominal AIOD cases increased. Open AIOD surgery was associated with higher 30-day mortality, increased return to the operating room, and increased wound complications vs open AAA repair. Multiple risk factors increased the odds for perioperative mortality. Thus, open abdominal aortic repair should be selectively applied to patients with fewer risk factors.

735MO Updated safety and efficacy from SURPASS, the phase I trial of ADP-A2M4CD8, a next-generation autologous T-cell receptor T-cell therapy, in previously treated patients with unresectable or metastatic tumors

ADP-A2M4CD8 is a next-generation, specific peptide enhanced affinity receptor T-cell therapy modified with addition of a CD8α co-receptor to treat human leukocyte antigen A*02–eligible patients (pts) with unresectable or metastatic tumors positive for the cancer testis antigen melanoma-associated antigen A4 (MAGE-A4). ADP-A2M4CD8 has demonstrated promising anti-tumor activity with a favorable benefit to risk profile in the ongoing phase 1 SURPASS trial.1 Here we report updated clinical outcomes with additional pts treated.

546P Pembrolizumab for microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) advanced endometrial cancer: Long-term follow-up results from KEYNOTE-158

Pembrolizumab (pembro) previously demonstrated robust and durable antitumor activity in patients with MSI-H/dMMR advanced endometrial cancer in the open-label, multicohort, phase 2 KEYNOTE-158 study (NCT02628067). Here we report updated efficacy and safety outcomes with a substantially longer follow-up in the patients enrolled. This analysis included those patients with previously treated, MSI-H/dMMR advanced endometrial cancer enrolled in cohorts D (advanced endometrial cancer of any MSI/MMR status) and K (any MSI-H/dMMR advanced solid tumor, except colorectal) of KEYNOTE-158. MSI-H/dMMR status was determined retrospectively by PCR at a central lab in cohort D and prospectively by PCR and/or IHC at a local lab in cohort K. Patients received pembro 200 mg Q3W for up to 35 cycles. Primary endpoint was ORR per RECIST v1.1 by independent central radiologic review. Secondary endpoints included DOR, PFS, OS, and safety. 94 patients with previously treated MSI-H/dMMR advanced endometrial cancer were included in this analysis. Median time from first dose to data cutoff (Jan 12, 2022) was 54.5 (range, 14.7–71.4) mo. Efficacy results are shown in the Table. ORR was 50% (95% CI, 39.5%–60.5%); responses were seen across all prior treatment lines. 4-y DOR rate was 66% by K-M estimate. Median (95% CI) PFS and OS were 13.1 (4.3‒25.7) mo and 65.4 (29.5‒NR) mo; 4-y PFS and OS rates were 37% and 59%, respectively. Treatment-related AEs occurred in 71 patients (76%); 13 patients (14%) had grade 3‒4 treatment-related AEs (no grade 5).Table: 546PAnalysis population (n = 94)ORR, % (95% CI)50 (39.5–60.5) CR, n (%)15 (16) PR, n (%)32 (34) SD, n (%)17 (18)ORR by prior treatment line, % (95% CI)a Neo-adjuvant and/or adjuvant therapy only (n = 10)40 (12.2–73.8) 1 line (n = 39)59 (42.1–74.4) >1 line (n = 45)44 (29.6–60.0)DOR, median (range),b mo63.2 (2.9–63.2) DOR ≥1 y,b %87 DOR ≥2 y,b %71 DOR ≥3 y,b %66 DOR ≥4 y,b %66Median PFS (95% CI),b mo13.1 (4.3–25.7) 4-y PFS rate,b %37Median OS (95% CI),b mo65.4 (29.5–NR) 4-y OS rate,b %59K-M, Kaplan-Meier; NR, not reached. aPercentages are based on number of patients in each subgroup. bK-M estimate Open table in a new tab K-M, Kaplan-Meier; NR, not reached. aPercentages are based on number of patients in each subgroup. bK-M estimate These updated results reconfirm the robust and durable antitumor activity of pembro and show encouraging survival outcomes in patients with advanced endometrial carcinoma that is MSI-H/dMMR, who have PD following prior systemic therapy and are not candidates for curative surgery or radiation, supporting the use of pembro in this setting.

1246P Multicenter phase Ib/II study of second-line varlitinib and paclitaxel in patients with EGFR/HER2 co-expressing advanced gastric cancer (K-MASTER-13)

Varlitinib is a small-molecule inhibitor of the tyrosine kinases EGFR, HER2, and HER4. We present a phase Ib/II study to evaluate the safety and efficacy of varlitinib in combination with weekly paclitaxel in EGFR/HER2 co-expressing advanced gastric cancer (AGC) patients. (KCT0003583). AGC patients who had failed 1st line fluoropyrimidine-containing chemotherapy, with evidence of both EGFR and HER2 overexpression by IHC (≥1+), were enrolled. Varlitinib [Dose 1: 300 mg BID, Dose -1: 300mg intermittent dose] and paclitaxel (80 mg/m2 D1,8,15) were investigated every 4 weeks. After determining the DLT and RP2D in phase Ib, phase II part was conducted to evaluate the anti-tumor activity with a primary endpoint of PFS. In the phase Ib study, 9 subjects were enrolled at the dose 1 level of varlitinib 300mg, of which 6 patients were evaluable for safety per protocol. Among the 6 evaluable patients, there was 1 DLT of Grade 4 AST/ALT elevation. The RP2D was varlitinib 300mg once daily combined with paclitaxel (80mg/m2 on days 1, 8, and 15). The median follow-up duration of 9.3 months [95% confidence interval (CI), 6.1-12.5]. Among 27 patients treated with RP2D including 5 subjects from Phase Ib, median PFS and OS were 4.1 (95% CI, 2.4-4.9 months) and 7.9 months (95% CI, 3.3-12.5 months), respectively. Among 16 patients with measurable disease and administered with RP2D, confirmed response and disease control was observed in 5 patients (ORR=31.3%) and 14 patients (DCR=87.5%), respectively. No definite association between EGFR or HER2 high expression and the efficacy of varlitinib and paclitaxel could be determined. Most common any grade of adverse events (AEs) were neutropenia (51.8% and 22.2% of Grade 3), diarrhea (27.3%), and AST/ALT elevation (22.2% and 11.1% of Grade 3). No treatment related death or unexpected AEs resulting in treatment cessation were observed with the RP2D. Varlitinib combined with paclitaxel revealed manageable toxicities and antitumor activity in patients with EGFR/HER2 co-expressing AGC who progressed after first-line chemotherapy. Updated outcomes for ongoing patients and biomarker analysis will be presented.

Early drug development in solid tumours: analysis of National Cancer Institute-sponsored phase 1 trials

The low expectation of clinical benefit from phase 1 cancer therapeutics trials might negatively affect patient and physician participation, study reimbursement, and slow the progress of oncology research. Advances in cancer drug development, meanwhile, might have favourably improved treatment responses; however, little comprehensive data exist describing the response and toxicity associated with phase 1 trials across solid tumours. The aim of the study is to evaluate the trend of toxicity and response in phase 1 trials for solid tumours over time. We analysed patient-level data from the Cancer Therapy Evaluation Program of the National Cancer Institute-sponsored investigator-initiated phase 1 trials for solid tumours, from Jan 1, 2000, to May 31, 2019. We assessed risks of treatment-related death (grade 5 toxicity ratings possibly, probably, or definitely attributable to treatment), all on-treatment deaths (deaths during protocol treatment regardless of attribution), grade 3-4 toxicity, and proportion of overall response (complete response and partial response) and complete response rate in the study periods of 2000-05, 2006-12, and 2013-2019, and evaluated their trends over time. We also analysed cancer type-specific and investigational agent-specific response, and analysed the trend of response in each cancer type over time. Univariate associations of overall response rates with patients' baseline characteristics (age, sex, performance status, BMI, albumin concentration, and haemoglobin concentration), enrolment period, investigational agents, and trial design were assessed using risk ratio based on the modified Poisson regression model. We analysed 465 protocols that enrolled 13 847 patients using 261 agents. 144 (31%) trials used a monotherapy and 321 (69%) used combination therapies. The overall treatment-related death rate was 0·7% (95% CI 0·5-0·8) across all periods. Risks of treatment-related deaths did not change over time (p=0·52). All on-treatment death risk during the study period was 8·0% (95% CI 7·6-8·5). The most common grade 3-4 adverse events were haematological; grade 3-4 neutropenia occurred in 2336 (16·9%) of 13 847 patients, lymphopenia in 1230 (8·9%), anaemia in 894 (6·5%), and thrombocytopenia in 979 (7·1%). The overall response rate for all trials during the study period was 12·2% (95% CI 11·5-12·8; 1133 of 9325 patients) and complete response rate was 2·7% (2·4-3·0; 249 of 9325). Overall response increased from 9·6% (95% CI 8·7-10·6) in 2000-05 to 18·0% (15·7-20·5) in 2013-19, and complete response rates from 2·5% (2·0-3·0) to 4·3% (3·2-5·7). Overall response rates for combination therapy were substantially higher than for monotherapy (15·8% [15·0-16·8] vs 3·5% [2·8-4·2]). The overall response by class of agents differed across diseases. Anti-angiogenesis agents were associated with higher overall response rate for bladder, colon, kidney and ovarian cancer. DNA repair inhibitors were associated with higher overall response rate in ovarian and pancreatic cancer. The rates of overall response over time differed markedly by disease; there were notable improvements in bladder, breast, and kidney cancer and melanoma, but no change in the low response of pancreatic and colon cancer. During the past 20 years, the response rate in phase 1 trials nearly doubled without an increase in the treatment-related death rate. However, there is significant heterogeneity in overall response by various factors such as cancer type, investigational agent, and trial design. Therefore, informed decision making is crucial for patients before participating in phase 1 trials. This study provides updated encouraging outcomes of modern phase 1 trials in solid tumours. National Cancer Institute.

SMARCB1 (INI-1)-Deficient Sinonasal Carcinoma: A Systematic Review and Pooled Analysis of Treatment Outcomes.

Simple SummarySMARCB1 (INI-1)-deficient sinonasal carcinoma is a rare but locally aggressive malignancy which usually presents very late with invasion into the orbits and intracranium, and compression of adjacent cranial nerves and their branches at diagnosis, and has a poor survival outcome. So far, less than 200 cases have been reported. The optimal treatment strategy for this rare but intractable malignancy is yet to be determined. We performed a systematic review and included patients treated at our institution for treatment outcome and survival analysis. Multivariable analysis revealed that T4b disease at diagnosis was the only prognostic factor of overall survival. In view of the extreme challenge of managing this malignancy, we are initiating a phase II trial on tazemetostat, an EHZ2 inhibitor, as induction therapy with systemic chemotherapy followed by radical surgery or chemoradiation, and as maintenance therapy for previously untreated stage III to IVA SMARCB1 (INI-1)-deficient sinonasal carcinoma.(1) Background: SMARCB1 (INI-1)-deficient sinonasal carcinoma is a rare sinonasal malignancy; since its discovery and description in 2014, less than 200 cases have been identified. It is almost impossible to perform randomized-controlled trials on novel therapy to improve treatment outcomes in view of its rarity. We performed a systematic review of all the published case reports/series and included our patients for survival analysis. (2) Methods: In this systematic review, we searched from PubMed-MEDLINE, EMBASE, Scopus, Cochrane Library, CINAHL, and Google Scholar for individual patient data to identify and retrieve all reported SMARCB1-deficient sinonasal carcinoma. Clarification on treatment details and the most updated survival outcomes from all authors of the published case reports/series were attempted. Survival analysis for overall survival (OS) and identification of OS prognostic factors were performed. This systematic review was registered with PROSPERO (CRD42022306671). (3) Results: A total of 67 publications were identified from the systematic review and literature search. After excluding other ineligible and duplicated publications, 192 patients reported were considered appropriate for further review. After excluding duplicates and patients with incomplete pretreatment details and survival outcomes, 120 patients were identified to have a complete set of data including baseline demographics, treatment details, and survival outcomes. Together with 8 patients treated in our institution, 128 patients were included into survival analysis. After a median follow up of 17.5 months (range 0.3–149.0), 50 (46.3%) patients died. The 1-year, 2-year and 3-year OS rates were 84.3% (95% CI % 77.6–91.0), 62.9% (95% CI 53.1–72.7), and 51.8% (95% CI 40.8–62.8), respectively, and the median OS was 39.0 months (95% CI 28.5–49.5). Males (p = 0.029) and T4b disease (p = 0.013) were significant OS prognostic factors in univariable analysis, while only T4b disease (p = 0.017) remained significant in multivariable analysis. (4) Conclusions: SMARCB1-deficient sinonasal carcinoma is an extremely aggressive sinonasal malignancy with a dismal prognosis. Early diagnosis and a multimodality treatment strategy are essential for a better treatment and survival outcome.

VITRECTOMY FOR DIABETIC COMPLICATIONS: A Pooled Analysis of Randomized Controlled Trials Using Modern Techniques and Equipment.

To report updated clinical outcomes in subjects undergoing pars plana vitrectomy (PPV) using modern techniques and equipment for the treatment of proliferative diabetic retinopathy-related complications. Pooled analysis of five randomized clinical trials conducted at the same institution and included both study and control subjects from the trials. There were 943 subjects who prospectively underwent small-gauge PPV with antivascular endothelial growth factor pretreatment for proliferative diabetic retinopathy-related complications and completed 6-month follow-up. The visual acuity of the study population improved from median 2.00 (interquartile range 1.3, 2.3) at baseline to median 1.00 (interquartile range 0.5, 1.3) at 6 months. One hundred and eighty-four patients (19.5%) achieved 20/50 or better acuity, and 652 patients (69.1%) achieved 20/200 or better acuity at 6 months. The vision improved or remained stable in 901 patients (95.5%), and 11 patients (1.2%) developed no light perception at 6 months. Intraoperative complications occurred in 343 cases (36.4%), and 199 cases (21.1%) experienced a postoperative complication. The most common postoperative complication was vitreous hemorrhage in 124 cases (62.3% of all complications). Unplanned secondary PPV was necessary in 86 cases (9.1%). This study reports updated clinical outcomes in patients undergoing PPV for proliferative diabetic retinopathy-related complications which compares favorably with the age before small-gauge PPV and antivascular endothelial growth factor pretreatment.

Abstract CT536: Tepotinib efficacy and safety in patients with MET exon 14 (METex14) skipping NSCLC

Abstract Introduction: In the primary analysis of VISION, tepotinib — a highly selective, potent MET inhibitor — demonstrated durable efficacy, and a tolerable safety profile in patients (pts) with METex14 skipping NSCLC. We report updated outcomes, with interim analyses from a confirmatory cohort. Methods: In the Phase II VISION study, pts with advanced/metastatic METex14 skipping NSCLC, identified by liquid (L+) and/or tissue (T+) biopsy, received 500 mg (450 mg active moiety) tepotinib once daily. All pts were assessed for safety; pts with ≥3 months’ follow-up were assessed for efficacy. Primary endpoint was objective response by independent review (RECIST v1.1). Secondary endpoints were disease control (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results: As of Feb 1, 2021, 7,882 pts were pre-screened, and 275 pts were analyzed for efficacy. Patients analyzed for efficacy had a median age of 72.4 years (range, 41-94]), 50.9% were female, 46.5% had smoking history, and median tumor load [target lesions by IRC] was 57.4 mm [range, 10.2-227.8]). Tumor load in L+ pts was 68.0 mm (11.6-227.8) and 52.9 mm (10.2-227.8) in T+ pts. In treatment-naïve pts (n=137), ORR was 54.0% (95% CI: 45.3, 62.6), DCR was 74.5% (66.3, 81.5), and &amp;gt;90% of pts had tumor shrinkage. Median (m) DOR was 32.7 months (9.0, not estimable), mPFS was 10.4 months (8.4, 15.3), and mOS was 17.6 months (13.4, 29.7). In previously treated pts (n=138), ORR was 44.2% (35.8, 52.9), DCR was 75.4% (67.3, 82.3), and &amp;gt;90% of pts had tumor shrinkage. mDOR was 11.1 months (8.4, 18.5), mPFS was 11.0 months (8.2, 12.4), and mOS was 19.9 months (15.8, 22.3). Meaningful clinical activity was observed in L+ and T+ pts (Table). Overall, 14.1% of pts discontinued due to TRAEs; tepotinib was well-tolerated across treatment lines (Table). Conclusions: Tepotinib demonstrated robust and durable clinical activity across treatment lines in pts with METex14 skipping NSCLC, with particularly durable efficacy in first line. TRAEs were manageable with few discontinuations. Table 1. Tepotinib efficacy and safety in patients with METex14 skipping NSCLC (VISION) Tepotinib efficacy (pts with ≥3 months’ follow-up in Cohorts A+C) Overall Treatment-naϊve (n=137) Previously treated (n=138) Combined (N=275) Liquid biopsy* (n=81) Tissue biopsy* (n=86) Liquid biopsy* (n=78) Tissue biopsy* (n=88) Objective response rate, % (95% CI) 49.1 (43.0, 55.2) 54.3 (42.9, 65.4) 54.7 (43.5, 65.4) 43.6 (32.4, 55.3) 47.7 (37.0, 58.6) Disease control rate, % (95% CI) 74.9 (69.4, 79.9) 71.6 (60.5, 81.1) 80.2 (70.2, 88.0) 69.2 (57.8, 79.2) 79.5 (69.6, 87.4) Median duration of response, months (95% CI) 13.8 (9.9, 19.4) 13.8 (7.2, ne) 32.7 (10.8, 32.7) 11.1 (8.4, 19.4) 10.1 (8.3, 15.7) Median progression-free survival, months (95% CI) 10.8 (8.5, 12.4) 8.5 (6.9, 11.3) 15.3 (9.6, ne) 8.3 (5.7, 11.0) 11.1 (8.2, 16.8) Median overall survival, months (95% CI) 19.7 (15.6, 22.1) 15.1 (9.5, 22.1) 29.7 (15.3, ne) 19.9 (12.8, 22.3) 22.3 (17.0, 27.2) Tepotinib safety (all pts who received tepotinib in Cohorts A+C) Overall (N=291) Treatment-naϊve (n=148) Previously treated (n=143) Treatment-related AEs†, n (%) Any grade 264 (90.7) 137 (92.6) 127 (88.8) Grade ≥3 86 (29.6) 49 (33.1) 37 (25.9) Leading to death 2 (0.7) 1 (0.7) 1 (0.7) Leading to a dose reduction 90 (30.9) 51 (34.5) 39 (27.3) Leading to temporary discontinuation 114 (39.2) 63 (42.6) 51 (35.7) Leading to permanent discontinuation 41 (14.1) 24 (16.2) 17 (11.9) All-cause AEs† in ≥20% of patients, n (%) Peripheral edema 191 (65.6) 98 (66.2) 93 (65.0) Nausea 88 (30.2) 51 (34.5) 37 (25.9) Diarrhea 81 (27.8) 42 (28.4) 39 (27.3) Hypoalbuminemia 81 (27.8) 41 (27.7) 40 (28.0) Blood creatinine increase 76 (26.1) 34 (23.0) 42 (29.4) Dyspnea 60 (20.6) 40 (27.0) 20 (14.0) Data cut-off: Feb 1, 2021. *Patients with METex14 skipping detected by both liquid and tissue biopsy are included in both analysis sets (overall, n=59; treatment-naïve, n=30; previously treated, n=29); testing by both methods was not required for enrollment. †AEs were defined as events that started within the day of first dose of trial treatment until 30 days after last dose of treatment or started prior to first dose but worsened during the treatment period. AEs were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events v4.03. AE, adverse event; CI, confidence interval; MET, mesenchymal-epithelial transition factor; METex14; MET exon 14; ne, not estimable. Citation Format: Marina C. Garassino, Xiuning Le, Wade T. Iam, Enriqueta Felip, Hiroshi Sakai, Remi Veillon, Egbert F. Smit, Julien Mazieres, Jo Raskin, Alexis B. Cortot, Karin Berghoff, Rolf Bruns, Gordon Otto, Paul K. Paik. Tepotinib efficacy and safety in patients with MET exon 14 (METex14) skipping NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT536.

Updated overall survival outcomes in ENZAMET (ANZUP 1304), an international, cooperative group trial of enzalutamide in metastatic hormone-sensitive prostate cancer (mHSPC).

LBA5004 Background: The first planned interim analysis of ENZAMET, with 243 deaths after a median follow-up of 34 months, revealed a clinically meaningful overall survival benefit in mHSPC with the addition of enzalutamide to standard of care (hazard ratio 0.67, 95% CI 0.52 to 0.86, p=0.002, Davis et al, NEJM 2019). We now present updated overall survival (OS) findings from the prespecified analysis triggered to occur after 470 deaths. Methods: We randomly assigned participants (pts) with mHSPC to treatment with testosterone suppression (TS) plus either a conventional non-steroidal anti-androgen (NSAA) or enzalutamide. Stratification factors included age, volume of disease (high vs low according to the CHAARTED definition), and planned use of concurrent docetaxel assigned by the treating physician (docetaxel yes vs no). Results: We randomized 1125 pts with a median age of 69 years, including 503 in the docetaxel stratum, and 602 with high volume metastatic disease. OS results in the table below are based on 476 deaths, a median follow-up of 68 months, and a cut-off date of 19JAN2022. The hazard rate for death was 30% lower among all those assigned enzalutamide versus control (p&lt;0.0001). Outcomes by volume status are shown (Table) as well as the subgroups of interest with M1 high or low volume disease at diagnosis selected for concurrent docetaxel. Conclusions: Enzalutamide added to TS, compared with an active comparator of NSAA, provided clinically meaningful improvements in OS for the combined overall cohort, which persisted with an additional 3 years of follow-up. The benefits were more pronounced in pts with low volume disease, and were also seen in the subgroup with M1 high volume mHSPC despite the relatively high survival with TS+docetaxel+NSAA. ENZAMET was led by ANZUP Cancer Trials Group and the University of Sydney NHMRC Clinical Trials Centre, with funding support from Astellas. Clinical trial information: NCT02446405. [Table: see text]

Updated Efficacy Outcomes of Anti-PD-1 Antibodies plus Multikinase Inhibitors for Patients with Advanced Gastric Cancer with or without Liver Metastases in Clinical Trials.

We previously reported preliminary activity of regorafenib plus nivolumab (REGONIVO) or lenvatinib plus pembrolizumab (LENPEM) in advanced gastric cancer (AGC). Meanwhile, several studies demonstrated liver metastases are less responsive to immunotherapy. Combined efficacy outcomes with a longer follow-up in a phase Ib trial of REGONIVO and a phase II trial of LENPEM were examined in AGC with or without liver metastases (REGONIVO plus LENPEM cohort). We also investigated the efficacy of anti-PD-1 monotherapies (anti-PD-1 monotherapy cohort). A comparison of the immune microenvironment between gastric primary tumors and liver metastases was also conducted by multiplex IHC. In the REGONIVO plus LENPEM cohort, with a median follow-up of 14.0 months, objective response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS) were 46%, 7.8 months, and 15.6 months in patients with liver metastases, while 69%, 6.9 months, and 15.5 months in those without. In the anti-PD-1 monotherapy cohort, with a median follow-up of 27.6 months, ORR, mPFS, and mOS were 9%, 1.4 months, and 6.4 months in patients with liver metastases, while 22%, 2.3 months, and 9.0 months in those without. Multiplex IHC revealed liver metastases were associated with an abundance of immune-suppressive cells, such as tumor-associated macrophages and regulatory T cells, with fewer CD8+ T cells compared with gastric primary tumors. Anti-PD-1 antibodies plus regorafenib or lenvatinib for AGC showed promising antitumor activity with a longer follow-up, irrespective of liver metastases status, despite a more immune-suppressive tumor microenvironment in liver metastases.

Preoperative durvalumab (D) with or without tremelimumab (T) for resectable head and neck squamous cell carcinoma (HNSCC): Updated results with high dimensional profiling of circulating immune cells.

6072 Background: Although PD-1 blockade has improved survival in patients with recurrent and/or metastatic HNSCC, safety and efficacy of neoadjuvant immunotherapy with PD-L1 inhibitor with or without CTLA-4 inhibitor has not been investigated. Here, we report the updated results of the safety and efficacy of a preoperative D with or without T (D+/-T) in patients with resectable HNSCC, accompanied with high dimensional profiling of circulating immune cells. Methods: Patients with locally advanced but resectable HNSCC were eligible. Enrolled patients were randomized into D or D+T, stratified by primary site and human papilloma virus (HPV) infection status. A single dose of preoperative D (1500mg) or D+T (1500mg+75mg) was administered, with surgery planned 2 to 8 weeks later for curative resection. Postoperative (chemo) radiation was prescribed based on standard guidelines, followed by maintenance with D every 4 weeks for 1 year. Dynamic changes in circulating immune cells were tracked with mass cytometry. The primary objective was to determine the local recurrence rate. Secondary endpoints included pathologic response, safety, survival outcome, and exploration of immune dynamics. Results: As of January 25th 2022 for the interim analysis, a total of 45 patients were completely enrolled and received surgical resection (D: 21 patients, D+T: 24 patients). Oropharyngeal cancer was most common (n = 23; 51.1%) and HPV-mediated cancer was observed in 20 patients (44.4%). Neoadjuvant D+/-T had acceptable safety profiles and was not associated with delays in surgery or unexpected adverse events. Tumor shrinkage was observed in 31 patients (68.9%), with 15.6% of average tumor shrinkage (range; 100.0% to -80.0%). Major pathologic response (no more than 10% of viable tumor cells) was achieved in 3 patients (6.7%), including 2 cases with pathologic complete response (4.4%). During median follow-up duration of 407 days after surgery, local recurrence and systemic recurrence were documented in 9 patients (20.0%) and 7 patients (15.6%), respectively. Median disease-free survival and overall survival was 910 days and not reached, respectively. High dimensional immune profiling with mass cytometry revealed that D+T disproportionally increased the frequency of regulatory T cells accompanied with the upregulation of their functional markers, which was absent in patients treated with D monotherapy. Conclusions: These updated data suggested that preoperative D+/-T was safe and feasible and had the potential to provide clinical benefits for patients with resectable HNSCC. Distinct immunologic changes in circulating immune cells were induced by each treatment regimen, warranting further investigation. The trial is ongoing and the updated outcomes with immune correlates will be presented in this ASCO. Clinical trial information: NCT03737968.

Phase I/II investigator-initiated study of olaparib and temozolomide in SCLC: Updated analysis and CNS outcomes.

8565 Background: Temozolomide has activity in small-cell lung cancer (SCLC), including patients (pts) with brain metastases (mets; Pietanza M, Clin Cancer Res 2012). Inhibition of Poly (ADP-ribose) polymerase (PARP) is another therapeutic strategy in SCLC. We hypothesized that olaparib plus temozolomide may be safe and effective for pts with relapsed SCLC and clinically active against CNS disease (Farago A, Cancer Discovery 2019). Here, we present an updated analysis of this combination in pts with relapsed SCLC, including a second cohort testing an alternative dosing strategy and an exploratory analysis of CNS-specific outcomes. Methods: In this phase I/II trial of olaparib plus temozolomide in pts with recurrent SCLC, pts were sequentially enrolled into two cohorts defined by dosing schedule. In cohort 1, olaparib was dosed on D1-7 of each 21d cycle. In cohort 2, olaparib was dosed on D1-21. Temozolomide was dosed on D1-7 in both cohorts. Each cohort had a phase I portion (conventional 3+3 dose-escalation) for determination of MTD and RP2D and a phase II portion with primary endpoint of ORR. Per protocol, eligible pts could have untreated asymptomatic brain mets &lt; 1cm and, after mandatory baseline imaging, CNS imaging was performed at investigator’s discretion. A post-hoc exploratory analysis of CNS-specific outcomes was performed using modified RECIST criteria (Long GV, Lancet Oncol 2012) in which brain mets ≥5mm were considered measurable, and intracranial response was independently assessed by an attending radiologist. Results: 66 pts with median of 2 prior lines of therapy (range, 1-7) were enrolled, 50 pts in cohort 1 and 16 pts in cohort 2. 33/66 (50%) pts had history of brain mets, 15/66 (23%) pts had untreated brain mets at enrollment. The confirmed ORR of cohort 2 was 7% (1/14 evaluable pts, 95% CI: 0.2-33.9%), and the updated confirmed ORR of the entire study population was 34% (21/62 evaluable pts, 95% CI: 22.3-47.0%). The most common adverse events were hematologic toxicities (thrombocytopenia, anemia, and neutropenia). 22/50 (44%) of cohort 1 pts and 4/16 (25%) of cohort 2 pts required dose reduction. Of 15 pts with untreated brain mets, best overall intracranial response (including both confirmed and unconfirmed responses) was CR in 6 pts, PR in 4 pts, SD in 3 pts and PD in 1 for a CNS disease control rate of 87% (95% CI: 59.5-98.3%). Of 10 pts with CR/PR as their best intracranial response, 4 responses were confirmed. With non-CNS progression as a competing risk, the probability of CNS progression among the entire study population was 17% (95% CI: 8.8-26.7%) at 6 months and 21% (95% CI: 12.1-32.0%) at 12 months. Conclusions: Olaparib and temozolomide may be an effective therapy for relapsed SCLC, especially for pts with CNS disease where we observed a high rate of intracranial disease control. Ongoing analyses regarding optimal dosing schedule will inform potential for future use of this combination. Clinical trial information: NCT02446704.

First-in-human study of SRF388, a first-in-class IL-27 targeting antibody, as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors.

2501 Background: The immunoregulatory cytokine IL-27 upregulates inhibitory immune checkpoint receptors (eg, PD-L1, TIGIT) and downregulates proinflammatory cytokines (eg, IFNγ, TNFα). SRF388 is a fully human IgG1 blocking antibody to IL-27 with potential to promote immune activation in the tumor microenvironment. A phase 1 study was conducted to establish the preliminary safety of SRF388 and to identify recommended phase 2 doses (RP2D) suitable for monotherapy and combination expansions (NCT04374877). Methods: The dose-escalation study (accelerated single patient followed by standard 3+3) enrolled patients (pts) with advanced treatment-refractory solid tumors. Upon RP2D selection, monotherapy and combination expansions opened for treatment-refractory clear cell renal cell cancer (ccRCC), hepatocellular cancer (HCC), and non-small cell lung cancer. SRF388 was administered IV every 4 weeks (wks) as monotherapy and every 3 wks with pembrolizumab. Tumor response was assessed by RECIST1.1. Results: The monotherapy dose-escalation enrolled 29 pts with doses ranging from 0.003 to 20 mg/kg. Median age was 64 years. Most pts were female (62%) with ECOG PS of 1 (72%). Approximately 80% had prior PD-(L)1 blockade, and 48% had ≥4 prior therapies. Treatment-related adverse events (TRAEs) occurred in 21%, and all were low grade. Fatigue was the only TRAE reported in ≥10% (n = 3). No dose-limiting toxicities (DLTs) or Grade ≥3 TRAEs were observed. Median time on study was 9 wks (range 0–59). One patient with highly treatment-refractory NSCLC experienced a confirmed partial response (PR) at 8 wks that was durable for 20 wks. Nine pts (31%) experienced disease stabilization at 8 wks, with 6 of 9 exhibiting durable disease control at 6 months. Of the 7 pts with ccRCC in the dose-escalation portion of the trial, 3 (43%) experienced durable disease control for ≥20 wks (range: 20-32). With doses up to 20 mg/kg, SRF388 PK remain linear with an estimated T1/2 of 10-12 days. PK characteristics and safety profile support dosing every 3 or 4 wks. Based on safety, tolerability, PK, peripheral pSTAT1 inhibition, and preliminary efficacy, 10 mg/kg was selected as the RP2D. Both the pembrolizumab safety cohort (n = 10) and Stage 1 of the ccRCC monotherapy expansion (n = 17) have fully enrolled. Of the 10 evaluable pts with ccRCC, 1 confirmed monotherapy PR has been reported, enabling Stage 2 initiation. Changes in several serum cytokines and chemokines were observed after SRF388 administration, including expected increase in circulating IL-27 levels. Conclusions: Results of IL-27 pathway blockade with a first-in-class therapeutic demonstrates that SRF388 has good tolerability with encouraging preliminary antitumor activity as a monotherapy. Updated data, including safety and clinical outcomes as well as correlative biomarker analyses, will be presented. Clinical trial information: NCT04374877.