Cycles Of Combination Therapy Research Articles

Hypomagnesemia as a predictor of the efficacy of combination EGFR-targeted drugs versus EGFR ADCs alone in HNSCC.

146 Background: EGFR-targeted drugs and ADCs in combination with EGFR-conjugated chemotherapy drugs can both cause hypomagnesemia. However, the predictive value of hypomagnesemia in response to treatment for head and neck squamous cell carcinoma (HNSCC) is unclear. Methods: This study retrospectively analyzed patients who participated in clinical trials of EGFR-targeted drugs and EGFR ADCs for HNSCC and solid tumors, from February 24, 2022, to March 25, 2024. The primary endpoint of the study was time to treatment failure (TTF). Results: This study conducted a retrospective analysis of 68 patients . All patients exhibited normal baseline serum magnesium levels prior to treatment, but following two cycles of treatment, varying degrees of hypomagnesemia were observed among them. Among the 46 patients who received 2 cycles of combination therapy with EGFR-targeted drugs, 33 were hypomagnesemia and 13 were normal serum magnesium, ORR[90.9%vs. 8.5%,(P=0.002)] (Table), TTF [151 days (95% CI: 212-380) vs. 87 days (95% CI: 52-230), HR 0.576 (95% CI: 0.270–1.230,P = 0.021)]. Among the 22 patients who received EGFR ADC alone for 2 cycles, 8 were hypomagnesemia and 14 were normal serum magnesium, ORR [37.5% vs.28.6%, (P=0.549)] (Table), TTF [97.5 days (95% CI: 68-300) vs. 108.5 days (95% CI: 60-160), HR of 0.877 (95% CI: 0.339–2.263; P = 0.547)]. Conclusions: The study demonstrates that, the occurrence of hypomagnesemia is associated with ORR and TTF following two cycles of combination of EFGR-targeted drugs, not observed in patients receiving EGFR ADCs as monotherapy in HNSCC. [Table: see text]

Interim safety and efficacy of BP1001 in a phase II acute myeloid leukemia (AML) study.

6511 Background: Oncogenic tyrosine kinases induce AML progression via the growth factor receptor bound protein-2 (Grb2). BP1001, a liposome-incorporated Grb2 antisense oligonucleotide,enhanced cancer cell sensitivity to chemotherapy, such as decitabine (DEC) and venetoclax (VEN). A multi-center open-label Phase II study was initiated to assess whether the BP1001 + DEC + VEN combination provides higher response rates than historically reported responses of DEC + VEN in newly diagnosed AML (including secondary AML) (cohort 1) or refractory/relapsed (R/R; cohort 2) AML patients (pts) considered unsuitable for intensive chemotherapy. Per protocol, when 19 evaluable pts are enrolled in each cohort, interim analysis will be performed to determine which cohort has ≥5 complete responses and will continue with enrollment. Methods: BP1001 was given, beginning on Day 4, at 60 mg/m2 IV, 2x weekly for a total of 8 doses over a 28-day cycle. DEC was given IV on days 1 to 5 at 20 mg/m2. VEN was given PO at 100 mg on day 1, 200 mg on day 2, and 400 mg from day 3 to day 14 or 21. Eligible pts were considered unsuitable for or refused intensive chemotherapy and had ECOG performance status of 0-2. Interim analysis was performed on Jan 24, 2024 on pts enrolled between July 28, 2020 and December 26, 2023. Evaluability for efficacy was defined as: completion of at least 4 cycles of combination therapy, documented Progressive Disease (PD) or any drug toxicity at any time, or CR/CRi/CRh prior to 4 cycles. Results: In Cohort 1, 31 newly diagnosed pts were enrolled; 20 evaluable pts (9 male: 45%) with a median age of 75 years (range, 69 - 84), treated with at least 1 cycle of BP1001 + DEC + VEN, had adverse-risk (n=12, ELN 2017 classification) or secondary AML (sAML; n=7) evolved from MDS (n=4), CMML (n=1) or treatment-related AML (n=2). Fifteen pts (75% of evaluable; 54% of enrolled) achieved CR/CRi/CRh; 2 pts achieved partial remission (PR) and 2 achieved stable disease (SD). In Cohort 2, 38 R/R pts were enrolled; 23 evaluable pts (13 male: 57%) with a median age of 63 years (range, 24 - 89), treated with at least 1 cycle of BP1001 + DEC + VEN, had adverse-risk (n=13) or sAML (n=5). Twelve pts (55% of evaluable; 32% of enrolled) achieved CR/CRi/CRh; 1 pt achieved PR, 8 achieved SD and 1 had treatment failure. Among the evaluable pts of both cohorts, adverse events were consistent with those expected with DEC, VEN and/or AML, including fatigue (72%), anemia (60%) and neutropenia (49%), while the most frequent serious adverse events were febrile neutropenia (26%) and sepsis (5%). Conclusions: BP1001 + DEC + VEN has been safely administered to pts without drug-related toxicity. Since >5 responses are observed in both cohorts, the study will continue with enrollment up to 98 and 54 evaluable pts in cohorts 1 and 2, respectively. Efficacy data are encouraging in a challenging population of frontline adverse-risk, sAML and R/R pts. Clinical trial information: NCT02781883 .

Phase II clinical trial of docetaxel and trastuzumab for HER2-positive advanced extramammary Paget's disease (EMPD-HER2DOC).

No consensus has been reached regarding the optimal chemotherapy for metastatic extramammary Paget's disease (EMPD), a rare cutaneous adenocarcinoma, because of the lack of solid evidence from prospective trials. However, the immunohistochemical profile of EMPD reportedly resembles that of breast cancer, particularly in terms of human epidermal growth factor receptor 2 (HER2) expression, suggesting that HER2 is a promising therapeutic target for advanced HER2-positive EMPD. In this phase II single-arm trial, 13 Japanese patients received intravenous trastuzumab (loading dose of 8 mg/kg and maintenance dose of 6 mg/kg) and docetaxel (75 mg/m2) every 3 weeks for up to 2 years. The docetaxel dose was reduced or discontinued according to its toxicity. The primary trial endpoints were objective response rate (ORR) after 3 cycles of treatment and safety throughout the study period. All 13 patients completed 3 cycles of combination therapy. The median follow-up was 27.9 months. The ORR was 76.9% (n = 10/13; 90% CI, 50.5-93.4). Frequently observed adverse events were neutropenia (100%), hypoalbuminemia (84.6%), and mucocutaneous infection (84.6%), all of which were well tolerated. The combination of docetaxel and trastuzumab demonstrated a favorable clinical effect and acceptable tolerability, which makes it a good treatment option for HER2-positive metastatic EMPD (ClinicalTrials.gov Identifier: UMIN000021311, jRCTs031180073).

A Phase Ib Study to Evaluate the Safety and Efficacy of Nivolumab in Combination with R-CHOP in High-Risk DLBCL

Introduction Chemoimmunotherapy with R-CHOP is an established standard of care for diffuse large B-cell lymphoma (DLBCL) but is not curative in all patients (pts). Approximately 20% of DLBCL have aberrations involving the PD-L1/PD-L2 locus. This justifies the investigation of PD-1 checkpoint inhibitors in pts with DLBCL. This Phase 1b study was conducted to determine the maximum tolerated dose (MTD) for nivolumab in combination with R-CHOP in pts with DLBCL and to evaluate the preliminary efficacy of the regimen. Methods Patients with newly diagnosed de novo DLBCL or transformed low-grade lymphoma (tLL) were enrolled from 2019-2022. Treatment comprised a lead-in phase (LIP) with nivolumab 240 mg x 1 followed 2 weeks later by combination nivolumab-R-CHOP given every 3 weeks for 6 cycles. For combination therapy, nivolumab was administered on Day 1 followed by R-CHOP on Days 1-5 (Days 2-6 for Cycle 1). To establish MTD with Phase 1, nivolumab dosing followed a modified 3+3 dose escalation, starting with 1 mg/kg (dose level 1), escalating to 240 mg (dose level 2). MTD was administered for the Phase Ib portion of the study. Primary endpoints were determination of MTD and rate of complete metabolic response (CMR) by PET/CT using Lugano 2014 as best response by completion of 6 cycles of combination therapy (EOT). Correlations of immune subsets with durability of response and toxicity were exploratory. Results Thirty-three patients were enrolled, of which 25 and 22 pts were evaluable for toxicity and efficacy, respectively. The majority were men (n=21, 64%), White (n=26, 79%) with ECOG performance status of 0-1 (n=30, 91%). Twenty-seven (82%) had advanced stage and/or intermediate/high risk IPI score and 20 (65%) had germinal center subtype. Fifteen (45%) and 16 (48.5%) had tLL (2 with prior therapy for LL prior to transformation) and MYC aberrancy (13 with gains; 2 with single-hit and 1 with double-hit rearrangements), respectively. A dose of 240 mg of nivolumab was established as MTD. Twenty of 22 (91%) achieved CMR and 2 partial metabolic response (PMR) by EOT with overall response in 100%. One pt died from COVID-19 after 4 cycles but was in CMR on interim imaging. With median follow-up of 12 months (mo), 4 pts had progression. Both pts with PMR by EOT have not relapsed. Estimated 18-mo OS & PFS were 95.4% & 71.6%, respectively. Correlation of PFS with PD-L1 expression is underway. Most common therapy-related adverse events (TRAEs) attributed to nivolumab-R-CHOP were fatigue in 22 (88%), HTN in 21 (84%), lymphopenia in 21 (84%), and neutropenia in 18 (72%). High-grade (grade 3/4) neutropenia occurred in 15 (60%) with growth factor use per discretion of treating physician. Fifteen (60%) pts had infections, 47% high-grade. Immunotoxicities (IT) were the most common TRAEs attributed to nivolumab in 18 pts (72%), including thyroiditis (n=5, 20%), dermatitis (n=4, 16%), hepatitis (n=3, 12%), and infusion reactions (n=3, 12%). Most common high-grade IT: 1 case each of colitis, hepatitis, myocarditis (discontinued nivolumab), and dermatitis (discontinued nivolumab). For biologic correlates (Figures 1 & 2): non-progressors (NP) were enriched for T regulatory cell (e.g., IFN-γ producing CD4+Foxp3+ phenotype) fragility while progressors (PD) were enriched for exhausted T cell immunophenotype (CD4+PD-1+CD39+) prior to both LIP and initiation of combination therapy (C1D1). Furthermore, exhausted-like T cell levels were significantly reduced at C1D1 in comparison to LIP in NP but not PD. Toxicities correlated to less exhausted-like effector T cell phenotype, decreased CD4+ naïve and central memory T cells, and increased circulating B cells and myeloid-derived suppressor cells. Conclusions This study demonstrates promising efficacy of frontline combination nivolumab-R-CHOP for high-risk DLBCL including pts with intermediate/high risk IPI, tLL, and MYC aberrancy. While limited by small sample size, this regimen resulted in response, PFS, and OS rates above historical rates reported in high-risk pts and provides basis for further evaluation of nivolumab-based therapies in such pts. We found correlations between progression, toxicity and specific immune subset populations. Attention to these biologic correlates as predictors of durable response and toxicity may allow for better patient selection to optimize benefits of therapeutic effect and risks of increased toxicity with nivolumab-based therapies in DLBCL.

Oral Decitabine/Cedazuridine Is a Tolerable and Effective Ambulatory Regimen for Patients with Advanced Myeloproliferative Neoplasms

Background: Treatment options are limited for patients (pts) with advanced myeloproliferative neoplasms (MPNs). Most pts become refractory to JAK2 inhibitor (JAKi) therapy by 3 years with subsequent survival of only 11-16 months. Sequential treatment with chromatin-modifying agents including decitabine (D) can upregulate CXCR4 expression, correct abnormal trafficking of myelofibrosis (MF) stem cells, and eliminate JAK2V617F+ MF stem and progenitor cells in preclinical models ( Wang et al, Cancer Res 2019, Blood 2010). Combination therapy with intravenous D and ruxolitinib (Rux) had a favorable effect on overall survival (OS) in a phase 2 study of MPN-accelerated/blast phase pts ( Mascarenhas et al, Blood Adv 2020) and prolonged survival in a cohort of DIPSS-plus high-risk MF pts ( Bader et al, Leuk Res 2015). Oral decitabine/cedazuridine (DC), therefore, represents an attractive ambulatory treatment option for pts with advanced MPNs. Methods: We retrospectively reviewed the electronic health records of pts with advanced high-risk MF (AHR-MF) or MPN- accelerated phase (MPN-AP) seen at our institution that were treated with DC with or without a JAKi from 1/2021-7/2023. MPN-AP was defined by the presence of 10-19% blasts in peripheral blood/ bone marrow. AHR-MF was defined by the presence of 4-9% circulating blasts or 5-9% blasts in the bone marrow, and/or refractoriness to a JAKi. Results: A total of 14 pts, 7 each with MPN-AP and AHR-MF, respectively received DC therapy (Table 1). Most pts (8/14 or 57%) were older than 75 years. All pts were classified as high risk/very high-risk (MIPPS70 plus v.2). Ten (71%) pts had one or more high molecular risk mutations ( ASXL1, EZH2, SRSF2, IDH1/2, U2AF1), with the most prevalent being ASXL1 mutations in 8/14 (57%) pts. Other somatic mutations included NF1, KRAS, NRAS, BRAF, GATA2, STAG2, DNMT3A and TET2 genes. Eight of the 14 pts (57%) had either an unfavorable or very high-risk karyotype (MIPSS70 plus v.2). Thirteen pts had previously failed JAKi therapy. The median number of cycles of DC therapy was 2 (range,1-6) and 4 (range,1-26) for MPN-AP and AHR-MF pts, respectively and 4/7 pts received a concurrent JAKi in each group. Two pts in AHR-MF cohort were successfully bridged to transplant. Two pts in the MPN-AP group discontinued treatment after cycle 1 due to neutropenic sepsis and progression to blast phase, respectively. Among MPN-AP pts who received ≥ 2 cycles of DC, circulating blasts were reduced to ≤ 5% in 4/5 pts, normalization of thrombocytopenia and improvement in hemoglobin by ≥ 1.5 g/dl each occurred in 3/5 pts (Fig.1). In the AHR-MF cohort, 6/7 pts received ≥ 2 cycles of DC with elimination of circulating blasts in one pt. WBC and platelet count were effectively reduced in 4/4 and 2/2 pts with baseline WBC of >50x 10 3/uL and platelet count >1000 x 10 3/uL, respectively. Spleen size reduction was achieved in two pts with combination of DC + Rux who were previously refractory to a JAKi. One pt achieved complete resolution of palpable splenomegaly after 2 cycles of combination therapy. The predominant treatment-related adverse event was neutropenic fever in three pts requiring hospitalization. DC cycle length was reduced from 5 to 3/28 days in 7/14 pts, which reduced the degree of therapy related neutropenia and anemia. Pts remained ambulatory during treatment except for hospitalizations related to neutropenic fever. With a median follow-up of 109 days (range, 28 days - 29 months), median OS has not been reached. Three pts in the MPN-AP cohort progressed to MPN-blast phase (BP), including two pts who only received one cycle of DC. Two pts with MPN-BP died after 28 and 68 days of DC therapy, respectively. None of the AHR-MF pts progressed to MPN-AP/BP. The most durable response was observed in a pt who has received a total of 26 cycles of DC + Rux with stable disease for >2 years and loss of BRAF and KRAS mutations after 9 months of treatment. Conclusions: DC therapy appears to be a well-tolerated and effective oral ambulatory regimen with clinically meaningful responses in elderly, transplant ineligible pts as well as a bridge to transplant in high-risk pts with advanced MPNs. The ease of outpatient administration significantly reduces pt treatment burdens and positively impacts their quality of life. These data provide a rationale for studying oral decitabine/cedazuridine +/- JAKi in a prospective manner, especially in pts with AHR-MF refractory to JAKi prior to evolution MPN-AP/BP.

Checkpoint Immunotherapy Is Associated with Preferential Activation of Tumor-Antigen Specific CD4 + T Cells in MDS

Background: Patients with intermediate and higher-risk MDS are generally treated with the DNA hypomethylating agents (HMAs) azacytidine and decitabine. These agents improve survival and cytopenias in ~50% of those treated; but only responders derive clinical benefit, and no pre-treatment response prediction has proven efficacy. There is thus an urgent need to develop new approaches to complement or enhance the response to standard-of-care HMA therapies. Studies suggest that HMAs might act in part via activation of anti-tumor immune mechanisms. Based upon this hypothesis a series of early phase trials combining immune checkpoint inhibitors (ICI: both anti-PD1/PDL1 and CTLA4) with azacitidine in MDS/AML patients were undertaken but clinical and immunological efficacy have proven disappointing. In these studies, the lack of antigen specificity made systematic assessment of the anti-MDS immune response and milieu challenging. Antigen specific assessments are particularly important in MDS patients treated with ICIs because distinct from solid tumors, myeloid stem cell cancers involve the populations of antigen presenting cells that modify the capacity for T-cell response, such as dendritic cells. Our group has shown that MDS/AML patients treated with decitabine show increased expression of NY-ESO-1, a well-characterized tumor antigen whose expression is normally suppressed through dense promoter hypermethylation. In our prior Phase I study, MDS patients received vaccination against NY-ESO-1 in combination with standard decitabine. This combination was not only safe, but it also induced NY-ESO-1 specific CD4 + and CD8 + T cell responses in most patients. We hypothesized that combining anti-NY-ESO-1 vaccination (an antigen specific approach) with decitabine and an ICI would allow us to understand the immune synapse in patients with MDS. Methods: We developed an investigator-initiated Phase 1 trial in transplant-ineligible patients with MDS/low blast count AML adding an anti-PD-1 ICI to our established combination of decitabine + NY-ESO-1 vaccination (#NCT 0335871). This open-label, non-randomized single center Phase 1 study used an HLA unrestricted NY-ESO-1 vaccine (CDX-1401 (1 mg) + poly-ICLC (1.8 mg)) in combination with standard dose decitabine (20mg/m2/d x 5 days) and nivolumab (3 mg/kg every 2 weeks), 4 cycles of combination therapy were planned on study; patients deriving clinical benefit could continue treatment at the discretion of the treating physician. The study was conducted in accordance with the Declaration of Helsinki and approved by the Roswell Park Cancer Institute (RPCI) Internal Review Board. Six patients were enrolled, treated, and completed > 4 cycles of decitabine; serial bone marrow and peripheral blood samples were collected for analysis. The combination was safe. Results: Two patients developed CR and the remainder had stable disease as the best response to therapy (Table 1). The majority of patients mounted NY-ESO-1 specific CD4 + T cell responses associated with up-regulation of anti-PD-1 immunotherapy gene signatures in the CD4 + memory T cell compartment. No responses in CD8 + T cells were seen. In seeking explanation for the disparate findings in CD4 + and CD8 + T-cell compartments, we examined conventional dendritic cell populations associated with activation of CD8 + T cells and identified that our patients had markedly reduced numbers of conventional dendritic cells marked by high expression of CD141 (cDC1). This population is critical for a successful response to immunotherapy. cDC1 from MDS patients also showed reduced expression of genes that are key for optimal T-cell activation and expansion. Conclusions: These results suggest that the use of immunotherapy to induce effective, cytotoxic anti-tumor T cell responses depends upon the myeloid immunologic milieu in MDS patients. The critical importance of cDC1 function has recently been described and appreciated in the context of solid tumor immunotherapy. The observation of both numerical and functional defects of this cell population in patients with myeloid neoplasia provides a possible explanation for the disappointing efficacy of immunotherapies in this disease state. Approaches to augment the number and function of specific cDC1 populations in myeloid disease might overcome this defect and thereby enhance the efficacy of immunotherapy for patients with MDS.

A Phase I/II Single Arm Study of Belantamab Mafodotin, Carfilzomib and Dexamethasone in Patients with Relapsed Multiple Myeloma: Planned Interim Analysis of Safety and Efficacy. Amarc 19-02 Belacard Study

Introduction Belantamab Mafodotin (Belamaf, B), a first in class anti-B-cell maturation antigen (BCMA) antibody-drug conjugate, is efficacious in triple-class exposed, relapsed and refractory multiple myeloma (RRMM). Combination therapy with carfilzomib and dexamethasone (Kd) is potentially synergistic through different anti-myeloma mechanisms of action. We report here a planned interim analysis of safety and responses after the first two cycles of combination therapy. Methods BelaCarD is an ongoing, single-arm, multicentre phase I/II study evaluating 8-weekly B dosing schedule in combination with Kd in patients (pts) with RRMM after 1-3 lines of therapy. B (2.5mg/kg) was administered intravenously (IV) on day (D)1 of every second 28D cycle; K 70mg/m2 IV D1 (20mg/m2 on C1D1), D8 and D15 of every cycle and dexamethasone 40mg weekly (20mg/m2 for pts >75 years). Treatment was continued until disease progression. Corneal adverse events (AEs) were graded as per the keratopathy and visual acuity (KVA) scale and all other AEs as per CTCAEv5. Confidence interval coefficients for response rates (RR) were adjusted using an alpha-spending function. The primary objective is progression free survival (PFS). Results As of 13 th July 2023, 65 pts (67% male) of the intended 70 have been enrolled. 55 pts (62% male) received minimum 2 cycles of B-Kd and were included in the protocol-specified interim analysis. The median age was 69.7 years (48-81); 18 pts (33%) had high-risk cytogenetics either at diagnosis or screening. ISS stage I, II, III occurred in 47.3%, 23.6% and 10% respectively. 25.5%, 38.2% and 34.6% pts had 1, 2 and 3 prior lines of therapy respectively including (exposed/refractory) bortezomib (90.9%/42%), K (3.6%/50%), lenalidomide (52.7%/44.8%), pomalidomide (5.5%/33%), anti-CD38 monoclonal Ab (mAb) (30.9%/52.9%), autologous stem cell transplant (ASCT) (41.8%). The median number of cycles received was 9 (2-27). Treatment-related AEs were reported in 93% of pts (Gr3 60%, Gr4 13%); most frequent were (all grade, Gr3, Gr4): blurred vision (40%, 7.3%, 0%), nausea/vomiting (29.1%, 3.6%, 0%), insomnia (23.6%, 10.9%, 0%), thrombocytopenia (23.6%, 10.9%, 5.5%). Ocular AEs occurred in 42 (79.2%) out of 53 evaluable pts including decline in best corrected visual acuity (BCVA) (total 77.2%, Gr1 9.4%, Gr2 33.9%, Gr3 33.9%) and keratopathy (K) (total 75.4%, Gr1 5.6%, Gr2 22.6%, Gr3 47.2%). Median time to reach worst-grade BCVA and K was 106 (25-309) and 76.5 (25-231) days respectively. Median time to return to Gr ≤1 BCVA and K was 61 (28-322) and 94 (30-326) days respectively. Ten pts had B-related SAEs (Gr 1/2 n=2, Gr 3 n=6, Gr 4 n=1, one pt died of sepsis). A second treatment-related death was due to pneumonia. Six pts discontinued therapy due to treatment-related AE including 4 due to B (corneal toxicity n=2, sepsis n=1, proteinuria n=1). Overall RR and ≥ VGPR by end of cycle 2 were 80% (97%CI: 65.3 - 90.5) and 40% (97%CI: 25.5 - 55.9) respectively. At estimated median potential follow-up of 13 months (4-38), the preliminary estimate of PFS at 24m was 56.1%. Conclusion B-Kd with an extended B schedule demonstrates a manageable safety profile. The preliminary efficacy data is encouraging with deep responses observed after only 2 cycles of therapy. Recruitment is close to completion with the main analysis to be conducted once all pts have completed the 12-month assessment. Acknowledgement: pts, their families and participating AMaRC members and sites as well as the support of GSK and funding support from the Victorian Cancer Agency.

A Phase I/II Trial to Evaluate the Safety, Pharmacokinetics, and Efficacy of Glofitamab As Monotherapy and in Combination with R-ICE Chemoimmunotherapy in Children and Young Adults with Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma (iMATRIX-GLO)

Background: Although rare,relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL) in children, adolescents, and young adults is an area of high unmet need, with 1-year overall survival rates of <30% and complete remission (CR) rates of 27% after treatment with R-ICE (rituximab, ifosfamide, carboplatin, and etoposide) chemoimmunotherapy (Burke et al. Leukemia 2020). New treatment regimens are urgently needed (Woessmann et al. Blood 2020; Burkhardt et al. Cancers (Basel) 2021). T-cell engagers have been identified as medicinal products with the greatest probability of being beneficial for the pediatric population (Pearson et al. Eur J Cancer 2019). Glofitamab is a CD20xCD3 T-cell engaging bispecific antibody that redirects T cells to eliminate B cells and is currently under investigation as monotherapy and in combination with chemoimmunotherapy for the treatment of adults with R/R B-NHL, with encouraging clinical activity and a manageable safety profile. Known risks associated with glofitamab are cytokine release syndrome (CRS), febrile neutropenia, tumor flare, tumor lysis syndrome, pyrexia, and infections. The safety profile of glofitamab in children is expected to be similar to that seen in adults. Study Design and Methods: iMATRIX-GLO (NCT05533775) is a Phase I/II, open-label, single-arm, two-part trial to evaluate the safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of glofitamab as monotherapy in children 6 months to <18 years of age with second and higher R/R B-NHL (i.e. relapse after 2 or more lines of treatment), or in combination with R-ICE in children and young adults ≤30 years of age with first R/R disease (i.e. relapse after the first line of treatment). Patients with a histologically confirmed diagnosis of CD20-positive R/R B-NHL are eligible. Study treatment is administered with a single dose of obinutuzumab pretreatment followed by glofitamab step doses and repeated glofitamab full doses every 21 days as monotherapy or in combination with R-ICE. Primary objectives and endpoints are the achievement of CR after up to three cycles of combination therapy (glofitamab plus R-ICE) as determined by the investigator according to the International Pediatric NHL Response Criteria for pediatric participants and Lugano Classification for young adult participants, evaluation of glofitamab safety (CRS by ASTCT 2019 criteria, otherwise by NCI CTCAE v5.0 criteria), tolerability, and PK as monotherapy and as combination therapy. The first patient was enrolled in November 2022 and the study is ongoing. The study is planned at 23 sites in 9 countries (Europe, Australia, North America, South Korea, and China).

A case of pancreatic cancer treated with chemotherapy combined with immunotherapy and targeted therapy.

A 68-year-old male was admitted due to fatigue and poor appetite and diagnosed pathologically as pancreatic adenocarcinoma with liver metastasis. The patient received two cycles of modified FOLFIRINOX plus immune checkpoint inhibitor (Penpulimab). However, the tumor did not shrink and the tumor marker CA199 level was even higher; then anlotinib was added to therapeutic regimen. After another 4 cycles of combined treatment the size of primary tumor and metastatic lesions were significantly reduced. Laparoscopic distal panceatectomy and splenectomy as well as liver metastasis resection was performed. Three cycles of combined therapy were adopted after surgery followed by maintained therapy with anlotinib plus Penpulimab. There was no evidence of tumor recurrence 19 months since diagnosis.

Safety and efficacy of immune checkpoint inhibitor (ICI) naïve cohort from study of PDS0101 and pembrolizumab in HPV16-positive head and neck squamous cell carcinoma (HNSCC).

6012 Background: Up to 70% of oropharyngeal cancers in the US are reported to be HPV-mediated with most caused by HPV16 infection. First line treatment for patients with unresectable, recurrent or metastatic (R/M) disease is pembrolizumab with or without chemotherapy, but most patients eventually experience disease progression. PDS0101 is a novel, investigational HPV16-targeted immunotherapy that stimulates a potent, targeted T cell attack against HPV16-positive cancers. Methods: VERSATILE-002 (NCT04260126) is an open-label, non-randomized, Simon 2-stage study evaluating the combination of PDS0101 and pembrolizumab in subjects with HPV16-positive R/M HNSCC in 2 cohorts: ICI-naïve and ICI-refractory. All subjects receive pembrolizumab IV Q3W with PDS0101 SC administered concurrently during Cycles 1, 2, 3, 4, and 12 (max 5 doses). The primary endpoint of the study is confirmed Best Overall Response per RECIST 1.1. Herein we update the safety, PFS, and OS data for the ICI-naïve subjects. Results: Forty-eight subjects who received at least one cycle of combination therapy (safety population) had a median age of 62.5 (range 45 – 83), were 93.8% male, 93.8% White, and 62.5% ECOG 0. Among this population, the median overall treatment duration in months was 3.5 (range 0.0 – 19.5). The median number of PDS0101 doses was 4 (range 1 – 5); 56.3% received 4 doses and 22.9% received 5 doses. The median number of pembrolizumab doses was 5 (range 1 – 29); 27.1% received ≥10 doses. Efficacy was evaluated in 34 subjects (47.1% with CPS ≥20) who had assessment of tumor response following treatment (efficacy population). Tumor reduction (maximum percent change from baseline) was seen in 23 (67.6%) subjects. Nine subjects (26.5%) had confirmed response including 1 CR and 8 PR, 15 subjects had SD (44.1%), and 9 subjects had PD (26.5%). One subject was not evaluable (2.9%). The median PFS was 10.4 months (95% CI 4.2, 15.3). Among the safety population, median overall survival was non-estimable due to the ongoing survival status of study subjects. The estimated 12-month OS rate was 87.1%. Thirty-three (68.5%) subjects had mild or moderate (Grade 1 or 2) PDS0101-related TEAE (TRAE); the most common were fatigue and injection site reactions (ISRs). Only 3 subjects (6.3%) had Grade 3 TRAEs: fatigue, ISR, blood alkaline phosphatase increased, and hyperglycemia. No subjects had Grade 4 or 5 TRAE. No subject came off study due to toxicity. Conclusions: PDS0101 with pembrolizumab is well tolerated in this ICI naïve R/M HPV-associated HNSCC population. Median PFS was 10.4 months which compares favorably to published median PFS of 2-3 months for approved ICIs when used as monotherapy in patients with similar PD-L1 levels. The estimated 12-month OS of 87.1% is promising compared to published results of about 36-50%. These results justify a confirmatory randomized, controlled study. Clinical trial information: NCT04260126 .

A Multi-Center Phase Ib Trial of the Histone Deactylase Inhibitor (HDACi) Entinostat in Combination with Anti-PD1 Antibody Pembrolizumab in Patients with Refractory/Relapsed Myelodysplastic Syndromes (RR-MDS) or Oligoblastic Acute Myeloid Leukemia (RR-AML) after Hypomethylating Agent (HMA) Failure

Introduction: Pts with MDS and HMA failure have a poor prognosis and need novel therapies. Success with anti-PD1 therapy in myeloid malignancies has been limited and resistance mechanisms are poorly understood. Preclinical data suggest that myeloid-derived suppressor cells (MDSCs) contribute to MDS progression (Chen et al. JCI 2013). and may mediate resistance to anti-PD1 therapy (Kim et al. PNAS 2014). As HDACi decrease MDSCs, synergistic anti-tumor efficacy with anti-PD-1 has been hypothesized leading to this phase Ib study (NCT02936752) of the HDACi entinostat and anti-PD1 antibody pembrolizumab in pts with MDS or oligoblastic AML and HMA failure. Methods: We conducted an investigator-initiated, NCI-Cancer Therapy Evaluation Program (NCI-CTEP)-sponsored, multicenter, dose escalation and expansion phase Ib trial. Adult (≥18 years) pts with MDS or oligoblastic AML (bone marrow [BM] blasts 20-30%) and HMA failure were enrolled. Pts had to have adequate end organ function and ECOG performance status ≤2. The dose-escalation part used 2 dose levels (DL1: entinostat 8mg PO on days 1 and 8 of each 21-day cycle; DL2: entinostat 8mg PO on days 1, 8, and 15 of each 21-day cycle) with pembrolizumab 200mg IV on day 1 of each 21-day cycle starting with cycle 2. In cycle 1, pts received only entinostat to determine its impact on MDSCs separately from pembrolizumab. Toxicities were tabulated and graded according to CTCAE-5. Dose-limiting toxicities (DLT) were defined as any of the following if deemed possibly related to trial therapy: Grade (G) 3/4 non-hematologic toxicity, any ≥G3 immune related adverse events (IrAEs) or any IrAE resulting in pembrolizumab interruption or discontinuation during the first 2 cycles of combined therapy. Hematologic AEs were considered a DLT only if they were unrelated to MDS and lasted for >42 days. The primary endpoint was safety and determination of the maximum tolerated dose. The secondary endpoint was the overall response rate defined as a composite of complete remission, partial remission, and hematologic improvement (HI) per the 2006 IWG response criteria in MDS and change in MDSCs and PD1/PDL-1 in BM. Results: Between 06/26/2017 and 02/03/2021, we enrolled 28 pts (25 MDS and 3 AML). Median age was 74 years (range [R], 57-86), all pts had received prior HMA with 5 pts (18%) having had ≥3 prior lines of therapy. Median IPSS-R at screening for MDS pts was 5.5 (R: 2-10). Baseline demographic and clinical characteristics are shown in Table 1. During dose escalation, 7 pts were enrolled in DL1 (1 pt not evaluable due to early disease progression during DLT period), and 6 pts were treated on DL2. There was 1 DLT on DL1 (G5 pneumonia/bronchoalveolar hemorrhage (BAH), while 2 pts experienced DLTs at DL2 (G3 pharyngeal mucositis and G3 anorexia). There were no hematologic DLTs during dose escalation. Thus, DL1 was expanded, and another 15 pts were enrolled at DL1. Across the entire study, pts received a median of 3 cycles of therapy (R: 1-12 cycles). The most frequent cause of treatment discontinuation was disease progression in 9 pts. Four pts died during the study, 2 due to therapy-related complications (1 from pneumonia/BAH, 1 from multi-organ failure which occurred after the DLT period in DL2). A summary of the AEs is presented in Table 2. Hematologic AEs were common. The most common non-hematologic ≥G3 AEs independent of treatment attribution were infection (32.1%), hypoxia/respiratory failure (10.7%) and dyspnea (10.7%). Potential IrAEs of any grade were reported in 5 pts including G3 pneumonitis in 2 pts. Serious AEs were reported in 14 pts; 8 of which were potentially attributed to treatment. Among the 19 pts with the first BM efficacy assessment after 3 months, no pt achieved a protocol-defined response. However, 2 pts had mCR (BM blasts decreased from a baseline of 7% and 10% to 2% and 4%, respectively) without HI. Twelve pts had stable disease, while 5 had progressive disease. With a median follow-up of 5.9 months (R: 0.5 - 59.1 months), median OS was 6.9 months (95% CI: 4.8 - 13.6 months). Correlative studies are being conducted. Conclusion: In this multi-center phase 1b investigator-initiated trial in MDS and oligoblastic AML pts after HMA failure, entinostat + pembrolizumab at DL1 was reasonably tolerated but had limited therapeutic efficacy. Ongoing correlative work will explore the disconnect between the preclinical and clinical data regarding potential synergy of entinostat + pembrolizumab. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

PD-1 inhibitor versus bevacizumab in combination with platinum-based chemotherapy for first-line treatment of advanced lung adenocarcinoma: A retrospective-real world study.

Chemotherapy combined with immunotherapy or anti-vascular therapy is both recommended by guidelines for first-line treatment of lung adenocarcinoma. However, no head-to-head clinical trial has ever compared which strategy is the optimal choice. This real-world retrospective study was done to compare the efficacy and treatment-related adverse events of immunotherapy and bevacizumab in combination with chemotherapy. From January 2018 to March 2021, we retrospectively collected 276 patients with advanced lung adenocarcinoma managed with chemotherapy combined with bevacizumab or PD-1 inhibitors at our center. Among them, 139 patients were treated with chemotherapy combined with bevacizumab, while 137 patients were treated with chemotherapy combined with PD-1 inhibitors. After receiving four cycles of combination therapy, all patients received maintenance therapy until disease progression. Progression-free survival (PFS), overall response rate (ORR), overall survival (OS), disease control rate (DCR), and adverse events (AE) were analyzed between the two groups. Compared to patients who received anti-vascular therapy, patients who underwent immunotherapy achieved better PFS (7.3 months vs. 10 months, p = 0.002) while ORR (40.9% vs. 51.1%, p = 0.093), as well as OS (18 months vs. 24 months, p = 0.060), had no statistical difference between the two groups. In the PD-L1-negative population, there was no statistical difference in PFS and OS between the two groups. (8.0 months VS. 6.0 months, p = 0.738; and 19 months vs. 13 months, p = 0.274). In the PD-L1-positive population, there was a significant benefit in PFS in the population receiving immunotherapy (7.0 months vs. 10.0 months, p = 0.009). Proteinuria and hypertension occurred more frequently in the bevacizumab-treated group (p = 0.001 and p = 0.002), whereas immune-related pneumonia and hypothyroidism occurred more frequently in the immunotherapy-treated group (p = 0.007 and p = 0.030). The addition of a PD-1 inhibitor was superior to bevacizumab in terms of PFS among patients with advanced lung adenocarcinoma. PD-L1-positive patients appeared to exhibit better PFS, OS, and ORR. Toxic reactions were manageable in both groups.

Response to chemotherapy combined with anlotinib plus anlotinib maintenance in intra-abdominal desmoplastic small round cell tumors (IADSRCT): a case report and literature review

BackgroundIntra-abdominal desmoplastic small round cell tumors (IADSRCT) are rare and aggressive neoplasia that are resistant to chemotherapy. Anlotinib is an oral multi-target tyrosine kinase inhibitor that also has anti-angiogenic and anti-proliferative properties. In this article, we report on a case showing effective and durable responses to chemotherapy combined with anlotinib in a young man with IADSRCT.Case presentationA 27-year-old man was admitted to our hospital complaining of a palpable periumbilical mass that had been present for longer than 4 months. The diagnosis of IADSRCT was confirmed by biopsy and immunohistochemistry. An extensive unresectable metastasis was found on the initial diagnosis. The patient received six cycles of chemotherapy combined with anlotinib, and maintenance therapy with anlotinib was recommended. Hematochezia, proteinuria and hypertension were observed, however, long-term maintenance therapy was well tolerated. A partial response was observed after two cycles of combined therapy and the patient was still alive with stable disease at the time of reporting.ConclusionsChemotherapy combined with anlotinib plus anlotinib maintenance showed promising efficacy and manageable toxicity in the treatment of advanced IADSRCT.

Treatment of lymphoma with rituximab and chemotherapy during pregnancy

Safety of chemoimmunotherapy during pregnancy for treatment of Non-Hodgkin’s lymphoma (NHL) is controversial. We review 37 cases of mothers with high grade NHL treated with rituximab and concurrent chemotherapy during pregnancy. Majority (95%) of mothers were treated in their second and third trimester, and a median of 4 cycles of combination therapy was administered. Complete remission occurred in 14/17 (82%) mothers whose disease outcomes were reported. There were 2 spontaneous abortions and 1 trimester fetal death that occurred in 3 mothers who received treatment in their first and second trimesters. Among the 34 (92%) live births, there were 6 cases of respiratory/cardiac complications requiring intervention and 5 cases of hematologic abnormalities reported. This review highlights the efficacy and safety of chemoimmunotherapy for mothers treated in second and third trimester. Further data is needed to establish recommendations for management of mothers with aggressive NHL in their first trimester of pregnancy.

Combined immunochemotherapy in patients with refractory/relapsed classical Hodgkin's lymphoma as a 2<sup>nd</sup> line treatment before autologous hematopoietic stem cell transplantation (preliminary results)

Aim. To study the efficacy and safety of combined immunochemotherapy according to the DHAp protocol + nivolumab in patients with refractory/relapsed classical Hodgkin's lymphoma before autologous hematopoietic stem cell transplantation.Materials and methods. The study consisted of 2 phases: 1st - immunotherapy with nivolumab (2 injections as monotherapy at a dose of 240 mg/day with 14 days interval); 2nd - combined immunochemotherapy according to the DHAp protocol + nivolumab (14 days after the 2nd administration of nivolumab): nivolumab 480 mg/day on day 1 in combination with chemotherapy according to the DHAp protocol, 4 cycles in total. The effectiveness of therapy was evaluated after 2 injections of nivolumab, after 2 and 4 cycles of combination therapy. from March 2020 to November 2021, 32 patients were included in the study. The median age was 34 (18-55) years.Results. As of November 2021, the result was evaluated in 32 patients after the 1st stage of treatment (nivolumab monotherapy). A complete response was obtained in 4 (12.5 %) patients, a partial response in 20 (62.5 %) patients, disease stabilization was noted in 5 (16 %) patients, an indeterminate response in 3 (9 %) patients. At the 2nd phase, the efficacy after the 2nd cycle of DHAp + nivolumab was evaluated in 31 patients (complete response was obtained in 19 (61 %), partial response in 11 (36 %)); the final efficacy evaluation (after the 4th cycle of DHAp + nivolumab) was performed in 30 patients, and all patients achieved response to therapy (complete response in 25 (83 %), partial response in 5 (17 %)). 2 patients were excluded from the study.Conclusion. preliminary results of combined immuno- and chemotherapy according to the DHAp protocol showed high efficacy and relatively low toxicity in patients with refractory/relapsed classical Hodgkin's lymphoma before autologous hematopoietic stem cell transplantation.

Preliminary Safety of PDS0101 (Versamune +HPVmix) and Pembrolizumab Combination Therapy in Subjects with Recurrent/Metastatic Human Papillomavirus-16 Positive Oropharyngeal Squamous Cell Carcinoma (OPSCC)

Purpose/Objective(s) Persistent HPV16 DNA infection is associated with up to 70% of OPSCC and recurrent/metastatic disease is often incurable and poorly palliated by standard therapies. Despite significant advances documented with checkpoint inhibitor (CPI) immunotherapy, clinical benefit and efficacy remains limited in most patients due to a lack of meaningful tumor-directed T cell responses. Major barriers to effective cancer vaccine delivery include a relative absence of shared neo-antigens between tumors and weak T-cell activation. PDS0101 is a T-cell activating immunotherapy directed against preserved HPV neoantigens E6/7 that is based on a cationic lipid nanoparticle platform that promotes antigen processing and cross presentation. It has been shown to specifically upregulate type I interferons, allowing generation of high levels of polyfunctional HPV16-specific CD8 and CD4 T cells in vivo as well as immune memory. VERSATILE-002 (NCT04260126) is a phase 2 study of the combination of PDS0101 and pembrolizumab in first line treatment (CPI naïve) and CPI refractory patients with recurrent or metastatic HPV16-related OPSCC. Herein, we report preliminary safety data for CPI naïve patients. Materials/Methods Subjects are treated with pembrolizumab 200mg IV every three weeks plus SC PDS0101 following pembrolizumab on days one of C1-4 and C12. An initial safety cohort was assessed during Cycle 1 and 21 days following, for dose limiting toxicity (DLT) and thereafter for safety and tolerability of the combination. Results Fifteen CPI naïve subjects, median age 60 yrs (range 46-68), all male, 14 (93%) of whom were White and not Hispanic or Latino, received at least one cycle of combination therapy. All were confirmed HPV16 postive and to have a CPS score >=1 (8 with CPS >=20); 8 (53%) were ECOG 0 and 93% had received prior curative intent HNSCC therapy. At the time of safety review, subjects had received a median of 4 doses (range 1-4) of PDS0101 and pembrolizumab. Treatment-emergent adverse events (TEAEs) were documented in 9 (60%) subjects: self-limited, Grade 1 local inject site reactions predominated (7 subjects, 47%), with occasional ≤ Gr2 fatigue, nausea or diarrhea (13% of subjects or fewer). Five subjects had serious adverse events (SAEs), all unrelated to PDS0101 and pembrolizumab. No DLTs, drug discontinuation related to toxicity or immune-related AEs have been documented to date. Conclusion The combination of PDS0101 and pembrolizumab is safe and well tolerated without evidence of enhanced or significant toxicity. Persistent HPV16 DNA infection is associated with up to 70% of OPSCC and recurrent/metastatic disease is often incurable and poorly palliated by standard therapies. Despite significant advances documented with checkpoint inhibitor (CPI) immunotherapy, clinical benefit and efficacy remains limited in most patients due to a lack of meaningful tumor-directed T cell responses. Major barriers to effective cancer vaccine delivery include a relative absence of shared neo-antigens between tumors and weak T-cell activation. PDS0101 is a T-cell activating immunotherapy directed against preserved HPV neoantigens E6/7 that is based on a cationic lipid nanoparticle platform that promotes antigen processing and cross presentation. It has been shown to specifically upregulate type I interferons, allowing generation of high levels of polyfunctional HPV16-specific CD8 and CD4 T cells in vivo as well as immune memory. VERSATILE-002 (NCT04260126) is a phase 2 study of the combination of PDS0101 and pembrolizumab in first line treatment (CPI naïve) and CPI refractory patients with recurrent or metastatic HPV16-related OPSCC. Herein, we report preliminary safety data for CPI naïve patients. Subjects are treated with pembrolizumab 200mg IV every three weeks plus SC PDS0101 following pembrolizumab on days one of C1-4 and C12. An initial safety cohort was assessed during Cycle 1 and 21 days following, for dose limiting toxicity (DLT) and thereafter for safety and tolerability of the combination. Fifteen CPI naïve subjects, median age 60 yrs (range 46-68), all male, 14 (93%) of whom were White and not Hispanic or Latino, received at least one cycle of combination therapy. All were confirmed HPV16 postive and to have a CPS score >=1 (8 with CPS >=20); 8 (53%) were ECOG 0 and 93% had received prior curative intent HNSCC therapy. At the time of safety review, subjects had received a median of 4 doses (range 1-4) of PDS0101 and pembrolizumab. Treatment-emergent adverse events (TEAEs) were documented in 9 (60%) subjects: self-limited, Grade 1 local inject site reactions predominated (7 subjects, 47%), with occasional ≤ Gr2 fatigue, nausea or diarrhea (13% of subjects or fewer). Five subjects had serious adverse events (SAEs), all unrelated to PDS0101 and pembrolizumab. No DLTs, drug discontinuation related to toxicity or immune-related AEs have been documented to date. The combination of PDS0101 and pembrolizumab is safe and well tolerated without evidence of enhanced or significant toxicity.

1378P A single-center, prospective, open-label, single-arm trial of sintilimab with paclitaxel and carboplatin as a neoadjuvant therapy for esophageal squamous carcinoma

Although neoadjuvant chemotherapy has been recommended for resectable ESCC patients, the 5-year overall survival rate was less than 50%. Immune checkpoint inhibitors have been shown to be efficient for advanced ESCC, while few studies focus on the neoadjuvant immunotherapy combined with chemotherapy. Herein, we designed a trial to evaluate the safety and efficacy of Sintilimab combined with paclitaxel and carboplatin for resectable ESCC. All patients had treatment-naïve resectable ESCC (stage II-ⅣA) that were confirmed by histopathology. Each patient received 2 cycles of combined therapy with sintilimab (200 mg), paclitaxel (135 mg/m2) and carboplatin (area under the curve = 5). The primary endpoint was the major pathologic response (MPR). Secondary endpoints were disease-free survival (DFS), overall survival (OS), R0 resection rate and safety profile. Between Oct. 1, 2019, and Apr. 1, 2021, we assessed 45 patients for screening, of whom 40 patients were enrolled. Neoadjuvant therapy was not associated with delays in surgery or increased surgical complications/mortality. The median follow-up was 7.7 months (range 2.0∼21.0 months). The 6-month local RFS and 6-month OS were 92.5% and 97.5%, respectively. Thirty-nine (97.5%) successfully underwent R0 resection. Of the 40 evaluable patients, 19 (47.5%) were MPR, 10 (25.0%) were pathologic complete response (pCR). Imaging evaluation was feasible in all 40 patients. Partial response (PR) was achieved in 33 (82.5%) and stable disease (SD) was observed in 7 (17.5%). The most common treatment-related grade 1-2 adverse events were thrombocytopenia (8, 20.0%), anemia (19, 47.5%), myelosuppression (6, 15.0%), appetite loss (10, 25%), hair loss (12, 30%) and liver dysfunction (3, 7.5%). The most frequent grade 3-4 events were myelosuppression (3, 7.5%), neutropenia (4, 10.0%), thrombocytopenia (1, 2.5%) and severe anemia (1, 2.5%). There was treatment-related deaths. Neoadjuvant sintilimab plus paclitaxel and carboplatin had manageable treatment-related toxic effects. This regimen induced pCR or MPR in 81.2% of resected tumor, demonstrating its antitumor efficacy in resectable ESCC.

PD-1 inhibitor combined with lenvatinib for unresectable liver cancer as the conversion therapy: An open-label, non-randomized, phase IV study.

e16173 Background: The combination of lenvatinib and PD-1 inhibitor has shown to be a promising regimen for advanced hepatocellular carcinoma (HCC). We aimed to assess the feasibility of conversion therapy by lenvatinib combined with PD-1 inhibitor in unresectable HCC in a non-randomized phase IV study (ChiCTR1900023914). Methods: Eligible patients had histologically or cytologically confirmed unresectable HCC (AASLD); BCLC B or C; an ECOG status of 0 or 1 and Child-Pugh A-B. Patients received lenvatinib (8-12mg, oral QD) and PD-1 inhibitor (IV Q3W) until disease progression, unacceptable toxicity or satisfied for curative surgery. Surgical patients received maintenance therapy based on the pathological evaluation (pCR: PD-1 inhibitor 6-12m, pPR: combination therapy 6-12m, pPD: personalized). The primary endpoint was conversion rate for surgery based on radiological assessment. The secondary endpoints were objective response rate (ORR), disease control rate (DCR), relapse-free survival (RFS) and overall survival (OS) by modified RECIST. Tumor tissue samples were collected at diagnosis and surgery. Immune cell subsets (CD8+ T cell, macrophage, NK cell) in tumor and stromal were measured by multiplex fluorescent immunohistochemistry. Whole exosome sequencing was performed with tumor samples and matched white blood cells. Results: and received the combination therapy. 49 patients were evaluated for the efficacy, 51.0% patients (5 CR, 17 PR and 3 SD) were conversed successfully based on their radiological evaluation after 3-7 cycles of combination therapy, among whom 15 patients (30.6%) actually received curative surgery upon comprehensive evaluation and patient preference. The median duration of follow-up was 271 days. The ORR was 53.1% (26/49, 5 CR and 21 PR) and the DCR was 69.4% (34/49). The median RFS and median OS of the 15 surgical patients were unreached. The 12-month OS was 74.1% and the 12-month RFS was 61.1%. Treatment-related adverse events occurred in 46.9% (23/49) of patients (grade ≥ 3, 6.1%). In both pre- and post-therapy tumor tissues, more CD8+ T cells (pre: p = 0.083, post: p = 0.007) and M1 macrophages (pre: p = 0.127, post: p = 0.120) were present in responders compared with non-responders. The conversion therapy could promote macrophage differentiating into M1 type in treatment-sensitive patients, as post-therapy tumoral M1/M2 ratio were higher in responders than non-responders (p = 0.073). Higher frequency of KMT2C mutation (missense and splicing, p = 0.040) were observed in response group. Conclusions: Combination of PD-1 inhibitor with lenvatinib as conversion therapy could benefit unresectable advanced HCC patients to achieve curative surgery. Tumor microenvironment and genomic characteristics may explain the potential mechanism of the clinical response. Clinical trial information: ChiCTR1900023914.

Updated results of ALTER-C002: Anlotinib combined with CAPEOX in first-line treatment of patients with RAS/BRAF wild-type unresectable metastatic colorectal cancer.

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]

Efficacy and biomarker analysis of neoadjuvant carrizumab plus apatinib in patients with local advanced biliary tract cancers.

e16126 Background: Camrelizumab (anti-PD-1 antibody) plus apatinib (VEGFR2 inhibitor) as combination therapy is highly effective in advanced osteosarcoma, hepatocellular carcinoma and extensive-stage SCLC. This study aimed to access the efficacy, safety and explore predictive biomarkers of neoadjuvant carrizumab plus apatinib in local advanced biliary tract cancers (BTCs) (ChiCTR2000034283). Methods: This single-arm, phase II trial enrolled patients with local advanced BTCs. Patients received camrelizumab 200 mg every 2 weeks plus apatinib 250 mg once per day for two cycles, clinical response was then evaluated. Gene expression profiling (GEP), using the 289-gene immune-related RNA panel sequencing, was performed on baseline tumor samples. Differential gene expression analysis was performed between responder (partial response and complete response) and non-responder (stable disease and progressive disease) using Wilcoxon rank-sum test. Results: Across these patients with local advanced BTCs, neoadjuvant camrelizumab plus apatinib demonstrated antitumor activity. Seventeen (n = 13 gallbladder carcinoma; n = 4 cholangiocarcinoma) response-evaluable patients received two cycles of combination therapy, of whom 12 (70.5%) patients achieved objective response, including 2 (11.7%) with complete response, and the DCR was 76.4%. To further assess the impact of the tumor microenvironment on the combination therapy response, we sequenced baseline tumor samples performed biomarker analyses using the 289-gene immune-related RNA panel. Of all enrolled patients with evaluable responses, 16 (94.1%) patients had available GEP data. Baseline tumor samples on differential genes revealed a significantly higher S100A8 (P = 0.004), IL1B (P = 0.002), KIR2DL3 (P = 0.007) expression in non-responders compared with responders. Extensive analyses on immune cell types were also performed. ECMES positive exhausted CD8 T cells (P = 0.009) and SIGLEC5 positive neutrophils (P = 0.0014) were significantly increased in baseline non-responders. In contrast, no significant differences of CD8 positive T cells, B-cells, cytotoxic cells, dendritic cells, macrophages cells or NK cells were found at baseline between groups. Meanwhile, signature scores were calculated using the Gene Set Variation Analysis package with publicly available gene signatures between responder and non-responder groups, and no noteworthy differences were found in TILs score, Cytolytic activity score, IFN-γ signature and Teff score. Conclusions: Neoadjuvant camrelizumab plus apatinib exhibited promising antitumor activity in patients with local advanced biliary tract cancers. Elevated S100A8, IL1B, KIR2DL3 expression levels may indicate resistance in clinical response. Increased ECMES positive exhausted CD8 T cells and SIGLEC5 positive neutrophils were predictive of response in non-responder tumors.