Progression-free Rates Research Articles

Ribosome biogenesis-based predictive biomarkers in endocrine therapy (Anastrozole) combined with mTOR inhibitor (Vistusertib) in endometrial cancer: translational study from the VICTORIA trial in collaboration with the GINECO group.

Resistance of advanced hormone-dependent endometrial carcinoma to endocrine therapy remains a worldwide clinical issue. We recently reported that the combination of Vistusertib (V, mTOR inhibitor) and Anastrozole (A, aromatase inhibitor) improves the progression-free rate compared to Anastrozole alone. However, a better patient selection based on biomarkers would improve patient outcome. We evaluate for the first time the usage of ribosome biogenesis (RiBi) factors as a source of innovative markers. Using 47 FFPE tumours (A n= 18; V + A n= 29), 32 blood samples (A n= 13; V + A n= 19) and 30 samples of total RNAs (A n= 12; V + A n= 18) from the VICTORIA clinical trial, we observed an association between RiBi-associated markers and drug activity or prediction of treatment response. NOP10 and NHP2 mRNA levels were significantly higher in non-responders compared to responders in the Vistusertib + Anastrozole arm (P= 0.0194 and P= 0.0002 respectively; i.e. 8 weeks progression-free survival as endpoint). This study provides RiBi-based markers relevant for a better selection of patients with advanced endometrial carcinoma by predicting the response of endocrine therapy combined with mTOR inhibitor.

Real-world Treatment Patterns and Clinical Outcomes Associated With Palbociclib Combination Therapy: A Multinational, Pooled Analysis From the Ibrance Real World Insights Study

PurposePalbociclib was the first cyclin-dependent kinase 4/6 inhibitor approved by the US Food and Drug Administration for use in combination with aromatase inhibitors (AIs) as initial endocrine-based therapy or with fulvestrant in postmenopausal women who previously received endocrine therapy based on data from randomized clinical trials. Real-world studies examining the effectiveness of palbociclib in large, diverse patient populations in routine clinical practice were needed. Patients and MethodsIbrance Real World Insights (IRIS) was a retrospective medical record review study of women with confirmed hormone receptor–positive, HER2-negative advanced/metastatic breast cancer treated with palbociclib plus an AI or with palbociclib plus fulvestrant according to approved indications. Participating physicians reviewed medical records of up to 16 sequentially presenting patients, collecting demographic and clinical data. Outcomes included objective response rates, progression-free rates, and survival rates overall and in patients stratified according to age, race and ethnicity, Eastern Cooperative Oncology Group (ECOG) performance status (PS), disease-free interval, visceral disease, liver metastases, bone-only metastases, and previous lines of therapy. FindingsData were abstracted by 417 physicians for 2954 patients in 13 countries; 1415 patients (47.9%) were ≥65 years of age, 369 patients (12.5%) had an ECOG PS ≥2 at initiation, and 835 patients (28.3%) were races other than White. The 12-month progression-free rate was 88% for palbociclib plus an AI and 79% for palbociclib plus fulvestrant; the 12-month survival rate was 96% in both groups. The objective response rates were 80% for palbociclib plus an AI and 75% for palbociclib plus fulvestrant. Palbociclib was similarly effective in most subgroups examined. ImplicationsData from IRIS provide in-depth, real-world evidence for the use of palbociclib in a range of breast cancer populations in multiple countries. These data support the findings of the randomized PALOMA-2 and PALOMA-3 studies.

Addition of Niraparib to Best Supportive Care as Maintenance Treatment in Patients with Advanced Urothelial Carcinoma Whose Disease Did Not Progress After First-line Platinum-based Chemotherapy: The Meet-URO12 Randomized Phase 2 Trial

BackgroundPlatinum-based chemotherapy (PBCT) is the standard first-line treatment for advanced urothelial carcinoma (UC). Potential cross-sensitivity can be hypothesized between platinum drugs and poly-ADP ribose-polymerase (PARP) inhibitors. ObjectiveTo compare maintenance treatment with the PARP inhibitor niraparib plus best supportive care (BSC) versus BSC alone in patients with advanced UC without disease progression after first-line PBCT. Design, setting, and participantsMeet-URO12 is a randomized, multicenter, open-label phase 2 trial. Patients with advanced UC, without disease progression after four to six cycles of PBCT, with Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, were enrolled between August 2019 and March 2021. Randomization was stratified by ECOG performance status (0/1) and response to PBCT (objective response/stable disease). InterventionPatients were randomized (2:1) to experimental arm A (niraparib 300 or 200 mg daily according to body weight and baseline platelets, plus BSC) or control arm B (BSC alone). Outcome measurements and statistical analysisThe primary endpoint was progression-free survival (PFS). The analysis was performed on an intention-to-treat basis. The secondary endpoints reported in this primary analysis are progression-free rate at 6 mo and safety (adverse event rate). Results and limitationsFifty-eight patients were randomized (39 in arm A and 19 in arm B). The median age was 69 yr, ECOG performance status was 0 in 66% and 1 in 34%; and the best response with chemotherapy was objective response in 55% and stable disease in 45%. The median PFS was 2.1 mo in arm A and 2.4 mo in arm B (hazard ratio 0.92; 95% confidence interval 0.49–1.75, p = 0.81). The 6-mo progression-free rates were 28.2% and 26.3%, respectively. The most common adverse events with niraparib were anemia (50%, grade [G]3 11%), thrombocytopenia (37%, G3–4 16%), neutropenia (21%, G3 5%), fatigue (32%, G3 16%), constipation (32%, G3 3%), mucositis (13%, G3 3%), and nausea (13%, G3 3%). The main limitation of the study is the small sample size: in March 2021, approval of maintenance avelumab for the same setting rendered randomization of patients in the control arm to BSC alone unethical, and accrual was stopped prematurely. ConclusionsAddition of maintenance niraparib to BSC after first-line PBCT did not demonstrate a significant improvement in PFS in patients with UC. These results do not support the conduction of a phase 3 trial with single agent niraparib in this population. Patient summaryIn this trial, we tested the efficacy of niraparib as maintenance treatment in patients affected by advanced urothelial cancer after the completion of first-line chemotherapy. We could not demonstrate a significant improvement in progression-free survival with maintenance niraparib.

Randomized placebo-controlled double-blind phase II study of zaltoprofen for patients with diffuse-type and unresectable localized tenosynovial giant cell tumors: The REALIZE study.

BackgroundA tenosynovial giant cell tumor (TGCT) is a locally aggressive benign neoplasm arising from intra- or extra-articular tissue, categorized as localized (L-TGCT, solitary lesion) and diffuse (D-TGCT, multiple lesions) TGCT. Surgical excision is the mainstay of the treatment, and a high local recurrence rate of approximately 50% has been reported. We focused on zaltoprofen, a nonsteroidal anti-inflammatory drug that can activate peroxisome proliferator-activated receptor gamma (PPARγ) and inhibit the proliferation of TGCT stromal cells. Therefore, we conducted a randomized trial to evaluate the safety and effectiveness of zaltoprofen in patients with D-TGCTs or unresectable L-TGCTs.MethodsThis randomized, placebo-controlled, double-blind, multicenter trial evaluated the safety and efficacy of zaltoprofen. In the treatment group, zaltoprofen (480 mg/day) was administered for 48 weeks; the placebo group received similar dosages without zaltoprofen. The primary outcome was progression-free rate (PFR) 48 weeks after treatment administration. Disease progression was defined as the following conditions requiring surgical intervention: 1) repetitive joint swelling due to hemorrhage, 2) joint range of motion limitation, 3) invasion of the adjacent cartilage or bone, 4) severe joint space narrowing, and 5) increased tumor size (target lesion).ResultsForty-one patients were allocated to the zaltoprofen (n=21) or placebo (n=20) groups. The PFR was not significant between the zaltoprofen group and the placebo group at 48 weeks (84.0% and 90.0%, respectively; p=0.619). The mean Japanese Orthopedic Association knee score significantly improved from baseline to week 48 in the zaltoprofen group (85.38 versus 93.75, p=0.027). There was a significant difference between the values at 48 weeks of placebo and zaltoprofen group (p=0.014). One severe adverse event (grade 3 hypertension) was observed in the zaltoprofen group.DiscussionThis is the first study to evaluate the efficacy and safety of zaltoprofen in patients with TGCT. No significant differences in PFR were observed between the groups at 48 weeks. Physical function significantly improved after zaltoprofen treatment. The safety profile of zaltoprofen was acceptable. This less invasive and safer treatment with zaltoprofen, compared to surgical removal, could be justified as a novel approach to treating TGCT. Further analysis of long-term administration of zaltoprofen should be considered in future studies.Clinical Trial RegistrationUniversity Hospital Medical Information Network Clinical Trials Registry, identifier (UMIN000025901).

781TiP AGADIR: A basket multicenter open-label phase II study evaluating the first in class TLR7/8 agonist BDB001 in combination with atezolizumab and stereotactic body radiation therapy in patients with advanced solid tumors

Monotherapy response rates to PD1/PDL1 monoclonal antibodies remain low, and additional therapies are required to fully exploit their potential. In this regard, strategies that target tumor-resident innate immune cells and induce local tumor proinflammatory responses, which recruit CD8+ TILs, represent a promising approach. One strategy to turn an immunologically cold tumor hot is to promote activation of antigen presenting cells (APC) by targeting the endosomal TLRs TLR3, TLR7, TLR8, TLR9. The first in class TLR7/8 agonist BDB001 can activate both myeloid dendritic cell mDC (which express TLR8) and plasmacytoid dendritic cell pDC (which express TLR7 and TLR9). Targeting both TLR7 and TLR8 allows for a more potent activation signal capable of overriding other inhibitory mechanisms, including turning a « cold » tumor into a « hot » tumor. Stereotactic body radiation therapy (SBRT) can also promote an antitumor systemic response (“abscopal effect”) through T cell-mediated activation of the adaptive immune system. AGADIR is a multi-cohort single-arm phase 2, multicenter, open-label study investigating BDB001 with atezolizumab in patients with advanced cancers: pancreatic adenocarcinoma (pop 1), virus-associated tumors (pop 2), previously exposed to PD1/PDL1 antibodies non-small cell lung cancer (pop 3) and bladder cancer (pop 5), soft-tissue sarcomas (pop 4), triple-negative breast cancer (pop 6). This study will enroll ∼247 patients with no standard treatment options available and ECOG 0–1. BDB0001 is given IV on days 1, 8, and 15 of cycles 1 to 3 and on day 1 every 3 weeks therafter. Atezolizumab is given on day 1 every 3 weeks. SBRT of metastatic lesion will start at least one week after the first dose of atezolizumab. The primary endpoints are disease control rate within 24 weeks of treatment in populations 1, 2, 3, 5 and 6 and progression-free rate at 6 months for population 4 (RECIST 1.1). Secondary endpoints include toxicity, overall and progression-free survival. Pharmacodynamic and other biomarkers will be explored. The first patient received study drug on June 2022. NCT03915678, 16 April 2019. Institut Bergonié, Bordeaux, France.

Nimotuzumab in the Treatment of Inoperable Esophageal Tumors of Epithelial Origin.

Background Nimotuzumab is a humanized monoclonal antibody that targets the epidermal growth factor receptor. It was approved in Cuba for the indication of inoperable malignant tumors of the esophagus of epithelial origin. The purpose of this study was to evaluate the safety, overall and progression-free survival, clinical response, and quality of life, in adult patients with inoperable esophageal tumors of epithelial origin treated with nimotuzumab in a practical context. Material and Methods. The number of patients who developed adverse events was determined, and the frequency, seriousness, causality, and severity of these adverse events were determined. It also determined the median of survival and progression-free survival and rates at 12 and 24 months and the quality of life. Results A total of 111 patients were included. The proportion of serious and related AE with the use of nimotuzumab was 1.3%. Most of the related AEs were mild and moderate, and the most frequent AEs were diarrhea, chills, and tremors. New diagnosed patients who received nimotuzumab concurrent with chemotherapy and radiotherapy reached a median OS of 12.2 months (95% CI, 6.9–17.5) and 12- and 24-month survival rates of 51.0% and 17.0%, respectively. Median PFS was 7.8 months (95% CI, 6.2–9.5), and 12- and 24-month PFS rates were 39.3% and 11.2%, respectively. A favorable evolution of the general state of health (p=0.03) was obtained from the beginning of treatment until month 12, with a significant reduction in the appearance of nausea (p=0.009), insomnia (p=0.04), constipation (p=0.04), eating difficulties (p=0.0006), and choking when swallowing (p=0.0001), but increased in dysphagia (p=0.02). Conclusions The administration of nimotuzumab was safe in the real-world setting. New diagnosed patients that received nimotuzumab concurrent with chemotherapy and radiotherapy reached a higher overall and progression-free survival and better quality of life than the rest of the patients. Trial registration is RPCEC00000215 (Cuban Registry of Clinical Trials; https://registroclinico.sld.cu/en/home). It is registered prospectively on June 30, 2016.

An in-Depth Analysis of Ovarian Cancer: Pathogenesis and Clinical Manifestation.

Ovarian cancer is characterized by the establishment of tolerance, the recurrence of disease, as well as a poor prognosis. Gene signatures in ovarian cancer cells enable cancer medicine research, therapy, prevention, & management problematic. Notwithstanding advances in tumor puncture surgery, novel combinations regimens, and abdominal radiation, which can provide outstanding reaction times, the bulk of gynecological tumor patients suffer from side effects & relapse. As a consequence, more therapy alternatives for individuals with ovarian cancer must always be studied to minimize side effects and improve progression-free and total response rates. The development of cancer medications is presently undergoing a renaissance in the quest for descriptive and prognostic ovarian cancer biomarkers. Nevertheless, abnormalities in the BRCA2 or BRCA1 genes, a variety of hereditary predispositions, unexplained onset and progression, molecular tumor diversity, and illness staging can all compromise the responsiveness and accuracy of such indicators. As a result, current ovarian cancer treatments must be supplemented with broad-spectrum & customized targeted therapeutic approaches. The objective of this review is to highlight recent contributions to the knowledge of the interrelations between selected ovarian tumor markers, various perception signs, and biochemical and molecular signaling processes, as well as one's interpretation of much more targeted and effective treatment interventions.

Abstract 3959: Targeting BCL2 family protein phosphorylation in venetoclax resistant lymphoid malignancies

Abstract Introduction: BCL2 family protein dysfunction is an important mediator of chemoresistance in lymphoid malignancies. Venetoclax (VEN), a BH3 mimetic that selectively targets the anti-apoptotic protein BCL2, is FDA approved for treatment of chronic lymphocytic leukemia (CLL), with clinical trials underway for other lymphoid malignancies. Despite the clinical efficacy of VEN monotherapy, complete remission and progression free rates are still relatively low, thereby indicating the existence of inherent or acquired mechanisms of resistance. Preclinically, increases in anti-apoptotic BCL2 and MCL1 phosphorylation (BCL2-P/MCL1-P) and MCL1 protein level have been implicated in chemoresistance. We therefore question if phosphorylation of these proteins may drive VEN resistance and if removing this modification may re-sensitize resistant cells to VEN induced cell death. Methodology: BH3 profiling (a functional assay that assesses mitochondrial apoptotic priming and anti-apoptotic protein dependence), western blot and cell death assays were performed. Result: We report that VEN acquired resistant DLBCL cell line (OCI-Ly1R) has increased BCL2-P, MCL1-P and MCL1 protein levels as compared to sensitive parental cell line (OCI-Ly1S), while inherently resistant DHL cell line (Su-DHL4) possesses higher MCL1-P and MCL1 protein levels as compared to OCI-Ly1S. We further show that this increase in phosphorylation status contributes to the induction of VEN resistance. Using BH3 profiling, we demonstrate that anti-apoptotic protein phosphorylation-driven VEN resistance involves a change in sensitivity to pro-apoptotic proteins, with an increase in sensitivity to MCL1 inhibition and reciprocal decrease in sensitivity to BCL2 inhibition. We further show that BCL2 and MCL1 dephosphorylation by PP2A activating drugs (PADs) re-sensitizes resistant cells to VEN treatment. Mechanistically, PADs such as the fingolimod (FTY720) not only dephosphorylate BCL2-P and MCL1-P, but also dissociate BAX from BCL2 and destabilize MCL1 protein. These changes lead to the rewiring of cellular sensitivity to BCL2 inhibition, thereby re-sensitizing both VEN acquired and inherent resistant cells to VEN induced cell death. Importantly, the PP2A activating effects of FTY720 were recapitulated in primary cells from the peripheral blood of 16 CLL patients, where FTY720 treatment also reduced BCL2-P, MCL1-P and MCL1 protein levels and dissociated BAX from BCL2. This led to an increased sensitivity to BCL2 inhibition and enhanced cell death upon combined treatment with FTY720 and VEN. Conclusion: Our work defines a new targetable mechanism of VEN resistance in lymphoid malignancies due to the phosphorylation of anti-apoptotic BCL2 family proteins. PADs re-sensitize resistant malignant cells to VEN treatment via dephosphorylation of anti-apoptotic proteins, suggesting a promising combination approach to explore further. Citation Format: Stephen J. Chong, Fen Zhu, Jolin X. Lai, Liam Hackett, Mary C. Collins, Shazib Pervaiz, Jean-Philippe Coppe, Matthew S. Davids. Targeting BCL2 family protein phosphorylation in venetoclax resistant lymphoid malignancies [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 3959.

Optimisation of Radiation Therapy in Bladder Preservation Therapy for Patients With Clinical Stage T2N0M0 Bladder Cancer

AimsA novel bladder preservation therapy, the OMC (Osaka Medical College) regimen, which combines radiation therapy with balloon-occluded arterial infusion of anticancer agents, is a treatment option for patients with muscle-invasive bladder cancer (MIBC). We retrospectively analysed the effects of changes in radiation dose and irradiation field on treatment efficacy and adverse events.The purpose of this study is to use the results of this study to help determine a course of radiation therapy for bladder preservation therapy of cT2N0M0 MIBC. Materials and methodsWe examined 352 patients with clinical stage T2N0M0 (cT2N0M0) MIBC classified into the following groups based on the irradiation method: group A, the whole pelvis (50 Gy/25 fractions) + local bladder (10 Gy/5 fractions); group B, the small pelvis (50 Gy/25 fractions) + local bladder (10 Gy/5 fractions); group C, the whole pelvis (40 Gy/20 fractions) + local bladder (10 Gy/5 fractions). ResultsThe complete response rate, 3-year overall survival and progression-free survival rates in group A were 92.9%, 94.9% and 82.1%, respectively; in group B were 87.2%, 86.7% and 76.7%, respectively; and in group C were 95.2%, 92.6% and 71.1%, respectively. No significant differences between the groups were noted. The incidence of ≥grade 3 urinary tract and gastrointestinal toxicities were not significantly different among the groups (group A: 7.8%, 1.7%; B, 11.1%, 0%; C, 7.1%, 1.8%, respectively). The 3-year progression-free rates of the common iliac lymph node (CILN) region in patients who received whole-pelvis and small-pelvis irradiation were 99.0 and 89.0% (P < 0.01), respectively, with the latter group having significantly high lymph node recurrence in the CILN region. ConclusionsOur findings showed that the optimal radiation therapy for patients with cT2N0M0 MIBC undergoing the OMC regimen is whole-pelvis irradiation including the CILN region, with a total dose of 50 Gy/25 fractions.

Idarubicin-Loaded DEB-TACE plus Lenvatinib versus Lenvatinib for patients with advanced hepatocellular carcinoma: A propensity score-matching analysis.

To investigate the efficacy and safety of lenvatinib and idarubicin-loaded drug-eluting beads transarterial chemoembolization (IDADEB-TACE) in primary advanced hepatocellular carcinoma (HCC). This retrospective study included patients with primary advanced HCC who received either lenvatinib monotherapy or lenvatinib plus IDADEB-TACE as first-line treatment from September 2019 to September 2020 at three institutes. Overall survival (OS), time to progression (TTP), objective response rate (ORR), and adverse events were compared. Propensity score-matching was used to reduce the influence of confounding factors on the outcomes. The study reviewed 118 patients who received lenvatinib plus IDADEB-TACE (LIDA group) and 182 who received lenvatinib alone (LEN group). After propensity score-matching, 78 pairs of patients remained. Compared to patients in the LEN group, those in the LIDA group had better post-treatment ORR (57.7% vs. 25.6%, p < 0.001, respectively), median OS and TTP (15.7 vs. 11.3 months, hazard ratio [HR]=0.50, p < 0.001; 8.0 vs. 5.0 months, HR=0.60, p=0.003, respectively), 6- and 12-month OS rates (88.5% vs. 71.4%; 67.6% vs. 43.4%, respectively), and progression-free rates at 6 and 12 months (60.3% vs. 42.3%; 21.1% vs. 10.3%, respectively). Vascular invasion, α-fetoprotein level, and treatment type were independent OS predictors, and vascular invasion and treatment type were independent TTP predictors. Incidences of nausea/vomiting, fever, abdominal pain, and increased ALT/AST were higher in the LIDA group than in the LEN group. Lenvatinib plus IDADEB-TACE is well-tolerated and more effective than lenvatinib monotherapy in patients with advanced HCC.

Randomized, placebo-controlled, double blind, phase II study of zaltoprofen for patients with diffuse-type and unresectable localized tenosynovial giant cell tumors.

11568 Background:A tenosynovial giant cell tumor (TGCT) is a locally aggressive benign neoplasm arising from intra- or extra-articular tissue, and categorized localized (L-TGCT) or diffuse-type (D-TGCT). D-TGCT most commonly develops in the knee or ankle. We revealed that zaltoprofen, a nonsteroidal anti-inflammatory drug possessing the ability to activate peroxisome proliferator-activated receptor gamma (PPARγ), can inhibit the proliferation of TGCT stromal cells via PPARγ. PPARγ is a ligand-activated transcription factor that belongs to the nuclear hormone receptor superfamily. Therefore, we conducted a randomized trial to evaluate whether zaltoprofen was effective for patients with TGCT. Methods:This study was a randomized, placebo-controlled, double-blind, multicenter trial to evaluate the safety and efficacy of zaltoprofen for patients with L-TGCT or D-TGCT. For the treatment group, zaltoprofen 480 mg/day was administered for 48 weeks. The primary outcome was the progression-free rate (PFR) at week 48 after treatment administration. Disease progression was defined as follows requiring surgical interventions: 1) repetitive joint swelling due to hemorrhage; 2) limited range of joint motion; 3) invasion of adjacent cartilage or bone; 4) severe joint space narrowing; or 5) increase in tumor size (target lesion). This study was registered at the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN000025901). Results:We allocated forty-one patients to zaltoprofen (n = 21; Z) or placebo (n = 20; P) groups. The mean age was 44 years (range, 26 to 66) in the group Z and 47 years (range, 24 to 69) in the group P. TGCTs located at a knee in 26 patients and at an ankle in 15 patients. The primary outcome of PFR for the group Z was not higher than that for the group P at week 48 (84.0% vs. 90.0%; p = 0.619). The objective tumor response was graded as partial response (PR) in 1 patient, stable disease (SD) in 19, and progressive disease (PD) in 1 for the group Z, and SD in 17 and PD in 3 for the group P. The mean musculoskeletal tumor society scoring system for group Z was significantly improved from baseline to week 48 (83.8% vs. 93.0%, p = 0.02), whereas that for the group P was not significantly improved (82.2% vs. 86.8%; p = 0.167). During the study period, one severe adverse event was observed (grade 3 hypertension) in the group Z. Conclusions:To our knowledge, this was the first study to evaluate the efficacy of zaltoprofen in patients with TGCT. The TGCT patients in zaltoprofen group did not have higher PER compared with those in the placebo group at week 48. Zaltoprofen appeared to improve the limb-function. Both groups presented with a stable disease course for 48 weeks, therefore, the long-term clinical course of TGCT should be clarified. Further analysis with long-term administration of zaltoprofen is considered for the future study. Clinical trial information: UMIN000025901.

Bortezomib sensitization of recurrent glioblastoma with unmethylated MGMT promoter to temozolomide, a phase II study (NCT03643549).

TPS2081 Background: Patients with glioblastoma with functional O6 methylguanine DNA methyltransferase ( MGMT) DNA repair enzyme gain limited benefit from temozolomide (TMZ). Bortezomib depletes the MGMT enzyme, restoring the tumor ́s susceptibility to TMZ, if the chemotherapy is administered in the precise schedule. Additionally, bortezomib inhibits the tumor growth by blocking autophagy flux. Thus, pre-treatment with bortezomib prior to temozolomide leads to DNA repair enzyme depletion and blockade of autophagy-induced survival signals. Methods: The academic, industry independent, multicenter, open label, single arm, non-randomized phase II trial is designed to investigate the survival benefits for patients treated with bortezomib 48hrs prior to TMZ. Efficacy of this therapy will be compared to historical cohorts receiving standard management. The study will include 53 patients with recurrent or progressive, MGMT unmethylated glioblastoma. The additional 10 patients were treated in the phase IB. All patients will receive a combination of bortezomib 1.3mg/m2 administered IV on days 1, 4, 7, during each 4-week chemotherapy cycle with PO TMZ at 200mg/m2 5 days/week q4w starting on day 3. Dose reduction of TMZ is allowed if reduced bone marrow tolerance is present. Major eligibility criteria include histologically confirmed glioblastoma with unmethylated MGMT promoter, MRI evidence of recurrence within 14 days prior to enrolment, age ≥ 18 years with life expectancy &gt; 8 weeks, KPS ≥ 70, radiologically (MRI) confirmed tumor relapse/progression ≥ 12 weeks since completed radiotherapy, tumor not available for radiosurgery, adequate bone marrow, renal and liver function, no contraindications for bortezomib and/or TMZ. Endpoints: Estimation of the median progression free survival (PFS) and overall survival (OS) of patients with recurrent or progressed glioblastoma as well as progression free rate at 6 months. Secondary objectives: Therapy response assessed by contrast enhanced MRI (RANO criteria) and neurological examination (NANO criteria) as well as identification of novel biomarkers that correlate with treatment response. Twenty-four of the planned 53 patients are enrolled. Five of them receive treatment. The prespecified activity goal for the first stage of the study was met. Discussion: Patients with glioblastoma harboring active MGMT enzyme have median survival of 12.7 months, compared to 21.7 months for patients with the MGMT gene promoter silenced by methylation. This dismal prognosis for the approx. 55% of GBM patients underscores the unmet need for novel combination therapies that sensitize the tumors to chemotherapy. Results from this trial will serve as preliminary evidence of the role of bortezomib administered in a precise manner to abolish the temozolomide resistance of GBM with unmethylated MGMT promotor. The study is currently active and recruiting. Clinical trial information: NCT03643549.

A phase II study, with a safety lead-in, to evaluate ATX-101, a peptide drug targeting PCNA, in advanced dedifferentiated liposarcoma and leiomyosarcoma.

TPS11587 Background: Soft tissue sarcoma (STS) is a heterogeneous malignancy of mesenchymal origin; leiomyosarcoma (LMS) and liposarcoma (LPS), two of the most common adult STS, are treated with first-line chemotherapy with objective response rates (ORRs) of 15-20%. There is an urgent need for novel therapeutics. ATX-101 is a small peptide comprised of a novel human AlkB homolog 2 proliferating cell nuclear antigen (PCNA) interacting motif termed APIM coupled to cellular and nuclear delivery domains. Via APIM, PCNA interacts with many cellular proteins important in the cellular stress and DNA damage responses, as well as intracellular signaling, apoptosis, metabolism, and anti-tumor immunity. In preclinical studies, ATX-101 demonstrated single-agent activity and potentiated other cytotoxic and targeted agents across multiple cancer models in vitro and in vivo, including LMS and LPS. In a phase I safety and pharmacokinetic study in solid tumors, ATX-101 was well tolerated and demonstrated prolonged disease stabilization in patients (pts) with heavily pretreated malignancies. This study will evaluate preliminary efficacy and further establish the safety profile of ATX-101 in advanced LMS and LPS. Methods: This is a single-arm, open-label, Simon 2-stage, phase II clinical trial of ATX-101 in pts with advanced LMS and LPS. Eligible pts have ECOG PS ≤2, progression on ≥1 prior line of therapy and disease measurable by RECIST v1.1 and amenable to image-guided biopsy. Pts receive ATX-101 60 mg/m2 IV weekly in continuous 21-day cycles. The 1° endpoint is progression free rate at 12 weeks (PFR12). A Simon 2-stage design is used to evaluate for improvement in PFR12 of ≤ 30% (null hypothesis) versus ≥ 55% (alternative hypothesis). The design calls for 34 pts with a safety lead-in among the first 10 pts enrolled. If 15/34 meet the PFR12 endpoint, the treatment is promising. This design yields 85% power and 1-sided type I error of 5%. 2° endpoints include progression free survival, ORR, and safety. 10 pts undergo tumor biopsies pre-treatment and during cycle 2. Tissue is used for correlative analysis interrogating ATX-101’s effects on the immune microenvironment through multiplex immunohistochemistry, DNA damage response through whole exome sequencing/RNAseq to evaluate for alterations in HR pathway component genes, and intracellular signaling pathways by Western blot for AKT/mTOR components. The study opened to accrual 12/2021. Clinical trial information: NCT05116683.

Extended duration of anti-PD-1 therapy, using reduced frequency dosing, in patients with advanced melanoma and Merkel cell carcinoma.

2588 Background: Optimal duration of treatment (DoT) with immune checkpoint inhibitors (ICI) in patients with metastatic melanoma (Mel) and Merkel cell carcinoma (MCC) is unclear. ICI discontinuation in Mel patients, especially those without CR, may be associated with a higher rate of progression over time, as compared to ICI continuation. Thus, extending DoT could improve outcomes. However, indefinite continuation at standard frequency doses (SFD) is not logistically or financially viable. Based on data from phase I studies suggesting sustained PD-1 receptor occupancy beyond 3 months after a single dose of nivolumab, we employed reduced frequency dosing (RFD) of anti-PD-1 antibodies every 2-3 months, to extend ICI duration beyond 2 years. Methods: This retrospective study analyzes patients in our skin cancer clinic with metastatic Mel and MCC who experienced initial clinical benefit with anti-PD-1 administered at SFD and then transitioned to RFD. We analyzed safety and efficacy endpoints including progression free survival (PFS) and rates of immune-related adverse events (irAE) with RFD. We also compared the pharmaceutical costs and patient-centered costs between 2 years of treatment at SFD versus extended DoT at RFD. Results: From 2014 – 2021, 23 patients with either metastatic Mel (N = 18) or MCC (N = 5) received anti-PD-1 therapy at RFD. Median DoT at SFD in this cohort was 1.1 years (range 0.2 – 2.2) with best objective tumor responses of CR (N =6), PR (N = 11), SD (N = 6). Median DoT at RFD was 1.2 years (range 0.2 – 3.5). The median follow-up for the entire cohort is 3.7 years (range 0.7 – 6.3) after ICI initiation. The 3-year PFS in Mel patients was 100% in those with CR (3/3), 89% with PR (8/9), and 50% with SD (3/6). The 3-year PFS in MCC was 100% in all 5 patients, including patients with CR (3/3) and with PR (2/2). Any-grade irAEs occurred in 43% of patients by 3 years on RFD, and grade 3/4 irAEs presented in 15%. Among the subset of 15 patients with DoT &gt;2 years (median 3.4 yr, range 2.0 – 5.0), total savings amounted to $1.1 million in drugs costs and 384 hours of clinic and travel time despite the increased DoT, as compared to the calculated values for 2-year DoT at SFD. Conclusions: RFD may provide an alternative approach to extending DoT in patients receiving ICI without additional logistical and financial burden, while preserving outcomes. Efficacy and safety data suggest sustained biologic activity of ICI with RFD administration. PK/PD analyses on patient samples are ongoing to further characterize the RFD approach. The RFD approach could be utilized to expand ICI access to communities with limited healthcare resources, thereby impacting cancer outcomes at a global scale.

Phase III randomized controlled trial comparing chemotherapy to best supportive care in advanced esophageal and gastroesophageal junction cancer.

4065 Background: Patients with advanced esophageal/gastroesophageal junction (GEJ) cancer have a dismal outcome. No study has unequivocally proven that systemic chemotherapy prolongs survival. Current NCCN guidelines recommend palliative/best supportive care as a first-line option for patients with unresectable locally advanced, recurrent, or metastatic esophageal/GEJ cancers. Methods: Phase III randomized controlled study conducted in the Department of Medical Oncology at the Tata Memorial Hospital (Mumbai, India) in patients with advanced unresectable or metastatic esophageal or GEJ cancer, planned for palliative intent therapy. Patients aged 18 to 70 years, with a performance status &lt; 2, were stratified based on histopathology, presence of metastatic disease and receipt of prior curative therapy, and randomized 1:1 to best supportive care alone, or best supportive care with chemotherapy consisting of intravenous paclitaxel 80 mg/m2 once-a-week, continued until disease progression or intolerable toxicity. Best supportive care consisted of patient education and counselling, non-chemotherapeutic palliative measures like radiation, or stenting, placement of feeding tube, analgesia, antiemesis and other supportive medications, nutritional support, and referral to a patient support group. Primary endpoint was overall survival (OS); secondary endpoints included progression free survival (PFS), response rate, adverse events, and quality of life. Results: Between May 2016 and Dec 2020, we recruited 281 patients; 143 to chemotherapy and 138 to best supportive care. Histopathology was squamous in 269 (95.7%) patients. In the 143 patients in the chemotherapy arm, median number of paclitaxel cycles was 12 (IQR, 7-23). The response rate was 32%. Grade &gt; 3 toxicities occurred in 82 (57%) patients who received paclitaxel; commonly hyponatremia (18%), anemia (11%), fatigue (10%), peripheral neuropathy (10%), infection (9%), and neutropenia (7%). Median PFS was 2.1 months (95% CI, 1.98-2.23) in the best supportive care arm, and 4.1 months in the chemotherapy arm (95% CI, 3.54-4.74); HR, 0.51 (95% CI, 0.39-0.64); P &lt; 0.001. The 1-year OS was 11.6% in the best supportive care arm, versus 30.8% in the chemotherapy arm. Median OS was 4.2 months (95% CI, 2.93-5.42) in the best supportive care arm, and 8.6 months in the chemotherapy arm (95% CI, 7.56-9.66); HR, 0.52 (95% CI, 0.40-0.66); P &lt; 0.001. Conclusions: Systemic chemotherapy significantly prolongs survival and should be considered the standard of care in patients with advanced esophageal and GEJ squamous cell carcinoma. Metronomic weekly paclitaxel is an attractive option, especially in LMICs with limited access to newer immunotherapy-based combination regimens. Clinical trial information: CTRI/2016/01/006474.

From bench to bedside and back: prognostic groups of Phase 2 study of second-line FOLFIRI-aflibercept in prospectively stratified, RAS wild type, anti-EGFR resistant, metastatic colorectal cancer patients: The DISTINCTIVE trial—A GISCAD study.

e15571 Background: Currently, no validated biomarkers are available for second-line anti-angiogenic treatment in RAS wild type (wt) metastatic colorectal cancer (mCRC) patients (pts) progressing after first-line anti-EGFR. Here, we present the results of a pre-planned interim analysis of the DISTINCTIVE trial (NCT04252456) on prognostic groups identified with the combination of hematologic parameters and based on the association of clinical and translational biomarkers. Methods: RAS wt mCRC pts progressing after first line oxaliplatin-based + anti-EGFR therapy receive FOLFIRI-aflibercept and are prospectively stratified in 2 groups according to Elisa-assessed baseline VEGFR2 plasma levels. Other circulating angiogenic factors are evaluated at specific timepoints. Clinical and laboratory data are collected to assess their correlation with outcome. Primary endpoint is overall survival (OS) according to VEGFR2 levels. Secondary endpoints are OS, progression free survival (PFS), response rate, safety and angiogenic factors levels. Statistical analysis is performed with MedCalc (survival distribution: Kaplan-Meier; survival comparison: log-rank test; multivariate analysis: logistic regression; cut-off: ROC curves). Results: Of 73 pts enrolled (04/2018-06/2020), 44 were eligible for interim analysis. Median OS was 11.9 months (m) (95% CI 10-14.2). We identified at first 2 prognostic groups: favorable prognosis (baseline monocytes ≤0.7x103/μL + RBC &gt; 3.81x106/μL + MRR≤1528) and unfavorable prognosis (monocytes &gt; 0.7x103/μL and/or RBC ≤3.81x106/μL and/or MRR &gt; 1528). OS was 14.2 months (m) (95% CI 10.467-14.2) in the favorable prognosis group vs 6.9 m (95% CI 4.867-9.133) in the unfavorable prognosis group (HR 0.008, p &lt; 0,0001). Then, we performed multivariate analysis on circulating angiogenic factors and on laboratory values; VEGFR2 levels at disease progression (PD) and baseline RBC maintained an independent role (Exp(b) 0.0891, p = 0.0464 and Exp(b) 0.1170, p = 0.0148, respectively). By combining these findings we separated pts in a favorable prognosis group (VEGFR2≤4ng/ml + RBC &gt; 3.81x106/μL) and unfavorable prognosis group (VEGFR2 &gt; 4ng/ml and/or RBC ≤ cut off). OS was significantly improved in the favorable prognostic group (14.2 m [95% CI 11.167-14.2] vs 9.1 m [95% CI 6. 367-10.067], HR 0.03, p = 0.0001). Conclusions: Our results showed the prognostic role of the combination of hematologic parameters and VEGFR2 levels + RBC count in RAS WT anti-EGFR resistant mCRC pts treated with FOLFIRI-Aflibercept. These findings represent a promising association of translational and clinical factors in predicting survival in the specific study population. Clinical trial information: NCT04252456.

Adjuvant chemotherapy followed by adjuvant radiotherapy for treatment of high risk endometrial cancers: A retrospective review.

e17626 Background: Endometrial cancer is the most common gynecologic malignancy in North America (1-3). Patients who are considered to be high risk for recurrence are commonly treated with a combination of adjuvant chemotherapy and radiation. However, the optimal sequence of these therapies has not been defined. The purpose of this study is to review our progression-free survival (PFS) outcomes and recurrence rates and compare to established outcomes in the literature. Methods: A retrospective chart review was performed on all patients diagnosed with endometrial cancer who received adjuvant chemotherapy and radiation between Jan. 1, 2005 to Dec. 31, 2017 at The Ottawa Hospital. Main inclusion criteria for the study were stage III endometrial cancers of any histology, stage I-II endometrial cancers with serous or clear cell histology and stage IV endometrioid adenocarcinomas of the endometrium. The primary outcome of interest is the overall progression-free survival (PFS), defined as the time from surgery to disease recurrence or death by any cause. Results: A total of 140 patients were included in the study. Of these, 52 (37.1%) had endometrioid histology, 75 (53.6%) had serous, and 11 (7.9%) had clear cell histology. Of the total sample, 41 (29.3%) were stage 1 at diagnosis, 24 (17.1%) were stage 2, 68 (48.6%) were stage 3 and 7 (5.0%) were stage 4. The median start time to chemotherapy was 49 days after initial surgery. 130 (92.9%) completed a total of 6 cycles of chemotherapy (majority treated with carboplatin and paclitaxel). 92% of the patients completed radiation following chemotherapy; majority received external beam radiation +/- a brachytherapy boost. Radiation was started withing 4-6 weeks of completing chemotherapy. 42 (30.0%) patients were diagnosed with a recurrence during the time of follow-up and 7 were diagnosed with progressive disease on treatment. Of the recurrences, 2 (4.8%) were local, 5 (11.9%) were locoregional, 8 (19.0%) were isolated para-aortic, and 27 (64.3%) were distant. The median follow-up time for our sample was 63.9 months. The median PFS and overall survival for our sample was not reached. The estimated mean 5 year PFS was 0.69 and OS was 0.66. Conclusions: Although radiation prevents locoregional recurrences, chemotherapy improves survival outcomes in locally advanced and aggressive histology endometrial cancer. Previous reported outcomes have been based on giving adjuvant radiation first, followed by chemotherapy (4,5). Our results demonstrate that giving adjuvant chemotherapy first and then delivering radiation after may be the optimal approach since it leads to survival outcomes that compare favourably with the published literature and very few locoregional relapses.

Real-world effectiveness of immune checkpoint inhibitors alone or in combination with chemotherapy in metastatic non–small cell lung cancer.

9055 Background: The benefit of combination immune checkpoint inhibitor (ICI) with chemotherapy over ICI monotherapy in non-small cell lung cancer (NSCLC) remains underexplored. Methods: This retrospective cohort included patients with metastatic NSCLC from a single-institution database treated with ICI monotherapy or with chemotherapy between 1/2014-2/2020. Clinical progression-free survival (PFS) and overall survival (OS) were the primary outcomes. Propensity score adjustment for clinical and sociodemographic characteristics was used for analysis of first-line treatment outcomes. Results: A total of 1,139 patients (54% male; median age, 64.9) were included. Adenocarcinoma histology, smoking history, higher PD-L1 expression, and lower metastatic stage associated with improved PFS. However, PD-L1 expression and smoking associated with PFS only in adenocarcinoma (LUAD); squamous (LUSC) patients had shorter PFS independent of PD-L1 and smoking history (PD-L1 &gt; 50% vs 1-49%: LUAD P &lt; 0.001; LUSC P = 0.69; Former vs never smoker: LUAD P = 0.008; LUSC P = 0.89). In first-line patients (n = 680), treatment with ICI plus chemotherapy (ICI-chemo) associated with higher progression-free rates at 3 and 6 months compared with ICI-monotherapy (ICI-chemo vs ICI-mono: 3-month PFS, 85.2% vs 68.8%, P = 0.001; 6-month PFS, 66.4% vs 52.6%, P = 0.008). However, there was no difference overall in PFS or OS in either the full or propensity-matched cohort. Treatment with ICI and chemotherapy concurrently vs sequentially was associated with similar PFS (log-rank P = 0.12). Conclusions: In this real-world cohort, the addition of chemotherapy to ICIs may protect against early progression but does not influence long-term outcomes. Treatment with sequential vs concurrent ICI and chemotherapy produced similar outcomes. These findings suggest that combination therapy may maximally benefit patients at risk of early progression.

Distinct clinical outcome of microcystic meningioma as a WHO grade 1 meningioma subtype.

To evaluate the clinicopathological characteristics, radiology, and long-term outcomes of microcystic meningiomas (MM) and compare it with other subtypes of meningiomas managed at a single neurosurgical center. A total of 87 consecutive patients who underwent surgical resection and were diagnosed as MM between 2005 and 2016 were enrolled for analysis. Clinicopathological, radiology, and prognostic information was collected and analyzed. Progression free survival (PFS) was compared with 659 patients with other subtypes of WHO grade 1 meningiomas and 167 patients with atypical meningiomas treated during the same period. Fifty six females and 31 males with MM were analyzed. Peri-tumor brain edema was frequent on T2 WI (85%).12 patients (13.8%) experienced tumor progression during the mean follow-up of 101.66 ± 40.92months. The median PFS was unavailable, and the 5, 10, and 15year progression-free rates were 96.9%, 84.0%, and 73.9%, respectively. Univariate COX analysis demonstrated skull base location and higher Ki-67 index as significant negative prognostic factors for PFS (P < 0.05); multivariate analysis identified tumor location and Ki-67 index as independent factors (P < 0.01), as well. Of note, the PFS of MM was worse than other WHO grade 1 subtypes (P < 0.001), but better than atypical meningiomas (P < 0.001), and the PFS differences were retained even when the analysis was limited to the patients receiving GTR (P < 0.05). The PFS of MM was worse than other WHO grade 1 subtypes and better than atypical meningiomas. Skull base location and higher Ki-67 index were independent negative prognostic factors in MM.

Combination Vistusertib and Anastrozole Shows Benefit in Endometrial Cancer.

The primary endpoint of 8-week progression-free rate was met with this combination.