Durable SD Research Articles

CTIM-03. IMMUNE CHECKPOINT INHIBITOR NIVOLUMAB IN PEOPLE WITH RECURRENT SELECT RARE CNS CANCERS: RESULTS OF INTERIM ANALYSIS IN A NON-HEAVILY PRETREATED COHORT

Abstract BACKGROUND There is a paucity of salvage therapies for patients with rare CNS tumors. Nivolumab (PD-1 inhibitor) is approved for a variety of systemic cancers. We developed a multisite basket Phase II trial to evaluate Nivolumab for patients with recurrence of one of 12 selected rare CNS cancers. Efficacy is measured by Disease Control Rate (DCR; confirmed CR/PR or durable SD for ≥ 6 months) in 2 cohorts: heavily and non-heavily pretreated (≥ 3 prior therapies, vs. ≤ 2; including radiation and/or standard or experimental drugs). Cohort 1 has been completed. We report efficacy results and safety data of a preplanned interim analysis in Cohort 2 (non-heavily pretreated). METHODS In addition to progressive disease, eligibility includes available tumor tissue; age ≥ 18; KPS ≥ 70; no steroids at trial entry. Planned accrual: 75 in each cohort. Nivolumab dose: 240 mg IV every 2 weeks (4 doses), followed by 480 mg every 4 weeks (14 additional doses). Interim analysis was planned when the sample size reached 32 in each cohort. RESULTS As of December 1, 2023, among 27 evaluable patients treated in the non-heavily pretreated cohort, 10 achieved SD ≥ 6 months (DCR 37%; 95% CI 19.4%,57.6%) – 6 high-grade meningiomas; 1 each: myxopapillary ependymoma with lung metastases; solitary fibrous tumor, gliomatosis (astrocytoma IDH mutant WHO grade 2), chordoma. A total of 56 Grade 3-5 AEs occurred; 13 (Grade 3-4) related to nivolumab, including Grade 3 gait disturbance (3); cerebral edema, cognitive disturbance, colitis, headache, hypotension, hypoxia, lymphopenia, pain, and pruritus (1 each), and one Grade 4 cerebral edema. The three Grade 5 AEs were disease-related. CONCLUSION Preliminary efficacy analysis exceeded the “go” boundary (i.e., > 5 responders) in the non-heavily pretreated cohort. Nivolumab showed an acceptable safety profile. Cohort 2 will continue to complete a planned accrual of 75 patients.

A phase 1 dose-escalation and expansion study of CUE-101, given as monotherapy and in combination with pembrolizumab, in patients with recurrent/metastatic HPV16+ head and neck squamous cell cancer (R/M HNSCC).

6004 Background: Immuno-STATs are modular T cell engagers engineered to selectively activate tumor-antigen specific CD8+ T cells via targeted delivery of cytokines. CUE-101, the first Immuno-STAT in clinical trials, is composed of a human leukocyte antigen (HLA) complex, HLA-A*0201, a peptide epitope derived from the HPV16 E7 protein and 4 molecules of attenuated human interleukin-2 (IL-2), to bind, expand, and activate HPV16-specific CD8+ T cells for the treatment of HPV16+ HNSCC. Methods: CUE-101-01 is an ongoing first-in-human study in HLA-A*0201 patients with HPV16+ R/M HNSCC. Escalating doses of CUE-101 monotherapy (0.06 mg/kg to 8 mg/kg) were evaluated in R/M HNSCC refractory to ≥ 1 platinum or checkpoint inhibitor (CPI) based therapy, alone or combined with pembrolizumab (1 mg/kg to 4 mg/kg + 200 mg pembrolizumab) in the first line treatment of PD-L1+ R/M HNSCCs. Enrollment at the recommended phase 2 dose (RP2D) was expanded. Therapy was administered every 3 weeks (Q3W) until disease progression or intolerable toxicity. Safety, PK/PD, and antitumor activity were assessed. Results: Enrollment in both monotherapy and combination cohorts is now completed (N=80 patients, 49 in monotherapy and 31 CUE-101 plus pembrolizumab). Following dose escalation, 4 mg/kg Q3W of CUE-101 was selected for RP2D for both monotherapy and pembrolizumab combination cohorts. At data cut-off, adverse events (AEs) have been manageable and 92% grade ≤2. The most frequent grade 3 AEs reported include lymphocyte count decreased (7.6%), anemia (6.3%), decreased appetite (5.1%) and infusion-related reactions (5.1%). In combination with pembrolizumab no unanticipated significant safety concerns have emerged. Exposure-dependent PD effects of CUE-101 are consistent with IL-2 pharmacology and indicate preferential expansion of CUE-101 on E7-specific T cells. Among the 19 evaluable patients treated with the RP2D of CUE-101 plus pembrolizumab, an ORR of 47% (1 CR, 8 PRs), a Disease Control Rate (ORR + durable SDs) of 74%, and mPFS of 5.8 months [95% CI 2.56; NA] were observed. A median OS has not been reached. Of the 9 patients with confirmed objective responses, all achieved >99% reduction in HPV16 cfDNA in plasma during their treatment course. Among the 19 evaluable monotherapy RP2D patients, 1 PR and 6 durable SD (SD ≥ 12 weeks) and mOS of 20.8 months [95% CI 11.0; NA] were observed. Conclusions: An ORR of 47% and a mPFS of 5.8 months were observed in R/M HNSCC patients treated with CUE-101 4 mg/kg + pembrolizumab as 1L therapy. A median OS of 20.8 was observed in patients treated with CUE-101 monotherapy as post-platinum/CPI therapy. CUE-101 continues to demonstrate safety, tolerability and meaningful clinical benefit in patients with HPV16+ R/M HNSCC. Clinical trial information: NCT03978689 .

Tregs, gMDSCs, and levels of soluble MICA as prognostic biomarkers for combined NEO-201 and pembrolizumab.

2530 Background: The humanized IgG1 monoclonal antibody NEO-201 binds to Core 1 and/or extended Core 1 O-glycans expressed by several human solid and blood tumors, as well as neutrophils, and mediates killing of cancer cells, neutrophils, regulatory T cells (Tregs) and granulocytic myeloid-derived suppressor cells (gMDSCs) via ADCC and CDC. Resistance to PD-1/PD-L1 blockade may be due to the accumulation of Tregs and gMDSCs in the tumor microenvironment (TME). NEO-201 was proven to bind and reduce the amount of circulating Tregs in cancer patients. This supports the rationale of the ongoing phase II clinical trial (NCT03476681) evaluating the activity of NEO-201 with pembrolizumab in adults with solid tumors resistant to prior checkpoint inhibitors. Furthermore, elevated serum levels of soluble MICA (sMICA) have been correlated with decreased NK cell activity. Methods: Cancer patients were treated each cycle with 3 doses of NEO-201 1.5mg/kg every 2 weeks and pembrolizumab 400mg IV every 6 weeks and imaged for response every 2 cycles. PBMCs and serum from cancer patients pre- and at multiple time points post-treatment were used to evaluate the percentage of circulating gMDSCs and Tregs (flow cytometry) and sMICA levels (ELISA). Results: NEO-201 recognizes naïve Tregs (nTregs: CD3+/CD4+/CD45RA+/Foxp3low cells) but not effector Tregs (eTregs: CD3+/CD4+/CD45RA-/Foxp3high cells). NEO-201 also binds to gMDSCs, defined as HLA-DRneg/CD33+/CD15+/ CD14neg/CD66b+ cells. In patients with durable SD, a patient with HNSCC (SD >11 months) showed >50% reduction of nTregs and >90% of gMDSCs at C3D1 (beginning of cycle 3) compared to baseline. One patient with cervical cancer (SD >8 months) showed 40% reduction of nTregs at C3D1 compared to baseline, while gMDSCs trended down to baseline levels at C3D1 after initial increase. Conversely, we observed a general uptrend of nTregs and gMDSCs in patients with PD after treatment. Median serum levels of sMICA pre-treatment were 33-fold higher in patients with PD compared to patients with SD. Levels of sMICA remained elevated in patients with PD and low in patients with SD at all time points post-treatment. Conclusions: Depletion of circulating Tregs and gMDSCs may prevent their accumulation in the TME and enhance the efficacy of pembrolizumab in subjects with tumors resistant to checkpoint inhibitors. The decrease in circulating nTregs and gMDSCs after treatment with NEO-201 and pembrolizumab was associated with durable SD. High levels of sMICA can impair ADCC mediated by NEO-201, resulting in poor clinical response. Low levels of sMICA in patients with SD, together with the reduction of both circulating nTregs and gMDSCs, could be favorable prognostic markers for clinical benefit following treatment with NEO-201 and pembrolizumab. Ongoing enrollment in this clinical trial will validate these findings in larger cohorts. Clinical trial information: NCT03476681 .

Effect of novel autologous immune training platform on end-stage patients with cancer.

2546 Background: SUPLEXA therapeutic cells are the initial autologous and non-engineered candidate to emerge from the novel ENLIST cells training platform. Manufacturing is robust, reproducible and with an acceptable cost of goods. The method requires 35 days to produce multiple doses. Multiple mechanisms of SUPLEXA therapeutic cells have been delineated and all appear to complement that of immune checkpoint inhibitors (ICIs) with SUPLEXA cells serving to enhance the number of primed anti-tumor host T cells while ICIs serve to increase the durability of primed T cells by blocking their premature down-regulation. Methods: A 35 patient Phase 1 single-agent study survey study is currently ongoing in Australia to test the safety and clinical activity of SUPLEXA cells in end-stage patients with various tumor types. No chemo preconditioning or concomitant cytokine treatment was employed. CYTOF analysis of longitudinal peripheral blood is used to monitor changes to the host immune system. Results: To date, SUPLEXA therapeutic cells have demonstrated safety and significant clinical benefit with an observed CR, PR, and many durable SD in approximately half the patients. Several solid tumor patients remain on study beyond 1 year and doing well. Longitudinal analysis of PBMCs from SUPLEXA cell treated cancer patients demonstrated durable changes in the composition of myeloid immune cell subsets in SUPLEXA treated patients, impacting the anti-tumor bias of the host immune system. Specifically, we identified a dramatic decrease in the number of peripheral myeloid derived suppressor cells (MDSCs), within 3 weeks of SUPLEXA treatment. In patients with CR and PR, we also identified stable increases in activated classical CD14+ blood monocytes. Conclusions: SUPLEXA therapeutic cells are a highly differentiated approach to cellular therapy. The first-in-human experience demonstrated a pristine safety profile and strong clinical benefit as a single-agent. The pharmacodynamic decrease of in the number of MDSCs, known to suppress the anti-tumor immune response and limit immune checkpoint inhibitors (ICIs) efficacy, supports the further clinical testing to test the hypothesis that the multiple mechanisms of SUPLEXA cells will enhance the clinical activity of ICIs. Clinical trial information: NCT05237206 .

Temozolomide and nivolumab in patients with refractory metastatic melanoma (MM).

e21521 Background: Immune checkpoint inhibitors (ICI) are the standard treatment for patients (pts) with MM. However, only a subset of pts respond to ICIs. Temozolomide (TEM) is used in refractory settings but with low objective response rates and no clear overall survival benefit. The efficacy of combined ICI + TEM is not well described. Methods: This was a single center, retrospective study of pts with MM who received treatment with nivolumab (NIVO) and TEM or TEM alone between 11/6/2013 and 11/6/2023. Demographic information, disease characteristics, LDH, treatment, toxicity, objective response, and outcomes were collected. Results: 34 patients were included. 16 were treated with NIVO + TEM and 18 were treated with TEM alone. In the NIVO + TEM group, 81% were male (n = 13) with median age of 59.5 years (range 20-79), and in the TEM group, 56% were male with median age 61 (range 35-81). For NIVO + TEM, 31% had partial response (PR; n = 5), 6% had stable disease (SD, n = 1), and 63% had progressive disease (PD; n = 10). For TEM, 11% had PR (n = 2), 22% had SD (n = 4), and 67% had PD (n = 12) (p = 0.37). For NIVO + TEM, 2 PRs were durable, ongoing at 442 and 741 days; 3 PRs were transient (85-179 days); 1 pt had durable SD ongoing at 201 days. For TEM, PR durations were 173 and 504 days, and SD durations between 213-435 days. Five pts with PD treated with NIVO + TEM had mixed responses (31%) compared with 1 pt treated with TEM (6%). Median progression free survival (PFS) was 80 days (range 11-748) for NIVO + TEM and 55.5 days (7-415) for TEM (p = 0.31). Median overall survival (OS) was 160 days (43-363) for NIVO + TEM and 118 days (7-1938) for TEM (p = 0.15). There were 26 adverse events (AEs) for NIVO + TEM (27% grade 1, 42% grade 2, 19% grade 3, and 12% grade 4; thrombocytopenia and pneumonitis), and 25 AEs for TEM (40% grade 1, 40% grade 2, 12% grade 3, and 8% grade 4; thrombocytopenia) [p = 0.64]. Conclusions: NIVO + TEM occasionally produced durable responses, although outcome metrics were not clearly superior to TEM alone in this small study. Further studies should quantify the benefit of ICI + chemotherapy regimens in refractory MM. [Table: see text]

Abstract 2716: The O-glycan epitope targeting anti-human carcinoma monoclonal antibody (mAb) NEO-201 can also target human regulatory T cells (Tregs)

Abstract Introduction:NEO-201 is a humanized IgG1 mAb that targets Core 1 and/or extended Core 1 O-glycans expressed by several human solid and blood tumors, as well as neutrophils, but it does not bind to most normal tissues and human immune cell subsets (B cells, CD4+ T cells, CD8+ T cells, NK cells, monocytes). Functional analysis revealed that NEO-201 mediates the killing of its target cells through ADCC and CDC. Previous study has shown that approximately 4.6% of CD4+ T cells express NEO-201 target antigen and that those CD4+ T cells have Tregs phenotype. In addition, in a recent published phase 1 study we observed that NEO-201 binds to CD4+/CD25+/, CD127−/, Foxp3+/, CD15s+ cells from peripheral blood mononuclear cells (PBMCs) from cancer patients with solid tumors. The purpose of this study was to further characterize the phenotype of the specific subset of CD4+ T cells expressing the NEO-201 target antigen. Experimental Design: Human PBMCs were obtained from 7 healthy donors (HD) collected at Osaka University and 6 cancer patients from our ongoing phase II clinical trial (Clinical Trial NCT03476681) evaluating the efficiency of the combination of NEO-201 with pembrolizumab in adults with solid tumors resistant to checkpoint inhibitors. Phenotypic analysis was performed by flow cytometry using NEO-201 and antibodies CD3, CD4, CD25, CD45RA, FoxP3, and CD15s. The same gating strategy was applied for both normal donors and patients to evaluate which fraction of CD4+ T cells is recognized by NEO-201. Fraction (Fr) 1 is naïve Treg, Fr ll is effector Treg, Fr lll is non-Treg, Fr lV is effector CD4 T cells and Fr V is naïve CD4 T cells. Results: Flow cytometry analysis of PBMCs revealed that NEO-201 recognizes naïve Tregs (nTregs: CD3+/CD4+/CD45RA+/Foxp3low cells) while it does not bind to effector Tregs (eTregs: CD3+/CD4+/CD45RA−/Foxp3high cells) in both HD and cancer patients. The % of nTregs in cancer patients was higher than HD. Preliminary results from the ongoing Phase II clinical trial showed that subjects with durable SD had a reduction of circulating nTregs after treatment with NEO-201 compared to baseline levels. Conclusions: NEO-201 binds to human Tregs with significantly higher % of binding to Fr l and a greater % of Tregs expressing NEO-201 target antigen in cancer patients compared to HD. It is conceivable that naïve Tregs in cancer patients express high levels of Core 1 O-glycans. Furthermore, when subjected to TCR stimulation, naïve Tregs undergo proliferation and differentiate into eTregs. eTregs can then infiltrate into tumor microenvironment (TME). These data suggest that depletion of circulating nTregs in cancer patients after NEO-201 treatment may prevent the differentiation of nTregs into eTregs and their accumulation in the TME. This study suggests the potential use of NEO-201 to reduce the Treg-mediated suppression of anticancer immunity. Citation Format: Atsushi Tanaka, Massimo Fantini, Philip M. Arlen, Christina M. Annunziata, Kwong Y. Tsang, Shimon Sakaguchi. The O-glycan epitope targeting anti-human carcinoma monoclonal antibody (mAb) NEO-201 can also target human regulatory T cells (Tregs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2716.

A phase 1 dose-escalation and expansion study of CUE-101, a novel HPV16 E7-pHLA-IL2-Fc fusion protein, given as monotherapy and in combination with pembrolizumab in patients with recurrent/metastatic HPV16+ head and neck cancer.

6013 Background: Immuno-STATs are modular T cell engagers engineered to selectively activate tumor-antigen specific CD8+ T cells via targeted delivery of cytokines. CUE-101, the first Immuno-STAT in clinical trials, is composed of a human leukocyte antigen (HLA) complex, HLA-A*0201, a peptide epitope derived from the HPV16 E7 protein, and 4 molecules of attenuated human interleukin-2 (IL-2) designed to bind, expand, and activate HPV16-specific CD8+ T cells for the treatment of HPV16+ cancers. Methods: CUE-101-01 is an ongoing first-in-human study in HLA-A*0201 patients with HPV16+ recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Escalating doses of CUE-101 monotherapy (0.06 mg/kg to 8 mg/kg) and in combination with pembrolizumab (1 mg/kg to 4 mg/kg + 200 mg pembrolizumab) were evaluated, followed by expanded enrollment at the recommended phase 2 dose (RP2D). Patients with R/M HNSCC refractory to ≥ 1 platinum-based or checkpoint inhibitor therapy received CUE-101 monotherapy. Patients with previously untreated PD-L1+ R/M HNSCC received CUE-101 + pembrolizumab as first-line treatment. Therapy was administered every 3 weeks until disease progression or intolerable toxicity. Safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity were assessed. Results: As of January 12, 2023, 67 patients were enrolled. A MTD was not established in monotherapy or combination-treated patients; 4 mg/kg of CUE-101, alone or in combination with pembrolizumab, was chosen as the RP2D dose in both cohorts. Monotherapy RP2D enrollment is complete and combination RP2D enrollment is ongoing. Frequent adverse events include fatigue (45%), anemia (34%), chills (27%), infusion related reactions (25%), constipation (22%), lymphopenia (22%) and nausea (22%). CUE-101 PK data demonstrate dose-dependent increases in drug exposure sustained with repeat dosing. PD data demonstrate selective expansion of HPV-16 E711-20-specific CD8+ T cells, sustained increase in NK cells and transient increase in Treg cells. Among 19 evaluable monotherapy RP2D patients, 1 PR and 6 durable SD (SD ≥ 12 weeks) were observed, with mOS of 24.4 months (9.1, NA). Among 12 evaluable RP2D combination patients to date, 5 PRs, and 2 durable SDs have been observed, with 71% (5/7) of patients expressing PD-L1 CPS ≤ 20. Conclusions: CUE-101 facilitates the targeted delivery of high concentrations of IL-2 to relevant tumor-specific CD8+ T cells. We demonstrate safety and tolerability with encouraging PD signals and antitumor activity with monotherapy and in combination with pembrolizumab in HPV+ R/M HNSCC patients. Enrollment continues in the CUE-101 and pembrolizumab combination cohort. Clinical trial information: Clinical trial information: NCT03978689 .

Abstract 3343: Durable response to osimertinib monotherapy as first line treatment in stage IVB lung adenocarcinoma with atypical EGFR L747P mutation

Abstract Background: Targeted therapy plays a critical role in NSCLC with a certain type of mutation. Osimertinib is a third generation EGFR tylosine kinase inhibitor (TKI) which is primarily indicated for NSCLC with EGFR exon 19 deletions or exon 21 L858R mutations. Although use of osimertinib is currently limited to patients with common EGFR mutations, it has been reported that patients with NSCLC harboring uncommon EGFR mutations demonstrated response to EGFR TKIs. Herein, we present a case of advanced adenocarcinoma of the lung with atypical EGFR L747P mutation that revealed a noteworthy durable response to osimertinib monotherapy as first line treatment. Case presentation: A 47-year-old woman with no smoking history presented with new-onset hemoptysis and cough. A chest CT scan showed a lobulated, spiculated 38 mm left upper lung mass with innumerable bilateral pulmonary nodules. CT-guided biopsy demonstrated adenocarcinoma of lung with PD-L1 1-2%. Subsequent PET-CT scan revealed hypermetabolic neoplasm in the left lower lobe with scattered area of abnormal focal FDG uptake within the liver. Brain MRI showed unremarkable findings. The patient was diagnosed with stage IVB adenocarcinoma of lung with multiple hepatic metastases. Circulating tumor DNA (ctDNA) NGS assay showed EGFR L747P [0.3% of variant allele frequency (VAF)] and tissue NGS assay revealed EGFR L747P missense variant c.2239_2240delinsCC (22.8% of VAF). The patient was started on osimertinib 80 mg daily. Follow up CT scan in six week demonstrated decrease in size of the left lower lobe lung mass to 32 mm. She has maintained durable SD for six months without any adverse effects. Most recent follow-up CT scan after eight months from the treatment demonstrated SD of the mass in the left lower lobe and less prominent numerous pulmonary nodules. Discussion: It has not been reported that osimertinib monotherapy is used as first line therapy in NSCLC with EGFR L747P mutation. We report the case of durable response to osimertinib in patients with advanced NSCLC with EGFR L747P mutation. Our case highlights the potential efficacy of osimertinib to NSCLC with atypical EGFR mutation. Although there was a clinical trial to explore clinical activity of osimertinib in patients with NSCLC harboring uncommon EGFR mutation, EGFR L747R mutation was not investigated at that time. To date, there are no ongoing clinical trials on the use of osimertinib in NSCLC with EGFR L747P mutation. Further investigations are warranted to confirm the efficacy of osimertinib in this type of mutation. Citation Format: Horyun Choi, Yeun Ho Lee, Jinah Kim, Leeseul Kim, Na Hyun Kim, Young Kwang Chae. Durable response to osimertinib monotherapy as first line treatment in stage IVB lung adenocarcinoma with atypical EGFR L747P mutation [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 3343.

Hormone therapy (HT) or capecitabine (CAP) as maintenance therapy following the first-line chemotherapy in HR+/HER2-ABC/MBC: Secondary endpoint adverse effects (AEs) and toxicity report of OVERSTEP Trial (ZJCH15001/CBCSG 035).

1068 Background: OVERSTEP (NCT02597868) is a multicenter, randomized clinical trial of capecitabine (CAP) versus endocrine therapy (HT) as maintenance therapy after 1st-line CAP-based combination chemotherapy in HR+/HER2- ABC/MBC. At 2020 SABCS conference, we reported the primary endpoint (progression-free survival, PFS) at follow-up of 24.3 months, at 2021 SABCS, repoted the PFS and OS at follow-up of 41.4 months. Here, we reported the secondary endpoint Adverse effects (AEs). Methods: Total of 181 patients with HR+ and HER2- MBC were enrolled in this study from Jun, 2013 to Jan, 2019. All the patients received at least 4 cycles of CAP-based combination regimen as 1st-line salvage chemotherapy. The patients who achieved CR, PR or durable SD by RECIST criteria entered into the maintenance therapy setting (MT), and randomly (1:1 ratio) assigned to either CAP single or HT group. Randomization was done centrally with stratification by endocrine sensitive or resistance and visceral or non-visceral metastasis. After combined chemotherapy, 75.14% (n=136) cases entered into the maintenance therapy setting, and 24.86% case were disease progressed (PD) during combined chemotherapy. After a median follow-up of 41.4 months (IQR 21.57-79.23), we reported the secondary endpoint Adverse effects (AEs). Results: In PPS, hematologic toxicities in ET group and CT group were as follows, anemia (69.6% vs 64.2%), leukopenia (60.8% vs 50.8%), neutropenia (66.7% vs 31.2%), thrombocytopenia (26.1% vs 26.9%). The non-hematologic toxicities were hand-foot syndrome (HFS) (33.3 vs 41.8%), increased ALT (50.7 % vs 37.3%), increased AST (53.6% vs 37.3%), hyperbilirubinemia (32.2% vs 25.4%), fatigue (14.5% vs 10.4%), hypokalemia (5.8% vs 4.5%), pneumonia (0.0% vs 6.0%), peripheral neuropathy (4.8% vs 0.0%),etc. Duration of maintenance, the AEs in the ET group were significantly lighter, just like anemia (0.0% vs 28.4%), leukopenia (5.8% vs 17.8%), neutropenia (5.8% vs 16.4%), thrombocytopenia (2.9% vs 22.4%) et al., the non-hematologic toxicities were HFS (0.0% vs 23.9%), increased ALT (4.3% vs 16.4%), increased AST (5.8% vs 16.4%), increased bilirubin (0.0% vs 10.4%), peripheral neuropathy (5.8% vs 0.0%). Moreover, the toxicities of grade 3/4 were in the CT maintenance group, anemia was 1 case (1.5%), neutropenia 2 cases (2.99%), HFS 5 Case (7.5%) and increased AST in 1 case (1.5%). The ET maintenance group had not any grade 3/4 AEs. Conclusions: For HR+ and HER2- MBC, after 1st-line salvage combined chemotherapy, HT maintenance therapy is superior to chemotherapy (capecitabine) maintenance in terms of efficacy and safety. But, if toxicity is well managed, the safety is still tolerated during chemotherapy maintenance. Therefore, in the post-CDK4/6 period, chemotherapy is still an option. Clinical trial information: NCT02597868.

Abstract P1-17-04: Hormone therapy (HT) brings more survival benefits than capecitabine (CAP) as maintenance therapy following the 1st-line chemotherapy in HR+/HER2-ABC/MBC: Update primary endpoint of OVERSTEP(ZJCHBC001)

Abstract Background: OVERSTEP is a multicenter, randomized clinical trial of capecitabine (CAP) versus endocrine therapy (HT) as maintenance therapy after 1st-line CAP-based combination chemotherapy in HR+/HER2- ABC/MBC. At 2020 SABCS conference, we have reported the primary endpoint (progression-free survival, PFS) of the OVERSTEP (NCT02597868) trial. With a median follow-up of 24.3 months,Median PFS (mPFS) of HT cohort was significantly longer than that of CAP group (17.5 months vs. 12.2 months, HR=0.625, 95%CI: 0.429-0.909, P=0.013). In this annual meeting, we will report the update of mPFS and the secondary endpoint (overall survival, OS). Methods: HR+ and HER2- metastatic breast cancer were enrolled in this study. All patients were histologically confirmed and received at least 4 cycles of CAP-based combination regimen as 1st-line salvage chemotherapy. The patients who achieved CR, PR or durable SD by RECIST criteria entered into the maintenance therapy setting (MT), and randomly (1:1 ratio) assigned to either CAP single or HT group. Randomization was done centrally with stratification by endocrine sensitive or resistance and visceral or non-visceral metastasis. The primary endpoint was mPFS, and the secondary endpoint was overall survival (OS), safety, et al. The superiority test was performed in all patients who received at least one dose maintenance therapy. The last follow-up ended in June 30, 2021. The medium follow-up duration was 41.4 months and the OS event was mature. Results: A total of 181 eligible patients were enrolled in this study from Jun 5, 2013 to Jan 14, 2019. After combined chemotherapy, 75.14% (n=136) cases entered into the maintenance therapy setting, and 24.86% case were disease progressed (PD) during combined chemotherapy. After a median follow-up of 41.4 months (IQR 21.57-79.23), the update mPFS in HT group remained superior to CAP cohort (17.7 months vs. 12.2 months, P=0.011). In addition, the median maintenance duration of HT group was significantly longer than that of CAP group (13.8 months vs. 7.4 months, P= 0.008). For endocrine sensitive patients, mPFS was greatly prolonged in HT group compared to CAP cohort (29.3 months vs. 14.8 months, HR=0.515, 95%CI: 0.269-0.988, P=0.042). Besides, in non-visceral metastasis patients, median PFS of HT group was 25.3 months which was longer than CAP subgroup 17.0 months (HR=0.54, 95%CI: 0.300-0.972, P=0.037). However, in endocrine resistance patients, there was no significant difference between HT and CAP group (13.6 months vs. 12.0 months, HR=0.791, 95%CI: 0.499-1.253, P=0.314). There was no difference observed between HT and CAP group in visceral involved cases (14.3 months vs. 11.0 months, HR= 0.668, 95%CI: 0.410-1.089, P=0.101). The median OS was 51.7 months (95%CI: 36.614-66.786) in HT cohort and 39.8 months (95%CI:14.083-65.517) in CAP group, respectively (HR=0.882, 95%CI: 0.550-1.414, P=0.600). Conclusions: For HR+ and HER2- MBC, after 1st-line salvage combined chemotherapy, HT maintenance therapy demonstrated sustained better survival benefits than CAP, especially for hormone sensitive or non-visceral involved patients. The primary endpoint of this study was successfully reached and the median OS was prolonged by 11.9-months. Citation Format: Xiao-Jia Wang, Jian Huang, Xi-ying Shao, Li Cai, Yong-mei Yin, Li-li Zhang, Peng Shen, Yan-xia Shi. Hormone therapy (HT) brings more survival benefits than capecitabine (CAP) as maintenance therapy following the 1st-line chemotherapy in HR+/HER2-ABC/MBC: Update primary endpoint of OVERSTEP(ZJCHBC001) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-17-04.

CTIM-32. IMMUNE CHECKPOINT INHIBITOR NIVOLUMAB IN PEOPLE WITH RECURRENT SELECT RARE CNS CANCERS: RESULTS OF INTERIM ANALYSIS IN A HEAVILY PRETREATED COHORT

Abstract INTRODUCTION Standard and experimental therapies for patients with rare CNS tumors are scarce. Nivolumab (PD-1 inhibitor) is approved for several non-CNS cancers. This ongoing Phase II trial (NCT03173950) will determine the efficacy of nivolumab in adults with recurrence/progression of one of 11 selected rare primary CNS tumors. Efficacy is measured by Disease Control Rate (DCR; confirmed CR/PR or durable SD for ≥ 6 months) in 2 cohorts: heavily and non-heavily pretreated patients (heavily pretreated: ≥ 3 prior therapies; non-heavily pretreated: ≤ 2). We report efficacy and safety results of a preplanned interim analysis in the heavily pretreated cohort. METHODS Eligibility includes recurrence/progression of an eligible tumor; age ≥ 18 years; tumor tissue available for histopathology, molecular and immune profiling; KPS ≥ 70; and no steroids at study entry. A total of 150 evaluable patients will be enrolled (75 to each cohort). Prior therapies include radiation and/or standard or investigational drugs. Nivolumab treatment is 240 mg IV every 2 weeks (4 doses); then 480 mg every 4 weeks (14 additional doses). Interim analysis was planned when sample size reached 32 in each cohort. RESULTS As of March 10, 2021, DCR exceeded the minimum required for interim analysis in the heavily pretreated cohort. Among 30 patients, 4 achieved SD > 6 months (medulloblastoma, anaplastic ependymoma, myxopapillary ependymoma, metastatic atypical meningioma). Safety profile (related AEs): grade 3 = 7; grade 4 = 1. Most frequent grade 3-5 AEs regardless of attribution: tumor progression (6); anemia, hydrocephalus, lymphopenia (3 each); cerebral edema, headache (2 each). CONCLUSION DCR exceeded the “go” boundary (i.e., > 2) in the heavily pretreated cohort. Nivolumab showed safety profile consistent with other studies. This cohort will continue to stage 2 and complete total accrual of 75 patients. The trial is currently being expanded to 10 additional sites across the BTTC/NCI-CONNECT consortium.

Patients with recurrent gynecologic cancers and Wnt activating mutations demonstrated greater clinical benefit when treated with DKN-01 therapy

<h3>Objectives:</h3> Dickkopf-1 (DKK1) modulates Wnt signaling, promotes tumor growth through a CKAP4-AKT signaling pathway and contributes to an immune suppressive tumor microenvironment. DKN-01 (D), a neutralizing DKK1 antibody has demonstrated safety and clinical activity in advanced gynecologic malignancies. Prior literature has reported an association of <i>CTNNB1</i> mutations and an aggressive biology and shorter survival in endometrioid endometrial cancer. We previously demonstrated <i>Wnt</i> activating mutations were associated with higher DKK1 tumoral expression in advanced gynecologic malignancies. <h3>Methods:</h3> Pts with recurrent gynecologic cancers [endometrial (EEC), ovarian (EOC) and carcinosarcoma (MMMT)] were treated with D as monotherapy (mono) or in combination with paclitaxel (pac) in a phase 2 basket trial (NCT03395080) whereby ≥50% must have had a <i>Wnt</i> signaling alteration. Here we report on the subgroup of pts with Wnt activating mutations (CTNNB1, RNF43, APC). Clopper-Pearson confidence intervals were used to study the association of <i>Wnt</i> activating mutations with clinical benefit (CR, PR or SD); Kaplan-Meier estimates/Cox-PH models were used for analyses of progression free survival (PFS) and overall survival (OS). <h3>Results:</h3> A total of 111 pts enrolled; 52 pts treated with D mono; 59 pts treated with D + pac. Mean number of prior therapies was 3.6 (range 1, 11) and 3.9 (range 1, 10) for D mono and D + pac, respectively. A total of 108 pts (97%) with available genetics; 23 pts (21%) had <i>Wnt</i> activating mutations [CTNNB1 (n=17), RNF43 (n=5), APC (n=3)]. <i>Wnt</i> activating mutations were more common in EEC (n=17/54, 31%) than EOC (n=2/33, 6%) and MMMT (n=4/24, 17%). Median duration of treatment with D was 6 cycles in pts with <i>Wnt</i> activating mutations compared with 3 cycles for pts without <i>Wnt</i> activating mutations. A total of 15 of 23 (65%) evaluable pts with <i>Wnt</i> activating mutations had clinical benefit [1 PR, 14 SD; durable SD (> 4 months) in 11 of 14 pts (48%)] compared with 34 of 76 (45%) evaluable pts [1 CR, 2 PR, 31 SD; durable SD (> 4 months) in 12 of 31 SD pts (16%)] without <i>Wnt</i> activating mutations. All 4 pts with an objective response had a <i>PIK3CA</i> mutation. Pts with <i>Wnt</i> activating mutations had longer PFS [median 5.5 mos; 95% CI (1.8, 6.0)] and OS [median 22.2 mos; 95% CI (7.3, NE)] compared with pts without <i>Wnt</i> activating mutations [median PFS 2.0 mos; 95% CI (1.8, 3.1)] and OS (median 9.9 mos; 95% CI (6.9, 12.5)]. <h3>Conclusions:</h3> D has single agent activity in a subgroup of pts with <i>Wnt</i> activating mutations, historically identified as a poor prognostic group, whereby they experienced greater clinical benefit and longer survival compared with pts without <i>Wnt</i> activating mutations. A notable finding was that all responding pts had PIK3CA mutations. This study is ongoing and updated results will be presented.

Targeting innate immunity with BXCL701 in combination with pembrolizumab in patients with advanced solid cancers: Phase 2 basket study.

2558 Background: BXCL701 is an oral competitive inhibitor of dipeptidyl peptidases (DPPs), primarily DPP8/9, which triggers the inflammasome to alert and prime immune cells, leading to induction of IL-18 and IL-1ß. BXCL701 therefore, can induce an innate immune reaction and tumor inflammation, bridging between innate and adaptive immunity, potentially leading to synergistic anticancer activity when combined with PD-1 antibody pembrolizumab. Methods: This is a phase 2, open-label, single-center study (NCT04171219) of oral BXCL701 0.3 mg BID on days 1-14 and intravenous pembrolizumab 200 mg on day 1 of a 21-day cycle with a safety lead-in to evaluate RECIST/iRECIST response rate in patients with advanced solid cancers. After confirming safety and dose limiting toxicities (DLT) in the first 6 patients, additional patients are being enrolled to an immune checkpoint inhibitors (iCPI) naïve cohort and iCPI pretreated cohort. Each cohort is planned to enroll 9 patients in the first stage, and if a partial (PR) or complete response (CR) is observed the cohort is expanded to a total of 17 patients in the second stage. The treatment is considered promising if at least 3 PRs or CRs are observed in a cohort of 17 patients. Results: As of February 11, 2021, 16 patients were treated; 5 patients (prostate cancer, endometrial cancer, liposarcoma, basal cell carcinoma, squamous cell carcinoma of unknown primary) were enrolled in the iCPI naïve cohort and 11 patients (leiomyosarcoma [2], squamous cell carcinoma of unknown primary, triple negative breast cancer, uveal melanoma, melanoma, uterine myxoid sarcoma, pleomorphic sarcoma, colorectal cancer, anaplastic astrocytoma, prostate cancer) were enrolled to iCPI pretreated cohort. Among all 16 patients, there was 1 episode of grade 4 hypotension (recovered) and 1 episode of grade 5 hypotension attributed to BXCL701, which resulted in implementation of risk-mitigation strategies such as gradual dose escalation and blood pressure monitoring. In the CPI naïve cohort, of 4 patients with available imaging, 1 had a PR (microsatellite stable endometrial cancer [-62%]) and 1 durable stable disease (SD -10%, basal cell carcinoma on therapy for 6+ months). In the CPI pretreated cohort, of 9 patients with available imaging, 1 had a PR (-31%, uveal melanoma) and 3 durable SD (-22%, pleomorphic sarcoma on therapy for 8+ months; +4%, squamous cell carcinoma of unknown primary on therapy for 6 months; +5%, uterine myxoid sarcoma on therapy for 6 months). Conclusions: BXCL701 in combination with pembrolizumab demonstrated encouraging signals of activity in selected difficult-to-treat cancers. Prespecified efficacy endpoints were met in the first stage and both cohorts will proceed to second-stage of the study Clinical trial information: NCT04171219.

Phase II study of SM-88 in Ewing's and other sarcomas.

e23505 Background: Sarcomas are rare heterogeneous malignancies. Once recurrent, cure is uncommon. SM-88 (racemetyrosine) is an amino acid analogue with no known cross resistance to typical sarcoma regimens. Based on previous anecdotal experience in Ewing’s (EWS) we initiated a Phase 2 trial (HopES) in EWS and other sarcomas (Ss) after &gt;1 prior systemic therapy. We now report preliminary data after having met prespecified continuation criteria. Methods: Open label prospective trial in 2 separate cohorts (EWS and Ss) of oral SM-88 used with MPS conditioning agents (SM-88 920 mg, methoxsalen 10 mg, phenytoin 50 mg, sirolimus 0.5 mg) all daily until progression. Results: As of Feb 5 2021, 10 pts with incurable sarcomas were enrolled; 4 had high risk but stable EWS. Average age 43.9 yrs (13–77); 70% white; 20% female. Median number of prior regimens 4 (1–9); 70% received prior RT; 50% prior surgery. Median time from initial diagnosis 39.5 months with 50% T2 (40% unknown), 30% M1 (30% unknown). Prespecified futility stopping was exceeded (i.e., &gt;1 of first 5 subjects/cohort) upon achieving clinical benefit in each. Stable disease was achieved in 75.0% (6/8 with available data). Time on treatment (TTx) exceeded last known TTx in 80% (95% CI 44.4–97.5). Median SM-88 TTx was 4.9 vs 2.9 mo for prior TTx (logrank HR 0.53; p=0.12). One EWS subject had unresectable disease that became resectable, was completely resected, and remained disease-free for ≥ 6 months. Prior to SM-88, longest TTx was 12 mo (on IT*) and shortest TTx 1 mo (on IEV*) vs SM-88 TTx of 11.9 mo. An angiosarcoma subject had a 21% reduction in the sum of all target lesions and exceeded all prior TTx (including 8 mo on Ap/N* with 12+ mo duration of treatment of SM-88). There were no serious drug-related AEs. ECOG performance remained stable for all. Conclusions: SM-88 has exceeded pre-specified futility in both cohorts (EWS maintenance and Ss salvage). HopES continues to enroll toward the planned total of 12 subjects to more precisely define its benefit in this ultra-orphan, extremely recalcitrant disease. This trial now confirms the previously reported clinical utility of oral SM-88 in EWS and other high-risk sarcomas. Based on durable response (&gt;6mo), SD and prolonged TTx, SM-88 warrants additional investigation in this setting. Clinical trial information: NCT03778996. [Table: see text]

Abstract PS11-25: Pilot trial of priming with oral TAK-228 and TAK-117 (PIKTOR) to increase DNA damage repair deficiency (DDRD) followed by cisplatin (cis) and nab paclitaxel (nab pac) in chemotherapy-pretreated metastatic triple negative breast cancer (metTNBC) pts

Abstract BACKGROUND: A subset of TNBCs have homologous recombination deficiency with upregulation of compensatory DNA repair pathways. The combination of TAK-228 and TAK-117 (PIKTOR), investigational oral TORC1/2 and PI3Kα selective inhibitors, respectively, is hypothesized to increase genomic instability (GI) and to increase DDRD, leading to increased sensitivity to DNA damaging chemotherapy and to checkpoint inhibitors in metTNBC pts. METHODS: 10 metTNBC pts received 4 mg PO TAK-228 and 200 mg PO TAK-117 QDx3d QW until disease progression (PD), followed by cis 75 mg/m2 plus nab pac 220 mg/m2 for up to 6 cycles. Primary endpoints were objective response rate with cis/nab pac and safety. Blood samples and biopsies of metastatic lesions were collected prior to and at PD on PIKTOR. Blood CTC analyses included enumeration, cell morphology, phenotypic heterogeneity, and predicted genomic instability (pGI) derived from cell phenotypes. RESULTS: 10 pts received PIKTOR followed by cis/nab pac. Median age: 51 yrs; median number of prior chemotherapy regimens was 3 (range, 1-5); 7 pts had prior carboplatin; sites of metastases: lymph nodes (n=8); lung (n=6); chest wall (n=1); bone (n=1); brain (n=1). Median time on PIKTOR was 8 wks (range, 3-14). With cis/nab pac, 1 pt had PR, 2 had SD &amp;gt; 6 mos, 1 had SD and 6 had PD. 2 SD pts (sites LNs and bone) and 1 PD pt (sites LNs), all carboplatin-pretreated, whose pre-PIKTOR BCs were PDL1-negative (2 pts) or unknown (1 pt) have durable SD on pembrolizumab post-cis/nab pac for 1+ yrs. PIKTOR related AEs ≥30% included: fatigue (90%); nausea (80%); diarrhea (60%); vomiting (40%); stomatitis (40%); hyperglycemia (30%); rash (30%); cough (30%); chest pain (30%). Incidence and grade of cis/nab pac-related AEs were not greater than expected with this regimen. At PD on PIKTOR, higher CTC burden and pGI+ CTCs were observed in a subset of pts suggesting that some CTCs may have developed greater GI with PIKTOR treatment. Next generation sequencing (NGS) and reverse phase protein array (RPPA) analyses of biomarkers of DNA repair pathways pre-and post-PIKTOR tissues are underway and will be presented at the meeting. CONCLUSIONS: Priming pts’ metTNBC with PIKTOR did not lead to durable responses with cis/nab pac in most pts in this pretreated population. However, 3/10 pts who had carboplatin-pretreated disease in LNs +/- bone, have highly durable SD on pembrolizumab following PIKTOR therapy. Citation Format: Joyce O'Shaughnessy, Esther San Roman Rodriguez, Priscilla Ontiveros, Rick Wenstrup, Tiziano Pramparo, Jessica Lang, Victoria Zismann, Natalia Briones, William Hendricks, Virginia Espina, Claudius Mueller, Maren K Levin. Pilot trial of priming with oral TAK-228 and TAK-117 (PIKTOR) to increase DNA damage repair deficiency (DDRD) followed by cisplatin (cis) and nab paclitaxel (nab pac) in chemotherapy-pretreated metastatic triple negative breast cancer (metTNBC) pts [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-25.

Abstract PO036: Patients with recurrent epithelial endometrial cancers (EEC) and Wnt signaling alterations demonstrated greater clinical benefit when treated with DKN-01 monotherapy

Abstract Background: Dickkopf-1 (DKK1) modulates Wnt signaling, promotes tumor growth through a CKAP4-AKT signaling pathway and contributes to an immune suppressive tumor microenvironment. DKN-01, a neutralizing DKK1 antibody has demonstrated safety and clinical activity in advanced gynecologic malignancies. We report response and survival outcomes in EEC patients (pts) treated with DKN-01 monotherapy by tumor genetics (Wnt signaling alterations and PI3K/AKT mutations). Methods: Pts with recurrent EEC were treated with DKN-01 as monotherapy (mono) or in combination with paclitaxel in a phase 2 basket trial (NCT03395080) whereby ≥50% must have had a Wnt signaling alteration. Here we report on EEC mono group only. Clopper-Pearson confidence intervals and logistic regression were used to study the association of Wnt signaling alterations with clinical benefit (CR, PR or SD) following DKN-01 monotherapy; Kaplan-Meier estimates/Cox-PH models were used for analyses of progression free survival (PFS) and overall survival (OS). Results: As of 30 December 2019, 29 EEC pts enrolled; 21 pts (72%) had Wnt signaling alterations [ARID1A most common (11 pts, 38%)] and 25 (86%) had PI3K/AKT mutations [PIK3CA in 13 pts (45%)]. Median number of prior therapies was 4 (range 1, 9); 20 pts (69%) had endometrioid histology and 19 pts (66%) had G2/G3 tumor grade at diagnosis. 26 pts were evaluable, 20 pts Wnt altered and 6 pts non-Wnt altered; 24 pts with and 2 pts without PI3K/AKT mutations. In the Wnt altered group, there was 1 cCR, 1 cPR, 8 SD (6 durable SD &amp;gt;120 days) and 10 PD compared with 0 responders, 1 SD and 5 PD in the non-Wnt altered group. In the 24 pts with PI3K/AKT mutations there was 1 cCR, 1 cPR, 8 SD (6 durable SD &amp;gt;120 days) and 14 PD compared with 1 SD and 1 PD in the 2 pts without PI3K/AKT mutations. The 2 responding pts had PI3KCA mutations in common. Probability of 6 month PFS/OS was 30% (95% CI:12.3, 50.1) and 70% (95% CI: 45.1, 85.3) for Wnt altered pts vs 18% (95% CI: 0.8, 53.8) and 50% (95% CI: 11.1, 80.4) for non-Wnt altered, respectively. Conclusions: DKN-01 has single agent activity in heavily pretreated EEC pts. EEC pts frequently had Wnt signaling alterations and PIK3/AKT mutations; greater clinical benefit was demonstrated in pts whose tumors had Wnt signaling alterations. This study is ongoing and updated results will be presented. Citation Format: Rebecca Arend, Cesar Castro, Erica Hamilton, Kristopher LyBarger, Linda Duska, Michael Kagey, William Bradley, Jasgit Sachdev, Cynthia A. Sirard, David M. O'Malley. Patients with recurrent epithelial endometrial cancers (EEC) and Wnt signaling alterations demonstrated greater clinical benefit when treated with DKN-01 monotherapy [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO036.

Sawdust-based superhydrophobic pellets for efficient oil-water separation

Severe water pollution by means of oil is the major issue worldwide. Emerging materials like superhydrophobic surfaces have shown immense potential to control this issue. Herein we utilized low-cost Sawdust-Polystyrene (SD – PS) composite and developed a facile strategy to prepare a free-standing superhydrophobic pellet for efficient oil-water separation. More importantly, the simple recovery of the absorbed oil is feasible. To achieve crack-free, regular and robust superhydrophobic SD – PS pellet, the concentration of polystyrene, the quantity of sawdust in polymer solution and thickness of the pellet was optimised. The surface morphology analysis confirmed an adequate binding between sawdust and polystyrene in composite structure with formation of micro-voids less than 100 μm that facilitated efficient oil-water separation. The superhydrophobic pellet exhibited oil-water separation efficiency higher than 90% for the oils and organic liquids like hexane, kerosene, diesel and coconut oil with excellent separation cycles around 30. The mechanically durable superhydrophobic SD – PS pellet could separate oil from muddy as well as warm water, which are more suitable for industrial applications.

TRLS-06. PHASE 1 EXPANSION STUDY OF IRINOTECAN LIPOSOME INJECTION (nal-IRI) IN PATIENTS WITH METASTATIC BREAST CANCER (mBC): FINDINGS FROM THE COHORT WITH ACTIVE BRAIN METASTASIS (BM)

BACKGROUND: nal-IRI is a liposomal formulation of irinotecan (topoisomerase-1 inhibitor). Preclinical data show that nal-IRI accumulates in BMs and prolongs survival in animal models of BM. Findings from a phase 1 expansion study (NCT01770353), evaluating patients with mBC and active BM, are reported. METHODS: This phase 1 expansion study enrolled patients with mBC who received multiple prior lines of cytotoxic therapy in the metastatic setting, including one cohort with mBC and active BM, defined as radiographic evidence of new or progressive central nervous system (CNS) metastases after radiation therapy with ≥1 lesion of ≥1 cm in the longest dimension on gadolinium-enhanced magnetic resonance imaging. Patients received nal-IRI 50 mg/m2 (free-base equivalent; FBE) every two weeks (q2w) as an intravenous infusion over 90 minutes, escalating to 70 mg/m2 FBE q2w, if tolerated. RECIST v1.1 and modified RECIST criteria were used to assses non-CNS and CNS disease, respectively. RESULTS: In total, 30 patients were enrolled (10 with active BM). Median age was 53 years (range 29–70 years) and median number of prior cytotoxic anti-cancer regimens was 3 (range 0–6); 29 patients received ≥1 dose of nal-IRI 50 mg/m2 FBE. Overall, nal-IRI monotherapy appeared to be well tolerated, and achieved ≥30% objective response rates for both CNS and non-CNS disease. Among the 10 patients with active BM, 6 achieved CNS disease control (3 partial responses [PRs] and 3 stable disease [SD]), including one patient with durable CNS SD and non-CNS PR for 2 years. Among 7 patients with serial evaluation of CNS metastases posttreatment, 6 patients achieved a reduction in target CNS lesions compared with baseline. CONCLUSION: Treatment with nal-IRI resulted in CNS disease control among 6 of 10 heavily pretreated patients with mBC and active BM. Further exploration of nal-IRI in patients with mBC and active BM is warranted.

Phase 1 combination therapy with pexidartinib (PEX) and sirolimus (S) to target tumor-associated macrophages in pigmented villonodular synovitis, malignant peripheral nerve sheath tumors, and other soft tissue sarcomas.

11055 Background: No effective therapy exists for unresectable malignant peripheral nerve sheath tumors (MPNSTs). We previously reported that the combination of PEX and the mTOR inhibitor S synergistically inhibited MPNST growth (CCR 20: 3146, 2014) by depleting M2 TAMs and by inhibiting receptor tyrosine kinases (RTKs), including c-KIT, PDGFR, CSF1R. We characterized the safety, tolerability, recommended phase 2 dose (RP2D) of PEX plus S in all sarcoma sub-types. Methods: Patients (pts) received PEX plus S orally in 28 days cycle as per Table. The RP2D was determined using the time-to-event continual reassessment method (TITE-CRM) in advanced sarcoma who have progressed on standard therapy. DLT was defined as any need for a dose reduction. Results: 24 pts were accrued (Acr) of which 18 were evaluable (MPNST – 6, pigmented villonodular synovitis (PVNS) – 3, leiomyosarcoma – 5, and other – 9). The mean age was 46y, 56% were male, and 67% had greater than 2 prior therapies. Most common ( &gt; 20%) grade 2 or higher TEAEs were anemia (33%), WBC count decrease (28%), fatigue, neutropenia, and lymphopenia (22% each). There were 5 dose limiting toxicities (DLT): 2 for elevated LFTs both of which resolved with dose reduction, 2 for supra-therapeutic S trough levels, and 1 for grade 5 dehydration at dose level (DL) 3. Four subjects experienced a partial response (PR; -44% to -77% by RECIST, 18 – 61 wks on therapy). Seven subjects experienced stable disease (SD; +19.7% to -20.7% by RECIST; 9.4 – 30 wks on therapy). Five subjects progressed on therapy and two subjects experienced early DLTs and did not undergo tumor assessment. The RP2D is DL 3 (S 2mg/PEX 1000mg) with an estimated probability of DLT of 26.7% as determined by TITE-CRM. This recommendation is based on a target DLT rate of 25%. TAMs and immune subtypes from available tissue specimens and historical controls will be presented. Conclusions: 1000mg of PEX in combination with 2mg of S daily has an acceptable safety profile. Objective responses and durable SD was observed in PNVS and MPNST patients justifying proceeding with a multi-center single arm phase 2 study in advanced MPNST. Clinical trial information: NCT02584647. [Table: see text]

First-in class selective AXL inhibitor bemcentinib (BGB324) in combination with LDAC or decitabine exerts anti-leukaemic activity in AML patients unfit for intensive chemotherapy: Phase II open-label study.

7043 Background: The RTK AXL represents a therapeutic target promoting AML cell proliferation and survival by pleiotropic mechanisms and is a negative regulator of anti-tumour immunity. Bemcentinib is a first-in-class, highly selective, oral AXL inhibitor that has previously shown encouraging anti-leukaemic activity as a monotherapy in r/r AML and hr-MDS. Methods: A monotherapy dose-escalation and expansion part of this trial is complete. In this second, phase II part of the study, 11 and 15 AML pts unfit for intensive chemotherapy received bemcentinib at RP2D (200 mg po/d) in combination with low-dose cytarabine (LDAC) and decitabine, respectively. Median age was 77 yr (range: 50-83), median screen myeloblast count 39% (3-95%) and 2/19 (11%) of pts evaluable for FLT3 were FLT3+. Plasma protein biomarker levels were measured using the DiscoveryMap v3.3 panel (Myriad RBM) at screen and following treatment. Results: The most common TRAEs (≥ 15% of pts) were ECG QT prolongation (35%) and diarrhoea (15%). Among these, 3 were Grade 3, and none 4 or 5. All TRAEs were manageable and/or reversible. As of Feb ‘19, 9 pts (2 de novo, 1 secondary, 6 r/r) in the bemcentinib + LDAC group were evaluable for response and 4 (44%; 2 de novo + 2 relapsed) achieved rapid CRi at C2D1. Responses were durable (range: 7 – 11 cycles) in 3 of the 4 responders. A further 2 pts (22%, 1 secondary + 1 relapsed) achieved durable SD (5 and 6 cycles). mPFS among the 5 pts with durable CRi or SD was 5 months (range: 3.5-7.7). Further, at the time of writing, 11 pts (8 de novo, 3 r/r) in the bemcentinib + decitabine group were evaluable for response of which 4 (36%, all de novo) achieved CRi after ≥ 4 cycles. One additional de novo pt achieved durable SD lasting for 5 cycles. Conclusions: Bemcentinib in combination with LDAC exerted early durable responses in patients with both de novo and relapsed AML whilst the combination of bemcentinib + decitabine exerted comparably fewer and later responses in de novo AML. Soluble biomarker correlations will be presented at the meeting. Both combinations were generally well-tolerated and further exploration is warranted. Clinical trial information: NCT02488408.