Common All-grade Adverse Events Research Articles

39 Safety profile of belzutifan monotherapy in patients with renal cell carcinoma: A pooled analysis of 4 clinical trials

Abstract Background The first-in-class hypoxia-inducible factor-2α inhibitor, belzutifan, is indicated in the United States for the treatment of certain patients with von Hippel-Lindau (VHL) disease–associated renal cell carcinoma (RCC), central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors not requiring immediate surgery and for patients with advanced RCC previously treated with a PD-(L)1 inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor. Due to its unique mechanism of action, belzutifan has a distinct safety profile. We characterized the safety profile of belzutifan monotherapy in a post hoc pooled analysis of patients with previously treated advanced clear cell RCC in the phase 1 LITESPARK-001 (NCT02974738), phase 3 LITESPARK-005 (NCT04195750), and phase 2 LITESPARK-013 (NCT04489771) studies and patients with RCC associated with VHL disease in the phase 2 LITESPARK-004 study (NCT03401788). Methods All patients who received ≥1 dose of belzutifan 120 mg orally once daily across the 4 studies were included. Severity of adverse events (AEs) were graded per the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03 or 5.0, and were descriptively summarized. Results A total of 576 patients were included (n = 58 [including 3 patients with advanced solid tumors other than RCC], LITESPARK-001; n = 381, LITESPARK-005; n = 76, LITESPARK-013; and n = 61, LITESPARK-004). Overall, 572 patients (99.3%) had ≥1 all-cause AE and 355 patients (61.6%) had ≥1 grade 3-5 AE. AEs led to dose modification (reduction, interruption, or discontinuation) in 288 patients (50.0%), although treatment discontinuation for AEs occurred in 37 patients (6.4%). The most common all-grade AEs were anemia (including patients with decreased hemoglobin; n = 485 [84.2%]; grade 3 or 4, n = 166 [28.8%]), fatigue (n = 246 [42.7%]; grade 3, n = 16 [2.8%]), nausea (n = 139 [24.1%]; grade 3, n = 5 [0.9%]), and dyspnea (n = 123 [21.4%]; grade 3 or 4, n = 10 [1.7%]). Hypoxia was reported in 94 patients (16.3%); grade 3 or 4 hypoxia occurred in 57 patients (9.9%). Summary and time to first onset of adverse drug reactions (AEs considered associated with belzutifan), including anemia and hypoxia, are reported in the table. Among 485 patients with anemia or decreased hemoglobin, 111 (22.9%) were treated with erythropoiesis-stimulating agent (ESA) only, 85 (17.5%) were treated with blood transfusions only, and 62 (12.8%) were treated with ESA and blood transfusions. Among 94 patients with hypoxia, 66 (70.2%) were treated with oxygen therapy. Treatment-related AEs occurred in 526 patients (91.3%) and 217 (37.7%) experienced a grade 3-5 treatment-related AE. One grade 5 adverse event (multiple organ dysfunction syndrome) was considered related to treatment. Conclusions To date, this is the largest pooled safety dataset for belzutifan monotherapy in patients with RCC. The results provide an in-depth characterization of the safety profile for belzutifan and the associated AE management strategies.

A phase Ib/II study of an anti-CD137 agonist antibody ADG106 in combination with weekly paclitaxel and dose-dense doxorubicin/cyclophosphamide.

e14507 Background: ADG106 is a fully human agonistic anti-CD137 IgG4 monoclonal antibody which modulates the tumor microenvironment and has demonstrated increased efficacy when added to chemotherapy in preclinical models. We studied the combination of ADG106 with chemotherapy. Methods: We conducted a phase Ib trial in patients with advanced solid tumors to determine the recommended phase 2 dose (RP2D) of ADG106 + weekly P (paclitaxel 80mg/m2) or ddAC (doxorubicin 60mg/m2, cyclophosphamide 600mg/m2 Q2W with pegfilgrastim), followed by a phase II trial of neoadjuvant ADG106 + weekly Px12→ADG106 + ddACx4→surgery in stage I-III HER2 negative breast cancer patients. In phase Ib, one dose of single agent ADG106 was administered followed 2 weeks later by ADG106 + ddAC (Cohort 1) or ADG106 + weekly P (Cohort 2). Dose levels (DL) of ADG106 were 50mg (DL-1), 100mg (DL1), 200mg (DL2). Serial tumor biopsies were performed at baseline, after single agent ADG106 and at disease progression in phase I, and at baseline, after single agent ADG106, after cycle 1 ADG106 + P, and at surgery in phase II for translational studies. Results: 11 patients were enrolled into Phase Ib with median 3 (range 2-11) prior lines of palliative systemic therapy. ADG106 + ddAC (n=2 at DL1) was deemed intolerable with 1 patient experiencing G4 neutropenia and the other G3 infection; thus ADG106 was not added to ddAC in phase II. No DLTs were observed in all patients receiving ADG106 + P (n=6 at DL1; n=3 at DL2); ADG106 RP2D was declared at 200mg + P. In this cohort, the most common all-grade AEs were neutropenia (n=6), peripheral neuropathy (n=6) and fatigue (n=6); significant ≥G3 AEs were infection (n=2) and G3 neutropenia (n=6). 5/11 (45%) patients in phase I achieved clinical benefit (CBR; PR=2, SD=3) which is clinically meaningful as 9/11 (82%) had prior taxane exposure. 18 of the planned 30 patients have been enrolled into Phase II (ADG106+weekly P→ddACx4→surgery); 10 have completed study treatment and 5 have undergone surgery. While on ADG106 + P, 4 patients experienced G3 adverse events (AEs): neutropenia (n=3), hypophosphatemia (n=1), fever (n=1). Most common G1-2 AEs were ALT elevation (n=4), acneiform rash (n=3) and peripheral neuropathy (n=3). While on ddAC alone, all AEs were low grade except for 1 patient who had G3 pneumonitis from Pneumocystis Jiroveci Pneumonia. 26 sets of matched tumor biopsies have been collected (9 in phase I; 17 in phase II) and will be tested for a panel of 40 markers by multiplex IHC, including CD137, PD-L1, and CD3/4/8. Conclusions: ADG106 when combined with ddAC exacerbates neutropenia and is not tolerable despite prophylactic pegfilgrastim. The RP2D of ADG106 in combination with P is 200mg and is safe and tolerable; manageable G3 neutropenia was the most common AE. There are no new safety signals thus far in Phase II. Further efficacy analyses and studies on tumor immune markers are ongoing. Clinical trial information: NCT05275777 .

Zanubrutinib in Mantle Cell Lymphoma Management: A Comprehensive Review.

The pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of zanbrutinib are described. Mantle cell lymphoma (MCL) is a mature B-cell lymphoma that is typically associated with unfavorable outcomes, and virtually all patients with MCL have refractory or relapsed disease despite aggressive treatment. The treatment paradigm for MCL has transformed dramatically over the past decade owing to rapid advancements in immunotherapy and molecular-targeted therapies. Zanubrutinib, a second-generation Bruton's tyrosine kinase inhibitor (BTKI) designated for mature B-cell non-Hodgkin's lymphoma (NHL), has drastically improved the survival outcomes in relapsed/refractory (R/R) MCL patients. This selective BTKI is a small molecule that functions by forming a covalent bond in the active site of BTK. The inhibition of BTK activity is essential for the signaling of B-cell antigen receptor (BCR) and cytokine receptor pathways. In a preclinical study, zanubrutinib inhibited malignant B-cell proliferation and reduced tumor growth. Zanubrutinib was granted FDA-accelerated approval based on the results of Phase I and II trials. The investigator-assessed overall response rate was 83.7%, of which 78% of patients achieved complete response. The median duration of response was 19.5 months, and the median progression-free survival was 22.1 months. The most common (≥20%) all-grade adverse events were low neutrophil count (46.5%), upper respiratory tract infection (38.4%), rash (36.0%), low white blood cell count (33.7%), and low platelet count (32.6%). Zanubrutinib is a selective, next-generation, orally active, irreversible BTK inhibitor. The selectivity of zanubrutinib and its superior efficacy, with a well-tolerated safety profile, have proven to be attractive options for other malignancies.

Abstract PD11-08: PD11-08 Trastuzumab deruxtecan (T-DXd) + durvalumab (D) as first-line (1L) treatment for unresectable locally advanced/metastatic hormone receptor-negative (HR−), HER2-low breast cancer: updated results from BEGONIA, a phase 1b/2 study

Abstract Background: Patients with HR− advanced/metastatic breast cancer (a/mBC) with a low level of HER2 (immunohistochemistry [IHC] score 1+ or IHC 2+ and negative in situ hybridization [ISH]) have poor prognosis. Combining 1L chemotherapy with immune checkpoint inhibitors can modestly improve outcomes vs chemotherapy alone, but treatment benefit is largely seen in patients with PD-L1+ disease. BEGONIA (NCT03742102) is an ongoing 2-part, open-label platform study, evaluating safety and efficacy of D, an anti–PD-L1 antibody, combined with other novel therapies in 1L triple-negative a/mBC, including HR−, HER2-low disease. T-DXd is a trastuzumab-topoisomerase I inhibitor antibody-drug conjugate that improves survival in patients with previously treated HR−, HER2-low mBC (NCT03734029; Modi NEJM 2022). Here, we report updated results of the T-DXd + D combination from BEGONIA. Methods: Patients with unresectable HR−, HER2-low (per local testing, IHC 2+/ISH−, IHC 1+/ISH−, or IHC 1+/ISH untested) a/mBC were enrolled in the T-DXd + D arm. Patients eligible for 1L treatment, regardless of PD-L1 status, received intravenous T-DXd 5.4 mg/kg + D 1120 mg every 3 weeks until progression or unacceptable toxicity. PD-L1, assessed using the VENTANA PD-L1 (SP263) Assay, was defined as high if ≥ 5% of the tumor area was populated by PD-L1–expressing tumor or immune cells. Primary endpoints were safety and tolerability. Secondary endpoints included investigator-assessed objective response rate (ORR; RECIST v1.1); progression-free survival [PFS]; and response duration. Patients included in the efficacy analysis had ≥ 2 on-treatment disease assessments, progressed, died, or withdrew from the study. Results: As of April 8, 2022, 56 patients received T-DXd + D (34 ongoing) and 46 were included in the efficacy analysis. Median (range) follow-up was 10.1 (0–22) months. Median age was 53.5 years, 71% had received prior treatment for early stage BC, and 64% had visceral metastases at baseline. Confirmed ORR was 26/46 (57%; 95% CI, 41–71) and unconfirmed ORR was 33/54 (61%; 95% CI, 47–74); 1/46 patients (2%) had complete and 25/46 (54%) had partial responses. Confirmed response occurred irrespective of PD-L1 expression (PD-L1 high ORR, 5/7 [71%]; PD-L1 low, 13/21 [62%]; PD-L1 missing, 8/18 [44%]). Median duration of response was not reached; however, 64% of patients remained in response at 12 month follow-up and 73% had an ongoing response at data cutoff. Median PFS was 12.6 months (95% CI, 8–not reached). Adverse events (AEs) were consistent with the agents’ known safety, with treatment-related AEs occurring in 49 patients (88%), any Grade 3/4 AEs in 18 patients (32%), and any serious AEs in 10 patients (18%). The most common all-Grade AEs were nausea (41 [73%]), fatigue (26 [46%]), and vomiting (17 [30%]). Adjudicated treatment-related interstitial lung disease/pneumonitis occurred for 5 patients (9%), which were mostly Grade 1 or 2 and 1 case of Grade 5 associated with COVID pneumonia. Seven patients (13%) and 21 patients (38%) had T-DXd dose reduction and dose delay, respectively; 22 (39%) had D dose delay. Seven patients (13%) discontinued treatment due to AEs. Conclusions: For patients with HR−, HER2-low a/mBC, T-DXd in combination with D in the 1L setting shows manageable safety and promising efficacy including durable responses and an encouraging PFS. Although subgroups were small, responses were observed irrespective of PD-L1 expression. Analysis of additional translational data is ongoing. Funding: AstraZeneca/Daiichi Sankyo Citation Format: Peter Schmid, Piotr Wysocki, Yeon H. Park, Jacek Jassem, Kyung Hae Jung, Simon Lord, Robert Huisden, Ross Stewart, Petra Vuković, Ana T. Nunes, Zbigniew Nowecki. PD11-08 Trastuzumab deruxtecan (T-DXd) + durvalumab (D) as first-line (1L) treatment for unresectable locally advanced/metastatic hormone receptor-negative (HR−), HER2-low breast cancer: updated results from BEGONIA, a phase 1b/2 study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD11-08.

Abstract PD11-09: PD11-09 Datopotamab deruxtecan (Dato-DXd) + durvalumab (D) as first-line (1L) treatment for unresectable locally advanced/metastatic triple-negative breast cancer (a/mTNBC): updated results from BEGONIA, a phase 1b/2 study

Abstract Background: Patients with a/mTNBC have limited treatment options and a poor prognosis (objective response rate [ORR] of 37%, median duration of response 6.5 months, median overall survival 15.5 months for 1L chemotherapy [Rugo, et al. Ann Oncol. 2021 LBA16]). Combining checkpoint inhibitors with 1L chemotherapy modestly improves outcomes but only in PD-L1–positive a/mTNBC, emphasizing a critical unmet need for patients with PD-L1–negative disease and for further improving outcomes in PD-L1–positive disease. BEGONIA (NCT03742102) is an ongoing 2-part, open-label platform study, evaluating safety and efficacy of D, an anti–PD-L1 antibody, combined with other novel therapies in 1L a/mTNBC, including Dato-DXd, an antibody-drug conjugate consisting of a humanized anti-TROP2 antibody covalently linked to a highly potent topoisomerase I inhibitor payload via a stable, tumor-selective, tetrapeptide-based cleavable linker. Early data from BEGONIA of D in combination with Dato-DXd showed promising responses. Here, we report updated results of Dato-DXd + D. Methods: Patients with unresectable a/mTNBC eligible for 1L treatment were enrolled, regardless of PD-L1 or TROP2 status, and received intravenous Dato-DXd 6 mg/kg + D 1120 mg every 3 weeks until progression or unacceptable toxicity. PD-L1, assessed using the VENTANA PD-L1 (SP263) Assay, was defined as high if ≥ 5% of the tumor area was populated by PD-L1–expressing tumor or immune cells. Primary endpoints were safety and tolerability. Secondary endpoints included investigator-assessed ORR (RECIST v1.1) and duration of response. Patients included in the efficacy analysis had ≥ 2 on-treatment disease assessments, progressed, died, or withdrew from the study. Results: As of April 8, 2022, 47 patients received Dato-DXd + D (39 ongoing) and 33 of those were included in the efficacy analysis. Median (range) follow-up was 7.5 (0–11) months. Patient age was a median of 51 years, 57% received prior treatment for early stage TNBC, and 60% had visceral metastases at baseline. Confirmed ORR was 26/33 (79%; 95% CI, 61–91); 2/33 patients (6%) had a complete response and 24/33 (73%) had a partial response. Confirmed response was irrespective of PD-L1 expression (PD-L1 high ORR, 4/5 [80%]; PD-L1 low, 16/21 [76%]; PD-L1 missing, 6/7 [86%] patients). Median duration of response was not reached; 100% of patients with a complete or partial response remained in response at 6 month follow-up, and 96% had an ongoing response at data cutoff. Adverse events (AEs) were manageable and consistent with the known safety profiles of each agent, with treatment-related AEs occurring in 41 patients (87%), any Grade 3/4 AEs in 17 patients (36%), and any serious AEs in 7 patients (15%). The most common all-Grade AEs were gastrointestinal (nausea in 26 patients [55%] and stomatitis in 24 patients [51%]). A low rate of diarrhea was reported (6 patients [13%], all Grade 1 or 2); 4 patients had anemia and 1 had neutropenia. There were no cases of interstitial lung disease/pneumonitis or thrombocytopenia. Nine patients (19%) and 11 patients (23%) underwent Dato-DXd dose reduction and delay, respectively; 14 (30%) had D dose delay. Treatment was discontinued due to an AE for 3 patients (6%). There were no deaths due to treatment-related AEs. Conclusions: In this updated analysis with additional patients and longer follow-up, the combination of Dato-DXd + D in 1L a/mTNBC demonstrated a manageable safety profile and compelling high response rates with promising durability. Although subgroups were small, responses occurred irrespective of PD-L1 expression. Further investigation of this treatment combination is warranted. Analysis of translational data is ongoing. Funding: AstraZeneca/Daiichi Sankyo Citation Format: Peter Schmid, Piotr Wysocki, Cynthia Ma, Yeon H. Park, Ricardo Fernandes, Simon Lord, Richard D. Baird, Catherine Prady, Kyung Hae Jung, Jamil Asselah, Robert Huisden, Ross Stewart, Petra Vuković, Ana T. Nunes, Zbigniew Nowecki. PD11-09 Datopotamab deruxtecan (Dato-DXd) + durvalumab (D) as first-line (1L) treatment for unresectable locally advanced/metastatic triple-negative breast cancer (a/mTNBC): updated results from BEGONIA, a phase 1b/2 study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD11-09.

Treatment-related adverse events associated with HER2-Targeted antibody-drug conjugates in clinical trials: a systematic review and meta-analysis.

Given the increasing use of HER2-targeted antibody-drug conjugates (ADCs) worldwide, the summary of toxicity incidence and profiles of these drugs is crucial to provide reference for clinical application. This meta-analysis aimed to estimate the mean incidences of treatment-related adverse events of HER2-targeted ADCs and to investigate the differences between different drugs and cancer types. We performed a systematic search of literature in PubMed, Embase, Web of Science, and Scopus databases from inception to February 1, 2022 and the last search was updated to August 1, 2022. Published prospective clinical trials on single-agent of the US Food and Drug Administration approved HER2-targeted ADCs with available count data regarding treatment-related adverse events were included. The primary outcomes were pooled incidences of treatment-related adverse events and differences between different drugs and cancer types. The data synthesis was performed using a Bayesian hierarchical modelling method and the protocol was registered in PROSPERO (CRD42022331627). A total of 39 studies (37 trials) involving 7688 patients across five cancer types were included in the final analysis. On pooling the data using Bayesian hierarchical modelling, the overall mean incidence of all-grade adverse events, high-grade adverse events, serious adverse events, and adverse events that resulted in drug discontinuation were 98.29% (95% CrI, 97.33%-99.07%, τ=1.49), 47.88% (95% CrI, 42.74%-53.17%, τ=0.37), 19.45% (95% CrI, 15.70%-23.67%, τ=0.55), and 10.52% (95% CrI, 8.03%-13.21%, τ=0.56), respectively. The most common all-grade adverse events were nausea (41.57%; 95% CrI, 40.46%-42.64%, τ=0.81), fatigue (35.86%; 95% CrI, 34.85%-36.96%, τ=0.65), and decreased appetite (28.84%; 95% CrI, 22.93%-36.87%, τ=0.76). The most common high-grade adverse events were thrombocytopenia (8.37%; 95% CrI, 7.75%-9.07%, τ=0.71), anaemia (6.49%; 95% CrI, 5.86%-7.11%, τ=1.06), and neutropenia (6.42%; 95% CrI, 5.76%-7.04%, τ=1.21). We found no difference in the mean incidences of adverse events among different cancer types, as well as different dosing regimens. However, trastuzumab deruxtecan (T-DXd) appeared to have higher mean incidences of adverse events compared with trastuzumab emtansine (T-DM1), especially for the higher dose of T-DXd (6.4mg/kg Q3W). The incidences of adverse events between two HER2-targeted ADCs were similar in different cancer types, but different HER2-targeted ADCs appeared to have different mean incidences of adverse events. The comprehensive summary of the adverse events of HER2-targeted ADCs is critical for clinicians caring for patients with cancer receiving HER2-targeted ADCs therapy. The National Natural Science Foundation of China (Grant No. 82073402) and Key R&D Plan of Hubei Province, China (No.2020BCA060) funded this study.

Subcutaneous Mosunetuzumab Is Active with a Manageable Safety Profile in Patients (pts) with Relapsed/Refractory (R/R) B-Cell Non-Hodgkin Lymphomas (B-NHLs): Updated Results from a Phase I/II Study

Background: Mosunetuzumab (Mosun), a CD20xCD3 T-cell engaging bispecific monoclonal antibody (Bi-mAb) that redirects T cells to eliminate malignant B cells, is the first Bi-mAb approved for R/R follicular lymphoma (FL; EMA 2022; Budde et al. Lancet Oncol 2022) and can be administered intravenously in the outpatient setting with a fixed treatment duration. A subcutaneous (SC) formulation that aims to improve safety and convenience is under evaluation. We present results for SC Mosun in a larger population with longer follow-up than previously reported (Bartlett et al. ASH 2021). Methods: GO29781 is a Phase I/II, open-label, multicenter dose-escalation and expansion study of Mosun in pts with R/R B-NHL (NCT02500407). Pts with ≥1 prior line of systemic therapy (dose-escalation) or ≥2 prior lines (dose-expansion) were included. SC Mosun was administered with step-up dosing in Cycle (C) 1, then given on Day (D) 1 of subsequent 21-day cycles. The first 2 dose-escalation groups received Mosun 5mg on C1D1, 15mg or 45mg on C1D8, and 45mg on C1D15 and D1 from C2 onwards (5/15/45mg [Group 1] and 5/45/45mg [Group 2], respectively). A third group received Mosun 5mg on C1D1, 45mg on C1D8, 90mg on C1D15 and C2D1, and 45mg on D1 from C3 onwards (5/45/90/90/45mg [Group 3]). Pts with a complete response (CR) after 8 cycles completed therapy; pts with a partial response or stable disease continued treatment up to 17 cycles. Primary objectives included safety, tolerability and identification of the recommended Phase II dose. Results: At data cut-off (May 20, 2022) 89 pts with R/R B-NHL received SC Mosun (Group 1: n=39, Group 2: n=47, Group 3: n=3). Most common histologies were diffuse large B-cell lymphoma (56%), transformed FL (19%) and FL (12%). Median (range) age was 68 years (24-88). Median number of prior systemic therapies was 3; 85.1% and 83.9% of pts were refractory to their last prior therapy or prior anti-CD20 therapy, respectively; 32.6% had received prior CAR T-cell therapy. Median (range) time on study was 9.9 months (m; 0.4-19.7) and cycles completed was 5 (1-17). No dose-limiting toxicities were observed in dose escalation. Most common all-Grade (Gr) adverse events (AEs) were injection-site reaction (62%; all Gr 1/2) and cytokine release syndrome (CRS; 27%; all Gr 1/2). Gr 3/4 and serious AEs were reported in 49% and 45% of pts, respectively. One AE led to Mosun discontinuation (COVID-19; Group 1). Gr 5 AEs were reported in 5 pts; none were considered Mosun-related by investigators (Group 1: n=3 [COVID-19 n=2; large intestine perforation n=1]; Group 2: n=2 [COVID-19 pneumonia and septic shock]). CRS was reported in 15/39 pts (38%), 8/47 pts (17%) and 1/3 pts in Groups 1, 2 and 3, respectively. Most CRS events occurred during C1. Median onset time since prior Mosun and median duration was 2 days (ranges 0-4 and 1-6, respectively). CRS events were low Gr (Gr 1: 18%; Gr 2: 9%; Figures 1 and 2) and all resolved; 2 pts (2%) received corticosteroids and 4 (5%) received tocilizumab for CRS. Neutropenia was reported in 19 pts (21%; Gr 3/4 in 17 [19%]) and febrile neutropenia in 1 pt (1%; Gr 3); median (range) neutropenia duration was 8 days (2-64). Serious infections were reported in 12 (14%) pts (Gr 3/4: n=8; Gr 5: n=4). Treatment-related neurological AEs possibly consistent with immune effector cell-associated neurotoxicity syndrome (ICANS) were reported in 3 pts (3%; all Gr 1: lethargy, memory impairment, and ICANS [confusion] with Gr 1 CRS); all resolved. Tumor flare was reported in 4 pts (4%; Gr 2: n=2; Gr 3: n=2); all resolved. All pts with indolent NHL (iNHL; all FL; 11/11) and 75/76 pts with aggressive NHL (aNHL) were enrolled ≥3 m prior to cut-off and included in the efficacy analysis. Overall response rate was 82% in iNHL and 36% in aNHL; CR rate was 64% in iNHL and 20% in aNHL, with 18/22 CRs (82%) ongoing at data cut-off. Median duration of response was 6.7 m (95% CI: 4.8-not estimable) in aNHL and not reached in iNHL (9-m event-free rate: 78% [95% CI: 51-100]). Conclusions: SC Mosun demonstrated single-agent activity similar to the intravenous formulation in pts with R/R B-NHL. SC Mosun with C1 step-up dosing had a manageable safety profile, including low CRS rates across dose schedules. Based on exposure-response considerations regarding tolerability and clinical activity, 5/45/45mg was chosen as the recommended dose. SC Mosun could improve outcomes in R/R B-NHL while increasing convenience and reducing healthcare resource utilization. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase Ib Dose-finding Study of Panobinostat and Ruxolitinib in Myelofibrosis.

A Phase Ib Dose-finding Study of Panobinostat and Ruxolitinib in Myelofibrosis.

P1638: EARLY USE OF ELTROMBOPAG IN ADULT PATIENTS WITH ITP WHO ARE REFRACTORY OR RELAPSED AFTER FIRST-LINE CORTICOSTEROID THERAPY – AN AD HOC ANALYSIS OF THE TAPER TRIAL RESULTS

Background: Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by reduced platelet count (<100×109/L) and increased bleeding risk in the absence of other causes. It is categorized by disease duration from diagnosis: newly diagnosed (ndITP; ≤3 months [mo]), persistent (pITP; 3-12 mo), and chronic (cITP; >12 mo). Eltrombopag (EPAG), a thrombopoietin receptor agonist, is approved in Europe for the treatment of ITP lasting ≥6 mo in patients (pts) refractory to other treatments. The TAPER trial (NCT03524612) was designed to assess sustained response off treatment following EPAG tapering in adults with ITP of any duration, who were refractory/had relapsed after first-line corticosteroids. Aims: To conduct an ad hoc analysis of the ongoing TAPER trial, assessing initial response to EPAG therapy according to time since ITP diagnosis (ndITP, pITP, cITP). Methods: Pts with ≥6 mo of data, or pts who discontinued the study prior to Month 6 were included. Newly enrolled pts with <6 mo of data were excluded. Pts were grouped according to time since ITP diagnosis at baseline (<3, 3 to <6, 6 to ≤12, and >12 mo). The main analysis of hematologic response (ie, percentage of pts with platelet count thresholds of ≥30, ≥50, and ≥100 ×109/L achieved at least once without rescue therapy) was restricted to data from the first 2 mo (~Day 57) to ensure pts were on treatment. Safety analyses were restricted up to and including Month 6. Results: A total of 82/105 (78%) pts from TAPER were included. Median (range) age was 49 (18-88) years and 58.5% were female. In the first 6 months, the median (interquartile range [IQR]) duration of EPAG exposure was 5.3 (2.6-6.0) mo, and median (IQR) dose was 53.2 (37.5-69.6) mg/day. The proportions of pts with platelet counts equal to or above the specified thresholds were comparable across the time-since-ITP-diagnosis groups, ranging from 69% to 100% (Fig. 1). The median time to a platelet count of ≥50×109/L was also comparable across groups, ranging from 8 to 17 days, and the median (IQR) increase in platelet count to ~Day 57 was 84.5×109/L (36.5-165.6). The percentages of pts without World Health Organization Grade 1-4 bleeding events increased from Day 1 to ~Day 57 across all groups (<3 mo: 39.5%→84%; 3 to <6 mo: 61%→100%; 6 to ≤12 mo: 50%→88%; >12 mo: 70%→89%). The most common all-grade adverse events (AEs) were headache (pts: 18% [<3 mo], 22% [3 to <6 mo], 12.5% [6 to ≤12 mo], 10% [>12 mo]) and thrombocytopenia (pts: 21% [<3 mo], 17% [3 to <6 mo], 12.5% [6 to ≤12 mo], 0% [>12 mo]). One pt (6%; 3 to <6 mo) had grade ≥3 headache; 5 (13%; <3 mo), 2 (11%; 3 to <6 mo), and 2 (12.5%; 6 to ≤12 mo) pts had grade ≥3 thrombocytopenia. There were 3 treatment-related severe AEs (intentional product misuse [<3 mo], infectious diarrhea secondary to EPAG, and pulmonary embolism [both 6 to ≤12 mo]). Two deaths were reported by the cut-off date (central nervous system hemorrhage [n=1; <3 mo]; intracranial hemorrhage [n=1; 3 to <6 mo]) that were not considered study drug related. Image:Summary/Conclusion: The data show that EPAG achieved comparable rates of platelet response and reduced the frequency and severity of bleeding events in pts with ndITP, pITP, and cITP. Safety findings were comparable across the 4 groups, and aligned with the well-established safety profile of EPAG. These findings suggest that EPAG is as efficacious and well tolerated in pts who receive it early following diagnosis as in those who receive it later.

S292: SUSTAINED RESPONSE OFF TREATMENT IN ELTROMBOPAG-TREATED PATIENTS WITH ITP WHO ARE REFRACTORY OR RELAPSED AFTER FIRST-LINE STEROIDS: PRIMARY ANALYSIS OF THE PHASE II TAPER TRIAL

Background: Corticosteroids (CSs) are the standard 1st-line treatment for primary immune thrombocytopenia (ITP); however, long-term CS use is associated with high relapse rates and considerable toxicity. Treatments that achieve a sustained response and reduce the need for long-term CS use are needed. Eltrombopag (EPAG) is a thrombopoietin receptor agonist (TPO-RA) indicated in Europe for the treatment of patients (pts) aged ≥1 year with primary ITP lasting ≥6 months who are refractory to other treatments (eg, CSs). Evidence suggests that a proportion of pts treated with TPO-RAs achieve sustained responses that are maintained after TPO-RA tapering and discontinuation; however, much of the evidence is retrospective with only a few prospective studies investigating sustained response off treatment (SRoT). Aims: TAPER (NCT03524612), a Phase II, open-label, prospective, single-arm study, aims to determine whether EPAG can induce SRoT in pts with ITP after 1st-line CS failure. Methods: Adult (≥18 years) pts with ITP who did not respond to or had relapsed after initial CS therapy, with platelet counts <30×109/L and assessed as needing treatment, were included. Patients received a 50 mg/day starting dose of EPAG (25 mg/day for East/Southeast Asian pts; 12.5 mg/day for Japanese pts in Japan), which could be increased up to 75 mg/day (50 mg/day in Japan) if needed. The primary endpoint was the number (%) of pts with SRoT by Month 12; SRoT was defined as achieving a complete response (CR, ie, platelet count ≥100×109/L), then maintaining a stable platelet count (no counts <70×109/L) for 2 months, followed by successful EPAG tapering and discontinuation with platelet counts ≥30×109/L and no bleeding events or rescue therapy. Patients with SRoT at Month 12 were followed for a further year. Secondary outcomes included SRoT duration and platelet count changes from baseline. Data to Month 12 are presented. Results: N=105 pts were enrolled. The median (interquartile range [IQR]) age was 46 (30-65) years; 61% were female. In the 1st 12 months, median (IQR) duration of exposure to EPAG was 5.6 (2.3-11.9) months and median (IQR) EPAG dose was 57.1 (37.5-69.0) mg/day. Overall, 89 pts (85%) achieved CR at least once and 65 pts (62%) maintained a platelet count ≥70×109/L for 2 months after CR. EPAG tapering and discontinuation was achieved in 44 pts (42%). The primary endpoint was met, with 32 pts (30.5% [95% confidence interval, 21.9-40.2]; P<0.001 [H1: P>15%; alpha: 0.05]) achieving SRoT until Month 12 (Fig. 1); SRoT was maintained from last dose to Month 12 for a median (IQR) of 33.3 (25.7-45.3) weeks. The median (IQR) absolute increase in platelet counts from baseline at Month 12 was 77.0×109/L (35.0-145.0). All-grade adverse events (AEs) occurred in 92/105 (88%) pts (grade ≥3 AEs: 33/105 [31%]). Treatment-related AEs occurred in 37 (35%) pts (8 [7.6%] grade ≥3). The most common all-grade AEs were headache (21% of pts with ≥1 event [grade ≥3: 1% of all pts]), thrombocytopenia (17% [10.5%]), and petechiae (11% [1%]). There were 4 deaths (none were considered treatment related): 3 were on-treatment (central nervous system hemorrhage [n=1], intracranial hemorrhage [n=1], metastases to peritoneum [n=1]) and 1 death (malignant neoplasm) occurred 238 days after last dose. Image:Summary/Conclusion: Data from the TAPER study indicate that a significant proportion of pts experience sustained response following tapering and discontinuation of EPAG, even after a relatively short duration of exposure. Overall EPAG was well tolerated with no unexpected AEs.

Ruxolitinib in chronic steroid-refractory graft-versus-host-disease.

e19053 Background: Ruxolitinib, an elective Janus Kinase (JAK) 1/2 inhibitor, has been approved by FDA for the treatment of steroid-refractory chronic graft-versus-host-disease (SR cGVHD) after the failure of one or two lines of systemic therapy in adult and pediatric patients 12 years and older. However, it remains underutilized despite promising results in the treatment of SR cGVHD. Methods: We did a comprehensive literature search across various data sets, including PubMed, Cochrane, and Embase, and presented data in ASH and ASCO. A review of the most recent data is summarized in this abstract. Results: Two retrospective cohort studies and one pilot prospective study evaluated ruxolitinib in SR cGVHD. In a retrospective cohort study by Yang et al., 36 patients with SR cGVHD treated with ruxolitinib showed complete response (CR) in 27.8% of patients with complete disappearance of cGVHD symptoms and partial response (PR) with symptom relief of 52.7% at a dose of 2.5 to 10 mg two times daily with ruxolitinib tapering one week after symptoms improvement. In the pilot prospective study by Mozo et al., 12 pediatric patients with SR cGVHD received ruxolitinib at a dose of 2.5 to 10 mg two times daily and showed CR in 8.3% of patients and PR in 82.7% of patients. Morozova et al. conducted a prospective pilot study in 20 patients with primary or secondary myelofibrosis who were treated with pre-transplant ruxolitinib 45 mg/day from ruxolitinib (45 mg) starting from seven days before transplant to 2 days before the transplant, and 15 mg from day five after transplant to day 100 after transplant along with cyclophosphamide 50 mg/kg on days three and four after transplant. PR was observed in 47.1% of patients at 6 months with the incidence of cGVHD of 20%. In Phase III trial by Zeiser et al. reported CR of 6.7% and PR of 43% in 165 patients treated with ruxolitinib at a dose of 10 mg daily for 6 cycles (28 days/cycle). The most common all-grade adverse events are listed here. Conclusions: Ruxolitinib was recently approved by FDA for the treatment of SR GVHD and should be utilized more due to its high effectiveness and tolerable safety profile.[Table: see text]

Olaparib outcomes in metastatic castration-resistant prostate cancer: First real-world experience in safety and efficacy from the Chinese mainland.

BackgroundOlaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has been approved for use in breast cancer susceptibility gene (BRCA)-mutated metastatic castration-resistant prostate cancer (mCPRC) patients. Our aim was to evaluate the adverse events (AEs) and efficacy of Olaparib in the treatment of mCRPC patients from the Chinese mainland.MethodsWe retrospectively included mCPRC patients treated with Olaparib more than for 28 days. Patients with alterations in 15 homologous recombination repair (HRR) genes were defined as the HRRmt group, and the rest were defined as the HRRwt group. The efficacy was analyzed by prostate-specific antigen (PSA) decreased rate and PSA progression-free survival (PFS). The partial response, good response, and high response of PSA were defined as a reduction of between 0% and 50%, greater than 50%, and greater than 90% from baseline.ResultsA total of 43 patients were enrolled in this study, including 26 HRRmt group patients and 17 HRRwt group patients. Two HRRwt patients received additional abiraterone therapy. A partial response, good response, and high response were achieved in 89% (23/26), 59% (15/26), and 15% (4/26) of HRRmt group patients, respectively. In HRRwt group, 59% (10/17), 35% (6/17), and 12% (2/17) of patients met the criteria of partial response, good response, and high response, respectively. Median PFS was 8.0 months in the HRRmt group and 3.0s months in the HRRwt group (HR, 0.61; 95% CI, 0.24–1.14; p = 0.148), respectively. All the 20 patients had AEs during Olaparib treatment. Ten episodes of grade 3 or 4 AEs were observed in four patients. The most common all-grade AEs were fatigue or asthenia (70%), anemia (65%), and decreased appetite (55%).ConclusionsMost of the AEs were tolerated, and Olaparib was effective in mCRPC patients with HRR deficiency. In addition, the underlying mechanism of the efficacy of Olaparib observed in HRRwt group patients remained explored.

Zanubrutinib in relapsed/refractory mantle cell lymphoma: long-term efficacy and safety results from a phase 2 study

AbstractBruton tyrosine kinase (BTK) inhibitor is an established treatment for relapsed/refractory (R/R) mantle cell lymphoma (MCL). Zanubrutinib, a highly selective BTK inhibitor, is approved for patients with MCL who have received ≥1 prior therapy. We report the long-term safety and efficacy results from the multicenter, open-label, phase 2 registration trial of zanubrutinib. Patients (n = 86) received oral zanubrutinib 160 mg twice daily. The primary endpoint was the overall response rate (ORR), assessed per Lugano 2014. After a median follow-up of 35.3 months, the ORR was 83.7%, with 77.9% achieving complete response (CR); the median duration of response was not reached. Median progression-free survival (PFS) was 33.0 months (95% confidence interval [CI], 19.4-NE). The 36-month PFS and overall survival (OS) rates were 47.6% (95% CI, 36.2-58.1) and 74.8% (95% CI, 63.7-83.0), respectively. The safety profile was largely unchanged with extended follow-up. Most common (≥20%) all-grade adverse events (AEs) were neutrophil count decreased (46.5%), upper respiratory tract infection (38.4%), rash (36.0%), white blood cell count decreased (33.7%), and platelet count decreased (32.6%); most were grade 1/2 events. Most common (≥10%) grade ≥3 AEs were neutrophil count decreased (18.6%) and pneumonia (12.8%). Rates of infection, neutropenia, and bleeding were highest in the first 6 months of therapy and decreased thereafter. No cases of atrial fibrillation/flutter, grade ≥3 cardiac AEs, second primary malignancies, or tumor lysis syndrome were reported. After extended follow-up, zanubrutinib demonstrated durable responses and a favorable safety profile in R/R MCL. The trial is registered at ClinicalTrials.gov as NCT03206970.

Abstract PD13-03: Ribociclib, everolimus, exemestane triplet therapy in HR+/HER2− advanced breast cancer after progression on a CDK4/6 inhibitor: Final efficacy, safety, and biomarker results from TRINITI-1

Abstract PD13-03: Ribociclib, everolimus, exemestane triplet therapy in HR+/HER2− advanced breast cancer after progression on a CDK4/6 inhibitor: Final efficacy, safety, and biomarker results from TRINITI-1

Abstract PD13-05: Alpelisib + fulvestrant in patients with PIK3CA-mutated, HR+, HER2— advanced breast cancer (ABC) who received chemotherapy or endocrine therapy (ET) as immediate prior treatment: BYLieve Cohort C primary results and exploratory biomarker analyses

Abstract Introduction: Alpelisib (ALP), an inhibitor and degrader of phosphatidylinositol-3-kinase α (PI3Kα), + fulvestrant (FUL) demonstrated efficacy in PIK3CA-mutated, HR+, HER2- ABC in the phase 3 SOLAR-1 trial, which included only 20 patients (pts) with prior CDK4/6 inhibitor (CDKi) in the PIK3CA-mutated cohort. BYLieve (NCT03056755), a phase 2, open-label, 3-cohort noncomparative study, evaluates ALP + endocrine therapy (ET; FUL or letrozole [LET]) in pts with PIK3CA-mutated, HR+, HER2- ABC, progressing on/after prior therapies, including CDKi + ET. Cohorts A and B were restricted to pts receiving CDKi + (aromatase inhibitor [AI] or FUL), respectively, as immediate prior therapy, but Cohort C included pts whose cancer progressed on/after AI (in adjuvant or metastatic setting), and who received chemotherapy (CT; any line), or ET (FUL or LET monotherapy or with targeted therapy, including CDKi + FUL, but not CDKi + AI) as immediate prior treatment. Cohorts A and B demonstrated efficacy and safety of ALP + ET after prior CDKi. Here, we report primary results and biomarker analyses from Cohort C.. Methods: Pts in Cohort C received ALP 300 mg orally QD + FUL 500 mg intramuscular Q28D + C1D15. The primary endpoint was assessed in each cohort separately and is the proportion of pts with centrally confirmed PIK3CA mutation alive and without disease progression at 6 mo per local assessment; 95% CIs are calculated using Clopper and Pearson (1934) exact method. The 95% CI lower bound of the primary endpoint &amp;gt;30% is clinically meaningful evidence of treatment effect. In an exploratory analysis of baseline biomarkers using ctDNA, progression-free survival (PFS) was estimated in pt subgroups per high (≥10%) or low (&amp;lt;10%) ctDNA fraction and ESR1 mutational status via Kaplan-Meier estimation.. Results: 127 pts were enrolled in Cohort C (1 pt discontinued prior to treatment start) with ≥6 mo follow-up by the cutoff date (14 Jun 2021); 115 had a centrally confirmed PIK3CA mutation. Median follow-up was 11.4 mo (range, 0-23 mo); 79 (62.7%) pts had ≥2 prior lines of therapy in the metastatic setting, 58 (46.0%) pts had prior CT exposure in the metastatic setting, and 41 (32.5%) pts had prior FUL exposure in the metastatic setting. The primary endpoint was met, with 48.7% (95% CI, 39.3%-58.2%) of pts alive and without disease progression at 6 mo. Median PFS (mPFS) was 5.6 mo (95% CI, 5.4-8.1 mo). The most common all-grade adverse events (AEs) by preferred term were hyperglycemia (n=82, 65.1%), diarrhea (n=66, 52.4%), nausea (n=51, 40.5%), and rash (n=49, 38.9%). Grade ≥3 AEs (≥10%) included hyperglycemia (n=30, 23.8%) and rash (n=17, 13.5%). AEs leading to discontinuation occurred in 15.1% (n=19) of pts; most frequent AEs leading to discontinuation were rash (n=5, 4.0%) and hyperglycemia (n=4, 3.2%). Exploratory biomarker analyses in 74 pts who had available baseline biomarker samples at data cutoff showed that pts with a low ctDNA fraction (n=23) had longer mPFS than pts with high ctDNA fraction (n=51; 16.7 [95% CI, 10.4-19.5] vs 5.4 [95% CI, 2.9-7.2] mo; p&amp;lt;0.001, HR=0.31 [95% CI, 0.2-0.6]). Efficacy was similar in pts with (n=20) and without (n=54) ESR1-mutated tumors (6.3 [95% CI, 2.8-8.3] vs 8.3 [95% CI, 5.5-16.7] mo; p=0.095, HR=0.59 [95% CI, 0.3-1.1]).. Conclusion: In Cohort A of BYLieve, efficacy of ALP + FUL suggests clinical benefit immediately after CDKi + AI; Cohort C confirms clinically relevant activity of ALP + FUL in a heterogeneous population, primarily treated in the third line or later, and potentially regardless of ESR1 status or ctDNA fraction, with no new safety signals detected. Together, these data confirm that ALP targets the effects of the PIK3CA-driver oncogene in HR+, HER2- ABC. Citation Format: Hope S Rugo, Patrick Neven, Isabel Saffie, Yeon Hee Park, Michelino De Laurentiis, Florence Lerebours, Eva Maria Ciruelos, Nicholas Turner, Dejan Juric, Ennan Gu, Christina H Arce, Mukta Joshi, Estelle Roux, Murat Akdere, Stephen Chia. Alpelisib + fulvestrant in patients with PIK3CA-mutated, HR+, HER2— advanced breast cancer (ABC) who received chemotherapy or endocrine therapy (ET) as immediate prior treatment: BYLieve Cohort C primary results and exploratory biomarker analyses [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 PD13-05.

Abstract P5-16-02: Updated efficacy, safety and translational data from MARIO-3, a phase II open-label study evaluating a novel triplet combination of eganelisib (IPI-549), atezolizumab (atezo), and nab-paclitaxel (nab-pac) as first-line (1L) therapy for locally advanced or metastatic triple-negative breast cancer (TNBC)

Abstract Background: Eganelisib is a first-in-class, oral, immuno-oncology macrophage reprogramming agent. The IMpassion130 randomized trial in 1L advanced TNBC has demonstrated improved efficacy with the addition of atezo to nab-pac in patients with PD-L1+ tumors. Adding eganelisib to the approved doublet of atezo and nab-pac is expected to improve patient benefit regardless of PD-L1 status. Methods: Eligible patients (pts) had measurable unresectable locally advanced or metastatic TNBC and no prior systemic therapy for advanced disease. A safety run-in assessed the safety of the triplet of oral eganelisib 30 mg daily in combination with IV nab-pac 100 mg/m2 given on days 1, 8, &amp; 15, and IV atezo 840 mg given on days 1 &amp; 15 of a 28 day cycle. After establishing tolerability and confirmation of the 30 mg dose in the safety run-in (n=6), the expansion phase of the phase II study was initiated to enroll approximately 60 pts (30 PD-L1+ and 30 PD-L1-). Cycles are repeated until loss of clinical benefit, unacceptable toxicity or consent withdrawal. The primary efficacy endpoint is confirmed complete response (CR) rate per RECIST v1.1. Secondary endpoints include the overall response rate (ORR), progression free survival and safety assessment. Results: As of 6/26/2021, data from the safety run-in and the expansion cohorts are reported for 43 pts evaluable for safety and 38 evaluable for efficacy defined as having at least one post-baseline tumor assessment. 2 CRs (2/38), 19 PRs (19/38), and 11 SDs (11/38) were observed with an ORR of 55.3% (21/38) and a disease control rate (DCR) of 84.2% (32/38). Responses were seen irrespective of PD-L1 status; in PD-L1+ pts, ORR is 66.7% (8/12) and DCR is 91.7% (11/12), and in PD-L1- pts, ORR is 47.8% (11/23) and DCR is 78.3% (18/23). The most common all-grade adverse events were nausea (51.2%), fatigue (48.8%), alopecia (32.6%), diarrhea (32.6%), rash maculo-papular (30.2%), ALT increased (27.9%), and AST increased (25.6%). The most common grade ≥3 adverse events were ALT increased (18.6%), AST increased (14.0%), neutrophil count decreased (9.3%) and rash maculo-papular (9.3%). The safety profile is acceptable and in line with expectations of component drugs with no additive or new safety signals. Translational data from paired biopsies show a shift in tumor associated macrophages towards an immune activated state as well as an increase in cytotoxic T cells. In addition, a subset of tumors with baseline PD-L1 negative status show conversion to PD-L1 positive status post treatment. Consistent with immune activation, increased interferon gamma signature, increased proinflammatory cytokines and T cell invigoration were observed in peripheral blood cells. Conclusions: The novel triplet regimen of eganelisib, atezo, and nab-pac shows promising anti-tumor activity (ORR 55.3% and DCR 84.2%) irrespective of PD-L1 status and has manageable toxicity. . Translational data from paired biopsies and peripheral blood show evidence of immune activation regardless of PD-L1 status as well as conversion from PD-L1 negative to PD-L1 positive subtype within a subset of patients treated with the triplet regimen. The expansion phase of the phase II study is currently enrolling. At the time of presentation, we will have updated efficacy, safety and translational data. Citation Format: Soliman Hatem, Jeffrey Hargis, Anthony Elias, Arielle Lee, Rachel Swart, Shaker Dahkil, Alexandra Drakaki, Vu Phan, Frederic Kass, Melody Cobleigh, Sanil Babu, Katherine Tkaczuk, Brenda O'Connell, Jennifer Roberts, Nora Zizlsperger, Erika Hamilton. Updated efficacy, safety and translational data from MARIO-3, a phase II open-label study evaluating a novel triplet combination of eganelisib (IPI-549), atezolizumab (atezo), and nab-paclitaxel (nab-pac) as first-line (1L) therapy for locally advanced or metastatic triple-negative breast cancer (TNBC) [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 P5-16-02.

A phase II study of chemotherapy in combination with telomerase peptide vaccine (GV1001) as second-line treatment in patients with metastatic colorectal cancer.

Background: GV1001 is a human telomerase peptide vaccine that induces a CD4/CD8 T-cell response against cancer cells, thereby affording an immunological anti-tumor effect. Here, we evaluated the efficacy and safety of GV1001 in combination with chemotherapy in patients with metastatic colorectal cancer who had failed first-line chemotherapy.Methods: This multicenter, non-randomized, single-arm phase II study recruited recurrent or metastatic colorectal cancer patients with measurable disease who had failed first-line chemotherapy. Patients received GV1001 and chemotherapy concomitantly based on a pre-established schedule. Cytotoxic chemotherapy and targeted agents (bevacizumab, cetuximab, or aflibercept) were allowed to be used at the discretion of the investigator. The primary endpoint was the disease control rate; secondary endpoints were the objective response rate, progression-free survival, overall survival, and safety outcomes. The baseline serum eotaxin level (a potential predictive biomarker of GV1001) was analyzed. To determine whether an adequate immune response had been induced, a delayed-type hypersensitivity test and a T-cell proliferation test were performed.Results: From May 13, 2015 to October 13, 2020, 56 patients with recurrent or metastatic colorectal cancer treated in seven hospitals of South Korea were enrolled. The median patient age was 64 years (range, 29-82 years); 67.9% were men. Of all patients, 66.1% had left-side colorectal cancer and the RAS mutation was present in 25%. The disease control rate and the objective response rates were 90.9% (95% confidence interval [CI]: 82.4-99.4%) and 34.1% (95% CI, 20.1-48.1%), respectively. The median progression-free survival was 7.1 months (95% CI, 5.2-9.1 months) and the median overall survival was 12.8 months (95% CI, 9.9-15.8 months). The most common all-grade adverse events were neutropenia (48.2%), nausea (26.8%), neuropathy (25.0%), stomatitis (21.4%), and diarrhea (21.4%). Immune response analysis showed that no patient had positive delayed-type hypersensitivity test results; antigen-specific T-cell proliferation was observed in only 28% of patients. The baseline eotaxin level was not associated with any efficacy outcome.Conclusion: Although no clear GV1001-specific immune response was observed, the addition of GV1001 vaccination to chemotherapy was tolerable and associated with modest efficacy outcomes.

Abstract P035: A phase 1 pharmacokinetic trial of single agent trametinib a MEK inhibitor in advanced cancer patients with hepatic dysfunction: An NCI Organ Dysfunction Working Group (ODWG) study (NCI 9591)

Abstract Background Trametinib (Mekinist ®) is an oral bioavailable MEK 1/2 inhibitor that is FDA approved in combination with BRAF inhibitor Dabrafenib for BRAFV600 mutant solid tumors. The single agent recommended phase 2 dose (RP2D) is 2 mg daily (QD). No clinical data is available on recommendation of trametinib dosing in various degrees of hepatic dysfunction (HD). This study was designed to evaluate RP2D, maximum tolerated dose (MTD), and pharmacokinetic (PK) profile of trametinib as primary endpoints in patients (pts) with genomically unselected advanced solid tumors with various degrees of HD. Methods Advanced cancer pts with ECOG ≤2, adequate renal and bone marrow functions, were stratified (NCI ODWG Criteria) into 4 HD groups: normal (NO), mild (ML), moderate (MD), severe (SV). NO group was enrolled as control subjects and was not evaluable for dose limiting toxicity (DLT). Trametinib was given QD on a 28-days cycle, with dose escalation based on a “3+3” design within each HD group (starting dose: NO, ML: 2mg; MD: 1.5 mg; SV: 1mg). Due to the long half-life of trametinib, PK samples were collected at days 15-16 in cycle 1. Differences in PK parameters among liver function groups were evaluated using analysis of variance (ANOVA). Results Out of 46 pts enrolled (2 pts ineligible), 44 (NO=17, ML=7, MD (1.5mg)=4, MD (2mg)=5, SV (1mg)=9, SV (1.5mg)=2) were evaluable for safety and 22 for PK analysis. The most common cancer type was GI-non CRC cancer (n=16, 36%). The most common all-grade treatment related adverse events (TRAEs) were acneiform rash (NO=53%, HD=48% of pts), nausea (NO=65%, HD=22%), diarrhea (NO=53%, HD=26%) and fatigue (NO=59%, HD=15%). Grade 3/4 TRAEs occurred in 27% (n=12) of pts (NO=8, 47%; HD=4, 15%). No treatment related deaths occurred. DLT was evaluable in 15 pts (ML=6, MD (1.5mg)=3, MD (2mg)=2, SV (1mg)=3 and SV (1.5mg)=1). One DLT (grade 3 acneiform rash) was observed in an SV pt (1.5mg). Dose interruptions or reductions due to TRAEs occurred in 15 pts (34%) [NO=9, 53%; ML=2, 29%; MD (1.5mg)=1, 33%; MD (2mg)=2, 33%; SV (1mg)=1, 11%; SV (1.5mg)=1; 50%]. Best response was stable disease in all HD groups (33 to 75%) and 54% in NO group. There were no significant differences for PK parameters of Cmax (p=0.18), Cmin (p=0.16), Cavg (p=0.62), or AUC0-24 (p=0.11) (NO vs ML, NO vs MD, NO vs SV, ML vs MD, ML vs SV, MD vs SV), when trametinib was normalized to 2 mg dose. However, only limited PK data were available for the MD (n=3) and SV (n=3) groups compared to NO (n=10) and ML (n=6) groups. Trametinib is heavily protein bound, with no correlation between serum albumin level and unbound trametinib fraction (p=0.26). Conclusion RP2D for trametinib in ML pts is 2 mg QD. There are insufficient number of evaluable pts to declare RP2D for MD and SV HD groups. No DLTs were noted in the highest dose cohorts that reached 3 evaluable pts: 1.5 mg QD in MD group, and 1 mg QD in SV group. It may be appropriate for pts with MD and SV HD to start trametinib at 1.5 mg QD and 1 mg QD respectively, and monitored closely for toxicity. Citation Format: Pei Jye Voon, Eric X. Chen, Helen X. Chen, Albert C. Lockhart, Solmaz Sahebjam, Karen Kelly, Ulka N. Vaishampayan, Vivek Subbiah, Albiruni R. Razak, Daniel J. Renouf, Sebastien J. Hotte, Arti Singh, Philippe L. Bedard, Aaron R. Hansen, Ivy S. Percy, Lisa Wang, Lee-Anne Stayner, Lillian L. Siu, Anna Spreafico. A phase 1 pharmacokinetic trial of single agent trametinib a MEK inhibitor in advanced cancer patients with hepatic dysfunction: An NCI Organ Dysfunction Working Group (ODWG) study (NCI 9591) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P035.

AGILE: A Global, Randomized, Double-Blind, Phase 3 Study of Ivosidenib + Azacitidine Versus Placebo + Azacitidine in Patients with Newly Diagnosed Acute Myeloid Leukemia with an IDH1 Mutation

AGILE: A Global, Randomized, Double-Blind, Phase 3 Study of Ivosidenib + Azacitidine Versus Placebo + Azacitidine in Patients with Newly Diagnosed Acute Myeloid Leukemia with an IDH1 Mutation

Completed Induction Phase Analysis of Magnify: Phase 3b Study of Lenalidomide + Rituximab (R 2) Followed By Maintenance in Relapsed/Refractory Indolent Non-Hodgkin Lymphoma

Completed Induction Phase Analysis of Magnify: Phase 3b Study of Lenalidomide + Rituximab (R 2) Followed By Maintenance in Relapsed/Refractory Indolent Non-Hodgkin Lymphoma