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Purpose Genomic alterations of BRAF and NRAS are oncogenic drivers in malignant melanoma and other solid tumors. Tovorafenib is an investigational, oral, selective, CNS-penetrant, small molecule, type II pan‑RAF inhibitor. This first-in-human phase 1 study explored the safety and antitumor activity of tovorafenib. Methods This two-part study in adult patients with relapsed or refractory advanced solid tumors included a dose escalation phase and a dose expansion phase including molecularly defined cohorts of patients with melanoma. Primary objectives were to evaluate the safety of tovorafenib administered once every other day (Q2D) or once weekly (QW), and to determine the maximum-tolerated and recommended phase 2 dose (RP2D) on these schedules. Secondary objectives included evaluation of antitumor activity and tovorafenib pharmacokinetics. Results Tovorafenib was administered to 149 patients (Q2D n = 110, QW n = 39). The RP2D of tovorafenib was defined as 200 mg Q2D or 600 mg QW. In the dose expansion phase, 58 (73%) of 80 patients in Q2D cohorts and 9 (47%) of 19 in the QW cohort had grade ≥ 3 adverse events. The most common of these overall were anemia (14 patients, 14%) and maculo-papular rash (8 patients, 8%). Responses were seen in 10 (15%) of 68 evaluable patients in the Q2D expansion phase, including in 8 of 16 (50%) patients with BRAF mutation-positive melanoma naïve to RAF and MEK inhibitors. In the QW dose expansion phase, there were no responses in 17 evaluable patients with NRAS mutation-positive melanoma naïve to RAF and MEK inhibitors; 9 patients (53%) had a best response of stable disease. QW dose administration was associated with minimal accumulation of tovorafenib in systemic circulation in the dose range of 400–800 mg. Conclusions The safety profile of both schedules was acceptable, with QW dosing at the RP2D of 600 mg QW preferred for future clinical studies. Antitumor activity of tovorafenib in BRAF-mutated melanoma was promising and justifies continued clinical development across multiple settings. ClinicalTrials.gov identifier NCT01425008.

Supplementary Table 1. Summary of 33 Patients Treated with Abemaciclib in Dose Escalation. Supplementary Table 2. Baseline patient and disease characteristics. Supplementary Table 3. Possibly related treatment-emergent adverse events (>10% all grades) for hormone receptorpositive breast cancer cohort (n=19) receiving combination therapy with abemaciclib plus fulvestrant. Supplementary Table 4. Summary of abemaciclib pharmacokinetic parameters following a single oral administration. Supplementary Table 5. Summary of abemaciclib pharmacokinetic parameters following repeated once-daily (Q24H) or twice-daily (Q12H) oral administration. Supplementary Table 6. Efficacy for NSCLC cohort, overall and by KRAS status. Supplementary Table 7. Efficacy for other tumor-specific cohorts.

Eftozanermin alfa (eftoza), a second-generation tumor necrosis factor-related apoptosis-inducing ligand receptor (TRAIL-R) agonist, induces apoptosis in tumor cells by activation of death receptors 4/5. This phase 1 dose-escalation/dose-optimization study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary activity of eftoza in patients with advanced solid tumors. Patients received eftoza 2.5–15 mg/kg intravenously on day 1 or day 1/day 8 every 21 days in the dose-escalation phase, and 1.25–7.5 mg/kg once-weekly (QW) in the dose-optimization phase. Dose-limiting toxicities (DLTs) were evaluated during the first treatment cycle to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Pharmacodynamic effects were evaluated in circulation and tumor tissue. A total of 105 patients were enrolled in the study (dose-escalation cohort, n = 57; dose-optimization cohort, n = 48 patients [n = 24, colorectal cancer (CRC); n = 24, pancreatic cancer (PaCA)]). In the dose-escalation cohort, seven patients experienced DLTs. MTD and RP2D were not determined. Most common treatment-related adverse events were increased alanine aminotransferase and aspartate aminotransferase levels, nausea, and fatigue. The one treatment-related death occurred due to respiratory failure. In the dose-optimization cohort, three patients (CRC, n = 2; PaCA, n = 1) had a partial response. Target engagement with regard to receptor saturation, and downstream apoptotic pathway activation in circulation and tumor were observed. Eftoza had acceptable safety, evidence of pharmacodynamic effects, and preliminary anticancer activity. The 7.5-mg/kg QW regimen was selected for future studies on the basis of safety findings, pharmacodynamic effects, and biomarker modulations. (Trial registration number: NCT03082209 (registered: March 17, 2017)).

In this first-in-human phase 1 study (NCT02964013; MK-7684-001), we investigated the safety and efficacy of the anti-TIGIT (T cell immunoglobulin and ITIM domain) antibody vibostolimab as monotherapy or in combination with pembrolizumab.Part A enrolled patients with advanced solid tumors, and part B enrolled patients with non-small-cell lung cancer (NSCLC). Patients received vibostolimab 2.1-700 mg alone or with pembrolizumab 200 mg in part A and vibostolimab 200 mg alone or with pembrolizumab 200 mg in part B. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and objective response rate (ORR) per RECIST v1.1.Part A enrolled 76 patients (monotherapy, 34; combination therapy, 42). No dose-limiting toxicities were reported. Across doses, 56% of patients receiving monotherapy and 62% receiving combination therapy had treatment-related adverse events (TRAEs); grade 3-4 TRAEs occurred in 9% and 17% of patients, respectively. The most common TRAEs were fatigue (15%) and pruritus (15%) with monotherapy and pruritus (17%) and rash (14%) with combination therapy. Confirmed ORR was 0% with monotherapy and 7% with combination therapy. In part B, 39 patients had anti-PD-1 (programmed cell death protein 1)/PD-L1 (programmed death-ligand 1)-naive NSCLC (all received combination therapy), and 67 had anti-PD-1/PD-L1-refractory NSCLC (monotherapy, 34; combination therapy, 33). In patients with anti-PD-1/PD-L1-naive NSCLC: 85% had TRAEs-the most common were pruritus (38%) and hypoalbuminemia (31%); confirmed ORR was 26%, with responses occurring in both PD-L1-positive and PD-L1-negative tumors. In patients with anti-PD-1/PD-L1-refractory NSCLC: 56% receiving monotherapy and 70% receiving combination therapy had TRAEs-the most common were rash and fatigue (21% each) with monotherapy and pruritus (36%) and fatigue (24%) with combination therapy; confirmed ORR was 3% with monotherapy and 3% with combination therapy.Vibostolimab plus pembrolizumab was well tolerated and demonstrated antitumor activity in patients with advanced solid tumors, including patients with advanced NSCLC.

Correlation analysis between pharmacodynamic and pharmacokinetic findings in part 1

Purpose:Avadomide is a novel, small-molecule therapeutic agent that modulates cereblon E3 ligase activity and exhibits potent antitumor and immunomodulatory activities. This first-in-human phase I study (NCT01421524) evaluated the safety and clinical activity of avadomide in patients with advanced solid tumors, non-Hodgkin lymphoma (NHL), and multiple myeloma.Patients and Methods:Thirty-four patients were treated with avadomide in 7 dose-escalation cohorts using a 3 + 3 design (0.5–3.5 mg, 28-day continuous dosing cycles). The primary objectives were to determine the dose-limiting toxicity (DLT), nontolerated dose (NTD), maximum tolerated dose (MTD), recommended phase II dose, and pharmacokinetics of avadomide. The secondary objective was to determine preliminary avadomide efficacy. Exploratory objectives included evaluation of pharmacodynamic effects of avadomide.Results:DLTs were reported in 2 patients, and grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 14 patients (41%). The most common TEAEs (≥15%) were fatigue, neutropenia, and diarrhea. The NTD and MTD were 3.5 and 3.0 mg, respectively. Of 5 patients with NHL, 1 achieved a complete response, and 2 had partial responses. Although no objective responses were observed in patients with solid tumors, 5 of 6 patients with brain cancer experienced nonprogression of ≥6 months. A dose-dependent relationship between Aiolos degradation in peripheral B and T cells occurred within 5 hours of the first dose of avadomide administered, starting at 0.5 mg.Conclusions:Avadomide monotherapy demonstrated acceptable safety and favorable pharmacokinetics in patients with solid tumors, NHL, and multiple myeloma. In addition, 3 objective responses were observed in NHL.

Supplementary Legend

Mean paclitaxel plasma concentrations following nab-paclitaxel administration alone or with CC-486 in part 1 arm B

Table S1. CC-486 Plus Carboplatin Dose Levels in Part 1 Arm A Table S2. CC-486 Plus nab-Paclitaxel Dose Levels in Part 1 Arm B Table S3. CC-486 Dose Levels in Part 1 Arm C Table S4. Number of Patients With Treatment Emergent Adverse Events for Part 1 Table S5. Number of Patients With Treatment-Emergent Adverse Events in Any Treatment Arm in Part 2 Table S6. Mean CC-486 Plasma Pharmacokinetic Parameters Table S7. Efficacy of CC-486 Alone or in Combination With Carboplatin or nab-Paclitaxel in Part 2 Table S8. Prior Treatment History of NPV Patients

Mean total carboplatin plasma concentration following carboplatin administration alone or with CC-486 in part 1 arm A

Supplementary Table S1. Summary of avadomide plasma pharmacokinetic parameters by day and dose level Supplementary Figure S1. Representative flow cytometry analysis of Aiolos degradation in peripheral B cells (A) and T cells (B). Supplementary Figure S2. IL-2 expression correlates with Aiolos degradation in treated primary human T cells in vitro.

Development of diffuse telangiectasias (highlighted by blue arrows) occurred on the upper chest, back, and face in a patient with ovarian granulosa cell tumor treated at the 0.75 mg/kg Q2W dose of STM 434.

Table S1:Summary of baseline pathological diagnosis; Table S2:Noncompartmental Pharmacokinetic Summary Following Oral Administration of ralimetinib on Day 1 and on Day 14 (Cycle 1) - Capsule Formulation; Table S3: Noncompartmental Pharmacokinetic Summary Following Oral Administration of ralimetinib on Day 1 and on Day 14 (Cycle 1) - Tablet Formulation

Purpose:STM 434 is a soluble receptor ligand trap targeting activin A, a protein in the TGFβ family that plays important roles in growth, differentiation, and cancer cachexia. This study evaluated the safety, antitumor activity, and metabolic effects of STM 434 in a first-in-human, multicenter, phase I clinical trial (NCT02262455).Patients and Methods:Patients with advanced solid tumors were enrolled in 8 dose cohorts ranging from 0.25 mg/kg every 4 weeks to 8 mg/kg every 2 weeks via a 3 + 3 dose-escalation design. The primary endpoint was maximum tolerated dose (MTD). Secondary endpoints included safety, pharmacokinetics, and response. As activin A is implicated in metabolism and muscle function, changes in key metabolic parameters, including lean body mass and 6-minute walk test, were serially measured.Results:Thirty-two patients were treated on study. The most common treatment-related adverse events were fatigue (41%) and mucocutaneous bleeding complications including epistaxis (34%) and gingival bleeding (22%), likely related to off-target inhibition of bone morphogenetic protein 9 (BMP9). STM 434 treatment resulted in the expected follicle-stimulating hormone level decreases in most patients and in metabolic parameter changes, including an increase in total lean body mass and 6-minute walk test distance. No responses were observed in the 30 evaluable patients, but the stable disease rate in patients with granulosa cell ovarian cancer was 10 of 12 (80%).Conclusions:Although no direct antitumor efficacy was documented, potentially clinically meaningful dose-related metabolic effects, including treatment of cancer cachexia, were observed that support further exploration of activin A inhibitors that limit BMP9 blockade.See related commentary by Bonilla and Oza, p. 5432

Purpose: This study evaluated the clinical relevance of the dual-targeting strategy involving PI3K/AKT/mTOR and RAF/MEK/ERK pathways.Experimental Design: We investigated safety, efficacy, and correlations between tumor genetic alterations and clinical benefit in 236 patients with advanced cancers treated with phase I study drugs targeting phosphoinositide 3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) pathways in our Phase I Clinical Trials Program.Results: Seventy-six (32.2%) patients received a PI3K pathway inhibitor in combination with a MAPK pathway inhibitor (D), whereas 124 (52.5%) and 36 (15.3%), respectively, received an inhibitor of either the PI3K or MAPK pathways (S). The rates of drug-related grade >III adverse events were 18.1% for (S) and 53.9% for (D; P < 0.001); the rates of dose-limiting toxicities were 9.4% for (S) and 18.4% for (D; P = 0.06). The most frequent grade >III adverse events were transaminase elevations, skin rash, and mucositis. In our comprehensive tumor genomic analysis, of 9 patients who harbored coactivation of both pathways (colorectal cancer, n = 7; melanoma, n = 2), all 5 patients treated with (D) had tumor regression ranging from 2% to 64%.Conclusions: These results suggest that dual inhibition of both pathways may potentially exhibit favorable efficacy compared with inhibition of either pathway, at the expense of greater toxicity. Furthermore, this parallel pathway targeting strategy may be especially important in patients with coexisting PI3K pathway genetic alterations and KRAS or BRAF mutations and suggests that molecular profiling and matching patients with combinations of these targeted drugs will need to be investigated in depth. Clin Cancer Res; 18(8); 2316–25. ©2012 AACR.

Trial Profile

Change and end of treatment values for albumin, hemoglobin, and absolute lymphocytes among the 32 patients are summarized below. Abbreviations: SD, stable disease.

Purpose: This phase Ib study (NCT02179918) evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of utomilumab, a fully human IgG2 mAb agonist of the T-cell costimulatory receptor 4-1BB/CD137 in combination with the humanized, PD-1–blocking IgG4 mAb pembrolizumab in patients with advanced solid tumors.Experimental Design: Utomilumab (0.45–5.0 mg/kg) and pembrolizumab (2 mg/kg) were administered intravenously every 3 weeks. Utomilumab dose escalation was conducted using the time-to-event continual reassessment method.Results: Twenty-three patients received combination treatment with no dose-limiting toxicities. Treatment-emergent adverse events were mostly grades 1 to 2, without any treatment-related discontinuations. Six patients (26.1%) had confirmed complete or partial responses. Pharmacokinetics and immunogenicity of utomilumab and pembrolizumab were similar when administered alone or in combination. A trend toward higher levels of activated memory/effector peripheral blood CD8+ T cells was observed in responders versus nonresponders.Conclusions: The safety, tolerability, and clinical activity demonstrated by utomilumab in combination with pembrolizumab support further investigation in patients with advanced solid tumors. Clin Cancer Res; 23(18); 5349–57. ©2017 AACR.See related commentary by Pérez-Ruiz et al., p. 5326

Purpose: p38 MAPK regulates the production of cytokines in the tumor microenvironment and enables cancer cells to survive despite oncogenic stress, radiotherapy, chemotherapy, and targeted therapies. Ralimetinib (LY2228820 dimesylate) is a selective small-molecule inhibitor of p38 MAPK. This phase I study aimed to evaluate the safety and tolerability of ralimetinib, as a single agent and in combination with tamoxifen, when administered orally to patients with advanced cancer.Experimental Design: The study design consisted of a dose-escalation phase performed in a 3+3 design (Part A; n = 54), two dose-confirmation phases [Part B at 420 mg (n = 18) and Part C at 300 mg (n = 8)], and a tumor-specific expansion phase in combination with tamoxifen for women with hormone receptor–positive metastatic breast cancer refractory to aromatase inhibitors (Part D; n = 9). Ralimetinib was administered orally every 12 hours on days 1 to 14 of a 28-day cycle.Results: Eighty-nine patients received ralimetinib at 11 dose levels (10, 20, 40, 65, 90, 120, 160, 200, 300, 420, and 560 mg). Plasma exposure of ralimetinib (Cmax and AUC) increased in a dose-dependent manner. After a single dose, ralimetinib inhibited p38 MAPK–induced phosphorylation of MAPKAP-K2 in peripheral blood mononuclear cells. The most common adverse events, possibly drug-related, included rash, fatigue, nausea, constipation, pruritus, and vomiting. The recommended phase II dose was 300 mg every 12 hours as monotherapy or in combination with tamoxifen. Although no patients achieved a complete response or partial response,19 patients (21.3%) achieved stable disease with a median duration of 3.7 months, with 9 of these patients on study for ≥6 cycles.Conclusions: Ralimetinib demonstrated acceptable safety, tolerability, and pharmacokinetics for patients with advanced cancer. Clin Cancer Res; 22(5); 1095–102. ©2015 AACR.

Table S1. Patient flow by dose group Table S2. PK parameters of utomilumab following multiple dosing Figure S1. Partial response in a patient with anaplastic thyroid carcinoma (utomilumab 3.6 mg/kg + pembrolizumab 2 mg/kg) at cycle 4 versus baseline. Figure S2. Mean concentration-time profile for pembrolizumab

Exposure to STM 434 among 32 patients is summarized below. Abbreviations: SD, stable disease; min, minimum; max: maximum.

CCR Translation for This Article from The Clinical Effect of the Dual-Targeting Strategy Involving PI3K/AKT/mTOR and RAS/MEK/ERK Pathways in Patients with Advanced Cancer

Pharmacodynamic Assessments

Purpose: This large two-part, three-arm phase I study examined the safety and tolerability of CC-486 (an oral formulation of azacitidine, a hypomethylating agent) alone or in combination with the cytotoxic agents, carboplatin or nab-paclitaxel, in patients with advanced unresectable solid tumors.Patients and Methods: Part 1 (n = 57) was a dose escalation of CC-486 alone (arm C) or with carboplatin (arm A) or nab-paclitaxel (arm B). The primary endpoint was safety, MTD, and recommended part 2 dose (RP2D) of CC-486. In part 2 (n = 112), the primary endpoint was the safety and tolerability of CC-486 administered at the RP2D for each treatment arm, in tumor-specific expansion cohorts. Secondary endpoints included pharmacokinetics, pharmacodynamics, and antitumor activity of CC-486.Results: At pharmacologically active doses CC-486 in combination with carboplatin or nab-paclitaxel had a tolerable safety profile and no drug–drug interactions. The CC-486 RP2D was determined as 300 mg (every day, days 1–14/21) in combination with carboplatin (arm A) or as monotherapy (arm C); and 200 mg in the same dosing regimen in combination with nab-paclitaxel (arm B). Albeit limited by the small sample size, CC-486 monotherapy resulted in partial responses (three/eight) and stable disease (four/eight) in patients with nasopharyngeal cancer. Three of the stable disease responses lasted more than 150 days.Conclusions: CC-486 is well tolerated alone or in combination with carboplatin or nab-paclitaxel. Exploratory analyses suggest clinical activity of CC-486 monotherapy in nasopharyngeal cancer and provided the basis for an ongoing phase II clinical trial (ClinicalTrials.gov identifier: NCT02269943). Clin Cancer Res; 24(17); 4072–80. ©2018 AACR.

Purpose New immuno-oncology therapies targeting programmed cell death receptor 1 (PD-1) have improved patient outcomes in a broad range of cancers. The objective of this analysis was to evaluate the PK, pharmacodynamics (PDy), and safety of dostarlimab monotherapy in adult patients with previously-treated advanced solid tumors who participated in parts 1 and 2A of the phase 1 GARNET study. Methods Part 1 featured a 3 + 3 weight-based dose–escalation study, in which 21 patients received dostarlimab 1, 3, or 10 mg/kg intravenously every 2 weeks. The 2 fixed-dose nonweight-based dosing regimens of dostarlimab 500 mg every 3 weeks (Q3W) and 1000 mg every 6 weeks (Q6W) were evaluated using a modified 6 + 6 design in part 2A (n = 13). In parts 1 and 2A, treatment with dostarlimab could continue for up to 2 years or until progression, unacceptable toxicity, patient withdrawal, investigator’s decision, or death. Results The dostarlimab PK profile was dose proportional, and maximal achievable receptor occupancy (RO) was observed at all dose levels in the weight-based and fixed-dose cohorts. Trough dostarlimab concentration after administration of dostarlimab 500 mg Q3W was similar to that after dostarlimab 1000 mg Q6W, the values of which (≈40 µg/mL) projected well above the lowest dostarlimab concentration required for full peripheral RO. No dose-limiting toxicities were observed. Conclusions Dostarlimab demonstrated consistent and predictable PK and associated PDy. The observed safety profile was acceptable and characteristic of the anti-PD-1 drug class. Trial registration: ClinicalTrials.gov, NCT02715284. Registration date: March 9, 2016.

Purpose:In this first-in-human study (NCT03564691) in advanced solid tumors, we investigated a novel first-in-class human IgG4 monoclonal antibody targeting the immunoglobulin-like transcript 4 (ILT4) receptor, MK-4830, as monotherapy and in combination with pembrolizumab.Patients and Methods:Patients with histologically/cytologically confirmed advanced solid tumors, measurable disease by RECIST v1.1, and evaluable baseline tumor sample received escalating doses of intravenous MK-4830 every 3 weeks as monotherapy (parts A and B) and in combination with pembrolizumab (part C). Safety and tolerability were the primary objectives. Pharmacokinetics, objective response rate per RECIST v1.1, and molecular biomarkers were also evaluated.Results:Of 84 patients, 50 received monotherapy and 34 received combination therapy. No dose-limiting toxicities were observed; maximum tolerated dose was not reached. MK-4830 showed dose-related target engagement. Eleven of 34 patients in the dose-escalation phase who received combination therapy achieved objective responses; 5 previously had progressive disease on anti–PD-1/PD-L1 therapies. Exploratory evaluation of the association between response and pretreatment gene expression related to interferon-gamma signaling in tumors suggested higher sensitivity to T-cell inflammation with combination therapy than historically expected with pembrolizumab monotherapy, with greater response at more moderate levels of inflammation.Conclusions:This first-in-class MK-4830 antibody dosed as monotherapy and in combination with pembrolizumab was well tolerated with no unexpected toxicities, and demonstrated dose-related evidence of target engagement and antitumor activity. Inflammation intrinsic to the ILT4 mechanism may be facilitated by alleviating the myeloid-suppressive components of the tumor microenvironment, supporting the target of ILT4 as a potential novel immunotherapy in combination with an anti–PD-1/PD-L1 agent.

A phase I study evaluated the safety, tolerability, and maximum-tolerated dose (MTD)/recommended phase II dose (RP2D) of FCN-437c, a novel, orally available cyclin-dependent kinase inhibitor (CDK4/6i), in participants with advanced/metastatic solid tumors (aSTs). FCN-437c was escalated from 50 mg (once daily [QD] on days 1–21 of 28-day cycles) to the MTD/RP2D. In the dose-expansion phase, patients with CDK4/6i-treated breast cancer, or KRAS-mutant (KRASmut) non-small-cell lung cancer (NSCLC) received the MTD. Twenty-two patients were enrolled. The most common tumors in the dose-escalation phase (n = 15) were breast, colorectal, and lung (each n = 4 [27.3%]). The dose-expansion phase included five (71.4%) patients with breast cancer and two (28.6%) with KRASmut NSCLC. Twenty (90.9%) participants experienced FCN-437c–related adverse events. Dose-limiting toxicities occurred in two (33.3%) participants (200-mg dose, dose-escalation phase): grade 3 neutropenia and grade 4 neutrophil count decreased. Due to toxicities reported at 150 mg QD, the MTD was de-escalated to 100 mg QD. One (4.5%) participant (KRASmut NSCLC, 100-mg dose) achieved a partial response lasting 724+ days, and five (22.7%) had stable disease lasting 56+ days. In conclusion, FCN-437c was well tolerated with encouraging signs of antitumor activity and disease control. Further exploration of FCN-437c in aSTs is warranted.

This first-in-human phase I study (NCT03179436) investigated anti-cytotoxic T-lymphocyte-associated protein 4 monoclonal antibody quavonlimab and anti-programmed death 1 monoclonal antibody pembrolizumab in patients with advanced solid tumors. The study was conducted in two parts: dose-escalation (part 1) and dose-confirmation (part 2). First-line treatment with quavonlimab + pembrolizumab conferred encouraging antitumor activity (objective response rate [ORR], 28%-40%) and was generally well tolerated (grade ≥ 3 treatment-related adverse events [TRAEs] were lowest with quavonlimab 25 mg every 6 weeks [Q6W] at 30% and highest with quavonlimab 75 mg Q3W at 57%) in non-small cell lung cancer. We present data from patients with extensive-stage small cell lung cancer (SCLC) receiving second-line or later therapy.Patients with stage III/IV SCLC received quavonlimab 75 mg Q6W plus pembrolizumab 200 mg Q3W for ≤ 2 years. Primary endpoints were safety and tolerability; ORRs as assessed by blinded independent central review per Response Evaluation Criteria In Solid Tumorsv1.1 was a secondary endpoint. Progression-free survival (PFS), overall survival (OS), and the correlation of response with PD-L1 expression were exploratory endpoints.Forty patients with extensive-stage SCLC received treatment; median follow-up was 13 months. Dose-limiting toxicity occurred in 4 patients (10%). TRAEs occurred in 80% of patients; grade 3 events occurred in 33% of patients and no grade 4/5 events were reported. Confirmed ORRs (95% CI) were 18% (7-33) among all patients, 7% (1-34) for PD-L1-positive tumors (n = 14), and 19% (5-42) for PD-L1-negative tumors (n = 21). Response duration ranged from 2.9 to 19.1+ months. Median PFS was 2.0 months; 6-month PFS rate was 26%. Median OS was 11.0 months; 6-month OS rate was 66%.Encouraging antitumor activity was observed with quavonlimab + pembrolizumab in patients with extensive-stage SCLC; responses were observed in PD-L1-positive and PD-L1-negative tumors. The combination was tolerable with manageable toxicities.

Summary Background Despite advances in the first-line treatment of metastatic renal cell carcinoma (RCC), there is an unmet need for options to address disease progression during or after treatment with immune checkpoint inhibitors (ICIs). Pembrolizumab and lenvatinib are active as monotherapies in RCC; thus, we aimed to evaluate the combination of lenvatinib plus pembrolizumab in these patients. Methods We report results of the metastatic RCC cohort from an open-label phase 1b/2 study of lenvatinib plus pembrolizumab in patients aged at least 18 years with selected solid tumours and an Eastern Cooperative Oncology Group performance status of 0–1. Oral lenvatinib at 20 mg was given once daily along with intravenous pembrolizumab at 200 mg once every 3 weeks. Patients remained on study drug treatment until disease progression, development of unacceptable toxicity, or withdrawal of consent. Efficacy was analysed in patients with clear cell metastatic RCC receiving study drug by previous therapy grouping: treatment naive, previously treated ICI naive (previously treated with at least one line of therapy but not with an anti-PD-1 or anti-PD-L1 ICI), and ICI pretreated (ie, anti-PD-1 or anti-PD-L1) patients. Safety was analysed in all enrolled and treated patients. The primary endpoint was the objective response rate at week 24 per immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) by investigator assessment. This trial is registered with ClinicalTrials.gov ( NCT02501096 ) and with the EU Clinical Trials Register (EudraCT2017-000300-26), and is closed to new participants. Findings Between July 21, 2015, and Oct 16, 2019, 145 patients were enrolled in the study. Two patients had non-clear cell RCC and were excluded from the efficacy analysis (one in the treatment-naive group and one in the ICI-pretreated group); thus, the population evaluated for efficacy comprised 143 patients (n=22 in the treatment-naive group, n=17 in the previously treated ICI-naive group, and n=104 in the ICI-pretreated group). All 145 enrolled patients were included in the safety analysis. The median follow-up was 19·8 months (IQR 14·3–28·4). The number of patients with an objective response at week 24 by irRECIST was 16 (72·7%, 95% CI 49·8–89·3) of 22 treatment-naive patients, seven (41·2%, 18·4–67·1) of 17 previously treated ICI-naive patients, and 58 (55·8%, 45·7–65·5) of 104 ICI-pretreated patients. Of 145 patients, 82 (57%) had grade 3 treatment-related adverse events and ten (7%) had grade 4 treatment-related adverse events. The most common grade 3 treatment-related adverse event was hypertension (30 [21%] of 145 patients). Treatment-related serious adverse events occurred in 36 (25%) patients, and there were three treatment-related deaths (upper gastrointestinal haemorrhage, sudden death, and pneumonia). Interpretation Lenvatinib plus pembrolizumab showed encouraging antitumour activity and a manageable safety profile and might be an option for post-ICI treatment of metastatic RCC. Funding Eisai and Merck Sharp & Dohme.

Tumor progression and immune evasion result from multiple oncogenic and immunosuppressive signals within the tumor microenvironment. The combined blockade of VEGF and inhibitory immune checkpoint signaling has been shown to enhance immune activation and tumor destruction in preclinical models. The LEAP clinical trial program is evaluating the safety and efficacy of lenvatinib (a multikinase inhibitor) plus pembrolizumab (a PD-1 inhibitor) across several solid tumor types. Preliminary results from ongoing trials demonstrate robust antitumor activity and durable responses across diverse tumor types with a manageable safety profile. Thus, lenvatinib plus pembrolizumab is anticipated to be an important potential new regimen for several solid cancers that currently have limited therapeutic options. Clinical trial registration: NCT03884101 , NCT03713593 , NCT03820986 , NCT03776136 , NCT03797326 , NCT03829319 , NCT03829332 , NCT03976375 , NCT04428151 , NCT04199104 , NCT03898180 , NCT04246177 (ClinicalTrials.gov).

Budigalimab is a humanized, recombinant, Fc mutated IgG1 monoclonal antibody targeting programmed cell death 1 (PD‐1) receptor, currently in phase I clinical trials. The safety, efficacy, pharmacokinetics (PKs), pharmacodynamics (PDs), and budigalimab dose selection from monotherapy dose escalation and multihistology expansion cohorts were evaluated in patients with previously treated advanced solid tumors who received budigalimab at 1, 3, or 10 mg/kg intravenously every 2 weeks (Q2W) in dose escalation, including Japanese patients that received 3 and 10 mg/kg Q2W. PK modeling and PK/PD assessments informed the dosing regimen in expansion phase using data from body‐weight‐based dosing in the escalation phase, based on which patients in the multihistology expansion cohort received flat doses of 250 mg Q2W or 500 mg every four weeks (Q4W). Immune‐related adverse events (AEs) were reported in 11 of 59 patients (18.6%), of which 1 of 59 (1.7%) was considered grade ≥ 3 and the safety profile of budigalimab was consistent with other PD‐1 targeting agents. No treatment‐related grade 5 AEs were reported. Four responses per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 were reported in the dose escalation cohort and none in the multihistology expansion cohort. PK of budigalimab was approximately dose proportional and sustained > 99% peripheral PD‐1 receptor saturation was observed by 2 hours postdosing, across doses. PK/PD and safety profiles were comparable between Japanese and Western patients, and exposure‐safety analyses did not indicate any trends. Observed PK and PD‐1 receptor saturation were consistent with model predictions for flat doses and less frequent regimens, validating the early application of PK modeling and PK/PD assessments to inform the recommended dose and regimen, following dose escalation.

Oncogenic drivers in solid tumors include aberrant activation of mesenchymal epithelial transition factor (MET) and AXL.This study investigated the safety and antitumor activity of glesatinib, a multitargeted receptor tyrosine kinase inhibitor that inhibits MET and AXL at clinically relevant doses, in combination with erlotinib or docetaxel.The phase I portion of this open-label, multicenter study included two parallel arms in which ascending doses of oral glesatinib (starting dose 96 mg/mTen dose levels of glesatinib across three glycolate formulations (unmicronized, micronized, or micronized version 2 [V2] tablets) available during the course of the study were investigated in 14 dose-escalation cohorts (n = 126). MTDs of unmicronized glesatinib plus erlotinib or docetaxel, and micronized glesatinib plus erlotinib were not reached. Micronized glesatinib 96 mg/mThe safety profile of glesatinib plus erlotinib or docetaxel was acceptable and there were no PK interactions. MADs of glesatinib 700 mg twice daily (micronized V2) with erlotinib 150 mg once daily or docetaxel 75 mg/mClinicalTrials.gov NCT00975767; 11 September 2009.

115 Background: BI 905711 is a tetravalent bispecific antibody that cross-links TRAILR2 with CDH17. This cross-linking drives CDH17-dependent TRAILR2 oligomerization, leading to caspase activation and eventual apoptosis, inhibiting tumor growth in preclinical models of GI cancer. Methods: This Phase Ia/b study of BI 905711 in patients (pts) with advanced GI cancers (NCT04137289) aimed to determine the maximum tolerated dose (MTD) based on the proportion of pts with dose-limiting toxicities (DLT) and explore preliminary antitumor activity. In Phase Ia, pts received BI 905711 every 14 days. One pt with colorectal cancer (CRC) was enrolled at each of the 2 lowest dose levels (0.02/0.06 mg/kg) and 4 pts with CRC were enrolled at each subsequent level (0.2/0.6/1.2/2.4/3.6/4.8 mg/kg). Up to 4 pts with non-CRC GI cancers were included at the dose level below the CRC cohort. Dose escalation was guided by a Bayesian logistic regression model. Results: As of 01 August 2022, 48 pts (CRC: n = 26; non-CRC: n = 22, including 13 with pancreatic ductal adenocarcinoma [PDAC]) had received BI 905711 (dose range 0.02–4.8 mg/kg); pts had a median age of 61 years (range 27–78) and had received a median of 3 (range 1–11) prior lines of treatment. No DLTs were observed and the MTD was not reached. 41 pts had AEs (grade [G] 3–5: 14 pts; serious: 13 pts). 17 pts had treatment-related AEs (TRAEs); 4 TRAEs were G3: AST increased (2 pts), fatigue and ALT increased (1 pt each). 1 pt had serious TRAEs: G2 decreased appetite and G3 fatigue. 2 pts had G1/2 infusion-related reactions that resolved and did not prevent resumption of treatment. PD biomarker modulation on the level of plasma caspase-3/7 activity was most common at 0.6 mg/kg (4/7 pts) or 1.2 mg/kg (2/6 pts). 13 pts achieved stable disease (SD) and 8 pts were progression-free for ≥4 months (PFS4). In pts with CRC, 6 pts achieved SD and 3 had PFS4. Among non-CRC pts, 7 pts achieved SD (PDAC: n = 6) and 5 had PFS4 (PDAC: n = 4). Median duration of treatment was 30.5 days (range 15–246) overall and 71 days (range 15–211) in the 0.6 mg/kg group (n = 8, predicted therapeutic dose; of whom 3 pts had PFS4: CRC: n = 1/4 [all CDH17+]; non-CRC: n = 2/4). Conclusions: In heavily pretreated pts, BI 905711 was associated with a tolerable safety profile and early signs of disease control. BI 905711 will be further assessed in Phase Ib in 4 dose groups: 0.6/1.2/2.4 mg/kg every 14 days, and 0.6 mg/kg weekly. Clinical trial information: NCT04137289 .

BackgroundBDB001 is an intravenously administered TLR 7/8 dual agonist immune modulator capable of reprogramming dendritic cells to produce antitumor activities. BDB001 monotherapy has demonstrated favorable tolerability and robust systemic immune activation leading to durable clinical responses in a Phase I trial. Here, we report on the safety and efficacy of BDB001 in combination with atezolizumab in a Phase I dose escalation/expansion trial in advanced solid tumors (NCT04196530).MethodsBDB001-102 is a Phase 1, open label, dose escalation/expansion trial of BDB001 (IV, Q1W) in combination with an anti-PD-L1 antibody, atezolizumab (IV, Q3W), in patients with advanced solid tumors. The primary endpoint was safety and tolerability. Secondary endpoints included efficacy, pharmacokinetics and pharmacodynamic profiling of immune activation.ResultsForty-one subjects with 17 different tumor types were enrolled across 4 dose levels. Fifty-nine percent were female, median age was 67 years (range, 32–80), median number of prior therapies was 3 (range, 0–8), and 63% of tumors had progressed on prior anti-PD-(L)1 therapy. Overall, BDB001 in combination with atezolizumab was well tolerated and 13 (31.7%) subjects did not experience any treatment related adverse events (TRAEs). No dose-limiting toxicities were observed. Common TRAEs were transient Grade 1 or 2 fatigue (31.7%), fever (26.8%) and chills/rigor (26.8%). Only 3 (7.3%) subjects experienced Grade 3 TRAEs of fatigue and nausea. There were no Grade 4 or 5 TRAEs and no new safety concerns. Pharmacodynamic evaluation of plasma cytokine levels showed robust increases in interferon gamma and interferon inducible protein-10 (IP-10) at BDB001 Dose Level 4. IP-10 induction was associated with clinical responses. Preliminary efficacy evaluation of the 19 subjects at Dose Level 4 showed durable and deep clinical responses in 3 (16%) subjects, 2 with urothelial carcinoma and 1 with anti-PD-1 mAb refractory NSCLC. All responders remain on treatment, with a duration of response ranging from 7.1+ to 34.1+ weeks. Ten (53%) subjects had stable disease (DCR 68%), 3 of whom had a reduction in tumor burden and were on treatment for over 18 weeks (up to 56 weeks).ConclusionsIntravenous BDB001 in combination with atezolizumab is well tolerated. Deep and durable clinical responses were observed in PD-1 refractory and naive patients, supported by robust systemic immune activation. BDB001 in combination with atezolizumab is a promising therapeutic option for patients with advanced solid tumors. A phase 2 trial (NCT03915678) of BDB001 in combination with atezolizumab and radiotherapy is currently enrolling patients.Ethics ApprovalThis study was approved by the institutional review boards at the five participating institutions. All subjects signed informed consent before enrolling in the clinical trial.

Background: Palbociclib is one of three CDK 4/6 inhibitors approved in combination with an aromatase inhibitor for treatment of hormone receptor-positive breast cancer. Although this combination therapy has been found effective in some patients, resistance often develops. To aid in developing new therapies for CDK4/6-resistant breast cancer and better understand resistance mechanisms, we established a PDX model, designated ST1799, from a patient with luminal A breast cancer which was responsive to palbociclib in vivo and then conditioned the model with chronic drug administration until resistant. The resistant model, designated ST1799/PBR, and the parent were characterized for receptor expression, genomic alterations and in vivo drug sensitivity. Methods: ST1799 was established from an axillary lymph node FNA taken from a 66-year-old woman pretreated with various chemo and hormone therapies. The resulting model was passaged and a cohort challenged with chronic palbociclib treatment to produce drug resistance. The parent ST1799 and resistant ST1799/PBR were subjected to various comparative analyses including receptor expression, NGS and RNAseq and response to various relevant therapies. Results: Both models retained high ER staining (3+) expression and demonstrated comparable histopathology. DNA-based analysis of the parent model confirmed variants concordant with clinical mutation analysis. Comparison of the parent and resistant clone using RNAseq identified several alterations in variants and expression. In vivo palbociclib reported significant (p Citation Format: Lizette Gamez, Alyssa Moriarty, Tomoyuki Mashimo, Kyriakos Papadopoulos, Drew Rasco, Amita Patnaik, Michael J Wick. Establishment and characterization of paired palbociclib-sensitive and resistant luminal A breast PDX models [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-03-10.

Purpose: STM 434 is a soluble receptor ligand trap targeting activin A, a protein in the TGFβ family that plays important roles in growth, differentiation, and cancer cachexia. This study evaluated the safety, antitumor activity, and metabolic effects of STM 434 in a first-in-human, multicenter, phase I clinical trial (NCT02262455). Patients and Methods: Patients with advanced solid tumors were enrolled in 8 dose cohorts ranging from 0.25 mg/kg every 4 weeks to 8 mg/kg every 2 weeks via a 3 + 3 dose-escalation design. The primary endpoint was maximum tolerated dose (MTD). Secondary endpoints included safety, pharmacokinetics, and response. As activin A is implicated in metabolism and muscle function, changes in key metabolic parameters, including lean body mass and 6-minute walk test, were serially measured. Results: Thirty-two patients were treated on study. The most common treatment-related adverse events were fatigue (41%) and mucocutaneous bleeding complications including epistaxis (34%) and gingival bleeding (22%), likely related to off-target inhibition of bone morphogenetic protein 9 (BMP9). STM 434 treatment resulted in the expected follicle-stimulating hormone level decreases in most patients and in metabolic parameter changes, including an increase in total lean body mass and 6-minute walk test distance. No responses were observed in the 30 evaluable patients, but the stable disease rate in patients with granulosa cell ovarian cancer was 10 of 12 (80%). Conclusions: Although no direct antitumor efficacy was documented, potentially clinically meaningful dose-related metabolic effects, including treatment of cancer cachexia, were observed that support further exploration of activin A inhibitors that limit BMP9 blockade. See related commentary by Bonilla and Oza, p. 5432

Background: Ibrutinib, a first-in-class, once-daily inhibitor of Bruton’s tyrosine kinase, is approved in the United States for the treatment of various B-cell malignancies. Preclinical data suggest synergistic antitumor activity of ibrutinib with programmed death-ligand 1 (PD-L1) inhibitors in solid tumors. This study evaluated ibrutinib plus durvalumab, a PD-L1-targeting antibody, in patients with relapsed/refractory solid tumors. Methods: This open-label, multicenter, phase 1b/2 study enrolled previously treated patients with stage III/IV pancreatic adenocarcinoma, breast cancer, or non-small cell lung cancer (NSCLC). Phase 1b determined the recommended phase 2 dose (RP2D). In phase 2, patients were treated at the RP2D to evaluate the safety and antitumor activity of ibrutinib plus durvalumab. Results: The RP2D was identified as ibrutinib 560 mg p.o. daily and durvalumab 10 mg/kg i.v. every 2 weeks, with 122 patients treated at the RP2D. Median age was 61 years, and the majority of patients (94%) had stage IV disease. Overall response rates (complete or partial responses) were 2% for pancreatic cancer, 3% for breast cancer, and 0% for NSCLC. Median progression-free survival was 1.7, 1.7, and 2.0 months in the pancreatic cancer, breast cancer, and NSCLC cohorts, respectively. Median overall survival was 4.2, 4.2, and 7.9 months in the pancreatic cancer, breast cancer, and NSCLC cohorts, respectively. The safety profiles observed across tumor types were consistent with the known safety profiles for ibrutinib and durvalumab. Grade ≥3 adverse events in ≥5% of all patients were hyponatremia (10%), dyspnea (7%), maculopapular rash (7%), pneumonia (7%), anemia (6%), and diarrhea (6%). Conclusions: The combination of ibrutinib 560 mg daily and durvalumab 10 mg/kg every 2 weeks had an acceptable safety profile. The antitumor activity of the ibrutinib-durvalumab combination was limited in our study population.

Purpose: Avadomide is a novel, small-molecule therapeutic agent that modulates cereblon E3 ligase activity and exhibits potent antitumor and immunomodulatory activities. This first-in-human phase I study (NCT01421524) evaluated the safety and clinical activity of avadomide in patients with advanced solid tumors, non-Hodgkin lymphoma (NHL), and multiple myeloma. Patients and Methods: Thirty-four patients were treated with avadomide in 7 dose-escalation cohorts using a 3 + 3 design (0.5–3.5 mg, 28-day continuous dosing cycles). The primary objectives were to determine the dose-limiting toxicity (DLT), nontolerated dose (NTD), maximum tolerated dose (MTD), recommended phase II dose, and pharmacokinetics of avadomide. The secondary objective was to determine preliminary avadomide efficacy. Exploratory objectives included evaluation of pharmacodynamic effects of avadomide. Results: DLTs were reported in 2 patients, and grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 14 patients (41%). The most common TEAEs (≥15%) were fatigue, neutropenia, and diarrhea. The NTD and MTD were 3.5 and 3.0 mg, respectively. Of 5 patients with NHL, 1 achieved a complete response, and 2 had partial responses. Although no objective responses were observed in patients with solid tumors, 5 of 6 patients with brain cancer experienced nonprogression of ≥6 months. A dose-dependent relationship between Aiolos degradation in peripheral B and T cells occurred within 5 hours of the first dose of avadomide administered, starting at 0.5 mg. Conclusions: Avadomide monotherapy demonstrated acceptable safety and favorable pharmacokinetics in patients with solid tumors, NHL, and multiple myeloma. In addition, 3 objective responses were observed in NHL.

Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by stromal fibrosis, hypoxia, and nutritional deprivation. PDAC tumors grow aggressively, diagnosis is typically made after metastasis and the disease remains associated with poor outcomes. The triplet chemotherapy regimen of gemcitabine, nab-paclitaxel with cisplatin was associated with a median overall survival of 16.4 months in patients with metastatic pancreatic cancer in the first-line setting (Jameson et al., 2020). Nutritional, metabolic interventions offer an opportunity to fundamentally change the tumor microenvironment and improve outcomes for patients. A medically supervised ketogenic diet (MSKD) defined as lower carbohydrate, lower protein, and higher fat can significantly reduce glucose and insulin and increase metabolically active ketone bodies. A ketogenic diet combined with triplet chemotherapy (gemcitabine, nab-paclitaxel, cisplatin) was shown to inhibit murine pancreatic KPC tumor growth and to triple the survival benefit of chemotherapy alone. The ketogenic diet combined with triple chemotherapy was associated with glucose depletion, altered TCA substrate usage, and NADH elevation. Methods: In this Phase II randomized clinical trial (NCT04631445), we are evaluating a medically supervised ketogenic diet (MSKD) versus a standard diet when combined with the triplet therapy in patients with treatment-naive advanced pancreatic cancer. The primary endpoint is progression free survival for triplet therapy while on MSKD or non-MSKD. Secondary endpoints include disease control rate (PR+ CR+ SD for at least 9 weeks), change in CA 19-9 (or CA125, or CEA if not expressers of CA 19-9), average insulin levels, HbA1c, body weight, a comparison of gut microbial diversity, changes in serum metabolites and quality of life via the EORTC QLQ-C30 assessment. Unlike prior ketogenic intervention studies, the MSKD is being supported by a continuous care nutrition intervention through Virta Health Corp, that offers tracking of daily ketone and glucose levels, a web-based software application, education, and communication with a remote care team to ensure sustained nutritional ketosis. A total of 40 patients with untreated metastatic PDAC are planned for enrollment, 20 randomized to each arm. The trial opened for accrual November 2020. Citation Format: Diana Hanna, Gayle S. Jameson, Drew W. Rasco, Angela Alistar, Richard C. Frank, Anthony B. El-Khoueiry, Julia E. Wiedmeier, Caroline Roberts, Brandon Fell, Sarah Hallberg, Denise Roe, Derek Cridebring, Joshua Rabinowitz, Stephen Thomas Gately, Daniel D. Von Hoff. Randomized Phase II trial of two different nutritional approaches for patients receiving treatment for their advanced pancreatic cancer [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 CT549.

9085 Background: Aberrant activation of the RAS-RAF-MEK-ERK pathway is common in human cancers. This is an open-label Phase 1 study of ASTX029, a dual-mechanism extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor, in subjects with relapsed/refractory solid tumors (NCT03520075). Methods: The primary objective is to identify a recommended Phase 2 dose. Subjects with relapsed/refractory solid tumors were eligible for Phase 1A with any molecular feature and for Phase 1B if the tumor demonstrated RAS or BRAF mutations. ASTX029 was administered orally daily on a continuous basis in 21-day cycles. Phase 1A was a modified 3+3 dose-escalation design based on dose-limiting toxicity (DLT) events. Phase 1B subjects were treated at the recommended dose for expansion (RDE) based on emerging safety, pharmacokinetic (PK), and pharmacodynamic (PD) data. Disease response was evaluated by RECIST v1.1. Results: 76 subjects were treated with at least one dose of ASTX029 in Phase 1A (n = 56) and Phase 1B (n = 20). In Phase 1A, ASTX029 was evaluated from 10 mg to 280 mg daily. Two subjects experienced grade 2 central serous retinopathy (CSR) within a few days of dosing at the 280 mg daily dose level (one event was declared a DLT). Both subjects recovered to baseline within days of dose interruption. CSR is an expected AE based on the class of drugs. At the selected RDE dose level of 200 mg daily, the mean PK exposure was 109% of target exposure (13,022 ng*hr/ml), defined as the level expected to have biological activity based on mouse models. As of the data cut-off of February 7, 2022, the most frequent grade ≥2 AEs experienced by subjects (≥5%) assessed as related to ASTX029 included ocular AEs (n = 6: all Grade 2); nausea (n = 7: all Grade 2); diarrhea (n = 6: 5 Grade 2, 1 Grade 3); fatigue (n = 4: all Grade 2); rash (n = 4, 3 Grade 2, 1 Grade 3). There were 52 serious AEs, all unrelated to ASTX029 except for one subject with Grade 3 malaise. Four subjects had a partial response, including KRAS-G12A BRAF-D549N non-small cell lung cancer (NSCLC; Phase 1A: 120 mg treated 20.0 months); KRAS-G12D pancreatic cancer (Phase 1A: 200 mg treated 2.1 months); KRAS-G13D NSCLC (Phase 1B; treated 10.6 months); KRAS-G12S NSCLC (Phase 1B; treated 10.4 months and ongoing). In all, two partial responses were observed out of 3 NSCLC subjects enrolled in Phase 1B. Phospho-ERK and phospho-RSK were evaluated for PD effect on fresh tumor biopsies obtained at baseline and cycle 2. A PD effect and decreased cell proliferation (Ki-67) were observed in 6 of 9 and 3 of 8 evaluable Phase 1B samples, respectively. The most common reason for ASTX029 discontinuation was disease progression. Conclusions: This Phase 1 study of the ERK1/2 inhibitor ASTX029 has identified a dose level of 200 mg daily continuously for investigation in the Phase 2 study. PK and PD data suggest target exposures are achieved with preliminary clinical activity, especially in KRAS-mutated NSCLC. Clinical trial information: NCT03520075.

TPS2688 Background: The major histocompatibility complex (MHC) class I-related proteins MICA and MICB are stress-inducible, surface glycoproteins that are up-regulated on human tumors. MICA/MICB are ligands for the activating receptor, Natural Killer Group 2 member D (NKG2D) expressed on Natural Killer (NK) cells, CD8+ T cells, γδ T cells and iNKT cells. Proteases in the tumor microenvironment cleave MICA/MICB from the cell surface which enables tumor cells to evade immune cell recognition and destruction by NKG2D-expressing cells. Increased concentrations of shed MICA have been observed in serum from patients across multiple tumor types and correlate with poor survival. CLN-619 is a humanized, clinical-stage, MICA/MICB-specific IgG1 monoclonal antibody that prevents the proteolytic release of MICA/MICB thereby exposing tumor cells for immune destruction through both NKG2D-mediated and antibody-dependent cell-mediated cytotoxicity (ADCC). The antibody has been shown to restore the MICA/MICB-NKG2D axis to promote NK-mediated tumor cell lysis (AACR Annual Meeting abstract 3506, April 2022). In mice bearing MICA/MICB-expressing human tumor xenografts, CLN-619 treatment yielded robust anti-tumor activity at low doses. MICA/MICB is expressed in a wide range of solid tumors. Therefore, CLN-619 is expected to have broad anti-tumor activity. Methods: CLN-619 is being evaluated in an open-label, non-randomized, dose-escalation (phase 1) study as monotherapy, and in combination with pembrolizumab, in patients with advanced solid tumors. Cohort expansion in patients with specific indications as monotherapy and in combination with pembrolizumab will be conducted. The phase 1 study explores ascending intravenous doses of CLN-619 as monotherapy (0.1, 0.3, 1.0, 3.0, 6.0 and 10.0 mg/kg) and in combination with pembrolizumab (200 mg) in 21-day cycles to identify the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). Key eligibility criteria include 1) histological or cytological diagnosis of cancer and 2) refractory metastatic disease, or locally advanced disease not amenable to local therapy. At the RP2D, CLN-619 monotherapy will be evaluated in non-small cell lung and cervical cancer. In parallel, a cohort of patients will be administered CLN-619 in combination with pembrolizumab. Serum levels of soluble MICA/MICB, identity of MICA/MICB alleles, phenotypes of peripheral blood mononuclear cells, cytokines and tumor biopsies will be investigated for correlative pharmacodynamic and predictive biomarkers. This clinical trial is in progress (NCT05117476) and has completed accrual of three participants at the first dose level. Clinical trial information: NCT05117476.

2506 Background: SUMOylation is a post-translational modification with a role in limiting type 1 interferon (IFN-1)-dependent immune responses. Subasumstat is a small-molecule inhibitor of SUMOylation with the potential to increase antitumor immunity and overcome tumor resistance to checkpoint inhibitors (CPI) by inducing IFN-1 signaling. Preclinical data suggest that subasumstat enhances antigen cross-presentation, promoting T cell dependent antitumor responses; subasumstat plus an anti-PD-1 CPI has shown synergistic tumor growth inhibition and activation of CD8+ T cells and natural killer cells in syngeneic mouse models. We report data from the dose escalation part of a phase 1b study of subasumstat with pembrolizumab in pts with relapsed/refractory, CPI-exposed, non-squamous non-small-cell lung cancer (NSCLC) or microsatellite-stable colorectal cancer (MSS-CRC). Methods: Pts received escalating doses (40, 60, 90, and 120 mg) of subasumstat IV in 3 dosing schedules: days 1 and 8 (QW), days 1, 4, 8, and 11 (BIW), or days 1, 8, and 15 (90 mg only) of 21-day cycles, plus pembrolizumab 200 mg IV on day 1 of each cycle for 2 years or until disease progression or unacceptable toxicity. Dose escalation was guided by Bayesian optimal interval design. Phase 1b primary objectives were safety, tolerability, and the recommended phase 2 dose of subasumstat with pembrolizumab. Results: As of October 13, 2021, 43 (35 MSS-CRC; 8 NSCLC) pts had received ≥1 dose of subasumstat (22 BIW [40–120 mg]; 15 QW [90 –120 mg]; 6 on days 1, 8, 15 [90 mg)]. Median number of treatment cycles was 3; 28 (65%) pts had discontinued treatment, 21 (49%) due to progressive disease. Median age was 58 years (range 34–77); 56% of pts were male. One pt had a dose-limiting toxicity of grade 3 angioedema at 120 mg BIW. The maximum tolerated dose was not identified. Treatment-emergent adverse events (TEAEs) occurred in 38 (88%) pts; subasumstat-related TEAEs occurred in 34 (79%) pts, and included chills in 20 (47%), pyrexia in 16 (37%), fatigue in 9 (21%), anemia in 6 (14%), and stomatitis in 5 pts (12%; 3 [50%] in the 120 mg BIW cohort). Grade ≥3 TEAEs occurred in 24 (56%) pts; subasumstat-related grade ≥3 TEAEs reported in 10 (23%) pts included anemia, pyrexia, and increased aspartate aminotransferase (2 [5%] pts each). Pharmacokinetic activity of subasumstat was linear and decreased in a tri-phasic manner. Subasumstat exerted pharmacodynamic activity including target engagement, SUMOylation inhibition and increased IFN-1 signaling. Partial responses were observed at ≥40 mg dose levels in pts with NSCLC and MSS-CRC. Conclusions: Subasumstat plus pembrolizumab showed a favorable safety profile and promising anti-tumor activity in pre-treated NSCLC and MSS-CRC pts. Updated data will be presented at the meeting. Subasumstat plus pembrolizumab is currently in phase 2 clinical development (NCT04381650). Clinical trial information: NCT04381650.

2521 Background: MT-6402 is a unique and potent PD-L1-targeted engineered toxin body (ETB) capable of directly killing PD-L1 expressing tumor and immune cells by internalization of a fused Shiga-like toxin A subunit (SLTA) resulting in permanent SLTA-mediated ribosomal inactivation. The targeting of PD-L1 expressing tumor cells may directly drive tumor regression whereas targeting of PD-L1 expressing immune cells may release immunosuppression and drive immune recognition of the tumor. MT-6402 also delivers an HLA-A*02 restricted cytomegalovirus (CMV) class I antigen into PD-L1 expressing cells (antigen seeding) that can be recognized by existing CMV-specific cytotoxic T cells. Methods: A first-in-human dose escalation and expansion study in patients with PD-L1-expressing advanced solid tumors was initiated in 2021. As of 1 Jan 2022, 6 patients received at least one dose of MT-6402, 4 of whom were eligible for Dose Limiting Toxicity (DLT) assessment in Cohort 1. Results: A significant reduction in CD14+ monocytes starting in cycle 2 was observed in patients on therapy after each MT-6402 administration, indicating an HLA-independent PD effect consistent with preclinical observations. 5 of 6 patients had a marked decrease in Monocytic Myeloid Derived Suppressor Cells (MDSC). The reduction in MDSC and monocytes in the periphery overlapped with increased CCL2 levels, a chemokine that directs movement of myeloid cells. One patient with osseous metastases from non-small cell lung cancer (NSCLC) who is HLA-A*02 and CMV+ showed complete CMV-specific T-cell extravasation at day 8 and serum cytokine signatures consistent with antigen dependent responses and T cell mobilization. This patient had reduced tracer uptake of metastatic bone lesions with 3/4 lesions resolving completely. A second HLA A*02 CMV+ patient followed a similar trend towards loss of peripheral CMV-specific T cells with a concurrent increase in total CD8 T cells. The CD8 T cells from these 2 patients had elevated T-bet expression from baseline, indicating antigen specific TCR stimulation and expansion. The activated immune response was also accompanied by increased IP-10 and IL-2 cytokine signatures in the serum. Consistent with these findings, one of these two patients had transient (1-12 h) grade 2 infusion related reaction and the other had transient (1-12 h) grade 2 cytokine release syndrome, both on Day 15. These results describe a novel approach to checkpoint modulation by MT-6402, that adds antigen seeding to PD-L1 directing mechanisms. MT-6402 was well tolerated and no DLT was observed in Cohort 1 (16 µg /kg, QW in 4-week cycles). Conclusions: Dose escalation is ongoing. The results hold promise for development of MT-6402 for solid tumors, including in the R/R setting. Data for additional patients will be presented at the meeting. Clinical trial information: NCT04795713.

Background GB1275 is a first-in-class CD11b modulator that reduced myeloid-derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs), repolarized M2 immunosuppressive TAMs to an M1 phenotype, and increased tumor infiltration of activated CD8+ T cells in preclinical models. Preclinical anti-tumor activity was observed with single-agent therapy and in combination with chemotherapy or immuno-oncology therapies.1 We report results from the dose escalation portion of an ongoing, first-in-human study of GB1275 monotherapy and combined with pembrolizumab in patients with specific advanced solid tumors. (NCT04060342) Methods This study comprises phase 1 dose escalation followed by phase 2 expansion in specific tumor types. In phase 1, cohorts of 3 to 6 patients with histologically confirmed, locally advanced/metastatic pancreatic, esophageal, gastric, MSS colorectal, metastatic castrate-resistant prostate cancer, or triple negative breast cancer are sequentially assigned to one of the ascending dose levels of GB1275 orally twice daily (BID) in 1 of 3 regimens: A (GB1275 monotherapy); B (GB1275 + pembrolizumab) commenced after completion of two cohorts of A; and C (GB1275 + nab-paclitaxel + gemcitabine) will be initiated after A. Patients in Regimens A and B had previously exhausted standard of care treatment options. Dose escalation was based on safety, including dose-limiting toxicity (DLT). Serial blood samples were collected for pharmacokinetic (PK) and biomarker analyses; tumor tissue was also collected for biomarker analysis. Results As of July 28, 2020, 36 patients were treated, 23 in Regimen A (GB1275 100 mg to 1200 mg BID) and 13 in Regimen B (GB1275 100 mg to 800 mg BID + pembrolizumab). No DLTs or adverse events requiring steroid treatment were reported. GB1275-related adverse events were reported in 19 (52.8%) patients; most were Grade 1 and most frequent events (≥10%) were dysesthesia (13.9%) and photosensitivity reaction (11.1%). Stable disease was reported in 4 (17%) patients in Regimen A and 6 (46%) in Regimen B with a median (range) exposure of 84 days (35–172). A dose-dependent increase in GB1275 exposure was observed. An increase in tumor infiltrating lymphocyte (TIL) counts was noted in both Regimens A and B. Other biomarker analyses in serial blood and tumor tissue are ongoing. Conclusions Dose escalation of GB1275, up to 1200 mg and 800 mg BID in Regimens A and B, respectively, demonstrated tolerability as monotherapy and combined with pembrolizumab. The maximum tolerated dose has not been reached. Preliminary observation of an increase in TILs after treatment is encouraging. Ethics Approval This ongoing study is being conducted in accordance with the Declaration of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines. The study was approved by the Ethics Boards of the University of Colorado Hospital, Washington University School of Medicine - Siteman Cancer Center, Memorial Sloan Kettering Cancer Center, The Sarah Cannon Research Institute/Tennessee Oncology, South Texas Accelerated Research Therapeutics, and The Royal Marsden NHS Foundation Trust. Reference Panni RZ, Herndon JM, Zuo C, et al. Agonism of CD11b reprograms innate immunity to sensitize pancreatic cancer to immunotherapies. Sci Transl Med 2019 Jul 3;11(499).

Background GB1275 is a first-in-class CD11b modulator in development as monotherapy and in combination with pembrolizumab or chemotherapy for the treatment of advanced solid tumors. Nonclinical data show that GB1275 reduced influx of tumor-associated myeloid-derived suppressor cells (MDSCs) and macrophages (TAMs), and repolarized M2 immuno-suppressive TAMs towards an M1 phenotype. We hypothesize that GB1275 administration can alleviate myeloid cell-mediated immunosuppressive effects and improve cancer treatment outcomes. A phase 1 trial evaluating GB1275 as monotherapy and in combination with pembrolizumab in specified advanced tumors in ongoing (NCT04060342). Methods Blood gene expression variations as well as core tissue biopsies pre- and post-treatment were assessed following GB1275 monotherapy and combination with pembrolizumab. After obtaining informed consent, peripheral blood for MDSCs was collected from 21 patients pre- and two weeks post-treatment; core tissue biopsies were collected from 13 patients pre- and post-treatment. The frequency of MDSCs in whole blood was measured using the Serametrix MDSC FACS Assay. Gene expression transcriptome profiles were generated using NovaSeq platform. CD8 staining was performed at Neogenomics, and tumor infiltrating lymphocyte (TIL) quantification was performed by an independent pathologist. Results Preliminary statistical analysis of MDSC immunophenotyping pre- and post- treatment is consistent with the proposed mechanism of GB1275, showing modulation of peripheral blood MDSCs in some patients. Preliminary gene expression analysis in the blood showed dose-dependent clusters following treatment with GB1275 alone. Moreover, the transcriptomic analysis revealed two unique expression patterns for patients treated with GB1275 monotherapy or in combination with pembrolizumab. Gene Set Enrichment Analysis showed that the CD11b pathway is downregulated in patients treated with GB1275. Analyses of TIL count revealed an increase in lymphocyte trafficking into the tumor after treatment with GB1275 alone or in combination with pembrolizumab. CD8 expression and transcriptomic analysis are underway and will be presented. Conclusions GB1275 alone or in combination with pembrolizumab demonstrates biological activity, which may be dose dependent. The observed increase in TILs after treatment is supportive of the mechanism of action of GB1275. Further biomarker analyses in blood and tissues are ongoing and will be correlated with clinical activity in a larger number of patients. Ethics Approval This ongoing study is being conducted in accordance with the the Declaration of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines. The study was approved by the Ethics Boards of University of Colorado Hospital, Washington University School of Medicine - Siteman Cancer Center, Memorial Sloan Kettering Cancer Center, The Sarah Cannon Research Institute/Tennessee Oncology, South Texas Accelerated Research Therapeutics, and The Royal Marsden NHS Foundation Trust.

Background TLR agonists mediate antitumor activity through dendritic cell (DC) activation. Most TLR agonists in development are administered intratumorally allowing for less than 30% of advanced solid tumor to be treated. BDB001 is an intravenously administered novel TLR7/8 agonist that activates plasmacytoid and myeloid DCs and has shown to have activity in preclinical studies. Here we report on BDB001 administration in patients with advanced solid tumors. Methods BDB001-101 is a Phase 1, open label, dose escalation/expansion trial of BDB001 administered intravenously weekly in patients with advanced solid tumors. The primary endpoint was safety and tolerability. Secondary endpoints included efficacy, pharmacokinetics and pharmacodynamic profiling of immune activation. Results Thirty-six subjects with 16 different tumor types were enrolled across 5 dose levels. Sixty seven percent were female, median age was 66 years (range, 38–88), median number of prior therapies was 4 (range, 0–12), and 61% of tumors had progressed on prior anti-PD-(L)1 therapy. BDB001 was well tolerated and a maximum tolerated dose was not reached. Eleven (30.5%) subjects had no treatment related adverse events (AEs) and the majority of AEs were Grade 1 or 2. Three (8.3%) subjects had Grade 3 AEs, including 2 with a cytokine release syndrome, both of whom were clinically stable and had symptoms fully resolved within 2 to 5 days. There were no Grade 4 or 5 AEs. The most common AEs included chills/rigor (19.4%), fever (19.4%), fatigue (11.1%), nausea (11.1%) and pruritus (11.1%). Of 32 subjects evaluable for efficacy, best overall response rate was: 6% durable partial response, 56% stable disease, 38% progressive disease, for a disease control rate of 62%. Durable responses were seen in renal cell carcinoma and non-small cell lung cancer. Interestingly, clinical activity favored subjects with tumors that had progressed on prior anti-PD-(L)1 therapy, compared to prior DNA-damaging chemotherapy, within 6 months of BDB001 initiation. Median time on treatment was 12.1 weeks (range, 3.1 – 68.0). Transcriptional profiling showed up-regulation of interferon inducible genes, activation of dendritic cells and macrophages. BDB001 also significantly increased serum levels of interferon gamma and interferon inducible protein-10 (IP-10). Conclusions Intravenously administered BDB001 monotherapy was well tolerated. Clinical responses were achieved, supported by BDB001-induced immune activation. Preliminary findings suggest that BDB001 is a promising therapeutic option for patients with tumors that progress on anti-PD-(L)1 therapy. BDB001 is also being evaluated in combination with pembrolizumab (anti-PD-1, NCT03486301) and with atezolizumab (anti-PD-L1, NCT04196530). Trial Registration NCT03486301 Ethics Approval This study was approved by the institutional review boards at the four participating institutions. All subjects signed informed consent before enrolling in the clinical trial.

PURPOSE To evaluate the safety, pharmacokinetics, and preliminary activity of bemarituzumab in patients with FGFR2b-overexpressing gastric and gastroesophageal junction adenocarcinoma (GEA). PATIENTS AND METHODS FPA144-001 was a phase I, open-label, multicenter trial consisting of the following 3 parts: part 1a involved dose escalation in patients with recurrent solid tumors at doses ranging from 0.3 to 15 mg/kg; part 1b involved dose escalation in patients with advanced-stage GEA; and part 2 involved dose expansion in patients with advanced-stage GEA that overexpressed FGFR2b at various levels (4 cohorts; high, medium, low, and no FGFR2b overexpression) and 1 cohort of patients with FGFR2b-overexpressing advanced-stage bladder cancer. RESULTS Seventy-nine patients were enrolled; 19 were enrolled in part 1a, 8 in part 1b, and 52 in part 2. No dose-limiting toxicities were reported, and the recommended dose was identified as 15 mg/kg every 2 weeks based on safety, tolerability, pharmacokinetic parameters, and clinical activity. The most frequent treatment-related adverse events (TRAEs) were fatigue (17.7%), nausea (11.4%), and dry eye (10.1%). Grade 3 TRAEs included nausea (2 patients) and anemia, neutropenia, increased AST, increased alkaline phosphatase, vomiting, and an infusion reaction (1 patient each). Three (10.7%) of 28 patients assigned to a cohort receiving a dose of ≥ 10 mg/kg every 2 weeks for ≥ 70 days reported reversible grade 2 corneal TRAEs. No TRAEs of grade ≥ 4 were reported. Five (17.9%; 95% CI, 6.1% to 36.9%) of 28 patients with high FGFR2b-overexpressing GEA had a confirmed partial response. CONCLUSION Overall, bemarituzumab seems to be well tolerated and demonstrated single-agent activity as late-line therapy in patients with advanced-stage GEA. Bemarituzumab is currently being evaluated in combination with chemotherapy in a phase III trial as front-line therapy for patients with high FGFR2b-overexpressing advanced-stage GEA.

Background Quavonlimab (MK-1308), a novel anti-CTLA-4 antibody, in combination with pembrolizumab was investigated in a phase I study. Patients and methods Dose-escalation (DE) phase: patients with advanced/metastatic solid tumors received an initial flat dose of quavonlimab as monotherapy [25 mg (cohort 1), 75 mg (cohort 2), or 200 mg (cohort 3)] followed by four treatments of the same quavonlimab dose plus pembrolizumab every 3 weeks (Q3W). Dose-confirmation phase (DC): patients with stage IIIB/IV non-small-cell lung cancer (NSCLC) received first-line quavonlimab [25 mg Q3W (arm A), 25 mg Q6W (arm B), 75 mg Q6W (arm C), or 75 mg Q3W (arm E)] plus pembrolizumab. Primary objectives were safety and tolerability and establishment of the recommended phase II dose (RP2D) of quavonlimab when used with pembrolizumab. Objective response rate (ORR) was a secondary endpoint. Efficacy based on PD-L1 expression, tumor mutational burden (TMB), and changes in circulating CD4+/CD8+ cells were exploratory endpoints. Results Thirty-nine patients were enrolled in DE [n = 14 (cohort 1); n = 17 (cohort 2); n = 8 (cohort 3)] and 134 in DC [n = 40 (arm A); n = 40 (arm B); n = 40 (arm C); n = 14 (arm E)]. Maximum-tolerated dose was not reached. Grade 3-5 treatment-related adverse events (AEs; graded according to NCI CTCAE v4.03) occurred in 0%, 23.5%, and 75.0% of patients in DE cohorts 1, 2, and 3, respectively, and 35.0%, 30.0%, 35.0%, and 57.1% of patients in DC arms A, B, C, and E, respectively. Efficacy was observed at all dose levels/schedules in patients with NSCLC. ORRs were 40.0% [95% confidence interval (CI), 24.9-56.7; arm A], 37.5% (95% CI, 22.7-54.2; arm B), 27.5% (95% CI, 14.6-43.9; arm C), and 35.7% (95% CI, 12.8-64.9; arm E). PD-L1 expression and total number of circulating CD4+ cells correlated with ORR. Conclusions Quavonlimab 25 mg Q6W plus pembrolizumab demonstrated similar efficacy and a better safety profile among all quavonlimab doses/schedules evaluated; this regimen was the chosen RP2D.

PURPOSE Modulation of vascular endothelial growth factor–mediated immune suppression via angiogenesis inhibition may augment the activity of immune checkpoint inhibitors. We report results from the dose-finding and initial phase II expansion of a phase Ib/II study of lenvatinib plus pembrolizumab in patients with selected advanced solid tumors. METHODS Eligible patients had metastatic renal cell carcinoma (RCC), endometrial cancer, squamous cell carcinoma of the head and neck (SCCHN), melanoma, non–small-cell lung cancer (NSCLC), or urothelial cancer. The primary objective of phase Ib was to determine the maximum tolerated dose (MTD) for lenvatinib plus pembrolizumab (200 mg intravenously every 3 weeks). In the preplanned phase II cohort expansion, the primary objective was objective response rate at week 24 (ORRweek 24) at the recommended phase II dose. RESULTS Overall, 137 patients were enrolled during phase Ib (n = 13) and the initial phase II expansion (n = 124). Two dose-limiting toxicities (DLTs; grade 3 arthralgia and grade 3 fatigue) were reported in the initial dose level (lenvatinib 24 mg/d plus pembrolizumab). No DLTs were observed in the subsequent dose–de-escalation cohort, establishing the MTD and recommended phase II dose at lenvatinib 20 mg/d plus pembrolizumab. ORRweek24 was as follows: RCC, 63% (19/30; 95% CI, 43.9% to 80.1%); endometrial cancer, 52% (12/23; 95% CI, 30.6% to 73.2%); melanoma, 48% (10/21; 95% CI, 25.7% to 70.2%); SCCHN, 36% (8/22; 95% CI, 17.2% to 59.3%); NSCLC, 33% (7/21; 95% CI, 14.6% to 57.0%); and urothelial cancer 25% (5/20; 95% CI, 8.7% to 49.1%). The most common treatment-related adverse events were fatigue (58%), diarrhea (52%), hypertension (47%), and hypothyroidism (42%). CONCLUSION Lenvatinib plus pembrolizumab demonstrated a manageable safety profile and promising antitumor activity in patients with selected solid tumor types.