A next-generation BRAF inhibitor overcomes resistance to BRAF inhibition in patients with BRAF-mutant cancers using pharmacokinetics-informed dose escalation.

RAF inhibitors have transformed treatment for BRAF V600-mutant cancer patients, but clinical benefit is limited by adaptive induction of ERK signaling, genetic alterations that induce BRAF V600 dimerization, and poor brain penetration. Next-generation pan-RAF dimer inhibitors are limited by narrow therapeutic index. PF-07799933 (ARRY-440) is a brain-penetrant, selective, pan-mutant BRAF inhibitor. PF-07799933 inhibited signaling in vitro, disrupted endogenous mutant-BRAF:wild-type-CRAF dimers, and spared wild-type ERK signaling. PF-07799933 ± binimetinib inhibited growth of mouse xenograft tumors driven by mutant BRAF that functions as dimers and by BRAF V600E with acquired resistance to current RAF inhibitors. We treated patients with treatment-refractory BRAF-mutant solid tumors in a first-in-human clinical trial (NCT05355701) that utilized a novel, flexible, pharmacokinetics-informed dose escalation design that allowed rapid achievement of PF-07799933 efficacious concentrations. PF-07799933 ± binimetinib was well-tolerated and resulted in multiple confirmed responses, systemically and in the brain, in BRAF-mutant cancer patients refractory to approved RAF inhibitors.

Datopotamab Deruxtecan in Advanced or Metastatic HR+/HER2- and Triple-Negative Breast Cancer: Results From the Phase I TROPION-PanTumor01 Study.

PURPOSE: Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate consisting of a humanized antitrophoblast cell-surface antigen 2 (TROP2) monoclonal antibody linked to a potent, exatecan-derived topoisomerase I inhibitor payload via a plasma-stable, selectively cleavable linker. PATIENTS AND METHODS: TROPION-PanTumor01 (ClinicalTrials.gov identifier: NCT03401385) is a phase I, dose-escalation, and dose-expansion study evaluating Dato-DXd in patients with previously treated solid tumors. The primary study objective was to assess the safety and tolerability of Dato-DXd. Secondary objectives included evaluation of antitumor activity and pharmacokinetics. Results from patients with advanced/metastatic hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer (BC) or triple-negative BC (TNBC) are reported. RESULTS: At data cutoff (July 22, 2022), 85 patients (HR+/HER2- BC = 41, and TNBC = 44) had received Dato-DXd. The objective response rate by blinded independent central review was 26.8% (95% CI, 14.2 to 42.9) and 31.8% (95% CI, 18.6 to 47.6) for patients with HR+/HER2- BC and TNBC, respectively. The median duration of response was not evaluable in the HR+/HER2- BC cohort and 16.8 months in the TNBC cohort. The median progression-free survival in patients with HR+/HER2- BC and TNBC was 8.3 and 4.4 months, respectively. All-cause treatment-emergent adverse events (TEAEs; any grade, grade ≥3) were observed in 100% and 41.5% of patients with HR+/HER2- BC and 100% and 52.3% of patients with TNBC. Stomatitis was the most common TEAE (any grade, grade ≥3) in both HR+/HER2- BC (82.9%, 9.8%) and TNBC (72.7%, 11.4%) cohorts. CONCLUSION: In patients with heavily pretreated advanced HR+/HER2- BC and TNBC, Dato-DXd demonstrated promising clinical activity and a manageable safety profile. Dato-DXd is currently being evaluated in phase III studies.

Phase I LITESPARK-001 study of belzutifan for advanced solid tumors: Extended 41-month follow-up in the clear cell renal cell carcinoma cohort.

BACKGROUND: Accumulation of the HIF-2α transcription factor is an oncogenic event implicated in the tumorigenesis of clear cell renal cell carcinoma (ccRCC). In the phase I LITESPARK-001 study, the first-in-class HIF-2α inhibitor belzutifan demonstrated antitumor activity and an acceptable safety profile for pretreated patients with advanced ccRCC. Updated data with additional follow-up of > 40 months are presented. METHODS: LITESPARK-001 is an ongoing open-label study with a 3 + 3 dose-escalation design followed by an expansion phase. Patients with ccRCC enrolled at 7 sites received belzutifan 120 mg orally once daily until disease progression, unacceptable toxicity, or patient withdrawal. The data cutoff date was July 15, 2021. The primary end point was identifying the maximum tolerated dose and/or the recommended phase II dose. Secondary end points included objective response rate (ORR) and duration of response (DOR) per RECIST v1.1 by investigator assessment and safety. RESULTS: Median follow-up was 41.2 months (range, 38.2-47.7). Patients received a median of 3 (range, 1-9) prior systemic therapies. Of 55 patients, 14 (25 %) achieved an objective response. Median DOR was not reached (range, 3.1 + to 38.0 + months). Adverse events (AEs) attributed to study treatment by investigator assessment were reported in 53 patients (96 %). 22 patients (40 %) had grade 3 treatment-related AEs; the most common were anemia (n = 13; 24 %) and hypoxia (n = 7; 13 %). No grade 4 or 5 treatment-related AEs occurred. CONCLUSION: After a median follow-up of 41.2 months, belzutifan monotherapy demonstrated durable antitumor activity in patients with advanced ccRCC and acceptable safety. CLINICALTRIALS: gov. NCT02974738.

MRTX1719 Is an MTA-Cooperative PRMT5 Inhibitor That Exhibits Synthetic Lethality in Preclinical Models and Patients with MTAP-Deleted Cancer.

Previous studies implicated protein arginine methyltransferase 5 (PRMT5) as a synthetic lethal target for MTAP-deleted (MTAP del) cancers; however, the pharmacologic characterization of small-molecule inhibitors that recapitulate the synthetic lethal phenotype has not been described. MRTX1719 selectively inhibited PRMT5 in the presence of MTA, which is elevated in MTAP del cancers, and inhibited PRMT5-dependent activity and cell viability with >70-fold selecti-vity in HCT116 MTAP del compared with HCT116 MTAP wild-type (WT) cells. MRTX1719 demonstrated dose-dependent antitumor activity and inhibition of PRMT5-dependent SDMA modification in MTAP del tumors. In contrast, MRTX1719 demonstrated minimal effects on SDMA and viability in MTAP WT tumor xenografts or hematopoietic cells. MRTX1719 demonstrated marked antitumor activity across a panel of xenograft models at well-tolerated doses. Early signs of clinical activity were observed including objective responses in patients with MTAP del melanoma, gallbladder adenocarcinoma, mesothelioma, non-small cell lung cancer, and malignant peripheral nerve sheath tumors from the phase I/II study. SIGNIFICANCE: PRMT5 was identified as a synthetic lethal target for MTAP del cancers; however, previous PRMT5 inhibitors do not selectively target this genotype. The differentiated binding mode of MRTX1719 leverages the elevated MTA in MTAP del cancers and represents a promising therapy for the ∼10% of patients with cancer with this biomarker. See related commentary by Mulvaney, p. 2310. This article is featured in Selected Articles from This Issue, p. 2293.

Phase I study of anti-epidermal growth factor receptor antibody-drug conjugate serclutamab talirine: Safety, pharmacokinetics, and antitumor activity in advanced glioblastoma.

Background: Serclutamab talirine (Ser-T, formerly ABBV-321) is an antibody-drug conjugate consisting of an antibody (AM-1-ABT-806) directed against activated epidermal growth factor receptor (EGFR) and a pyrrolobenzodiazepine dimer. We investigated Ser-T monotherapy in a phase I, first-in-human, dose-escalation, and dose-expansion study in patients with advanced solid tumors associated with EGFR overexpression. Methods: Eligible patients (≥18 years) had advanced, histologically confirmed solid tumors associated with EGFR overexpression (centralized testing). Patients received Ser-T intravenously once every 4 weeks (Q4W; 5-50 µg/kg) in the dose-escalation phase. Herein, preliminary antitumor activity at the recommended phase II dose (RP2D) is reported only for patients with glioblastoma (n = 24); additional assessments included all treated patients. Results: Sixty-two patients (median age: 58 years) were enrolled within the dose-escalation (n = 43) and dose-expansion (n = 19) phases. One dose-limiting toxicity, grade 3 aspartate aminotransferase and alanine aminotransferase elevation, occurred at 20 µg/kg during dose escalation. The Ser-T RP2D regimen of 50 µg/kg × 1 (loading dose) followed by 25 µg/kg Q4W (maintenance dose) was administered during dose expansion. Fatigue (37%) was the only treatment-emergent adverse event (AE) occurring in >25% of patients. Two patients (3%) reported mild treatment-related ocular AEs (eye pruritus). Responses in patients with glioblastoma included 1 partial response (~33 months), 6 stable disease, and 14 progressive disease (not evaluable: n = 3). Conclusions: Ser-T monotherapy at doses up to 50 µg/kg initial dose, followed by 25 µg/kg Q4W demonstrated a tolerable safety profile with minimal antitumor activity observed in patients with glioblastoma. The glioblastoma dose-expansion cohort was closed due to a lack of efficacy (NCT03234712).

A Phase 1 First-in-Human Study of FS118, a Tetravalent Bispecific Antibody Targeting LAG-3 and PD-L1 in Patients with Advanced Cancer and PD-L1 Resistance.

PURPOSE: This phase 1 study (NCT03440437) evaluated the safety, tolerability, pharmacokinetics (PK), and activity of FS118, a bispecific antibody-targeting LAG-3 and PD-L1, in patients with advanced cancer resistant to anti-PD-(L)1 therapy. PATIENTS AND METHODS: Patients with solid tumors, refractory to anti-PD-(L)1-based therapy, received intravenous FS118 weekly with an accelerated dose titration design (800 µg to 0.3 mg/kg) followed by 3+3 ascending dose expansion (1 to 20 mg/kg). Primary objectives were safety, tolerability, and PK. Additional endpoints included antitumor activity, immunogenicity, and pharmacodynamics. RESULTS: Forty-three patients with a median of three prior regimens in the locally advanced/metastatic setting, including at least one anti-PD-(L)1 regimen, received FS118 monotherapy. FS118 was well tolerated, with no serious adverse events relating to FS118 reported. No dose-limiting toxicities (DLT) were observed, and an MTD was not reached. The recommended phase 2 dose of FS118 was established as 10 mg/kg weekly. The terminal half-life was 3.9 days. Immunogenicity was transient. Pharmacodynamic activity was prolonged throughout dosing as demonstrated by sustained elevation of soluble LAG-3 and increased peripheral effector cells. The overall disease control rate (DCR) was 46.5%; this disease control was observed as stable disease, except for one late partial response. Disease control of 54.8% was observed in patients receiving 1 mg/kg or greater who had acquired resistance to PD-(L)1-targeted therapy. CONCLUSIONS: FS118 was well tolerated with no DLTs observed up to and including 20 mg/kg QW. Further studies are warranted to determine clinical benefit in patients who have become refractory to anti-PD-(L)1 therapy. See related commentary by Karapetyan and Luke, p. 835.

First-in-Human Phase I/II ICONIC Trial of the ICOS Agonist Vopratelimab Alone and with Nivolumab: ICOS-High CD4 T-Cell Populations and Predictors of Response.

PURPOSE: The first-in-human phase I/II ICONIC trial evaluated an investigational inducible costimulator (ICOS) agonist, vopratelimab, alone and in combination with nivolumab in patients with advanced solid tumors. PATIENTS AND METHODS: In phase I, patients were treated with escalating doses of intravenous vopratelimab alone or with nivolumab. Primary objectives were safety, tolerability, MTD, and recommended phase II dose (RP2D). Phase II enriched for ICOS-positive (ICOS+) tumors; patients were treated with vopratelimab at the monotherapy RP2D alone or with nivolumab. Pharmacokinetics, pharmacodynamics, and predictive biomarkers of response to vopratelimab were assessed. RESULTS: ICONIC enrolled 201 patients. Vopratelimab alone and with nivolumab was well tolerated; phase I established 0.3 mg/kg every 3 weeks as the vopratelimab RP2D. Vopratelimab resulted in modest objective response rates of 1.4% and with nivolumab of 2.3%. The prospective selection for ICOS+ tumors did not enrich for responses. A vopratelimab-specific peripheral blood pharmacodynamic biomarker, ICOS-high (ICOS-hi) CD4 T cells, was identified in a subset of patients who demonstrated greater clinical benefit versus those with no emergence of these cells [overall survival (OS), P = 0.0025]. A potential genomic predictive biomarker of ICOS-hi CD4 T-cell emergence was identified that demonstrated improvement in clinical outcomes, including OS (P = 0.0062). CONCLUSIONS: Vopratelimab demonstrated a favorable safety profile alone and in combination with nivolumab. Efficacy was observed only in a subset of patients with a vopratelimab-specific pharmacodynamic biomarker. A potential predictive biomarker of response was identified, which is being prospectively evaluated in a randomized phase II non-small cell lung cancer trial. See related commentary by Lee and Fong, p. 3633.

Phase I Study of Glesatinib (MGCD265) in Combination with Erlotinib or Docetaxel in Patients with Advanced Solid Tumors.

BACKGROUND: Oncogenic drivers in solid tumors include aberrant activation of mesenchymal epithelial transition factor (MET) and AXL. OBJECTIVE: 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. PATIENTS AND METHODS: 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/m2) were administered with erlotinib or docetaxel (starting doses 100 mg once daily and 50 mg/m2, respectively) using a modified 3 + 3 design. Maximum tolerated dose (MTD) was based on dose-limiting toxicities (DLTs) during the first 21-day treatment cycle. Enrollment focused on patients with solid tumor types typically associated with MET aberration and/or AXL overexpression. The primary objective was to determine the safety profile of the treatment combinations. Antitumor activity and pharmacokinetics (PK) were also assessed. RESULTS: Ten 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/m2 plus docetaxel exceeded the MTD. Further dosing focused on glesatinib micronized V2: maximum administered dose (MAD) was 700 mg twice daily with erlotinib 150 mg once daily or docetaxel 75 mg/m2 every 3 weeks. DLTs, acceptable at lower glesatinib (micronized V2) dose levels, occurred in two of five and two of six patients at the MADs of glesatinib + erlotinib and glesatinib + docetaxel, respectively. Across all cohorts, the most frequent treatment-related adverse events were diarrhea (glesatinib + erlotinib: 84.1%; glesatinib + docetaxel: 45.6%), fatigue (46.4%, 70.4%), and nausea (30.4%, 35.1%). The objective response rate was 1.8% and 12.0% in all glesatinib + erlotinib and glesatinib + docetaxel cohorts, respectively. CONCLUSIONS: The 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/m2 every 3 weeks exceeded the MTD by a small margin. Modest signals of efficacy were observed with these treatment combinations in non-genetically selected patients with advanced solid tumors. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov NCT00975767; 11 September 2009.

First-in-Human Phase I/IB Dose-Finding Study of Adagrasib (MRTX849) in Patients With Advanced KRASG12C Solid Tumors (KRYSTAL-1).

PURPOSE: Adagrasib (MRTX849) is an oral, highly selective, small-molecule, covalent inhibitor of KRASG12C. We report results from a phase I/IB study of adagrasib in non-small-cell lung cancer, colorectal cancer, and other solid tumors harboring the KRASG12C mutation. MATERIALS AND METHODS: Patients with advanced KRASG12C-mutant solid tumors were treated with adagrasib 150 mg orally once daily, 300 mg once daily, 600 mg once daily, 1,200 mg once daily, or 600 mg orally twice a day using an accelerated titration design, which transitioned to a modified toxicity probability interval design when a predefined degree of toxicity was observed or target adagrasib exposure was achieved. Safety, pharmacokinetics, and clinical activity were evaluated. RESULTS: Twenty-five patients were enrolled and received at least one dose of adagrasib. The recommended phase II dose (RP2D) was 600 mg twice a day on the basis of safety, tolerability, and observed pharmacokinetics properties. No maximum tolerated dose was formally defined. After a median follow-up of 19.6 months, eight of 15 patients (53.3%; 95% CI, 26.6 to 78.7) with RECIST-evaluable KRASG12C-mutant non-small-cell lung cancer treated at 600 mg twice a day achieved a confirmed partial response. The median duration of response was 16.4 months (95% CI, 3.1 to not estimable). The median progression-free survival was 11.1 months (95% CI, 2.6 to not estimable). One of two patients with KRASG12C-mutant colorectal cancer treated at 600 mg twice a day achieved a partial response (duration of response, 4.2 months). At the RP2D, the most common treatment-related adverse events (any grade) were nausea (80.0%), diarrhea (70.0%), vomiting (50.0%), and fatigue (45.0%). The most common grade 3-4 treatment-related adverse event was fatigue (15.0%). CONCLUSION: Adagrasib 600 mg twice a day was well tolerated and exhibited antitumor activity in patients with advanced solid tumors harboring the KRASG12C mutation.

First-in-Human Phase I Study of Envafolimab, a Novel Subcutaneous Single-Domain Anti-PD-L1 Antibody, in Patients with Advanced Solid Tumors.

LESSONS LEARNED: Subcutaneous injection was an effective route of administration for envafolimab with a favorable pharmacokinetic profile in patients with previously treated advanced solid tumors. Subcutaneous envafolimab was well tolerated and had durable antitumor activity at a wide range of doses and schedules. Envafolimab has the potential to be a more convenient option than currently approved intravenous PD-1/PD-L1 inhibitors. BACKGROUND: Envafolimab is a novel fusion of a humanized single-domain PD-L1 antibody and human IgG1 Fc fragment formulated for subcutaneous injection. This study explored the safety and feasibility of subcutaneous administration of envafolimab as an alternative to intravenous administration of PD-1/PD-L1 inhibitors in the treatment of advanced, refractory solid tumors. METHODS: This was a first-in-human, open-label phase I trial. In a dose-escalation phase, patients received subcutaneous envafolimab 0.01-10 mg/kg once weekly following a modified 3+3 design. In a dose-exploration phase, patients received subcutaneous envafolimab 300 mg once every 4 weeks. RESULTS: Twenty-eight patients were enrolled (dose escalation n = 18, dose exploration n = 10, median age 66 years; 71% male; ECOG performance score = 0 [21%] or 1 [79%]). No dose-limiting toxicities or injection-site reactions were reported. Envafolimab demonstrated dose-proportional increases in area under the time-concentration curve and maximum plasma concentration. Median time to maximum plasma concentration was 4-7 days. In the dose-exploration phase, terminal half-life was 14 days after dose 1 in cycle 1 and 23 days at steady state. Three patients experienced a confirmed partial response. CONCLUSION: Subcutaneous envafolimab had a favorable safety and pharmacokinetic profile, with promising preliminary antitumor activity in patients with advanced solid tumors.

Phase I Trial of Cemiplimab, Radiotherapy, Cyclophosphamide, and Granulocyte Macrophage Colony-Stimulating Factor in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma.

LESSONS LEARNED: Cemiplimab in combination with radiation therapy, cyclophosphamide, and granulocyte macrophage colony-stimulating factor did not demonstrate efficacy above what can be achieved with other PD-1 inhibitor monotherapies in patients with refractory and metastatic head and neck squamous cell carcinoma. The safety profile of cemiplimab combination therapy was consistent with previously reported safety profiles of cemiplimab monotherapy. No new safety signal was observed. BACKGROUND: Refractory and metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) generally does not respond to PD-1 inhibitor monotherapy. Cemiplimab is a human anti-PD-1 monoclonal antibody. An expansion cohort enrolled patients with R/M HNSCC in a phase I study combining cemiplimab plus radiation therapy (RT), cyclophosphamide, and granulocyte macrophage colony-stimulating factor (GM-CSF). METHODS: Patients with R/M HNSCC refractory to at least first-line therapy and for whom palliative RT is clinically indicated received cemiplimab plus RT, cyclophosphamide, and GM-CSF. The co-primary objectives were the safety, tolerability, and efficacy of cemiplimab plus RT, cyclophosphamide, and GM-CSF in 15 patients with R/M HNSCC. RESULTS: Fifteen patients were enrolled. Patients discontinued treatment due to progression of disease. The most common treatment-emergent adverse events (TEAEs) of any grade were fatigue (40.0%), constipation (26.7%), and asthenia, dyspnea, maculo-papular rash, and pneumonia (each 20%). The only grade ≥3 TEAE that occurred in two patients was pneumonia (13.3%). By investigator assessment, there was one partial response (6.7%); disease control rate was 40.0% (95% confidence interval [CI], 16.3-67.7; five patients with stable disease); seven patients had progressive disease, and two were not evaluable. Median progression-free survival by investigator assessment was 1.8 months (95% CI, 1.7-4.7). CONCLUSION: The regimen demonstrated tolerability but not efficacy above that which can be achieved with anti-PD-1 inhibitor monotherapy for R/M HNSCC.

Inhibition of hypoxia-inducible factor-2α in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis.

Hypoxia-inducible factor-2α (HIF-2α) is a transcription factor that frequently accumulates in clear cell renal cell carcinoma (ccRCC), resulting in constitutive activation of genes involved in carcinogenesis. Belzutifan (MK-6482, previously known as PT2977) is a potent, selective small molecule inhibitor of HIF-2α. Maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics and anti-tumor activity of belzutifan were evaluated in this first-in-human phase 1 study (NCT02974738). Patients had advanced solid tumors (dose-escalation cohort) or previously treated advanced ccRCC (dose-expansion cohort). Belzutifan was administered orally using a 3 + 3 dose-escalation design, followed by expansion at the recommended phase 2 dose (RP2D) in patients with ccRCC. In the dose-escalation cohort (n = 43), no dose-limiting toxicities occurred at doses up to 160 mg once daily, and the maximum tolerated dose was not reached; the RP2D was 120 mg once daily. Plasma erythropoietin reductions were observed at all doses; erythropoietin concentrations correlated with plasma concentrations of belzutifan. In patients with ccRCC who received 120 mg once daily (n = 55), the confirmed objective response rate was 25% (all partial responses), and the median progression-free survival was 14.5 months. The most common grade ≥3 adverse events were anemia (27%) and hypoxia (16%). Belzutifan was well tolerated and demonstrated preliminary anti-tumor activity in heavily pre-treated patients, suggesting that HIF-2α inhibition might offer an effective treatment for ccRCC.

Tolerability and antitumor activity of cemiplimab, a human monoclonal anti-PD-1, as monotherapy in patients with pretreated non-small cell lung cancer (NSCLC): Data from the Phase 1 NSCLC expansion cohort.

OBJECTIVES: Blockade of programmed cell death-1 (PD-1) and its ligand (PD-L1) has transformed the treatment of NSCLC. In a first-in-human, Phase 1, dose escalation and cohort expansion study, cemiplimab, a monoclonal antibody directed against PD-1, was evaluated for the treatment of patients with advanced solid tumors (NCT02383212). Here, we report results in patients with advanced NSCLC from the dose expansion cohort. MATERIALS AND METHODS: Immune-checkpoint inhibitor naive patients with advanced NSCLC (stage III/IV), irrespective of PD-L1 status, who had progressed after, or were refractory to first- or later-line therapy were enrolled and received cemiplimab 200 mg every 2 weeks intravenously for up to 48 weeks. Primary study objectives were to assess safety and tolerability, and to evaluate clinical activity of cemiplimab. RESULTS: Twenty patients with NSCLC were enrolled. Median age was 64.0 years (range: 50-82); 65.0 % were male; 80.0 % had an ECOG performance status of 1; 60.0 % had a histology of adenocarcinoma. Median number of prior lines of systemic therapy was 2 (range: 1-4). Median duration of follow-up was 7.0 months (range: 1.0-18.2). All patients experienced ≥1 treatment-emergent adverse event (TEAE) of any grade. Most common TEAEs were arthralgia, asthenia, cough, and dyspnea (each 4/20; 20.0 %). Grade ≥3 TEAEs occurred in 60.0 % (12/20) of patients. Of patients with measurable disease per independent central review (ICR), five had partial response (PR), four had stable disease (SD) and 10 had progressive disease. Objective response rate (ORR; complete response + PR) was 25.0 % (95 % CI: 8.7-49.1 %). Duration of response exceeded 8 months in four of the five responding patients at the time of data cut-off (April 30, 2019). The disease control rate per ICR (ORR + SD) was 50.0 % (95 % CI: 27.2-72.8 %). CONCLUSION: Cemiplimab showed an acceptable safety profile and demonstrated antitumor activity in pretreated patients with NSCLC.

Fixed Dose of Cemiplimab in Patients with Advanced Malignancies Based on Population Pharmacokinetic Analysis.

INTRODUCTION: This study outlined cemiplimab intravenous (IV) dosing strategy to move from body weight (BW)-based 3 mg/kg every-2-week (Q2W) dosing in first-in-human study (study 1423; NCT02383212) to fixed 350 mg every-3-week (Q3W) dosing, utilizing population pharmacokinetics (PopPK) modeling and simulations, and supported by a limited dataset from a phase 2 study (study 1540; NCT02760498). METHODS: Cemiplimab concentration data from a total of 505 patients were pooled from study 1423 in advanced malignancies and study 1540 in advanced cutaneous squamous cell carcinoma (CSCC). All patients received weight-based cemiplimab dose (1, 3, 10 mg/kg Q2W or 3 mg/kg Q3W) except 4% who received 200 mg Q2W. A linear two-compartment PopPK model incorporating covariates that improved goodness-of-fit statistics was developed to compare cemiplimab exposure at 350 mg Q3W versus 3 mg/kg Q2W. Upon availability, observed cemiplimab concentration at 350 mg Q3W in study 1540 was then compared with the simulated values. RESULTS: Post hoc estimates of cemiplimab exposure and variability (505 patients; weight range 30.9-156 kg; median 76.1 kg) at steady state were found to be similar at 350 mg Q3W and 3 mg/kg Q2W. Effect of BW on cemiplimab exposure was described by exposure versus BW plots and at extreme BW. Overlay of individual observed cemiplimab concentrations in 51 patients with metastatic CSCC on simulated concentration-time profiles in 2000 patients at 350 mg Q3W confirmed cemiplimab exposure similarity and demonstrated the robustness of dose optimization based on PopPK modeling and simulations. CONCLUSIONS: Cemiplimab 350 mg Q3W is being further investigated in multiple indications.

Pegilodecakin as monotherapy or in combination with anti-PD-1 or tyrosine kinase inhibitor in heavily pretreated patients with advanced renal cell carcinoma: Final results of cohorts A, G, H and I of IVY Phase I study.

Interleukin (IL)-10 has anti-inflammatory and CD8+ T-cell-stimulating properties. Pegilodecakin (pegylated recombinant human IL-10) induces intratumoral antigen-specific CD8 + T-cells and upregulates IFNγ and major histocompatibility complexes (MHC) I and II. Pegilodecakin has single-agent activity with manageable toxicity in advanced renal cell carcinama (aRCC) (data cutoff 24 March 2016). Pegilodecakin with pembrolizumab or nivolumab revealed clinical activity in aRCC (data cutoff 1 July 2018). Here, we report for the first time the results of pegilodecakin+ pazopanib, and final results for monotherapy and long-term follow-up with pegilodecakin + anti-programmed cell death 1 (anti-PD-1) inhibitors (data cutoff 19 February 2019). Phase 1/1b multi-cohort dose escalation IVY study enrolled 353 patients. Sixty-six patients with aRCC were treated with pegilodecakin alone or with pazopanib or anti-PD-1 inhibitor in cohorts A, G, H and I (data cutoff 19 February 2019). Primary endpoints included safety and tolerability. Secondary endpoint was tumor response by immune-related response criteria (irRC). Pegilodecakin plus nivolumab or pembrolizumab yielded median progression-free survival (mPFS) of 13.9 months and 6-month PFS probability of 60%, 76% 1-year overall survival (OS) probability and 61% 2-year OS probability. Pegilodecakin monotherapy produced mPFS of 1.8 months, 6-month PFS probability 25%, 1-year OS 50%, and 2-year OS 17%. Median OS was not reached in both combinations. Objective response rates (ORRs) were 33% with pazopanib and 43% with anti-PD-1. Most common Grade 3/4 treatment-related adverse events included anemia, thrombocytopenia and hypertriglyceridemia. In these heavily pretreated renal cell carcinama cohorts of IVY, pegilodecakin+anti-PD-1 inhibitor showed promising clinical activity. Safety profile of pegilodecakin alone and with anti-PD-1 inhibitors was consistent as previously reported.

Phase I, first-in-human trial of programmed cell death receptor-1 (PD-1) inhibitor, JTX-4014, in adult patients with advanced, refractory, solid tumors.

BACKGROUND: Inhibition of programmed cell death receptor protein-1 (PD-1) has proven to be a highly effective strategy for immunotherapy of cancer. Approvals of both PD-1 and PD-L1 inhibitors [PD-(L)1i] in multiple tumor types are evidence of the durable benefits they provide to patients with cancer. In this first-in-human trial, we assessed the safety and tolerability of JTX-4014, a fully human antibody targeting PD-1. METHODS: JTX-4014 was administered to 18 patients with multiple solid tumor types who had not previously received a PD-(L)1i. The primary objectives were to evaluate the safety and tolerability of JTX-4014 and determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). Secondary objectives included evaluation of the pharmacokinetics (PK) of JTX-4014, anti-drug antibodies (ADA) against JTX-4014, and clinical activity. RESULTS: JTX-4014 was well tolerated and no new safety signals were identified as compared with other PD-1is. The MTD was not reached and the RP2D was selected, based on PK modelling and supportive safety data, to be 500 mg every 3 weeks or 1000 mg every 6 weeks. Clinical activity, based on RECIST v1.1 criteria, demonstrated an overall response rate of 16.7% (n = 3) with one complete and two partial responses and a disease control rate of 44.4% (n = 8). The responses occurred at different doses in patients with PD-L1 positive tumors and in tumor types that are not typically PD-1i responsive. CONCLUSIONS: Further development of JTX-4014 is warranted as a monotherapy or in combination with other innovative cancer therapies. TRIAL REGISTRATION NUMBER: NCT03790488, December 31 2018.

Immunologic and tumor responses of pegilodecakin with 5-FU/LV and oxaliplatin (FOLFOX) in pancreatic ductal adenocarcinoma (PDAC).

Background Treatment options for pancreatic ductal adenocarcinoma (PDAC) are limited and checkpoint blockade inhibitors have been disappointing in this disease. Pegilodecakin has demonstrated single agent anti-tumor activity in immune-sensitive tumors. Phase 1 and preclinical data indicate synergy of pegilodecakin with 5-FU and platins. We assessed the safety and activity of pegilodecakin+FOLFOX in patients with PDAC. Methods IVY (NCT02009449) was an open-label phase 1b trial in the United States. Here we report on all enrolled patients from cohort C. Heavily pretreated patients were treated with pegilodecakin (self-administered subcutaneously daily at 2.5, 5, or 10 µg/kg) + 5-flurouracil/leucovorin/oxaliplatin (FOLFOX), dosed per manufacturers prescribing information, until tumor progression. Eligible patients had measurable disease per immune-related response criteria (irRC), were ≥ 18 years of age, and had ECOG performance status of 0 or 1. Patients were evaluated for primary(safety) and secondary (tumor response per irRC) endpoints. Results From 5 August 2014-12 July 2016, 39 patients enrolled in cohort C. All patients were evaluable for safety. In this advanced population, regimen had manageable toxicities with no immune-related adverse events (irAEs) greater than grade 1. The most common grade 3/4/5 TEAEs were thrombocytopenia (21[53.8%] of 39) and anemia (17[43.6%] of 39). In evaluable PDAC patients, the best overall response of pegilodecakin+FOLFOX was 3(14%) with CRs in 2(9%) patients. Conclusions Pegilodecakin+FOLFOX had an acceptable tolerability profile in PDAC, with no substantial irAEs seen, and promising efficacy with the combination yielding a 2-year OS of 24% (95% CI 10-42). These data led to the phase 3 study with pegilodecakin+FOLFOX as second-line therapy of PDAC (SEQUOIA).

Phase I Study of MK-4166, an Anti-human Glucocorticoid-Induced TNF Receptor Antibody, Alone or with Pembrolizumab in Advanced Solid Tumors.

PURPOSE: In this first-in-human phase I study (NCT02132754), we explored MK-4166 [humanized IgG1 agonist mAb targeting glucocorticoid-induced TNF receptor (GITR)] with and without pembrolizumab in advanced solid tumors. PATIENTS AND METHODS: MK-4166 was tested alone (0.0015-900 mg i.v. every 3 weeks for four doses) or with pembrolizumab (200 mg i.v. every 3 weeks for ≤35 doses) in patients with metastatic solid tumors (dose escalation/confirmation) and advanced melanoma (expansion). Primary objectives were to evaluate the safety and tolerability and establish the MTD of MK-4166. Exploratory endpoints were objective response rate (ORR) and T cell-inflamed gene expression profile (GEP) analysis using RNA from baseline tumor samples. RESULTS: A total of 113 patients were enrolled [monotherapy, n = 48; combination therapy, n = 65 (20 in the expansion)]. Forty-six patients (40.7%) had grade ≥3 adverse events, 9 (8.0%) of which were treatment related. No treatment-related deaths were observed. One dose-limiting toxicity event with monotherapy (bladder perforation in patient with neobladder) was considered related to study drug. MTD was not reached. MK-4166 pharmacodynamics showed decreased GITR availability on circulating T cells with increasing doses. One objective response (ORR, 2.2%) was achieved with combination therapy in the dose escalation/confirmation (n = 45). In the expansion, 8 of 13 patients with immune checkpoint inhibitor (ICI)-naïve melanoma achieved a response (ORR, 62%; 95% confidence interval, 32-86; 5 complete responses and 3 partial responses). None of the ICI-pretreated patients (n = 7) responded. High response rates were observed in ICI-naïve patients irrespective of GEP status. CONCLUSIONS: MK-4166 900 mg i.v. every 3 weeks as monotherapy and with pembrolizumab was tolerable. Responses were observed with combination therapy, mostly in patients with ICI-naïve melanoma.