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BackgroundNKTR-255 is an investigational IL-15Rα-dependent, polymer-conjugated, recombinant human IL-15 agonist designed to provide sustained pharmacodynamic (PD) responses without the need for daily dosing. NKTR-255 engages all IL-15 receptor binding complexes to expand, proliferate and activate natural killer (NK) and CD8+ T-cells. This Phase 1b/2 trial (NCT04616196) evaluates NKTR-255+cetuximab in highly refractory patients with head-and-neck squamous cell carcinoma (HNSCC) or colorectal cancer (CRC).MethodsSuccessive cohorts received escalating doses of NKTR-255 (q3w) +cetuximab (250mg/m< sup >2 weekly), 1 week after a loading dose of cetuximab alone. Safety (CTCAEv5.0; MTD/recommended Phase 2 dose [RP2D]) and efficacy (RECISTv1.1) were measured. PK/PD analyses were conducted, including assessment by flow cytometry/plasma cytokine analysis. Fold-change was calculated as treatment over baseline for NKTR-255 (baseline=1).ResultsAs of August 15, 2021, 12 patients had received ≥1 dose of NKTR-255+cetuximab; (37–70 years; 92% male; HNSCC n=4, CRC n=8; NKTR-255 1.5µg/kg n=7, NKTR-255 3.0µg/kg n=5). Patients had received a median 3.5 lines of prior therapy for metastatic disease. 11 patients had no response to the most recent prior therapy. Of the 12 patients, seven remain on treatment, with five not yet reaching first scan. RP2D has not yet been reached; dose escalation is ongoing.10 patients experienced an AE; one G5 AE occurred (due to progression). Seven patients reported NKTR-255-related AEs (all G1-2, except one G3 [which resolved in 24 hours]). Any-cause AEs in ≥20% were acneiform dermatitis, fatigue, and infusion-related reaction.Treatment-induced transient changes in inflammatory cytokines, including IFNy, MCP-1 and IL-6, at 1.5µg/kg (n=3) peaked 4 hours post-infusion and resolved by 24-48 hours. Mean T1/2 of NKTR-255 (1.5µg/kg dose, first cycle) was 27.8 hours.Dose-dependent expansion of NK and CD8+ T-cells was observed in peripheral blood. For NK cells, mean peak fold-change was ~4-fold and ~6-fold, and for CD8+ T-cells was ~2-fold and ~3-fold (1.5µg/kg and 3µg/kg dose levels, respectively). NK and CD8+ T-cells demonstrated increased Ki67+ proliferative ability.As of August 15, four patients in the 1.5µg/kg NKTR-255 dose cohort were response-evaluable: one CRC patient (4 prior metastatic treatment lines) reported a confirmed PR (–52%) after 3 cycles; two HNSCC patients reported SD.ConclusionsNKTR-255 was biologically active and led to expansion and proliferation of NK and CD8+ T-cells. Early dose-escalation data suggest that NKTR-255+cetuximab is safe and tolerable with preliminary anti-tumor activity. Updated data will be presented. NKTR-255, alone and in combination with daratumumab and rituximab, is also being evaluated in liquid tumors.AcknowledgementsThe authors thank the patients and their families involved in the trial.Trial RegistrationNCT04616196Ethics ApprovalThe study was approved by site IRBs.ConsentN/A

BackgroundTHOR-707 (SAR444245) is a recombinant human IL-2 molecule irreversibly bound to a PEG chain to block alpha-binding while retaining near-native affinity for beta/gamma IL-2 receptor subunits. We report updated results from the ongoing HAMMER phase 1/2 trial.MethodsSAR444245 was given via IV infusion as monotherapy Q2W [A] or Q3W [B], with pembrolizumab 200mg IV Q3W [C], or Q3W with cetuximab 400mg/m2 IV on D1 then 250mg/m2 IV QW [D] after pre-medication and peri-infusion hydration. A 3+3 design was used to identify the MTD/RP2D in pts with advanced solid tumors. Key objectives included assessments of safety, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD).Results68 pts, median age 61.5 (37–78) yrs with median 3 (1–10) prior therapies enrolled. Most common tumors: melanoma (n=10), colorectal (n=11). Doses tested by cohort: [A]: 8–16 µg/kg (n=9); [B]: 8–40 µg/kg (n=29); [C]: 8–32 µg/kg (n=20); [D]: 16–24 µg/kg (n=10). The most common (>30%) AEs included pyrexia (52.5%), nausea (50.0%), flu-like symptoms (44.1%), vomiting (36.8%), chills (32.4%), fatigue (32.4%), AST elevation (30.9%). AEs generally resolved promptly with supportive care. Grade(G) 3/4 (>5%) related AEs included ALT/AST elevation (5.9%), and decreased lymphocyte count (26.5% within first 24 hrs, recovering by 48–72 hrs, this lymphocyte migration is mechanistically consistent with immune cell margination). G3/4 CRS was observed in 2 pts. Two DLTs occurred: G3 infusion reaction (32 µg/kg [B]) and G3 AST/ALT/G2 bilirubin elevation with G2 CRS (24 µg/kg [C]). No vascular leak syndrome, QTc prolongation, cardiac, or end organ toxicity was observed. Half-life was ~10 h. Sustained increases in CD8 T and NK cells were observed (fold relative to baseline): monotherapy (1–9.4x and 2–43.3x); with pembrolizumab (0.5–5.78x and 1.5–26.9x); with cetuximab (1.3–7.57x and 3.6–45.4x). Max CD4 and eosinophils increased to 136 cell/µL and 1078 cell/µL. No IL-5 elevation or ADAs were observed. Transient IL-6 increases in 4 pts (500, 627, 1000, 1100 pg/mL) were not associated with AEs. Four pts had confirmed PRs (1 PD1-treated SCC, unknown primary [B]; 2 PD1-naïve BCC and 1 PD1-treated HNSCC [C]); 3 pts had minor responses -- prostate (-24%) and PD1-treated melanoma (-17%) [B]; PD1-treated NSCLC (¬-29%) [C] -- after ≥2 scans. 23 pts completed ≥5 cycles.ConclusionsSAR444245 was well tolerated and demonstrated antitumor activity in heavily pretreated patients, including prior checkpoint inhibitor therapy. Clinical safety, efficacy and PD suggest a wide therapeutic window. Combination with pembrolizumab and cetuximab leveraged SAR44245’s effects on CD8 T and NK cells.Trial RegistrationNCT04009681Ethics ApprovalThe clinical trial was approved by each institutions ethics’ and review board prior to beginning study enrollment.

BackgroundPancreatic cancer (PaC) is immune-quiescent and resistant to single-agent checkpoint inhibitor (CPI). NT-I7 (efineptakin alfa) is the first-in-class long-acting IL-7 that can increase T-cell infiltration in the tumor microenvironment (TME) and may enhance tumor responsiveness to CPI therapy. We hypothesize that the combination of NT-I7 and pembrolizumab may result in enhanced efficacy in CPI-naïve advanced PaC.MethodsThis is an open-label, phase 2a, study in subjects with relapsed/refractory (R/R) tumors, including CPI-naïve R/R PaC. Subjects received NT-I7 intramuscularly at 1200 µg/kg every 6 weeks (Q6W) plus pembro 200 mg intravenously Q3W. Antitumor activity based on Overall Response Rate (ORR) was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Biomarker analyses of peripheral blood and tumor biopsies were performed.ResultsAs of 15-July-2021, 26 subjects were enrolled in the CPI naïve R/R PaC cohort. Median age 69 years [31–81], ECOG PS 0 (35%), 1 (65%). Twenty-one (81%) subjects had ≥ 2 prior therapies All subjects had metastatic or locally advanced disease at enrollment. The median duration of follow-up was 3.3 months. Among 10 subjects with at least 1 post-treatment tumor assessment, the RECIST1.1-based ORR and disease-control rate (DCR) were 10% and 50%, respectively. One subject with MSS and TMB of 1, achieved a confirmed partial response (cPR) with 65% tumor reduction and drastically improving CA19-9. Treatment-related adverse events (AEs) occurred in 14 (53.8%) subjects, 9 (34.6%) G1–2, 3 (11.5%) G3; 2 (7.7%) G4; no G5 AEs were reported. No subjects discontinued from treatment due to AE. NT-I7 + pembro elicited a significant increase in the peripheral absolute lymphocyte count that peaked at week 3 (>3X from baseline, p15X, pConclusionsThe chemo-free combination of NT-I7 + pembro was well tolerated and showed promising anti-tumor activity in subjects with CPI-naïve R/R PaC. Increased TSCM and CD8+ T-cell infiltration within TME may be the underlying mechanisms of action for the observed efficacy. These results support continued evaluation of NT-I7 + pembro in subjects with CPI-naïve R/R PaC.AcknowledgementsThe authors thank ICON for their partnership in conducting this trial.Trial RegistrationNCT04332653Ethics ApprovalThe trial was approved by MD Anderson IRB (#2020–0008_MOD001), Mary Crowley IRB (#20–13) and Advarra IRB (#Pro00042639)All participant gave informed consent prior to study enrollment.

BackgroundCheckpoint inhibitor (CPI) monotherapy is ineffective for microsatellite stable colorectal cancer (MSS-CRC). NT-I7 (efineptakin alfa) is the first-in-class long-acting IL-7 that can increase T-cell infiltration in the tumor microenvironment (TME). We hypothesize that NT-I7 may create a favorable immune-reactive TME to enhance the efficacy of CPI when combined with pembrolizumab (pembro).MethodsThis is an open-label, phase 2a study in subjects with relapsed/refractory (R/R) tumors, including CPI-naïve R/R MSS-CRC. Subjects received the recommended-phase-2-dose of NT-I7 intramuscularly at 1200 µg/kg every 6 weeks (Q6W) plus pembro 200 mg intravenously Q3W. Preliminary anti-tumor activity based on Overall Response Rate (ORR) was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as a primary objective and by iRECIST as an exploratory objective. Biomarker analyses in peripheral blood and tumor biopsies were performed.ResultsAs of 15-July-2021, 19 subjects were enrolled in the CPI-naïve R/R MSS-CRC cohort. Six subjects are ongoing. Median age 58 years [37–81], ECOG PS 0 (26%), 1 (74%). Sixteen (84%) subjects received ≥ 2 prior therapies. All subjects had metastatic or locally advanced disease at enrollment. The median duration of follow-up was 4.64 months. Among 15 evaluable subjects, disease-control rate (DCR) based on RECIST1.1 was 47% and 1 subject achieved partial response per iRECIST (iPR) with 33% tumor reduction. Treatment-related adverse events (AEs) occurred in 14 (73.7%) subjects, 9 (47.4%) G1–2 events and 5 (26.3%) G3 events; no G4 or G5 AEs were reported. No subjects discontinued from the study due to AE. NT-I7 + pembro elicited a significant increase in the absolute lymphocyte count that peaked at week 3 (>3X from baseline, p25X from baseline, pConclusionsThe chemo-free combination of NT-I7 + pembro was well tolerated and showed encouraging anti-tumor activity in subjects with CPI-naïve R/R MSS-CRC. Increased TSCM and CD8+ T-cell infiltration in TME may be the underlying mechanisms of action for the observed efficacy. These results support continued evaluation of NT-I7 + pembro in CPI-naïve subjects with R/R MSS-CRC.AcknowledgementsThe authors thank ICON for their partnership in conducting this trial.Trial RegistrationNCT04332653Ethics ApprovalThe trial was approved by MD Anderson IRB (#2020–0008_MOD001), Mary Crowley IRB (#20–13) and Advarra IRB (#Pro00042639)All participant gave informed consent prior to study enrollment.

BackgroundTransforming growth factor-beta 1 (TGFβ1) plays an important role in mediating the primary resistance to PD-1/PD-L1 [PD-(L)1] blockade. SRK-181 is a fully human monoclonal antibody that selectively inhibits latent TGFβ1 activation. Mouse tumor models (bladder, melanoma, and breast cancer) demonstrated that treatment with SRK-181+anti-PD-1 overcame primary anti-PD-1 resistance. Four-week GLP nonclinical toxicology studies showed that SRK-181 has improved safety profile (no cardiotoxicities) compared to broad TGFβ pathway inhibition.MethodsThe DRAGON trial (NCT04291079) is an ongoing open-label, phase 1 study. Part A of the study follows a standard 3+3 dose escalation design to determine the dose for Part B. Part B (expansion phase) evaluates combination treatment in patients with non-small cell lung cancer (NSCLC), urothelial carcinoma, melanoma, or other advanced solid tumors. SRK-181 is administered IV every 3 or 2 weeks (Q3W/Q2W) alone in patients with advanced solid tumors (Part A1), or in combination with anti-PD-(L)1 in patients who did not respond to prior anti-PD-(L)1 therapy (Part A2/B).ResultsAs of 7 June 2021, 25 patients have enrolled to Part A; median 4 prior lines of therapies (range 1–9). Cancer types: colorectal, ovarian, prostate, and unknown primary (Part A1); liver, melanoma, NSCLC, oropharynx, renal cell carcinoma (RCC) and uterine (Part A2). In Part A1, 15 patients were treated with SRK-181 monotherapy at doses of 80, 240, 800, 1600, 2400, 3000mg Q3W, with no dose limiting toxicity (DLT) observed. The last cohort (2000mg Q2W) remains under evaluation. The most common treatment-related AEs (TRAE, >10%) of any grade were decreased appetite and fatigue (each: 13.3%, n=2). Six patients had stable disease (SD) as best response (2/colorectal cancer, 1/prostate cancer, and 3/ovarian cancer). Three ovarian cancer patients were stable ≥153 days with tumor regressions. In Part A2, 10 patients were treated with SRK-181 at doses of 240, 800 and 1600mg Q3W+pembrolizumab. No DLT was observed up to 800mg. 1600mg Q3W is under evaluation. No TRAE (>10%) of any grade were observed. One confirmed RECIST1.1 partial response (PR) was observed (800mg) in a patient with anti-PD-1 resistant RCC and 2 patients had best response of SD (1/oropharynx cancer, 1/liver cancer). The half-life of SRK-181 ranged from 3.9 to 19.3 days across the doses tested.ConclusionsAs of 7 June 2021, SRK-181 has been well tolerated as monotherapy and in combination with anti-PD-(L)1. One RECIST1.1 PR (800mg) was observed in a patient with anti-PD-1 resistant RCC. Next planned dose in Part A2 will be 2400mg Q3W.Trial RegistrationDRAGON trial (NCT04291079)Ethics ApprovalThe human study was approved by the Massachusetts General Hospital and Beth Israel Deaconess Medical Center (20–286), Sarah Cannon Research Institute (1276118), Mary Crowley Cancer Research (20–06), MD Anderson Cancer Center (2020–0110) Institutional Review Boards with written informed consent obtained from each participant and/or their legal representative, as appropriate.