Purpose/Objective(s) In the phase 3 ADRIATIC study (NCT03703297) in patients (pts) with LS-SCLC without progression after concurrent chemoradiotherapy (cCRT), D as consolidation tx significantly improved OS and PFS vs placebo (P) at the first planned interim analysis. D was well tolerated and AEs were consistent with the known safety profile. Here we present pneumonitis/radiation pneumonitis and imAEs. Materials/Methods 530 eligible pts with stage I–III LS-SCLC (stage I/II inoperable), WHO PS 0/1, and no progression after cCRT, were randomized 1–42 days after cCRT to D 1500 mg or P every 4 weeks until investigator-determined progression or intolerable toxicity, or for a maximum of 24 months. Safety was a secondary endpoint. Given the similar clinical presentation of pneumonitis resulting from prior RT (radiation pneumonitis) or immunotherapy (immune-mediated pneumonitis), these events were analyzed as a grouped term to better estimate their frequency. imAEs were also assessed. Results 262 pts received D and 265 received P. Pneumonitis/radiation pneumonitis (preferred terms of immune-mediated lung disease, interstitial lung disease, pneumonitis, radiation fibrosis–lung, and radiation pneumonitis) occurred in 38% (n=100) vs 30% (n=80) of pts in the D vs P arm (maximum grade 3/4 3% vs 3%; grade 5 0.4% vs 0%; leading to tx discontinuation 9% vs 3%). Median time from first study drug dose to onset (mTTO) of pneumonitis/radiation pneumonitis was 56 days (range 1–594) vs 56 days (2–228) in the D vs P arm; 40/100 events in the D arm and 23/80 in the P arm had resolved at data cutoff (Jan 15, 2024). imAEs occurred in 32% vs 10% of pts in the D vs P arm (maximum grade 3/4 5% vs 2%; grade 5 0.4% vs 0%; leading to tx discontinuation 7% vs 3%). 14% vs 6% of pts in the D vs P arms received high-dose steroids and 1% vs 0.4% received immunosuppressants to manage imAEs. The table shows mTTO, resolution, and median time to resolution (mTTR) for the most common imAEs. Conclusion In ADRIATIC, pneumonitis/radiation pneumonitis was common in both arms in this population who had received prior RT, and imAEs were as expected in the D arm; these events were mainly low grade and led to low rates of tx discontinuation, supporting the favorable benefit-risk profile for consolidation D after cCRT in LS-SCLC.

Lurbinectedin (Zepzelca®), a selective inhibitor of oncogenic transcription, received accelerated approval from the US Food and Drug Administration on June 15, 2020, as monotherapy (3.2 mg/m2 by 1-hour IV infusion every 3 weeks) for the treatment of adults with metastatic small-cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy. Approval was based on overall response rate (ORR; 35.2%) and median duration of response (5.3 months) in a phase 2 study. In addition to SCLC, antitumor activity with lurbinectedin as monotherapy or in combination with additional therapeutic agents has been observed in other advanced solid tumors. The EMERGE-201 study will evaluate the efficacy and safety of lurbinectedin monotherapy in adults with advanced (metastatic and/or unresectable) large-cell neuroendocrine tumor (LCNET) of the lung, as well as in other advanced (metastatic and/or unresectable) solid tumors with high unmet medical needs, including urothelial cancer (UC) and homologous recombination–deficient (HRD) tumor-agnostic malignancies.

Galectin-9 (gal9) is a promising novel target for the treatment of both solid tumors and hematologic malignancies. When overexpressed, gal9 has broad immunosuppressor effects disabling immune-mediated cancer attack via T cell modulation, macrophages and other immune functions. LYT-200 is a fully human, anti-gal9, IgG4 monoclonal antibody that blocks gal9 mediated immunosuppression and protumor function. Safety, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of LYT-200 are being assessed in this Phase 1/2 trial (NCT04666688) in advanced solid tumors as monotherapy and in combination with a PD-1 inhibitor, tislelizumab (TIS) in patients (pts) with relapsed, refractory head and neck squamous cell carcinoma (HNSCC) or urothelial cancer (UC) where gal9's role is thought to be prominent. In monotherapy, 20 pts received IV LYT-200 in 7 escalation dose cohorts of 0.2 mg/kg to 16 mg/kg Q2W or 10 mg/kg QW. Median prior regimens (MPR) were 4 (1-7). No DLTs or LYT-200 related SAEs or G≥3 AEs were seen. LYT-200 related AEs of G≤2 were seen in 5 pts. 2 infusion related reactions (IRR) occurred in pts with IRRs on prior treatment. Single-agent cohorts have completed with 10 mg/kg QW selected as clinically relevant dose. Of 19 RECIST evaluable pts, 3 had stable disease (SD): 2 pancreatic cancer pts at 2 mg/kg QW and 6.3 mg Q2W with SD for 18 and 4 months (mo), and a colorectal cancer pt for 13 mo at 10 mg/kg QW. In the initial LYT-200/TIS combination cohort (LYT-200 6.3 mg/kg QW + TIS 300 mg Q4W) 6 pts have started treatment with 4 RECIST evaluable to date. MPR was 3 (1-5). No DLTs, irAEs or treatment related SAEs or G≥3 AEs. Of the 3 evaluable HNSCC pts, there have been 2 responses: 1 CR on treatment 9+mo and 1 PR on treatment 8+ mo. The 1 evaluable UC pt has had SD for 4+ mo, with near resolution of pleural effusion and ascites. LYT-200 has linear, dose-proportional PK. Geometric mean LYT-200 half-life is 6.6 days, supporting QW dosing. LYT-200 has an acceptable safety profile in monotherapy and TIS combination, with observed antitumor activity in R/R pts who historically have very low response rates to an anti-PD1 agent alone. Enrollment into LYT-200 + TIS arms continues. The presentation will include additional safety, PK, PD and efficacy data.

Immunotherapy alone or combined with chemotherapy (CT) has transformed first-line treatment of metastatic NSCLC. Nevertheless, median PFS typically remains <1 year in clinical studies, highlighting the need for novel treatment strategies. Increased DNA damage triggered through poly (ADP-ribose) polymerase (PARP) inhibition may modify tumour immunogenicity, sensitising tumours to immunotherapy. ORION evaluates the efficacy and safety of durvalumab (D; PD-L1 inhibitor) plus olaparib (O; PARP inhibitor) as maintenance therapy.

Targeted agents have activity against indicated tumors, but data are limited in other tumor types with relevant alterations. MyPathway (NCT02091141) is a tissue-agnostic, non-randomized, phase IIa multiple basket trial assessing targeted agent activity for advanced solid tumors with matched alterations but no FDA indication. We previously reported objective response rates (ORR) from MyPathway in pts with HER2 amplification and/or overexpression (23.3%; pertuzumab + trastuzumab [P+H]), tumor mutational burden ≥16 mut/Mb (TMB-H; 38.1%; atezolizumab), and ALK rearrangements and alterations (30% and 0%; alectinib).

Despite intrinsic resistance to immunotherapy, some NSCLC tumors are susceptible to T-cell-mediated antitumor effects. Targeting multiple cancer immunity processes may enhance response in relapsed or refractory NSCLC. The CD226 Axis includes the T- and NK-cell inhibitory receptors TIGIT, CD96, and PVRIG (CD112R); the T-/NK-cell activating receptor CD226 (DNAM-1); and cognate ligands CD155 (PVR) and CD112. These immune receptors play a critical role regulating antitumor responses. The immune checkpoints TIGIT, CD96, and PVRIG may prevent CD226’s interactions with CD155 and CD112, directly impairing NK- and T-cell function; this impairment reduces antitumor response.

RP-3500 is an oral inhibitor of ATR (ATRi) in development for the treatment of patients (pts) with advanced solid tumors carrying alterations in ATRi-sensitizing genes. We report popPK co-variates and effect on QT prolongation in 120 pts treated with RP-3500 in the phase 1 TRESR study (NCT04497116). PK samples were collected from 120 pts on multiple days across doses and schedules during the dose-finding portion of the study. Pt demographics and baseline characteristics were collected at study enrollment. Triplicate electrocardiograms (ECGs) were collected prior to any drug administration and in conjunction with PK sampling at time points up to 4 hr post-RP-3500 dose. A popPK model was developed using Phoenix WinNonLin. PK co-variates were analyzed to assess the effect of age, sex, body weight (BW), body surface area (BSA), and renal/hepatic function on RP-3500 PK. Changes in ECG parameters were evaluated in an ER assessment. Plasma PK samples (N=2627) from 120 pts were analyzed; 85 pts were sampled on at least 3 different days. The PK data set encompassed an RP-3500 dose range of 5–200 mg QD and BID across 2 different weekly regimens: 5 days on/2 days off, 3 days on/4 days off. RP-3500 PK was well described using a 2-compartment model with a lag-time incorporated to accurately describe drug absorption. Preliminary co-variate analysis suggested some variation in RP-3500 PK according to BW and BSA. There was no significant impact on PK values in patients with mild renal or hepatic impairment. Among patients with moderate renal impairment, a small reduction in clearance was observed with limited impact on other compartmental PK values. Results of the initial ER assessment showed no RP-3500-related changes in QT intervals. These popPK results from TRESR confirm a predictable RP-3500 PK profile with low variability. Importantly, the data indicate that RP-3500-induced changes in QT are unlikely, and strongly support further clinical development of RP-3500 with limited ECG evaluation. Further investigation into the potential need for moderate renal impairment-, BW- or BSA-adjusted RP-3500 dosing is ongoing.

RP-3500 is an oral ATR inhibitor (ATRi) in development for the treatment of patients (pts) with advanced solid tumors carrying alterations in ATRi-sensitizing genes. The dose-escalation portion of the TRESR study (NCT04497116) evaluated RP-3500 5–200 mg once daily (QD) or twice daily at defined intermittent schedules in 120 pts. RP-3500 plasma levels were assessed and PK parameters were determined by non-compartmental analysis (Phoenix WinNonLin) in pts with evaluable plasma concentration-time points. To determine the effect of food on RP-3500 PK, 12 pts received a single dose of RP-3500 following a standard high-fat meal on Day -3 and after a 24-hr fast on Day 1. Serial blood samples were collected for PK analysis at baseline and after RP-3500 administration. 120 pts had sufficient data on day 1, cycle 1, to report PK parameters. Overall, 323 plasma concentration-time profiles were collected. Plasma exposure was dose-linear with low within-pt variability and a T½ of ∼6 hr. No accumulation of RP-3500 was observed after multiple doses were given. At therapeutic doses of 120 mg and 160 mg QD on day 1, cycle 1, mean AUC0-24 was 33.6 and 48.2 μg٠hr/mL, respectively, and mean Cmax was 5.74 and 7.64 μg/mL, respectively. Within the therapeutic dose range, median Tmax was 2 hr (range 0.5–6). When administered with a high fat meal, RP-3500 median Tmax was delayed by 3 hrs and mean Cmax was reduced by 45% compared with fasting values within this cohort. Mean AUC0-24 was 16% lower compared with AUC0-24 in the fasted state. Importantly, the plasma levels required for the pharmacological activity of RP-3500 did not substantially differ between the fed and fasted states. The PK profile of RP-3500 is predictable with low observed variability. RP-3500 given orally to pts at recommended doses of 120-160 mg QD on 3 days/week, with or without food, reaches or exceeds preclinically defined target exposure requirements (Roulston et al., Mol Cancer Ther. 2021). RP-3500 can be administered with or without food without affecting PK parameters relevant to tolerability and therapeutic window.

Dose-finding studies typically establish a maximum tolerated dose, a recent shift from this "more is better" approach towards long-term tolerability is of interest. The ongoing RP-3500 TRESR study (NCT04497116) used a comprehensive, non-randomized, dose-finding approach, focusing on longer-term tolerability to establish a patient (pt)-specific therapeutic dose level. Bayesian Optimal Interval-based dose escalation was informed by preclinical in vivo pharmacokinetic (PK)/pharmacodynamic (PD) models (LoVo/Granta-519), clinical PK, PD biomarkers (γ-H2AX), circulating tumor DNA (ctDNA) and safety data. The optimal recommended phase 2 dose (RP2D) schedule (3 days (d) on/4d off) and efficacious dose level (>100mg) for target inhibition were chosen based on pre-clinical and clinical PK and safety data. Decrease in ctDNA mean variant allele frequency (mVAF) was a surrogate of RP-3500 activity. PK/PD modelling contributed to RP2D selection. Hematology data within Cycle 1 were used to develop a nomogram to mitigate anemia, an on-target toxicity. Pts (N=120) with recurrent tumors with selected ATR-inhibitor–sensitizing DNA damage response alterations were enrolled in the dose-escalation portion of TRESR. A subset of pts in three dose-expansion cohorts (N=25/34/26) below the highest evaluated, non-tolerated dose (200mg, 3d on/4d off) was assessed for long term safety (Table).Table: 5MORP-3500 safety120 mg QD, (3d on/4d off) continuous (N=25)160 mg QD, (3d on/4d off) continuous (N=34)160 mg QD, (3d on/4d off) 2 wks on/1 wk off (N=26)Number of cycles completed (median, range)3 (1–9)2 (0–12)2 (0–8)Pts with any Grade 3 anemia, %242615Pts with Grade 3 anemia with transfusion, %16188Reticulocyte maximum decrease in Cycle 1 (median %)576577Monocyte maximum decrease in Cycle 1 (median %)506060RP-3500-related non-hematological Grade 3 toxicity, %430Pts with any dose reduction, %12214ctDNA mVAF decrease in Cycle 2 (%)64.7 (N=17)64.3 (N=14)75.0 (N=4) Open table in a new tab This dose optimization approach using large pt cohorts at three dosing regimens provides robust evidence to support RP-3500 RP2D in the ongoing studies (160mg, 3d on/4d off, continuous). Consistency of ctDNA mVAF decrease across cohorts supports the selected RP-3500 dose level. The hematological toxicity nomogram currently in early clinical testing will guide individualized treatment modifications to further reduce anemia rates while maintaining the therapeutic range of 120-160 mg of RP-3500.

NRG1 (Neuregulin-1) gene fusions are rare oncogenic drivers found in 0.2% of solid tumors, including lung, pancreatic, gallbladder, breast, ovarian, colorectal, neuroendocrine, and sarcomas. NRG1 is the predominant ligand of HER3 and to a lesser extent HER4. NRG1 fusion proteins retaining an active EGF-like domain drive tumorigenesis and proliferation through aberrant HER3 activation. Importantly, NRG1 fusions are often mutually exclusive with other known driver alterations. NRG1 fusions have been correlated with worse overall and disease-free survival and poor response to treatment with standard therapies including chemotherapy, PD-(L)1 checkpoint inhibitors and combinations of these agents. Inhibition of HER3 and its dimerization partners represents a rational and novel therapeutic approach for tumors harboring an NRG1 fusion supported by case studies of clinical responses to anti-HER3 antibodies or pan-ERBB (tyrosine kinase inhibitors) TKIs like afatinib. Seribantumab is a fully human IgG2 mAb against HER3 uniquely able to inhibit NRG1-dependent activation of HER3, HER3-HER2 dimerization, and downstream signaling through the PI3K/AKT and MAPK pathways. The clinical safety profile of seribantumab has been well characterized through prior monotherapy and combination studies in over 800 patients. CRESTONE is an open label, multicenter Phase 2 basket trial of seribantumab in adult patients with NRG1 fusion-positive locally advanced or metastatic solid tumors who have progressed on or are nonresponsive to available therapies. The trial will enroll at least 75 previously treated patients across three cohorts. Cohort 1 (N=55) will include patients who have not received prior treatment with any ERBB targeted therapy. Cohort 2 (up to N=10) will include patients who have progressed after prior treatment which includes ERBB targeted therapy. Cohort 3 (up to N=10) will include patients harboring NRG1 fusions without an EGF-like binding domain. NRG1 fusion status for enrollment will be determined through a local CLIA or similarly accredited molecular assay. NRG1 fusion status for patients in Cohort 1 will be centrally confirmed using an RNA-based NGS assay. This study will evaluate a novel dosing regimen of weekly induction, biweekly consolidation, and Q3W maintenance designed to rapidly achieve steady state levels, optimize exposure, and deliver maximal NRG1 inhibition. The primary endpoint is ORR per RECIST v1.1 by independent radiologic review. Secondary endpoints include duration of response (DoR), safety, PFS, OS, and overall clinical benefit rate. An interim analysis is planned following enrollment of 20 patients in Cohort 1. CRESTONE is open and accruing patients in the United States. Clinical trial information: NCT04383210.