Abstract
Background
LHC165 is a Toll-like receptor (TLR)-7 agonist that generates an effective tumor antigen-specific T-cell adaptive immune response as well as durable antitumor responses. We aimed to evaluate the safety, tolerability, efficacy, dose-limiting toxicities, and pharmacokinetics (PK) of LHC165 single agent (SA) ± spartalizumab [PDR001; anti-programmed cell death protein 1 (PD-1)] in adult patients with advanced solid tumors.
Materials and methods
In this phase I/Ib, open-label, dose-escalation/expansion study, patients received LHC165 SA 100-600 μg biweekly through intratumoral (IT) injection and LHC165 600 μg biweekly + spartalizumab 400 mg Q4W through intravenous (IV) infusion.
Results
Forty-five patients were enrolled: 21 patients received LHC165 SA, and 24 patients received LHC165 + spartalizumab. The median duration of exposure was 8 weeks (range 2-129 weeks). No maximum tolerated dose was reached. Recommended dose expansion was established as LHC165 600 μg biweekly as SA and in combination with spartalizumab 400 mg Q4W. The most common drug-related adverse events (AEs) were pyrexia (22.2%), pruritus (13.3%), chills (11.1%), and asthenia (4.4%). The only serious AE (SAE) suspected to be related to the study drug was grade 3 pancreatitis (n = 1). Across all tumor types, overall response rate and disease control were 6.7% and 17.8%, respectively. Overall median progression-free survival (PFS) and immune-related PFS was 1.7 months. LHC165 serum PK demonstrated an initial rapid release followed by a slower release due to continued release of LHC165 from the injection site.
Conclusions
LHC165 demonstrated acceptable safety and tolerability both as SA and in combination with spartalizumab, and evidence of limited antitumor activity was seen in adult patients with relapsed/refractory or metastatic solid tumors.
Key words: LHC165, TLR7 agonist, PDR001, advanced solid tumors
Highlights
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This is a first-in-human study of LHC165, an IT TLR agonist, in adult patients with advanced malignancies.
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LHC165 showed limited antitumor activity and acceptable safety with/without spartalizumab, an IV PD-1 inhibitor.
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AEs with LHC165 therapy were generally mild to moderate, manageable with dose reductions and treatment delays.
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The recommended dose for expansion was LHC165 600 μg biweekly IT and spartalizumab 400 mg every 4 weeks IV.
Introduction
Toll-like receptors (TLRs) are pattern recognition receptors1 that bridge innate and adaptive immunity by initiating immune signaling in response to pathogen-associated molecular patterns and damage-associated molecular patterns.2,3 TLR-7 receptors are predominantly expressed in plasmacytoid dendritic cells (DCs) within intracellular endosomes and bind to single-strand RNA.4,5 Upon ligand binding, TLR-7 undergoes conformational changes that recruit the downstream adaptor protein myeloid differentiation factor 88, resulting in the release of nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) from its inhibitor.6 NF-κB translocates to the nucleus, inducing the expression of inflammatory cytokines such as interleukin-1 (IL-1), IL-6, and type 1 interferons (IFNs). This activates IFN production regulator-positive antigen-presenting cells (APCs) and, subsequently, type 2 IFNs and effector T cells, thereby enhancing the antitumor immune response.6
TLR-7 agonism can promote antitumoral immunity by activating innate immune cells in the tumor microenvironment (TME), enhancing antigen presentation, and reversing antitumor immunosupression.7 Synthetic TLR agonists have shown to induce strong cytokine responses, resulting in the polarization of the TME and antitumor activity.8
LHC165, a TLR-7 agonist administered intratumorally (IT), has the potential to initiate immune surveillance conditions in the TME, promoting effective systemic antitumor-specific immunity at the injected and distal untreated sites. A preclinical study of LHC165 demonstrated antitumor activity, sustained IT retention, a large therapeutic window, and the abscopal effect in mice.9 Compared with systemic administration,10,11 IT administration of LHC165 adsorbed to aluminum hydroxide has shown extended retention at the injection site, reduced systemic exposure, localized immune priming, and less systemic inflammation. Such localized delivery to the TME may be more effective and better tolerated than systemic dosing of innate immune agonists, which are often associated with high toxicity.10,11 To enhance retention within the tumor, LHC165 was adsorbed on to aluminum hydroxide.12 Aluminum hydroxide bound to LHC165 may shift the immune response to T helper 1 (Th1) profile,13 thereby promoting a strong adaptive immune response and enhancing the local priming effects.
The IT administration of LHC165 augments the priming of specific CD8+ T-cell responses with the intent of initiating immune surveillance conditions in the TME that favor the development of an effective systemic antitumor-specific immunity at the injected site and distal untreated sites.
Tumor cell resistance may be mediated by an increase in regulatory T cells within the TME.14 Cold tumors are characterized by a low mutational load, low major histocompatibility complex class I expression, and low programmed cell death ligand 1 (PD-L1) expression.15 Therefore, the combination of a TLR-7 agonist with spartalizumab may augment tumor cell response in both immunogenic (hot) and non-immunogenic (cold) TME.
Spartalizumab (PDR001) is a humanized immunoglobulin G4 (IgG4) anti-programmed cell death protein-1 (anti–PD-1) monoclonal antibody and high-affinity anti–PD-1/ligand-1 (PD-1/L-1) inhibitor. Engagement with PD-1 and its ligands negatively regulates T-cell signaling and function and mediates immune tolerance.16 Spartalizumab demonstrated an overall response rate (ORR) of 24% based on immune-related response criteria, providing evidence of promising activity in patients with advanced anaplastic thyroid carcinoma.17 In preclinical models, LHC165 increased PD-L1 expression on APCs and enhanced immune response when combined with an anti–PD-L1 inhibitor. One goal of the TLR-7 agonist was to convert cold tumors (with low immunogenicity) to hot tumors by recruiting immune cells to the tumor site (through cytokine and chemokine secretion) and increasing DC priming and antigen presentation. There is a rationale and evidence for combining TLR-7 agonists with checkpoint inhibitors (CPIs), which enhance the immune response to produce synergistic antitumor activity and generate robust abscopal responses.18,19
Here, we report the results of a first-in-human (FIH) phase I/Ib study to establish the maximum tolerated dose (MTD) and/or recommended dose (RD) and to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of LHC165 single agent (SA) and in combination with spartalizumab in adult patients with advanced solid tumor malignancies with accessible lesions amenable to IT administration of LHC165.
Materials and methods
Study design and patient eligibility
This was a phase I/Ib, prospective, open-label, multicenter, non-randomized study (NCT03301896)20 of LHC165 as an SA and in combination with spartalizumab in patients with relapsed/refractory (R/R) solid tumors.
The study protocol and amendments were reviewed and approved by an independent ethics committee or an institutional review board for each site. The study was conducted in accordance with the Good Clinical Practice guidelines and the guiding principles of the Declaration of Helsinki and applicable regulatory requirements. Written informed consent was obtained from all patients before enrollment into the study.
The study included dose-escalation and dose-expansion phases (Supplementary Figure S1, available at https://doi.org/10.1016/j.esmoop.2024.103643). The dose-escalation phase included two SA groups, namely (a) LHC165 biweekly dosing and (b) LHC165 monthly dosing, and two combination groups, namely (c) LHC165 biweekly dosing + spartalizumab monthly dosing and (d) LHC165 monthly dosing + spartalizumab monthly dosing. The dose-expansion phase included two groups, namely (e) LHC165 SA at the selected MTD/RD dosing schedule and (f) LHC165 600 μg biweekly + spartalizumab 400 mg Q4W. The dose-escalation phase was designed to establish the MTD and/or RD and safety and tolerability of LHC165 SA as well as LHC165 in combination with spartalizumab. The monthly dosing schedule was not opened for enrollment due to the lack of biologic evidence to support the effectiveness of a longer dosing interval. Dose-escalation decisions were guided by an adaptive Bayesian hierarchical logistic regression model alongside the escalation with overdose control principle, accounting patient tolerability, safety considerations, and available clinical data (please refer to the Supplementary Material, available at https://doi.org/10.1016/j.esmoop.2024.103643).
Based on PK, safety, and preliminary efficacy data, groups b, d, and e were not opened for enrollment during the study.
Patient population
Eligible patients were aged ≥18 years with a histologically confirmed diagnosis of metastatic and/or advanced solid tumors, non-curative treatment by surgery, and an Eastern Cooperative Oncology Group (ECOG) performance status score of ≤2. Patients had to have at least two sites of disease amenable to biopsy. Patients with measurable disease at baseline [as determined by Response Evaluation Criteria in Solid Tumors (RECIST v1.1)],21 who had progressed despite standard-of-care (SOC) treatment or were intolerant to SOC treatment, were included in the study. For specific inclusion requirements by tumor type/group and exclusion criteria, please refer to the Supplementary Material, available at https://doi.org/10.1016/j.esmoop.2024.103643.
Treatment
Patients in both the SA and combination groups received LHC165 as IT injections during a 28-day cycle on days 1 and 15 (biweekly schedule) in cycles 1 and 2, followed by a two-cycle dosing pause (cycles 3 and 4), and then repeat injections on days 1 and 15 (biweekly schedule) for cycles 5 and 6. In total, patients received eight injections of LHC165, at doses ranging from 100 μg to 600 μg, over the course of six treatment cycles, with each cycle lasting for 28 days. Patients in the combination group received LHC165 in combination with spartalizumab 400 mg once every 4 weeks (Q4W) starting from cycle 1 day 1 until disease progression through intravenous infusion over 30 min. Dose escalation was continued until the MTD or a suitable lower dose for expansion was identified. Each expansion group began after the respective MTD/RD at the selected schedule of the LHC165 SA or combination dose was determined. For material related to MTD evaluation, refer to the Supplementary Material, available at https://doi.org/10.1016/j.esmoop.2024.103643.
Study endpoints and assessments
The primary endpoint of the study was to determine the safety and tolerability of LHC165 SA and in combination with spartalizumab in patients with solid tumors and to evaluate the MTD/RD for dose expansion. All patients who received study treatment were included in the safety analysis (see Supplementary Material, available at https://doi.org/10.1016/j.esmoop.2024.103643, for more information). Adverse events (AEs) were assessed and graded using Common Terminology Criteria for Adverse Events (CTCAE) v4.03.22 Key secondary endpoints were to determine best overall response (BOR) or immune-related BOR (iBOR), ORR, or immune-related ORR (iORR), progression-free survival (PFS) or immune-related PFS (iPFS), duration of response (DOR) or immune-related DOR (iDOR), and disease control rate [DCR, defined as the proportion of patients with a BOR of complete response (CR) or partial response (PR) or stable disease (SD)] according to RECIST v1.121 and immune RECIST (iRECIST).23 Additional secondary endpoints were to further characterize the PK profile of LHC165 and spartalizumab in serum and the derived PK parameters and to evaluate tumor-infiltrating lymphocytes (e.g. CD8) in injected and distal tumor specimens.
Pharmacokinetics assessment
PK parameters were determined using non-compartmental methods. After the IT administration of LHC165 Q2W 100-600 μg SA and in combination with spartalizumab 400 mg Q4W, 42 patients’ (93.3%) PK profiles were evaluated. Serum concentrations of LHC165 and spartalizumab were determined with validated liquid chromatography–tandem mass spectrometry assays. Please refer to Supplementary Material, available at https://doi.org/10.1016/j.esmoop.2024.103643, for information on blood sample collection.
Biomarker assessment
Changes in biomarkers were used to investigate the effect of LHC165 SA and in combination with spartalizumab at the molecular and cellular levels as well as to evaluate how the changes in biomarkers might relate to exposure and clinical outcomes. Biopsy tissues were used to investigate LHC165 and spartalizumab target modulation with established immunohistochemical (IHC) methods. Please refer to the Supplementary Material, available at https://doi.org/10.1016/j.esmoop.2024.103643, for more details.
Statistical analyses
Dose-escalation and dose-expansion data were summarized together, as only five patients were assessed for dose expansion. The duration of exposure (DOE) to LHC165 and spartalizumab as well as dose intensity (computed as the ratio of actual cumulative dose received and actual DOE) and relative dose intensity (the ratio of dose intensity to planned cumulative dose/DOE) were summarized separately using descriptive statistics, by treatment group and overall. ORR/iORR and DCR/iDCR were summarized as point estimates, and the corresponding 90% exact confidence intervals (CIs) were computed using the Clopper–Pearson method. BOR/iBOR was summarized by treatment group. Kaplan–Meier (KM) plots and related estimates (median and related 90% CI; rate at 3, 6, 9, 12, 18, and 24 months) of PFS were provided for LHC165 SA and in combination with spartalizumab. Changes in biomarkers in blood, tumor samples, and imaging assessments were summarized using descriptive analysis and correlation with clinical response and exposure where feasible. All parameters were estimated using SAS (version 9.4).
Results
Patient characteristics and disposition
A total of 45 patients were enrolled between 31 January 2018 and 30 June 2022. The dose-escalation phase included 21 patients who received LHC165 100-600 μg biweekly through IT injection SA and 24 patients who received IT administration of LHC165 in combination with spartalizumab 400 mg Q4W through intravenous infusion over 30 min. At the cut-off date (30 June 2022), the median DOE was 8 weeks (range 2-129 weeks). All 45 patients were included in the efficacy and safety analysis sets. The baseline characteristics are summarized in Table 1. The most frequent tumor entities were melanoma (33.3%) and head and neck squamous cell carcinoma (HNSCC; 22.2%).
Table 1.
Baseline demographic and clinical characteristics of patients with advanced malignancies, treated with LHC165 SA and in combination with spartalizumab
| LHC165 SA patients n = 21 | LHC165 + spartalizumab patients n = 24 | All patients N = 45 |
|
|---|---|---|---|
| Age (years), median (range) | 61.0 (44-79) | 51.0 (26-82) | 56.0 (26-82) |
| Sex, n (%) | |||
| Male | 10 (47.6) | 12 (50.0) | 22 (48.9) |
| Female | 11 (52.4) | 12 (50.0) | 23 (51.1) |
| ECOG PS, n (%) | |||
| 0 | 8 (38.1) | 13 (54.2) | 21 (46.7) |
| 1 | 13 (61.9) | 11 (45.8) | 24 (53.3) |
| Cancer diagnosis, n (%) | |||
| HNSCC | 9 (42.9) | 1 (4.2) | 10 (22.2) |
| Melanoma | 4 (19.0) | 11 (45.8) | 15 (33.3) |
| Liposarcoma | 0 | 1 (4.2) | 1 (2.2) |
| TNBC | 4 (19.0) | 3 (12.5) | 7 (15.6) |
| Breast cancer | 1 (4.8) | 3 (12.5) | 4 (8.9) |
| Sarcoma | 1 (4.8) | 0 | 1 (2.2) |
| CRC | 1 (4.8) | 0 | 1 (2.2) |
| Mesothelioma | 1 (4.8) | 1 (4.2) | 2 (4.4) |
| Othersa | 0 | 4 (16.7) | 4 (8.9) |
| Number of patients with at least one treatment permanent discontinuation by reason, n (%) | |||
| Adverse event | 2 (9.5) | 2 (8.3) | 4 (8.9) |
| Per protocol | 1 (4.8) | 1 (4.2) | 2 (4.4) |
| Physician decision | 0 | 3 (12.5) | 3 (6.7) |
| Patient decision | 2 (9.5) | 2 (8.3) | 4 (8.9) |
| Unspecified | 10 (47.6) | 10 (41.7) | 20 (44.4) |
| Prior antineoplastic regimens, n (%) | |||
| No | 1 (4.8) | 1 (4.2) | 2 (4.4) |
| Yes | 20 (95.2) | 23 (95.8) | 43 (95.6) |
| Immuno-oncology therapeutic class at last treatment, n (%) | |||
| Anti–CTLA-4 | 2 (9.5) | 2 (8.3) | 4 (8.9) |
| Anti–LAG-3 | 2 (9.5) | 1 (4.2) | 3 (6.7) |
| Anti–PD-1 | 5 (23.8) | 9 (37.5) | 14 (31.1) |
| Anti–PD-L1 | 0 | 1 (4.2) | 1 (2.2) |
| Anti–ICOS | 0 | 1 (4.2) | 1 (2.2) |
| NON-IO | 13 (61.9) | 10 (41.7) | 23 (51.1) |
| OX 40 agonist | 0 | 1 (4.2) | 1 (2.2) |
| TGF-β | 0 | 1 (4.2) | 1 (2.2) |
| UNK | 0 | 1 (4.2) | 1 (2.2) |
CRC, colorectal cancer; CTLA-4, cytotoxic T-lymphocyte-associated antigen 4; ECOG, Eastern Cooperative Oncology Group; HNSCC, head and neck squamous cell carcinoma; ICOS, inducible co-stimulator; IO, immuno-oncology; LAG-3, lymphocyte-activation gene 3; PD-1, programmed cell death protein 1; PD-L1, programmed cell death ligand 1; PS, performance status; SA, single agent; TGF-β, transforming growth factor beta; TNBC, triple-negative breast cancer; UNK, unknown.
Other cancers include nasopharyngeal cancer, anal cancer, pseudomyxoma peritonei, and gastrointestinal stromal tumor.
All patients discontinued the study treatment. In the LHC165 SA group, patients discontinued due to progressive disease [PD; 15 (71.4%)], AE [hypotension; not related to treatment; 1 (4.8%)], death [respiratory failure; not related to treatment; 1 (4.8%)], patient’s decision [2 (9.5%)], and study treatment completion [2 (9.5%)]. In the LHC165 in combination with spartalizumab group, patients discontinued study treatment due to PD [17 (70.8%)], patient’s decision [2 (8.3%)], AE [pancreatitis; dose-limiting toxicity (DLT); 1 (4.2%)], study termination [1 (4.2%)], death [fatal septic shock; not related to treatment; 1 (4.2%)], and physician’s decision [2 (8.3%)].
Safety and tolerability
Adverse events
Overall, 40 of 45 patients (88.9%) experienced at least one AE of any grade, regardless of its relationship with LHC165 or spartalizumab. Across all dose levels, 16 of 45 patients (35.6%) experienced treatment-related AEs (TRAEs, all grades), with 2 of 21 patients (9.5%) and 14 of 24 patients (58.3%) experiencing one or more TRAE in the LHC165 SA and combination groups, respectively. The reported TRAEs in the study included pyrexia [10 (22.2%)], pruritus [6 (13.3%)], chills [5 (11.1%)], and asthenia [2 (4.4%)], as shown in Table 2, with no instances of grade ≥3 TRAEs reported.
Table 2.
AEs,a suspected to be related to LHC165 or spartalizumab
| Preferred terms n (%) | LHC165 SA patients n = 21 |
LHC165 + spartalizumab patients n = 24 |
All patients N = 45 |
|||
|---|---|---|---|---|---|---|
| All grades | Grade ≥3 | All grades | Grade ≥3 | All grades | Grade ≥3 | |
| ≥1 AE | 2 (9.5) | 0 | 14 (58.3) | 0 | 16 (35.6) | 0 |
| Pyrexia | 2 (9.5) | 0 | 8 (33.3) | 0 | 10 (22.2) | 0 |
| Pruritus | 0 | 0 | 6 (25.0) | 0 | 6 (13.3) | 0 |
| Chills | 1 (4.8) | 0 | 4 (16.7) | 0 | 5 (11.1) | 0 |
| Asthenia | 0 | 0 | 2 (8.3) | 0 | 2 (4.4) | 0 |
| TRAEs leading to discontinuation | ||||||
| Pancreatitis | 0 | 0 | 1 (4.2) | 1 (4.2) | 1 (2.2) | 1 (2.2) |
MedDRA v25.0, CTCAE v4.03.
AE, adverse event; SA, single agent; TRAE, treatment-related adverse event.
All patients, all grades, safety set.
Overall, two patients (4.4%) had at least one AE leading to treatment discontinuation, of which pancreatitis was a TRAE (Table 2). Five patients (11.1%) had at least one AE leading to dose interruption or dose adjustment. The AEs leading to dose interruption or dose adjustment were aspartate aminotransferase increased [2 (4.4%)] as well as alanine aminotransferase increased, fatigue, gastroesophageal reflux disease, hyponatremia, and suspected COVID-19 [all 1 (2.2%) each].
Serious adverse events
Ten patients (22.2%) experienced at least one SAE, regardless of its relationship with LHC165 and spartalizumab. These SAEs included anemia, bacteremia, hyponatremia, hypotension, intestinal obstruction, leukocytosis, lower abdominal pain, pancreatitis, respiratory failure, septic shock, skin ulcer, tendon rupture, and tumor-associated fever, each reported in one patient (2.2%). An SAE suspected to be related to LHC165 and spartalizumab reported in one patient (2.2%) was grade 3 pancreatitis. No AEs specific to aluminum toxicity were reported, and the mean (standard deviation) aluminum level of 0.26 (0.088) μmol/L was observed at baseline, 0.24 (0.087) μmol/L at cycle 1 day 15 (C1D15), and 0.30 (0.128) μmol/L at end of treatment.
Across all dose levels, 40 of 45 patients (88.9%) experienced non-SAEs (≥10%). The most common non-SAEs (≥20%) were pyrexia [17 (37.8%)] and anemia [11 (24.4%); Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2024.103643].
Pharmacokinetics analysis
Serum concentration of LHC165 demonstrated an initial rapid release, followed by a slower release phase. Non-adsorbed LHC165 released quickly, followed by continued release from the injection site. LHC165 concentration decreased slowly, with a median terminal half-life (t½) ranging from 13.2 to 37.3 h on C1D1 of LHC165 SA treatment, due to the continued release of LHC165 from the injection site. The variability [geometric coefficient of variation % (Geo-CV%)] of the PK exposure was relatively high due to the variable release of LHC165 from the injection site. Geo-CV% of maximum concentration (Cmax) ranged from 41.8 to 165.8 pg/ml and overall exposure [AUC to the last quantifiable concentration (AUClast)] ranged from 49.9 to 93.2 h∗pg/ml on C1D1 following LHC165 SA treatment. Despite the high degree of variability, the Cmax and AUClast increased in a dose-dependent manner. No accumulation in serum LHC165 was observed after multiple IT injections; the Cmax and AUClast between C1D1 and C2D15 were comparable. A median terminal t½ of 262 h was observed on C1D1 of LHC165 in combination with spartalizumab treatment. Geo-CV% of Cmax ranged from 19.1 to 36.1 pg/ml, and AUClast ranged from 15.2 to 108.8 h∗pg/ml on C1D1 following LHC165 in combination with spartalizumab treatment. No evidence of drug–drug interaction was observed between LHC165 and spartalizumab as indicated by comparable exposure between the LHC165 SA and combination groups. Serum concentration–time profiles for biweekly treatment with LHC165 SA and in combination with spartalizumab are shown in Supplementary Figure S2, available at https://doi.org/10.1016/j.esmoop.2024.103643. The key PK parameters for LHC165 SA and in combination with spartalizumab—C1D1 and C2D15—are shown in Supplementary Table S2, available at https://doi.org/10.1016/j.esmoop.2024.103643.
Dose escalation and MTD declaration
Based on preclinical safety, tolerability, PK/pharmacodynamics data, and exploratory human PK projections, the starting dose was 100 μg LHC165. In the LHC165 SA group, 21 patients were treated with LHC165 at dose levels of 100 μg (n = 4), 200 μg (n = 4), 400 μg (n = 9), and 600 μg (n = 4) on a biweekly schedule. In the combination group, 24 patients were treated with LHC165 at dose levels of 100 μg (n = 3), 200 μg (n = 4), 400 μg (n = 8), and 600 μg (n = 9) on a biweekly schedule in combination with 400 mg of spartalizumab administered on day 1 of each cycle. No DLTs were observed in the LHC165 SA group during dose escalation. However, in the combination group, one patient experienced a treatment-related DLT in the form of two episodes of grade 3 pancreatitis at LHC165 400 μg. The episodes resolved, but the patient permanently discontinued the study treatment. The MTD was not reached during the study. The dose-escalation part of the study was completed, and the RD for expansion (RDE) was established as LHC165 600 μg biweekly as SA and in combination with spartalizumab 400 mg Q4W. Four patients with melanoma and one patient with HNSCC on LHC165 600 μg in combination with spartalizumab entered the dose-expansion study.
Efficacy
BOR signifying treatment effectiveness per RECIST v1.1 was available for 45 patients. Of 21 patients in the LHC165 SA group, 1 (4.8%) achieved PR, 14 (66.7%) had PD, and 6 (28.6%) had unknown (UNK) responses. Of 24 patients in the combination group, 2 (8.3%) achieved PR, 5 (20.8%) had SD, 13 (54.2%) had PD, and 4 (16.7%) had UNK responses. Per RECIST v1.1, one patient had PR over 23.2 months (695 days) but had UNK response since the tumor evaluations were carried out >30 days after the last dose. All three patients with PR in both groups received prior immuno-oncology drugs (nivolumab for HNSCC and melanoma, and pembrolizumab for HNSCC). BOR per RECISTv1.1 by treatment group is described in Table 3 and that per iRECIST in Supplementary Table S3, available at https://doi.org/10.1016/j.esmoop.2024.103643. Best percentage change of tumor size from baseline for all patients is shown in Supplementary Figure S3, available at https://doi.org/10.1016/j.esmoop.2024.103643. The DCR for all patients was 17.8% [90% CI (9.2% to 29.8%)]. The ORR (CR + PR) across all tumor types was 6.7% [90% CI (1.8% to 16.3%)].
Table 3.
Summary of best overall response per RECIST v1.1 criteria
| Response | LHC165 SA patients n = 21 | LHC165 + spartalizumab patients n = 24 | All patients N = 45 |
|---|---|---|---|
| Best overall response, n (%) | |||
| CR | 0 | 0 | 0 |
| PR | 1 (4.8) | 2 (8.3) | 3 (6.7) |
| SD | 0 | 5 (20.8) | 5 (11.1) |
| PD | 14 (66.7) | 13 (54.2) | 27 (60.0) |
| Unknown | 6 (28.6) | 4 (16.7) | 10 (22.2) |
| ORR (CR + PR), n (%) | 1 (4.8) | 2 (8.3) | 3 (6.7) |
| 90% CIa | (0.2-20.7) | (1.5-24.0) | (1.8-16.3) |
| DCR (CR + PR + SD), n (%) | 1 (4.8) | 7 (29.2) | 8 (17.8) |
| 90% CIa | (0.2-20.7) | (14.6-47.9) | (9.2-29.8) |
| DOR (months) | |||
| n | 1 | 2 | 3 |
| Median (range) | 3.81 (3.8-3.8) | 21.74 (13.8-29.7) | 13.77 (3.8-29.7) |
CI, confidence interval; CR, complete response; DCR, disease control rate; DOR, duration of response; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease.
The 90% CIs for ORR and DCR were computed using the Clopper–Pearson method.
DOE to the study intervention categorized by treatment groups is depicted in Figure 1. The median DOE for LHC165 was 5.9 weeks (range 2.0-25.0 weeks) for patients treated with LHC165 SA and 8.0 weeks (3.9-32.7 weeks) for patients treated with LHC165 in combination with spartalizumab. For patients treated with LHC165 in combination with spartalizumab, the median DOE for spartalizumab was 11.9 weeks (4.0-129.0 weeks); notably, five patients (20.9%) received spartalizumab treatment for longer than 24 weeks.
Figure 1.
Duration of exposure by treatment group (A) LHC165 SA and (B) LHC165 + spartalizumab combination. PD, progressive disease; PR, partial response; SA, single agent; SD, stable disease.
Progression-free survival and immune-related progression-free survival
The KM analysis of PFS showed an overall median PFS of 1.7 months [90% CI (1.4-1.8 months)] with 1.4 months [90% CI (1.0-1.7 months)] for patients treated with LHC165 SA (Figure 2A and B) and 1.8 months [90% CI (1.6-3.6 months)] for patients treated with LHC165 in combination with spartalizumab (Figure 2C and D).
Figure 2.
Kaplan–Meier plots for progression-free survival of patients with (A) LHC165 SA as per RECIST v1.1; (B) LHC165 SA as per iRECIST; (C) LHC165 in combination with spartalizumab as per RECIST v1.1; (D) LHC165 in combination with spartalizumab as per iRECIST. The PFS rates per RECIST v1.1 and iRECIST at 3, 6, 12, 18, and 24 months, respectively, were 11.8%, 11.8%, 5.9%, 5.9%, and 5.9%, respectively, for patients treated with LHC165 SA and 37%, 21.2%, 15.9%, 15.9%, and 7.9%, respectively, for patients treated with LHC165 in combination with spartalizumab. CI, confidence interval; PFS, progression-free survival; SA, single agent.
Pharmacodynamics/biomarkers
A total of 19 patients (n = 5 for the SA arm and n = 14 for the combination arm) were included in the IHC analyses, and 14 patients (n = 2 for the SA arm, n = 12 for the combination arm) with paired biopsies were included in the RNA-sequencing (RNA-Seq) analyses. IHC analysis revealed higher baseline tumoral levels of CD8, CD68, and PD-L1 in patients with PR and SD (Supplementary Figure S4, available at https://doi.org/10.1016/j.esmoop.2024.103643). Similarly, tumoral RNA-Seq showed higher T-cell inflammation at baseline in patients with PR (Supplementary Figure S5, available at https://doi.org/10.1016/j.esmoop.2024.103643). Overall, the baseline biomarker data suggest that an immune-hot TME may be necessary for response to LHC165.
Patients with PR or SD demonstrated more consistent on-treatment increases in CD8 and CD68 IHC expression than patients with PD (Supplementary Figure S6, available at https://doi.org/10.1016/j.esmoop.2024.103643). Similarly, tumoral RNA-Seq data revealed an increase in T-cell inflammation signature and natural killer cell signature, with treatment being more consistent in patients with SD and PR than in those with PD (Supplementary Figure S5, available at https://doi.org/10.1016/j.esmoop.2024.103643).
Discussion
This phase I/Ib study investigated the safety, tolerability, and preliminary efficacy of LHC165, a synthetic TLR-7 agonist, SA and in combination with spartalizumab in 45 patients with R/R accessible solid tumors. This is the FIH, early-phase clinical study to use targeted IT administration of the TLR agonist. The MTD was not reached in this study. The RDE was determined as 600 μg biweekly for LHC165 SA and in combination with spartalizumab 400 mg Q4W, based on safety, tolerability, PK, pharmacodynamic, and clinical activity consisting of ORR and PFS.
This study showed that the ORR and DCR per RECIST v1.1 were 6.7% and 17.8%, respectively, across all tumor types, with varying DOEs to different treatment regimens, resulting in median PFS and iPFS of 1.7 months. One patient had multiple PR with unknown BOR since tumor evaluations, but the patient did achieve a PR per RECIST v1.1 criteria.
LHC165 SA and in combination with spartalizumab 400 mg was generally well tolerated with mostly mild to moderate AEs; none were considered serious. Most AEs were manageable with mitigation strategies such as dose reductions and treatment delays. The only treatment-related SAE was grade 3 pancreatitis in one patient. LHC165 was administered with adsorbed aluminum hydroxide, raising the potential for aluminum toxicity. Although the maximum observed aluminum value during the study was 0.520 μmol (below mild elevation levels i.e. >1.85 μmol/L), an aluminum content of 1.2 mg associated with the proposed LHC165 RDE dose (600 μg) approached the maximum allowable limit of 1.25 mg aluminum/dose set forth in the Code of Federal Regulations for biological products and the European Pharmacopoeia for allergen products. Therefore, LHC165 SA was not explored further. Although sample sizes were small, our IHC and RNA-Seq biomarker data suggested that patients with immune-hot TMEs responded better than patients with cold TMEs. These data indicate that certain immunosuppressive mechanisms in the tumor remain unresponsive despite TLR-7 agonism alone, or in combination with anti–PD-1 therapy, necessitating combination with other therapeutic agents that can target other immune-suppressive mechanisms. Given the potential to both stimulate and enhance antitumor immunity, as well as the number of planned/active clinical studies, it is apparent that clinicians see promise in the use of TLR agonists to treat cancer. Preliminary data suggest that TLR7 and TLR9 agonists, used alone or in combination with approved immune CPIs, exhibit antitumor activity. TLR agonists potentially convert cold tumors into hot tumors by inducing pro-inflammatory cytokines and attracting effector T cells into the tumor tissue, thus bridging the gap between innate and adaptive immunity.
Adaptive designs offer efficiency in evaluating the efficacy and safety of novel TLR agonists, considering the conflicting roles of TLRs in different tumor types. These designs require fewer patients and shorter evaluation periods compared to traditional trial designs. In this study, tumoral biomarkers were analyzed for baseline correlations with response and immune changes in the tumors. Due to the small sample size for responders, only trends could be observed.
Systemic administration of TLR agonists often showed limited tolerability. However, local IT administration of LHC165 reduced side-effects and increased IT retention. In a phase Ib study, SD-101, an IT TLR-9 agonist combined with pembrolizumab, showed efficacy in patients with unresectable or metastatic melanoma [ORR: 9 (78%) naive, 13 (15%) anti–PD-1].24 SD-101 in combination with pembrolizumab showed tolerable toxicities consisting of influenza-like symptoms, myalgia, headache, injection-site pain, and fatigue.24 In a phase II trial in anti–PD-1 treatment-naive patients with HNSCC, intralesional SD-101 combined with pembrolizumab showed a median DOR of 7.0 months, a higher response rate (44%) in human papillomavirus-positive patients, and PFS and overall survival of 19% and 65%, respectively, at 9 months.25 MEDI9197, an IT TLR-7/8 dual agonist, showed tolerable toxicities, including grade 3/4 cytokine release syndrome, pyrexia, fatigue, chills, decreased lymphocyte count, nausea, and injection-site pain in patients with solid tumors.26 Tilsotolimod, an IT TLR-9 agonist, demonstrated good tolerability with no reported TRAEs in a phase Ib study.27 Although tilsotolimod demonstrated marked increase in tumor immune infiltration, the jury is still out on the importance of converting cold tumors hot in overcoming checkpoint blockade resistance.28
Key limitations of this study include disease progression and limited efficacy, despite remarkable responses in a few patients. Pharmacodynamic biomarker data suggest that responders tended to have higher immune infiltration in the tumor than non-responders; however, contribution from spartalizumab cannot be ruled out.
In summary, LHC165 demonstrated acceptable safety and tolerability both as SA and in combination with spartalizumab, with preliminary evidence of antitumor activity. LHC165 serum PK assessment demonstrated an initial rapid release followed by a slower release. This reflects quick release of non-adsorbed LHC165, followed by continued release from the injection site. Exposure of LHC165 increased with dose, and no interaction was observed with spartalizumab. LHC165 is delivered through IT injection, limiting the potential systemic toxicities noted with other TLR agonists. The declared MTD was LHC165 600 μg ± spartalizumab 400 mg. LHC165 in combination with spartalizumab may warrant future investigation in a large group of patients with HNSCC and cutaneous melanoma.
Acknowledgements
The authors thank the patients who participated in this clinical trial, their families, and the staff who assisted the study at each center. The authors also acknowledge Somesh Choudhary, Shiling Ruan, and Kun Xu for their work on LHC165 and this study. The authors thank Krunal Vasant Kavathiya and Subham Das, Novartis Healthcare Pvt. Ltd., Hyderabad, India, for medical writing and editorial assistance with the manuscript.
Funding
This work was supported by Novartis Pharmaceuticals Corporation. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation.
Disclosure
GC reports grants or contracts from Merck; consulting fees from BMS, Roche, Pfizer, Novartis, Eli Lilly, AstraZeneca, Daiichi Sankyo, Merck, Seagen, Ellipses, Gilead, and Menarini; payment or honoraria from Eli Lilly, Pfizer, Relay, Gilead, and Novartis; and support for attending meetings or travel from Daiichi Sankyo. MMJ reports grants and contracts for institution from Roche, Novartis, and Puma Biotechnology; consulting fees from Novartis, Roche, Eli Lilly, AstraZeneca, Amgen, Taiho Oncology, Daiichi Sankyo, Puma Biotechnology, and Menarini; payment or honoraria from Roche, Eli Lilly, AstraZeneca, Amgen, Taiho Oncology, Daiichi Sankyo, PUMA, and Menarini; participation on a data safety monitoring board or advisory board from Novartis, Roche, Eli Lilly, AstraZeneca, Amgen, Taiho Oncology, and Daiichi Sankyo; and leadership or fiduciary role for GEICAM as chairman and TRIO as board of directors. TS reports grants and contracts for institution from Eli Lilly, Loxo Oncology, AbbVie, Daiichi Sankyo, BMS, Eisai, AstraZeneca, Takeda Oncology, Incyte, Chordia Therapeutics, 3D Medicines, SymBio Pharmaceuticals, PharmaMar, Astellas Pharma, and Pfizer; consulting fees for advisory role/safety monitoring committee from Chordia Therapeutics, Chugai, Kyowa Kirin, AbbVie, and Daiichi Sankyo; payment or honoraria as speakers bureaus from Chugai, MSD, Eli Lilly, and IQVIA; support for attending meetings and travel from Eisai; participation on a data safety monitoring board or advisory board from Chugai, Chordia Therapeutics, Kyowa Kirin, AbbVie, and Daiichi Sankyo. FMB reports grants and contracts for institution from Aileron Therapeutics, AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., Klus Pharma, Takeda Pharmaceutical, Novartis, Puma Biotechnology Inc., and Taiho Pharmaceutical Co; consulting fees from Black Diamond, Biovica, Eisai, FogPharma, Immunomedics, Inflection Biosciences, Karyopharm Therapeutics, Loxo Oncology, Mersana Therapeutics, OnCusp Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Sanofi, Silverback Therapeutics, Spectrum Pharmaceuticals, Theratechnologies, and Zentalis; payment or honoraria from Dava Oncology; support for attending meetings and/or travel from European Organisation for Research and Treatment of Cancer (EORTC), European Society for Medical Oncology (ESMO), Cholangiocarcinoma Foundation, and Dava Oncology; and advisory board from Black Diamond, Biovica, Eisai, FogPharma, Immunomedics, Inflection Biosciences, Karyopharm Therapeutics, Loxo Oncology, Mersana Therapeutics, OnCusp Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Sanofi, Silverback Therapeutics, Spectrum Pharmaceuticals, Theratechnologies, and Zentalis. AR reports payment or honoraria as speaker fee from BMS and Novartis; travel and meeting support from Pierre Fabre and MSD; and advisory board for Pierre Fabre and MSD. PJS reports grants by German Research Foundation; consulting fees from Zeiss (Germany) and MSD (Germany); patents planned for non-linear laryngoscope for larynx surgery (pending); participation on a data safety monitoring board or advisory board from BMS (Germany), MSD (Germany), and Zeiss (Germany); and stocks from SURAG Medical.
NSP reports stocks from Novartis; patent filed by Novartis. NSP, MI, NH, JW, XC, HB, AC, and JO are employees of Novartis at the time of study conduct. NH, JW, XC, HB, and AC report stocks from Novartis. ML reports current employment with IQVIA and is contracted by Novartis. JO reports stocks from Novartis and support for attending meetings and/or travel from Novartis as business travel expenses. EGC reports grants or contracts from Novartis, Roche, Thermo Fisher Scientific, AstraZeneca, Taiho, BeiGene, and Janssen; consulting fees from Roche, Ellipses Pharma, Boehringer Ingelheim, Janssen Global Services, Seattle Genetics, Thermo Fisher Scientific, MabDiscovery, Anaveon, F-Star Therapeutics, Hengrui, Sanofi, Incyte, and Medscape; payment or honoraria from Merck Sharp & Dohme, Roche, Thermo Fisher Scientific, Eli Lilly, Novartis, and SeaGen; PI or co-PI for institution from Adaptimmune LLC, Affimed GmbH, Amgen SA, Anaveon AG, AstraZeneca AB, Bicycletx Ltd, BioInvent International AB, Biontech SE, Biontech Small Molecules GmbH, Boehringer Ingelheim International GmbH, Catalym GmbH, Cyclacel Pharmaceuticals, Cytovation AS, CytomX, F. Hoffmann La Roche Ltd, F-Star Beta Limited, Genentech Inc., Genmab B.V., HiFiBio Therapeutics, Hutchison Medipharma Limited, Icon, Imcheck Therapeutics, Immunocore Ltd, Incyte Corporation, Incyte Europe Sàrl, Janssen-Cilag International NV, Janssen-Cilag SA, Laboratorios Servier SL, Medimmune LLC, Merck & Co., Inc., Merck KGaA, Novartis Farmacéutica, S.A., Peptomyc, Pfizer Slu, Relay Therapeutics, Replimmune, Ribon Therapeutics, Ryvu Therapeutics SA, Seattle Genetics Inc., SOTIO, SQZ Biotechnologies, Symphogen A/S, Taiho Pharma USA Inc., and T-Knife GmbH; and employment from NEXT Oncology.
Data sharing
Novartis is committed to sharing access to patient-level data and supporting clinical documents from eligible studies with qualified external researchers. These requests are reviewed and approved by an independent review panel based on scientific merit. All data provided are anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.
Supplementary data
References
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