Abstract
Purpose:
STAT3 is important in promoting a pro-oncogenic tumor microenvironment. This first randomized trial of a STAT3-targeting ASO with pembrolizumab assessed whether this first-line combination would improve outcomes compared with pembrolizumab alone in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).
Patients and Methods:
This multicenter, randomized, open-label, controlled study (NCT05814666) enrolled patients with previously untreated R/M-HNSCC with positive PD-L1 expression (combined positive score [CPS] ≥1). Patients were stratified by CPS (1–19; ≥20) and randomized 2:1 to danvatirsen 3mg/kg IV weekly (with 2 loading doses in week 1) plus pembrolizumab 200mg IV every 3 weeks or pembrolizumab alone. Patients received 21-day treatment cycles until progressive disease, unacceptable toxicity, or voluntary withdrawal. Primary endpoint was overall response rate (ORR: partial + complete response per RECIST-v1.1).
Results:
69 patients were randomized and 66 treated (51 [77.3%] male), 45 with danvatirsen + pembrolizumab, 21 with pembrolizumab alone. Enrolment was stopped due to lack of response in the CPS 1–19 cohort after ≥1 scan (~6 weeks of treatment) and in the CPS ≥20 cohort after ≥2 scans (~12 weeks). In the final analysis, ORRs were 15.6% and 14.3%, respectively (risk difference 1.3, P=1.0). The treatment-emergent adverse-event rate was increased in the combination arm (97.8% vs 85.7%), and the combination side effect profile was similar to previous danvatirsen studies.
Conclusions:
Combination danvatirsen + pembrolizumab did not improve ORR compared to pembrolizumab alone in first-line treatment of R/M-HNSCC. Further exploration of STAT3-targeted approaches is needed within the context of immunotherapy.
Introduction
Head and neck cancer is the sixth most common cancer worldwide, with the predominant histology being head and neck squamous cell carcinoma (HNSCC) (1,2). In the United States, HNSCC accounts for 3% of all cancers diagnosed annually and 2% of cancer-related deaths, while globally, HNSCC accounts for approximately 4.5% of cancer diagnoses and deaths each year (3).
The majority of patients with HNSCC initially present with locally advanced disease. Despite aggressive, combined modality treatment, a significant proportion of patients develop recurrent or metastatic (R/M) disease that is no longer amenable to curative therapy (1). Existing first-line systemic treatment options for patients with previously untreated R/M HNSCC include the programmed death-1 (PD-1) inhibitor pembrolizumab in biomarker (PD-ligand-1 [PD-L1]) positive disease or in combination with platinum and 5-FU regardless of biomarker status (1,4). Immunotherapy (single agent nivolumab or pembrolizumab monotherapy) has also been approved for second-line treatment in platinum-refractory R/M HNSCC patients (4–7). Although pembrolizumab has shown improved survival and better safety profile compared to the EXTREME regimen (cetuximab plus cisplatin/carboplatin plus fluorouracil), outcomes remain poor in the first-line previously untreated setting, with median survival 12–15 months (1). Thus, there remains an unmet need to improve response rate and clinical outcomes.
Signal transducer and activator of transcription 3 (STAT3) belongs to the STAT family of transcription factors and is a promising cancer drug target because of its pleiotropic involvement in tumorigenesis. STAT3 regulates the expression of many genes directly important to the survival of tumor cells (8,9) and plays a central role in promoting a pro-oncogenic tumor micro-environment through recruitment of stromal and immune cells to the TME (8). STAT3 is also reported to promote tumor cell proliferation, immune evasion of tumor cells, angiogenesis, and metastasis (10–12). While STAT3 has long been a target of interest in oncology, it has been difficult to successfully modulate with therapeutics to date. We hypothesized that targeting downregulation of the messenger RNA (mRNA) via an antisense approach could succeed where other attempts have failed.
Danvatirsen is an antisense oligonucleotide (ASO) designed to target and downregulate expression of human STAT3 mRNA. Danvatirsen is a 3–10-3 gapmer, generation 2.5 ASO complementary to human STAT3. It consists of 3 constrained ethyl (cEt)-modified residues on either end and a phosphothiorate modified backbone (13). Danvatirsen was previously studied in multiple trials in liquid and solid tumors (13–16) and showed limited responses as a monotherapy, and a modest improvement in pathologic response in the neoadjuvant non-small cell lung cancer (NSCLC) setting in combination with the PD-L1 inhibitor durvalumab (14). In the Phase I study by Hong D et al, biopsies demonstrated that danvatirsen successfully decreased STAT3 mRNA and protein levels (13). Furthermore, using paired biopsies from patients with lymphoma, danvatirsen was shown to remodel the suppressive TME by promotion of proinflammatory gene expression in patients' tumors (17). The SCORES study, a phase 1b/2a trial, was conducted in R/M HNSCC and included 5 expansion cohorts of 12–66 patients each who received danvatirsen 3 mg/kg weekly either as monotherapy or in combination with durvalumab (18). In the 3 cohorts that treated immunotherapy-naïve patients with danvatirsen plus durvalumab, responses were modestly better compared to historic control (19) and were more generous in patients with PD-L1 expression. In addition, the CR was higher in PD-L1 expressing patients, indicating a potentially clinically meaningful benefit in this group (19).
This phase 2 randomized study was intended to generate new information about the efficacy and safety of the investigational agent danvatirsen when combined with pembrolizumab in the first-line treatment of R/M HNSCC and to support future studies of the combination treatment (20).
Patients and Methods
Study design and participants
This multicenter, randomized, open-label, controlled, phase 2 study was conducted across 22 centers (a combination of community-based clinics and hospitals) in 3 countries (United States, United Kingdom, and South Korea) (for study representativeness refer to Supplementary Table 1). Ethics approval was obtained from the institutional review board and/or ethics committee at each study site. The study was conducted in accordance with the International Conference on Harmonization Good Clinical Practice Guidelines and the Declaration of Helsinki. The protocol is available online. This study is registered with ClinicalTrials.gov, NCT05814666. All patients provided written, informed consent prior to participation in the study.
Eligible patients were aged ≥18 years with histologically or cytologically proven R/M HNSCC with detectable PD-L1 expression in tumor, defined as combined positive score (CPS) ≥1 (local assessment). This first-line, PD-L1 positive patient population was chosen because danvatirsen was most effective in patients naïve to immunotherapy and because pembrolizumab is the only immunotherapy approved as monotherapy in the first-line, biomarker positive R/M HNSCC setting. Patients were required to have presence of measurable tumor per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Eligible primary tumor locations were the oropharynx, oral cavity, hypopharynx, and larynx. Key exclusion criteria included prior therapy for R/M HNSCC (systemic therapy for locoregionally recurrent HNSCC that was completed >3 months prior to signing consent was allowed if given as part of multimodal treatment for locally advanced disease); disease suitable for local therapy with curative intent; prior therapy with anti-PD-1, anti-PD-L1, or anti-PD-L2; or radiation therapy (or other non-systemic therapy) within 2 weeks of Day 1 of study treatment. Because a greater effect was observed in the higher (CPS ≥20) PD-L1 expressing patients in SCORES, patients were divided into 2 cohorts based on CPS status.
Patients’ sex at birth, race, and ethnicity data were collected via self-report. An adaptive design described in the statistical section of the protocol was included to manage enrolment into the CPS 1–19 cohort. Specifically, if no more than 1 patient achieved a response (confirmed or unconfirmed CR or PR within the first 2 scans) in the first 10 patients enrolled in the combination arm for this subgroup, there was to be no further enrolment in this subgroup, and the study would continue to enroll only in the CPS ≥20 subgroup. In order to prevent additional enrollment in the CPS 1–19 group while the initial data matured, a planned pause in enrollment would occur after 10 patients if none had responded by that time.
Randomization and masking
Eligible patients were randomized 2:1 to first-line danvatirsen plus pembrolizumab or first-line pembrolizumab alone, respectively, by means of a centrally managed, interactive response technology system. Patients were stratified by baseline CPS (CPS ≥1 and <20 vs. CPS ≥20). Treatments were given in an open-label manner without masking.
Procedures
Patients who were assessed as eligible during the screening period proceeded to therapy, during which they received 21-day treatment cycles until progressive disease (PD), death, unacceptable toxicity, or voluntary withdrawal. Danvatirsen was administered via intravenous (IV) infusion at 3 mg/kg on Days 1, 3, and 5 of Cycle 1 Week 1 with a ±1 day dosing window and ensuring >1 day between each dose. Danvatirsen was dosed weekly thereafter on Days 8 and 15 of Cycle 1 and Days 1, 8, and 15 of each subsequent 3-week cycle. Starting at Cycle 1 Week 2, danvatirsen had a ±2-day dosing window. Pembrolizumab 200 mg was administered via IV infusion on Day 1 (±7-day dosing window) of each 3-week treatment cycle. The total amount of danvatirsen administered for each weight-based dose was not adjusted during the study based on patient weight changes.
Patients had radiologic tumor assessments every 6 weeks, regardless of treatment delays, until objective disease progression, initiation of new anticancer treatment, death, withdrawal of consent, or end of study, whichever occurred first. Treatment-emergent adverse events (TEAEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Assessments were performed locally.
Safety was assessed on a continuous basis. In addition, a Safety Review Committee (SRC) was used and formally assessed safety data when the first 9 patients randomized completed ≥1 cycle of study treatment and approximately every 6 months thereafter.
Outcomes
The primary endpoint was confirmed ORR (partial response [PR] + complete response [CR] defined according to RECIST v1.1) and included all patients who received ≥1 dose of study treatment based on the treatment assigned at randomization.
Secondary endpoints included safety and tolerability outcomes (TEAEs, treatment-emergent serious adverse events [SAEs], and hematology laboratory values); duration of response (DOR) by RECIST v1.1; disease control rate (DCR) and CR rate by RECIST v1.1; ORR and DOR by RECIST v1.1 in tumors with CPS ≥20 and ≥50; and progression-free survival (PFS) by RECIST v1.1, defined as the time from randomization to the first documentation of PD or death from any cause, whichever came first.
Statistical analysis
Sample size considerations were based on monitoring the primary efficacy endpoint, ORR, using a 2-arm Bayesian optimal phase 2 (BOP2) design (21). The primary efficacy evaluation was the magnitude of ORR in each treatment arm and the probability that the combination arm ORR was superior to that of the control (monotherapy) arm. The design was optimized to maximize power under H0:ORRcon = 0.15 and ORRcomb = 0.43, while controlling type I error rate at 1-sided 0.05. The 2:1 combination:control randomization used for the 2 arms would yield 83% power at the 1-sided 5% alpha based on the decision rule to reject the null hypothesis and conclude that the combination arm is superior compared to the control. The Full Analysis Set (FAS) was the primary analysis set for efficacy analyses, and included all patients who received ≥1 dose of the treatment assigned at randomization.
The Safety Analysis Set (SAS) was the primary analysis set for safety analyses, and included all patients who received ≥1 dose of study treatment based on the actual treatment received.
An interim futility analysis was planned when ORR could be assessed for the first 39 patients who had completed 6 weeks of treatment (with ≥1 tumor assessment via radiologic scan) or if patients discontinued from the trial.
Data sharing
Flamingo Therapeutics had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Following the closure of the sponsoring company, the study database is no longer accessible and the authors do not have the ability to provide the underlying data. All available data are included in the article and its supplementary files. Questions can be directed to the corresponding author.
Results
Between 2 January 2024 and 12 May 2025, 69 patients were randomized and 66 patients treated (15 [22.7%] female and 51 [77.3%] male). 45 were assigned to danvatirsen plus pembrolizumab and 24 to pembrolizumab alone. Three patients assigned to pembrolizumab alone withdrew prior to receiving treatment (Figure 1).
Figure 1.
Trial profile
Mean age was 64.7 years, 51 subjects (77.3%) were male, 44 (66.7%) had an ECOG performance status of 1, and 16 (24.2%) were positive for HPV with 14 (21.2%) having a confirmed HPV related oropharyngeal carcinomas (OPCA). A total of 45 (68.2%) had prior chemotherapy and 62 (93.4%) prior radiation prior to enrollment (Table 1).
Table 1.
Baseline characteristics of the safety analysis set
| Danvatirsen + Pembrolizumab (N=45) | Pembrolizumab (N=21) | Overall (N=66) | |
|---|---|---|---|
| Age, years | |||
| Mean (SD) | 64.3 (11.68) | 65.7 (9.35) | 64.7 (10.94) |
| Min, Max | 29, 86 | 45, 83 | 29, 86 |
| Age category (years), n (%) | |||
| <65 | 19 (42.2) | 8 (38.1) | 27 (40.9) |
| ≥65 | 26 (57.8) | 13 (61.9) | 39 (59.1) |
| ≥65 to <75 | 21 (46.7) | 10 (47.6) | 31 (47.0) |
| ≥75 | 5 (11.1) | 3 (14.3) | 8 (12.1) |
| Sex at birth, n (%) | |||
| Female | 11 (24.4) | 4 (19.0) | 15 (22.7) |
| Male | 34 (75.6) | 17 (81.0) | 51 (77.3) |
| Ethnicity, n (%) | |||
| Hispanic or Latino | 3 (6.7) | 1 (4.8) | 4 (6.1) |
| Not Hispanic or Latino | 41 (91.1) | 19 (90.5) | 60 (90.9) |
| Not reported or unknown | 1 (2.2) | 1 (4.8) | 2 (3.0) |
| Race, n (%) | |||
| Asian | 13 (28.9) | 1 (4.8) | 14 (21.2) |
| White | 24 (53.3) | 18 (85.7) | 42 (63.6) |
| Black or African American | 3 (6.7) | 1 (4.8) | 4 (6.1) |
| Other | 4 (8.9) | 0 | 4 (6.1) |
| Not reported | 1 (2.2) | 1 (4.8) | 2 (3.0) |
| Country, n (%) | |||
| Korea | 11 (24.4) | 0 | 11 (16.7) |
| United Kingdom | 10 (22.2) | 3 (14.3) | 13 (19.7) |
| United States of America | 24 (53.3) | 18 (85.7) | 42 (63.6) |
| ECOG performance status, n (%) | |||
| 0 - Fully active | 15 (33.3) | 7 (33.3) | 22 (33.3) |
| 1 -Restricted physically | 30 (66.7) | 14 (66.7) | 44 (66.7) |
| Total number of lesions at baseline | |||
| Mean (SD) | 3.3 (1.69) | 3.5 (2.20) | 3.4 (1.86) |
| Min, Max | 1, 8 | 1, 8 | 1, 8 |
| Initial diagnosis – primary tumor location, n (%) | |||
| Oropharynx | 17 (37.8) | 5 (23.8) | 22 (33.3) |
| HPV+ | 10 (22.2) | 4 (19.0) | 14 (21.2) |
| Oral cavity | 16 (35.6) | 13 (61.9) | 29 (43.9) |
| Hypopharynx | 4 (8.9) | 1 (4.8) | 5 (7.6) |
| Larynx | 7 (15.6) | 2 (9.5) | 9 (13.6) |
| Stage at Baseline, n (%) | |||
| II | 4 (8.9) | 1 (4.8) | 5 (7.6) |
| III | 2 (4.4) | 2 (9.5) | 4 (6.1) |
| IV | 10 (22.2) | 4 (19.0) | 14 (21.2) |
| IVa | 5 (11.1) | 4 (19.0) | 9 (13.6) |
| IVb | 4 (8.9) | 1 (4.8) | 5 (7.6) |
| IVc | 20 (44.4) | 9 (42.9) | 29 (43.9) |
| HPV Status, n (%) | |||
| Positive | 11 (24.4) | 5 (23.8) | 16 (24.2) |
| Negative | 20 (44.4) | 6 (28.6) | 26 (39.4) |
| Unknown | 14 (31.1) | 10 (47.6) | 24 (36.4) |
| Combined Positive Score, n (%) | |||
| 1–19 | 12 (26.7) | 7 (33.3) | 19 (28.8) |
| ≥20 | 33 (73.3) | 14 (66.7) | 47 (71.2) |
| Prior Chemotherapy | 29 (64.4) | 16 (76.2) | 45 (68.2) |
| Prior Radiotherapy | 41 (91.1) | 21 (100) | 62 (93.4) |
Per the planned futility monitoring criteria for the subgroup of patients with CPS 1–19, enrolment in this subgroup was discontinued as ≤1 out of 10 patients receiving the combination achieved a response within 12 weeks. Subsequently, the study continued to enroll in the CPS ≥20 subgroup only. As the interim futility analysis intended for the first 39 patients (included 40 patients) was not met, enrollment proceeded. However, because this interim analysis was done with a relatively premature data and noted withdrawal of consent for 3 patients on the control arm prior to treatment (resulting in a reduced number of patients in the CPS ≥20 subgroup for comparison), the Steering Committee recommended a second interim analysis with more mature data. This second, unplanned interim analysis was conducted for efficacy only (ORR) based on a larger proportion of patients in the CPS ≥20 group who had ≥2 scans (~12 weeks of treatment). The decision to include patients who received up to ~12 weeks of treatment was driven by the SCORES study, where 60% of responses occurred at the second post-dose assessment or later.
In this second unplanned analysis, ORRs of 22.22% and 20.00% were observed in the danvatirsen plus pembrolizumab arm and pembrolizumab alone arms, respectively, in the subgroup of patients with CPS ≥20. As a result, and with the lack of an apparent clinical benefit signal of danvatirsen and pembrolizumab, the study was stopped. All active patients were transitioned off study and subject enrolment was closed on 01 June 2025. The planned data analysis proceeded with a data cutoff date of 19 Jun 2025 and these final results are presented here. As shown in Table 2, ORRs in the overall group were 15.6% and 14.3% in the patients in the danvatirsen + pembrolizumab and pembrolizumab alone arms, respectively (risk difference 1.3, P=1.0); ORRs were 18.2% and 21.4%, respectively, in the subgroup of patients with CPS ≥20 (risk difference −3.2) (Figure 2). Median (95% CI) PFS was 3.52 (1.48, 6.83) months and 2.92 (1.41, −) months, respectively.
Table 2.
Objective response rate, duration of response, and progression-free survival – final interim analysis data from the full analysis set.
| Final interim analysis | Danvatirsen + Pembrolizumab (N=45) | Pembrolizumab (N=21) |
|---|---|---|
| ORR, in all patients, n (%) a | 7 (15.6) | 3 (14.3) |
| 90% CI | (7.5, 27.2) | (4, 32.9) |
| Risk difference (90% CI) | 1.3 (−14.1, 16.7) | — |
| Fisher’s exact 2-tailed P value | 1.0000 | — |
| ORR, in patients with CPS ≥20, n (%) | 6 (18.2) | 3 (21.4) |
| 90% CI | (8.2, 32.8) | (6.1, 46.6) |
| Risk difference (90% CI) | −3.2(−24.4, 17.9) | — |
| ORR, in patients with CPS <20, n (%) | 1 (8.3) | 0 |
| 90% CI | (0.4, 33.9) | (0, 34.8) |
| Risk difference (90% CI) | 8.3 (−4.8, 21.5) | — |
| Subjects with confirmed CR or PR, n (%) | 7 (15.6) | 3 (14.3) |
| Event, n (%) | 2 (28.6) | 0 |
| Death | 0 | — |
| Progressive disease | 2 (28.6) | — |
| Censored event, n (%) | 5 (71.4) | 3 (100) |
| New anticancer therapy prior to PD | 0 | 0 |
| PD or death after missed tumour assessment | 0 | 0 |
| Withdrawal or lost to follow-up | 0 | 0 |
| No PD or death | 5 (71.4) | 3 (100) |
| Kaplan-Meier estimate of duration of response, median (95% CI) months | 6.36 (5.68, −) | − (−, −) |
| Min, Max | 1.68, 7.03 | 1.61, 6.93 |
| Kaplan-Meier estimate: PFS (months), median (95% CI) b | 3.52 (1.48, 6.83) | 2.92 (1.41, −) |
CI: confidence intervals; CR: complete response; DOR: duration of response; ORR: objective response rate; PFS: progression-free survival; PR: partial response.
Percentages are based on the number of subjects in the Full Analysis Set.
ORR is defined as the proportion of patients with a confirmed objective response (CR or PR). CIs for ORR are calculated using the Clopper-Pearson method. The risk difference and corresponding confidence intervals are calculated as the difference between response rates and corresponding CIs, respectively, between treatment groups.
PFS is defined as the time from randomization to the first of either disease progression or death from any cause. Survival probabilities are calculated using the Kaplan-Meier method. CIs are calculated using Greenwood’s formula.
Figure 2. Waterfall plot showing maximum percent change from baseline in sum of target lesions in the full analysis set.
CR = Complete Response; PD = Progressive Disease; PR = Partial Response; SD = Stable Disease; * = Response confirmed by repeat assessments at least 4 weeks after initial CR or PR. Reference lines are based on RECIST v1.1 criteria.
More patients assigned to danvatirsen + pembrolizumab had TEAEs (97.8%) than did patients assigned to pembrolizumab (85.7%) (Table 3; for the full presentation of all TEAEs, see Supplementary Table 2). TEAEs occurring in ≥10% of patients in the overall group are shown in Table 3. TEAEs occurring at a rate of ≥20% of patients in the danvatirsen + pembrolizumab group included alanine aminotransferase (ALT) increased (42.2% vs 0 in the pembrolizumab alone group, respectively), anemia (31.1% vs 19.0%), fatigue (37.8% vs 38.1%), aspartate aminotransferase increased (35.6% vs 0), diarrhea (20.0% vs 19.0%), nausea (22.2% vs 4.8%), and constipation (22.2% vs 9.5%). SAEs occurred in 25 (55.6%) patients in the danvatirsen + pembrolizumab group vs 6 (28.6%) in the pembrolizumab alone (see Supplementary Table 3 for full presentation of SAEs). Treatment-related SAEs occurring in >1 patient included hepatitis (2 patients in the danvatirsen + pembrolizumab group vs 0 in the pembrolizumab group) and ALT increased (3 vs 0, respectively). Eight subjects in the danvatirsen + pembrolizumab and 4 subjects in the pembrolizumab group experienced TEAEs leading to death. One of the 8 deaths was considered possibly related to study drug; a subject experienced Klebsiella pneumonia - the investigator deemed this SAE possibly related to danvatirsen whereas the Safety Review Committee considered it unrelated to danvatirsen. The combination of danvatirsen and pembrolizumab was generally well tolerated and generally similar to previous danvatirsen studies and passed two formal reviews by the Safety Review Committee. In the danvatirsen + pembrolizumab group, median duration of treatment with any study drug was 2.982 months (range 0.03 to 9.36) and median number of doses given was 10.0 (range 1 to 36) (Figure 3). In the pembrolizumab group, median duration of treatment with pembrolizumab was 2.825 (range 0.03 to 10.38).
Table 3.
TEAEs occurring in ≥10% of patients in the overall group – final interim analysis data from the safety analysis set
| Final interim analysis Preferred Term |
Danvatirsen + Pembrolizumab (N=45) n (%) |
Pembrolizumab (N=21) n (%) |
Overall (N=66) n (%) |
|---|---|---|---|
| Any TEAE | 44 (97.8) | 18 (85.7) | 62 (93.9) |
| Alanine aminotransferase increased | 19 (42.2) | 0 | 19 (28.8) |
| Anemia | 14 (31.1) | 4 (19.0) | 18 (27.3) |
| Fatigue | 17 (37.8) | 8 (38.1) | 25 (37.9) |
| Platelet count decreased | 8 (17.8) | 0 | 8 (12.1) |
| Aspartate aminotransferase increased | 16 (35.6) | 0 | 16 (24.2) |
| Diarrhea | 9 (20.0) | 4 (19.0) | 13 (19.7) |
| Nausea | 10 (22.2) | 1 (4.8) | 11 (16.7) |
| Constipation | 10 (22.2) | 2 (9.5) | 12 (18.2) |
| Vomiting | 7 (15.6) | 2 (9.5) | 9 (13.6) |
| Arthralgia | 8 (17.8) | 0 | 8 (12.1) |
| Back pain | 6 (13.3) | 4 (19.0) | 10 (15.2) |
| Neutropenia | 3 (6.7) | 0 | 3 (4.5) |
| Dyspnea | 6 (13.3) | 2 (9.5) | 8 (12.1) |
| Pneumonia | 6 (13.3) | 1 (4.8) | 9, 7 (10.6) |
| Dysphagia | 5 (11.1) | 2 (9.5) | 8, 7 (10.6) |
| Hypothyroidism | 5 (11.1) | 2 (9.5) | 7, 7 (10.6) |
TEAE: treatment-emergent adverse event.
n = number of patients.
Percentages are based on the number of patients in the Safety Analysis Set.
Figure 3. Swimmer’s plot showing duration of treatment in the full analysis set.
CR= Complete Response; PR= Partial Response; SD= Stable Disease; PD= Progressive Disease; NE= Not Evaluable; DSC= Discontinued With no Tumor Assessments.
Discussion
This is the first randomized trial of danvatirsen in combination with pembrolizumab versus pembrolizumab in R/M HNSCC. A recent meta-analysis of 8 studies evaluating immunotherapy (nivolumab, pembrolizumab, durvalumab, avelumab) in patients with R/M HNSCC confirmed the beneficial use of ICIs, with an improved OS compared to standard of care (hazard ratio 0.86, 95% CI 0.85–1.37), and a decreased risk for drug-related TEAEs of Grade 3 or higher (odds ratio 0.35, 95% CI 0.17–0.73) (22). However, novel therapeutic combinatorial approaches are needed as only about 15%−20% of patients with R/M HNSCC experience a durable response to approved ICIs (23). As STAT3 inhibition is a biologically compelling anti-cancer approach, especially when combined with ICIs, the antisense-oligonucleotide danvatirsen in combination with pembrolizumab was hypothesized as an advantageous strategy in patients with R/M HNSCC.
This phase 2 trial was stopped after the unplanned interim futility analysis suggested that danvatirsen combined with pembrolizumab was unlikely to improve outcomes over pembrolizumab alone for patients with R/M HNSCC, and final interim phase 2 results did not show a statistically significant signal of efficacy of danvatirsen plus pembrolizumab.
The lack of clinical benefit observed in the combination versus single agent pembrolizumab may be attributable to several factors, including the incomplete or heterogeneous suppression of STAT3 signaling, as well as possible compensatory immune-suppressive pathways within the TME. The relatively small sample size of the study precluded a deeper look into possible benefactors of the combination based on specific clinical scenarios, such as HPV, or biomarker specific factors relevant to STAT3 and/or immunotherapy. Unlike prior observations, we did not note additional benefit of the combination compared to pembrolizumab alone, including the subgroup of patients with CPS ≥20, as was the case in the SCORES study. This further emphasizes the value of randomized trials. Nevertheless, seeking an early signal in a relatively small randomized trial limits the number of patients exposed unnecessarily to an ineffective experimental strategy, an advantage worth highlighting.
Potential reasons for the lack of additional benefit of danvatirsen could be the possible ineffectiveness to functionally reducing STAT3 expression in the tumor microenvironment, or that targeting STAT3 with an ASO was not an effective anti-tumor intervention in this setting. While translational studies, including optional paired biopsies and STAT3 expression in peripheral blood mononuclear cells (PBMC), were planned, only 3 patients volunteered for the biopsies. Results were inconclusive and were impacted by poor tissue quality. The PBMC assessment was omitted due to the premature termination of the trial. Thus, it cannot be concluded whether the negative results were due to an ASO platform or an ineffectiveness of STAT3 targeting in this setting.
Despite an overall well tolerated combination regimen, there was a noted increase in TEAE rate in the combination arm, namely increased LFTs, in addition to neutropenia and notable cases of pneumonia. Specifically in regard to the increased LTFs, this TEAE has been reported at similar rates in previous studies of danvatirsen. Despite the possible contribution of danvatirsen to these toxicities, an under-reporting in the control arm could have occurred in an open label design where investigators were not compelled to report familiar side effects to single agent pembrolizumab. In addition, the small sample size could have contributed to these observed imbalances. Notable is the observation of tumor hemorrhages in 6 patients, which was not associated with thrombocytopenia.
Limitations of the study are noteworthy and include a small sample size within an open label design, potential site variability as to RECIST assessments and local CPS measurements, in addition to imbalances among the subgroup of patients with CPS ≥20 in the two arms as well as 3 patients on the pembrolizumab alone arm not receiving study drug.
In the context of limited therapeutic progress beyond single agent PD-1 inhibitors or chemoimmunotherapy in the first line R/M HNSCC, the combination of danvatirsen plus pembrolizumab was not better than pembrolizumab alone in this phase 2 randomized study. Although the open-label design may have biased the control arm towards decreased reporting of adverse events, the combination arm was generally well tolerated. The randomization of a small sample size saved resources and allowed for a limited number of patients to be exposed to an experimental drug. Finally, despite the multiple setbacks, the compelling biological relevance of STAT3 in tumor-intrinsic signaling as well as its immune suppressive properties in solid tumors including HNSCC supports continued alternative and more refined evaluations of STAT3-directed approaches with a focus on novel combinations and biomarker-driven patient selection.
Supplementary Material
Statement of Translational Relevance.
STAT3 plays a central role in promoting a pro-oncogenic tumor microenvironment. Danvatirsen, an antisense oligonucleotide (ASO) designed to downregulate expression of human STAT3 mRNA, revealed encouraging responses in combination with anti PD-L1 therapy in a single arm study. This first phase 2 randomized clinical trial of danvatirsen in combination with pembrolizumab assessed whether first-line treatment of recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) with this combination could improve outcomes compared with pembrolizumab alone. Among 69 patients with R/M HNSCC, the overall response rate was not significantly different between patients treated with danvatirsen plus pembrolizumab (15.6%) compared with pembrolizumab alone (14.3%). These findings raise the prospects for future improved and refined evaluations of STAT3 directed approaches in combination with immunotherapy in R/M HNSCC.
Acknowledgments
Flamingo Therapeutics funded this study and had a role in study design, data collection, data analysis, data interpretation, and writing of this report. Ionis Pharmaceutics licensed danvatirsen to Flamingo for this clinical trial and provided advice on the trial design. This work was supported by NCI grants UG1CA233247 to NFS and was written in collaboration with all authors. The authors acknowledge Dr. Anthea Hammond (Department of Hematology and Medical Oncology, Emory University) for editorial assistance.
Footnotes
Conflict of interest disclosure statement
Dr. Nabil Saba reports funding through federal grants UG1 CA233247, U54 CA274513, and grants from Exelixis and BMS, and having compensated or non-compensated advisory role with: Astra Zeneca, Eisai Medical, Exelixis, Merck, Merck EMD Serono, Pfizer, Kura, Vaccinex, CUE, BionTech, GSK, TOSK, Seagen, Flamingo, Infinity, Inovio, Aveo, Medscape, Onclive, Uptodate, BMS, J&J, Surface Oncology, Urogen, Summit, Guidepoints, Astex, Imugene, Faron Pharmaceutical, Coherus, Adagene, Fulgent, Reddy Laboratories, Merus, Springer, Nanobiotix, Taiho. Dr. Kavin Harrington reports Scientific Advisory Boards/Steering Committee memberships: ALX Oncology; Amgen; Arch Oncology; AstraZeneca; Beigene; Bicara; BMS; Boehringer-Ingelheim; Codiak; Eisai; Flamingo Therapeutics; GSK; Johnson and Johnson; Merck-Serono; MSD; Nanobiotix; Onchilles; One Carbon; PDS Biotech; Pfizer; PsiVac; Qbiotics; Replimune; VacV. Research Funding: AstraZeneca; Boehringer-Ingelheim; Replimune.
Dr Marshall Posner reports Honoraria: Coherus; Consultant - DSMB, SAB: Merck, Vivan Therapeutics, Frizent, Merus, Aveo, Frennec. Employment: TGH/Cancer Center of South Florida Membership: ASCO, ESMO, AACR; Patents: Anti-Viral and Anti-Bacterial Antibodies.
Dr Antonio Jimeno reports: principal investigator on National Institutes of Health grants P50CA261605, R01CA149456, R01CA213102; stock/options ownership in Suvica, Tolerance Bio, and Champions Oncology; A.J. a one-time BlueDot Bio, Purple Biotech, and Johnson & Johnson advisor; A.J.’s institution has contracts with Cantargia, DebioPharm, Flamingo, Genentech, Iovance, Khar Biopharma, Merck, Moderna, Pfizer, Sanofi, and Tolerance Bio for basic and clinical research. The remaining authors declare no conflict of interest.
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