Abstract
PURPOSE
TrilynX was a randomized, double-blind, phase III study evaluating the addition of xevinapant (an inhibitor of apoptosis proteins inhibitor) or placebo to chemoradiotherapy (CRT) in patients with unresected locally advanced squamous cell carcinoma of the head and neck (LA SCCHN).
METHODS
Patients with unresected LA SCCHN (oropharynx [p16-negative only], hypopharynx, or larynx) were randomly assigned 1:1 to six cycles of oral xevinapant 200 mg/day or matched placebo (once daily on Days 1-14 of a 21-day cycle) plus CRT for the first three cycles (cisplatin [100 mg/m2 once on Day 2 of every cycle] plus intensity-modulated radiotherapy [70 Gy; 35 fractions of 2 Gy/day, 5 days/week]). The primary end point was event-free survival (EFS) assessed by the blinded independent review committee. Progression-free survival, overall survival (OS), and safety were secondary end points.
RESULTS
Between September 20, 2020, and February 27, 2023, 730 patients were randomly assigned to xevinapant plus CRT (n = 364) or placebo plus CRT (n = 366). The median (95% CI) EFS was 19.4 months (14.5 to not estimable) with xevinapant and 33.1 months (21.0 to not estimable) with placebo (hazard ratio [HR], 1.33 [95% CI, 1.05 to 1.67]; P = .9919). OS was worse in the xevinapant arm (HR, 1.39 [95% CI, 1.04 to 1.86]). Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 320 (87.9%; xevinapant) and 286 (80.3%; placebo) patients; anemia (78 [21.4%] v 51 [14.3%]) and neutropenia (71 [19.5%] v 69 [19.4%]) were the most common. Serious TEAEs occurred in 194 (53.3%; xevinapant) and 129 (36.2%; placebo) patients. TEAEs leading to death occurred in 22 (6.0%; xevinapant) and 13 (3.7%; placebo) patients.
CONCLUSION
Xevinapant plus CRT did not improve EFS (EFS was shorter with xevinapant v placebo) and demonstrated an unfavorable safety profile versus placebo plus CRT in patients with unresected LA SCCHN.
BACKGROUND
Head and neck cancer, the sixth most common cancer worldwide, accounted for 891,453 new cases and 458,107 deaths globally in 2022.1 Most (≈90%) cases are squamous cell carcinomas,2 and ≈60% of patients with squamous cell carcinoma of the head and neck (SCCHN) are diagnosed with locally advanced (LA) disease.3,4 Current guidelines recommend resection followed by risk-based postoperative management or chemoradiotherapy (CRT) with curative intent.3,5 For patients who will not receive surgery (≈50%; eg, because of surgical unresectability or patients rejecting surgery), definitive cisplatin-based CRT with curative intent has been standard-of-care treatment.3,5 Patients with human papillomavirus–negative LA SCCHN experience local or distant recurrence in up to 50% of cases, depending on risk factors.6 Furthermore, immune checkpoint inhibitor–based combinations failed to improve outcomes in phase III studies of unresected LA SCCHN.7-9 New treatment options are needed.
CONTEXT
Key Objective
This study evaluated xevinapant plus chemoradiotherapy (CRT) versus matched placebo plus CRT for unresected locally advanced squamous cell carcinoma of the head and neck (LA SCCHN).
Knowledge Generated
Treatment with xevinapant plus CRT did not result in improved median event-free survival (EFS) versus placebo plus CRT for the treatment of unresected LA SCCHN—in fact, median EFS was shorter with xevinapant. The safety profile of xevinapant plus CRT was worse than that of placebo plus CRT, resulting in more grade 3 or higher treatment-emergent adverse events (TEAEs) as well as serious TEAEs and TEAEs that led to death.
Relevance (M.L. Gillison)
The addition of the second mitochondrial-derived activator of caspases mimetic xevinapant to cisplatin-based chemoradiation for local-regionally advanced head and neck squamous cell cancer lead to increased high-grade adverse events, distant metastases and death. All ongoing trials in head and neck cancer with this agent were appropriately canceled, and further investigation is warranted to elucidate tumor intrinsic and extrinsic factors that contributed to increased rates of distant metastasis.*
*Relevance section written by JCO Associate Editor Maura L. Gillison, MD, PhD.
Inhibitor of apoptosis proteins (IAPs) are regulators of apoptosis10-14 often overexpressed in cancers such as SCCHN.15,16 IAPs inhibit caspases, enabling apoptosis evasion and treatment resistance.17-20 A randomized phase II study of xevinapant (oral, small-molecule IAP inhibitor), administered for three cycles with concomitant CRT, in unresected LA SCCHN demonstrated a significant locoregional control (LRC) improvement at 18 months after the end of CRT (primary end point) and a manageable safety profile versus matched placebo plus CRT.21 The risk of death after 5 years was more than halved with xevinapant plus CRT, and progression-free survival (PFS) after 3 years was markedly improved versus placebo.22 Here, we report an interim analysis of the phase III TrilynX study investigating xevinapant plus CRT versus placebo plus CRT in patients with unresected LA SCCHN.
METHODS
Study Design
TrilynX was an international, double-blind, phase III study (ClinicalTrials.gov identifier: NCT04459715) that was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines (International Council for Harmonisation). Patients were randomly assigned 1:1 (dynamic allocation) to xevinapant plus CRT or matched placebo plus CRT, with stratification by region (North America/Western Europe/rest of the world), primary tumor site (larynx/other), lymph node involvement (N0-1/N2/N3), and tumor size (T4/other). All patients provided written informed consent before random assignment; the study protocol and amendments were approved by the institutional review board or the independent ethics committee at each participating center.
Patients
Patients (18 years or older) had histologically confirmed unresected LA SCCHN (stage III, IVA, or IVB per the American Joint Committee on Cancer–International Union for Cancer Staging Manual, 8th edition) of the oropharynx, hypopharynx, or larynx, evaluable by computed tomography or magnetic resonance imaging scan per RECIST 1.1; an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1; no hearing loss (by clinical assessment) or grade ≤2 hearing impairment (per National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] v5.0); and adequate hematologic, hepatic, and renal function. Key exclusion criteria included previous definitive or adjuvant radiotherapy (RT) to the head and neck region or systemic SCCHN treatment, primary tumor site other than described above, and metastatic disease (stage IVC). Patients with human papillomavirus–associated oropharyngeal tumors (determined by p16 immunohistochemistry) and oral cavity tumors were excluded because of limited experience with xevinapant in these populations.21 Full details are provided in the Data Supplement (online only).
Treatments
Patients received six cycles of xevinapant (200 mg once daily; oral or via feeding tube) or matched placebo once daily on Days 1-14 of a 21-day cycle plus CRT (cisplatin 100 mg/m2; once on Day 2 of every 3-week cycle [up to three cycles] and intensity-modulated RT [IMRT; 70 Gy; 35 fractions of 2 Gy/day] 5 days/week). Treatment was administered until six cycles were completed or until disease progression, unacceptable toxicity, consent withdrawal, protocol deviation with safety risk, pregnancy, investigator decision, or early study termination.
Two sequential dose reductions of xevinapant (by 50 mg/day) and cisplatin (by 25 mg/m2) were permitted. In the instance of specific cisplatin-related toxicities after the first dose, patients could switch to carboplatin (area under the concentration v time curve of 5 or 4; Day 2 of each subsequent cycle depending on toxicity).
Outcomes and Assessments
The primary end point was event-free survival (EFS), assessed by the blinded independent review committee (BIRC; per RECIST 1.1) and defined as the time from random assignment to the first occurrence of clinical/radiologic disease progression, primary treatment failure before achieving a complete response (CR), radiologic/clinical relapse after achieving a locoregional CR, second cancers unless pathologic findings exclude squamous histology, or death from any cause. Assessments were performed during screening, at the end-of-treatment visit, at Months 7 and 9, every 3 months up to 36 months, and every 6 months thereafter, until premature study discontinuation or the last on-study patient reached the 60-month follow-up. 18F-fluorodeoxyglucose–positron emission tomography was to be performed at screening and the end-of-treatment visit. Secondary end points included overall survival (OS), PFS by BIRC, LRC by investigator assessment, overall response rate (ORR) by BIRC, duration of response (DoR) by BIRC, time to subsequent anticancer therapy, and safety. Full end point definitions are provided in the Data Supplement.
Tumor assessments were continued until disease progression (per RECIST 1.1) or the last on-study patient reached the 60-month follow-up. Patients with disease progression were followed for approximately every 3 months until the end of the study.
Safety was assessed in all patients who received at least one dose of study treatment (safety population). Safety and changes in laboratory values were graded by NCI CTCAE v5.0. All AEs were collected until the end-of-treatment visit; serious AEs were collected until the end-of-study visit.
Statistical Analysis
It was estimated that 700 patients would need to be randomly assigned based on an assumed median EFS of 17 months for the control arm and a hazard ratio (HR) of 0.73. The final EFS analysis used a one-sided stratified log-rank test (stratification factors: lymph node involvement [N0-1/N2/N3] and tumor size [T4/other]). Based on the assumed HR, it was estimated that 429 events were needed to provide a power of approximately 90% to claim superiority of the experimental versus control arm. A prespecified interim analysis (presented here) was expected to be conducted after ≥279 EFS events (assessed by BIRC) were observed (65% of the total events for the primary EFS analysis). Data were first reviewed by the independent data monitoring committee, which informed the sponsor that the predefined futility boundary (HR, 0.876; P = .1277 at 293 observed events) was crossed.
Time-to-event data were estimated using the Kaplan-Meier method; HRs were estimated using a Cox proportional hazard regression model (adjusted for random assignment factors). EFS and OS were tested in a predefined hierarchical fixed-sequence testing procedure that preserved the one-sided type I error rate at 2.5%; OS was only to be tested if EFS analyses were positive.
RESULTS
Between September 20, 2020, and February 27, 2023, 730 patients were randomly assigned to xevinapant plus CRT (n = 364) or placebo plus CRT (n = 366) at 229 sites in 26 countries (Fig 1; Data Supplement, Table S1). Baseline demographics and clinical characteristics were generally balanced between arms (Table 1). The median age was 61.0 (xevinapant) and 60.0 (placebo) years. The site of primary tumor was larynx in 31.9% and 30.9%, hypopharynx in 28.8% and 25.4%, and oropharynx in 39.3% and 43.7%; the stage at baseline was III in 28.0% and 24.0%, IVA in 53.8% and 55.7%, and IVB in 18.1% and 20.2%, respectively.
FIG 1.
Patient disposition (CONSORT diagram). aTwo patients assigned to the placebo arm erroneously received xevinapant treatment because of error at the site and were therefore reassigned to the xevinapant arm for safety analyses. CRT, chemoradiotherapy; EFS, event-free survival.
TABLE 1.
Baseline Demographics and Clinical Characteristics in the Intention-to-Treat Population
| Characteristic | Xevinapant Plus CRT (n = 364) | Placebo Plus CRT (n = 366) |
|---|---|---|
| Age, years, median (IQR) | 61.0 (55-66) | 60.0 (54-66) |
| Sex, No. (%) | ||
| Male | 300 (82.4) | 309 (84.4) |
| Female | 64 (17.6) | 57 (15.6) |
| Geographical region, No. (%) | ||
| Asia | 59 (16.2) | 59 (16.1) |
| Australasia | 3 (0.8) | 2 (0.5) |
| Eastern Europe | 54 (14.8) | 57 (15.6) |
| Middle East | 4 (1.1) | 5 (1.4) |
| North America | 25 (6.9) | 23 (6.3) |
| South America | 40 (11.0) | 37 (10.1) |
| Western Europe | 179 (49.2) | 183 (50.0) |
| Race and ethnicity, No. (%) | ||
| Asian | 59 (16.2) | 60 (16.4) |
| Black or African American | 5 (1.4) | 6 (1.6) |
| White | 253 (69.5) | 256 (69.9) |
| Other | 5 (1.4) | 9 (2.5) |
| Missing | 42 (11.5) | 35 (9.6) |
| Smoking history, No. (%) | ||
| Never smoked | 29 (8.0) | 30 (8.2) |
| Current smoker | 162 (44.5) | 155 (42.3) |
| Former smoker | 173 (47.5) | 181 (49.5) |
| Median pack-years (IQR) | 40 (30-50) | 40 (25-50) |
| Current alcohol consumer, No. (%) | ||
| Yes | 199 (54.7) | 207 (56.6) |
| No | 165 (45.3) | 159 (43.4) |
| Eastern Cooperative Oncology Group performance status, No. (%) | ||
| 0 | 182 (50.0) | 194 (53.0) |
| 1 | 180 (49.5) | 170 (46.4) |
| 2 | 2 (0.5) | 2 (0.5) |
| Feeding tube in place, No. (%) | ||
| Yes | 93 (25.5) | 84 (23.0) |
| No | 271 (74.5) | 282 (77.0) |
| Time since initial diagnosis, months, median (IQR) | 1.48 (1.12-2.00) | 1.40 (1.08-2.07) |
| Site of primary tumor, No. (%) | ||
| Larynx | 116 (31.9) | 113 (30.9) |
| Hypopharynx | 105 (28.8) | 93 (25.4) |
| Oropharynxa | 143 (39.3) | 160 (43.7) |
| Disease stage at baseline, No. (%) | ||
| III | 102 (28.0) | 88 (24.0) |
| IVA | 196 (53.8) | 204 (55.7) |
| IVB | 66 (18.1) | 74 (20.2) |
| Tumor stage at baseline, No. (%) | ||
| T1-T3 | 238 (65.4) | 239 (65.3) |
| T4a or T4b | 126 (34.6) | 127 (34.7) |
| Nodal stage at baseline, No. (%) | ||
| Nx | 0 | 1 (0.3) |
| N0 or N1 | 130 (35.7) | 125 (34.2) |
| N2 | 179 (49.2) | 184 (50.3) |
| N3 | 55 (15.1) | 56 (15.3) |
Abbreviation: CRT, chemoradiotherapy.
Patients with cancer of the oropharynx had to be human papillomavirus–negative to be included in the study.
In the xevinapant and placebo arms, 362 (99.5%) and 358 (97.8%) patients received at least one dose of study treatment (Fig 1). Study treatment was discontinued by 117 (32.1%) and 62 (16.9%) patients; AEs were the most common reason in both arms (xevinapant, 65 [17.9%]; placebo, 29 [7.9%] patients). Two patients assigned to the placebo arm erroneously received xevinapant treatment because of error at the site and were therefore reassigned to the xevinapant arm for safety analyses. The data cutoff for this analysis was April 8, 2024. At the time of analysis, there were 106 (29.1%; xevinapant) and 80 (22.5%; placebo) deaths. In both arms, the most frequent cause of death was cancer under study (66 [18.1%] and 48 [13.5%] patients).
The median treatment duration was 18.0 weeks in both arms (Table 2). The median IMRT dose was 70 Gy (IQR, 70-70) in both arms; more patients in the xevinapant arm received a dose of 50 to <70 Gy (15 [4.1%] v 5 [1.4%]) or ≤50 Gy (26 [7.1%] v 15 [4.2%]). The median cumulative cisplatin dose was 200 mg/m2 (IQR, 200-300 mg/m2) in the xevinapant arm and 275 mg/m2 (IQR, 200-300 mg/m2) in the placebo arm. Subsequent anticancer therapy was received by 70 (19.2%; xevinapant) and 47 (12.8%; placebo) patients (Data Supplement, Table S3).
TABLE 2.
Treatment Exposure in the Safety Population
| Parameter | Xevinapant Plus CRT (n = 364) | Placebo Plus CRT (n = 356) |
|---|---|---|
| Treatment cycles, No. (%) | ||
| 1 | 364 (100.0) | 356 (100.0) |
| 2 | 337 (92.6) | 337 (94.7) |
| 3 | 304 (83.5) | 319 (89.6) |
| 4 | 266 (73.1) | 310 (87.1) |
| 5 | 263 (72.3) | 307 (86.2) |
| 6 | 246 (67.6) | 297 (83.4) |
| Overall treatment duration, weeks, median (IQR)a | 18.00 (11.21-18.14) | 18.00 (18.00-18.29) |
| Median total cumulative dose of xevinapant or placebo (IQR), mg | 15,400 (8,200-16,800) | 16,600 (14,300-16,800) |
| Median dose intensity of once daily xevinapant or placebo (IQR), mg/day | 130.08 (116.67-133.33) | 133.33 (126.69-133.33) |
| Cycles of cisplatin, No. (%) | ||
| 1 | 360 (98.9) | 349 (98.0) |
| 2 | 286 (78.6) | 296 (83.1) |
| 3 | 187 (51.4) | 206 (57.9) |
| Total cumulative dose of cisplatin, mg/m2 (IQR) | 200 (200-300) | 275 (200-300) |
| 100 to <200, No. (%) | 87 (23.9) | 68 (19.1) |
| 200 to <300, No. (%) | 138 (37.9) | 117 (32.9) |
| ≥300, No. (%) | 135 (37.1) | 166 (46.6) |
| No. of cycles of carboplatin, No. (%) | ||
| 1 | 0 | 1 (0.3) |
| 2 | 35 (9.6) | 31 (8.7) |
| 3 | 44 (12.1) | 51 (14.3) |
| Median total cumulative dose of carboplatin, AUC (IQR) | 5.0 (5.0-10.0) | 5.0 (5.0-9.0) |
| Median total cumulative dose of radiotherapy, Gy (IQR) | 70 (70-70) | 70 (70-70) |
| Total cumulative dose of radiotherapy, Gy, No. (%) | ||
| <50 | 26 (7.1) | 15 (4.2) |
| 50 to <70 | 15 (4.1) | 5 (1.4) |
| ≥70 | 323 (88.7) | 335 (94.1) |
| Missing | 0 | 1 (0.3) |
NOTE. The safety population included all patients who received at least one dose of study treatment.
Abbreviations: CRT, chemoradiotherapy; IMRT, intensity-modulated radiotherapy.
Overall treatment duration is defined as the maximum duration of treatment and is calculated as (date of last dose – date of first dose + x)/7, where x = 8 for xevinapant/placebo, x = 21 for cisplatin/carboplatin, and x = 3 for IMRT.
At data cutoff, the median follow-up was 18 months in both arms. The median EFS by BIRC was 19.4 (157 events; 95% CI, 14.5 months to not estimable [NE]) versus 33.1 (136 events; 95% CI, 21.0 months to NE) months with xevinapant versus placebo (HR, 1.33 [95% CI, 1.05 to 1.67]; P = .9919; Fig 2A). EFS events because of death, clinical/radiologic disease progression, and primary treatment failure before achieving a CR occurred more frequently with xevinapant (Data Supplement, Table S4). EFS by BIRC was consistent across prespecified subgroups (Fig 2B). The median EFS (per investigator) was 17.6 months (95% CI, 13.3 months to NE) with xevinapant and not reached (27.2 months to NE) with placebo (HR, 1.35; 95% CI, 1.07 to 1.70). EFS concordance rates between BIRC and investigator assessment were 90.7% and 86.9%.
FIG 2.
EFS in the intention-to-treat population: (A) Kaplan-Meier estimates of EFS by BIRC in the overall population and (B) forest plot of EFS in prespecified subgroups. BIRC, blinded independent review committee; CRT, chemoradiotherapy; EFS, event-free survival; HR, hazard ratio; NE, not estimable; NR, not reported; P, placebo; X, xevinapant.
PFS and OS were not improved but were numerically worse with xevinapant versus placebo (Figs 3A and 3B). The median PFS was 26.8 (95% CI, 15.9 months to NE) versus 33.1 (95% CI, 22.8 months to NE) months (HR, 1.24; 95% CI, 0.97 to 1.57). Median OS was not reached in either arm (106 v 81 events; HR, 1.39; 95% CI, 1.04 to 1.86). LRC assessment showed no difference between arms (HR, 1.05; 95% CI, 0.74 to 1.50); median LRC was not reached in either arm (Fig 3C). Competing risk analysis of locoregional failure showed equal risk across arms (Fig 3D); risk of distant failure was higher with xevinapant (Fig 3E). The proportion of patients with progression events that constituted locoregional or distant failure is provided (Data Supplement, Table S5). The ORR was 73.6% versus 77.9% at 12 months; median DoR was not reached in either arm (Data Supplement, Fig S1). A CR at 12 months was reported in 194 (53.3%) and 222 (60.7%) patients.
FIG 3.
Efficacy in the intention-to-treat population. (A) Kaplan-Meier estimates of PFS by BIRC, (B) Kaplan-Meier estimates of OS, (C) Kaplan-Meier estimates of LRC, (D) competing risk analysis of locoregional failure, and (E) competing risk analysis of distant failure. BIRC, blinded independent review committee; CRT, chemoradiotherapy; HR, hazard ratio; LRC, locoregional control; NE, not estimable; NR, not reached; OS, overall survival; PFS, progression-free survival.
Treatment-emergent AEs (TEAEs; any grade, any cause) occurred in 362 (99.5%) patients in the xevinapant arm and 351 (98.6%) patients in the placebo arm (Table 3). The most common TEAEs were anemia (55.5%), stomatitis (55.5%), and weight decreased (52.2%) with xevinapant, and anemia (51.4%), nausea (46.9%), and stomatitis (46.1%) with placebo (Table 4). The most common grade ≥3 TEAEs were anemia (21.4% and 14.3%) and neutropenia (19.5% and 19.4%) in both arms. The rate of infection, including infective pneumonia, was higher with xevinapant (9.3%) versus placebo (3.7%; Data Supplement, Table S6). Grade ≥3 pneumonia (any cause) occurred in 29 (8.0%) versus 11 (3.1%) patients. Serious TEAEs occurred in 194 (53.3%) and 129 (36.2%) patients. TEAEs that resulted in dose reduction of any treatment occurred more frequently with xevinapant (87 [23.9%] v 62 [17.4%]). TEAEs resulting in temporary interruption of any treatment occurred in 260 (71.4%) and 208 (58.4%) patients. TEAEs that led to permanent discontinuation of any treatment occurred in 139 (38.2%) and 87 (24.4%) patients (Data Supplement, Tables S7-S9). TEAEs led to death in 22 (6.0%) and 13 (3.7%) patients, including six (1.6%) and one (0.3%) patients who had pneumonia that led to death and two (0.5%) and two (0.6%) patients who had sepsis that led to death.
TABLE 3.
Summary of Safety
| TEAE | Xevinapant Plus CRT (n = 364), No. (%) | Placebo Plus CRT (n = 356), No. (%) |
|---|---|---|
| Any TEAE of any grade | 362 (99.5) | 351 (98.6) |
| Any grade ≥3 TEAE | 320 (87.9) | 286 (80.3) |
| Any grade ≥4 TEAE | 117 (32.1) | 71 (19.9) |
| Any serious TEAE | 194 (53.3) | 129 (36.2) |
| Any TEAE leading to dose reduction of study treatment | 87 (23.9) | 62 (17.4) |
| Reduction of xevinapant/placebo | 34 (9.3) | 17 (4.8) |
| Reduction of chemotherapy | 65 (17.9) | 52 (14.6) |
| Reduction of IMRT | 0 | 0 |
| Any TEAE leading to temporary interruption of study treatment | 260 (71.4) | 208 (58.4) |
| Interruption of xevinapant/placebo | 206 (56.6) | 147 (41.3) |
| Interruption of chemotherapy | 153 (42.0) | 121 (34.0) |
| Interruption of IMRT | 84 (23.1) | 68 (19.1) |
| Any TEAE leading to permanent discontinuation of study treatment | 139 (38.2) | 87 (24.4) |
| Discontinuation of xevinapant/placebo | 71 (19.5) | 30 (8.4) |
| Discontinuation of chemotherapy | 106 (29.1) | 76 (21.3) |
| Discontinuation of IMRT | 19 (5.2) | 9 (2.5) |
| Any TEAE leading to death | 22 (6.0) | 13 (3.7) |
NOTE. Assessed in the safety population (all patients who received at least one dose of study treatment).
Abbreviations: CRT, chemoradiotherapy; IMRT, intensity-modulated radiotherapy; TEAE, treatment-emergent adverse event.
TABLE 4.
TEAEs of Any Grade Occurring in ≥10% of Patients and All Grade 5 TEAEs in Either Treatment Arm
| TEAE | Xevinapant Plus CRT (n = 364), No. (%) | Placebo Plus CRT (n = 356), No. (%) | ||||||
|---|---|---|---|---|---|---|---|---|
| Grade 1 to 2 | Grade 3 | Grade 4 | Grade 5 | Grade 1 to 2 | Grade 3 | Grade 4 | Grade 5 | |
| Anemia | 124 (34.1) | 75 (20.6) | 3 (0.8) | 0 | 132 (37.1) | 49 (13.8) | 2 (0.6) | 0 |
| Stomatitis | 150 (41.2) | 48 (13.2) | 4 (1.1) | 0 | 127 (35.7) | 37 (10.4) | 0 | 0 |
| Weight decreased | 167 (45.9) | 23 (6.3) | 0 | 0 | 145 (40.7) | 14 (3.9) | 0 | 0 |
| Radiation skin injury | 146 (40.1) | 19 (5.2) | 0 | 0 | 146 (41.0) | 13 (3.7) | 1 (0.3) | 0 |
| Dysphagia | 85 (23.4) | 65 (17.9) | 1 (0.3) | 0 | 68 (19.1) | 36 (10.1) | 1 (0.3) | 0 |
| Nausea | 125 (34.3) | 20 (5.5) | 1 (0.3) | 0 | 149 (41.9) | 18 (5.1) | 0 | 0 |
| Dry mouth | 132 (36.3) | 5 (1.4) | 0 | 0 | 122 (34.3) | 2 (0.6) | 0 | 0 |
| Constipation | 124 (34.1) | 2 (0.5) | 0 | 0 | 123 (34.6) | 2 (0.6) | 0 | 0 |
| Neutropenia | 45 (12.4) | 57 (15.7) | 14 (3.8) | 0 | 32 (9.0) | 59 (16.6) | 10 (2.8) | 0 |
| Dysgeusia | 103 (28.3) | 2 (0.5) | 1 (0.3) | 0 | 109 (30.6) | 2 (0.6) | 0 | 0 |
| Asthenia | 86 (23.6) | 15 (4.1) | 0 | 0 | 65 (18.3) | 4 (1.1) | 0 | 0 |
| Blood creatinine increased | 77 (21.2) | 12 (3.3) | 3 (0.8) | 0 | 79 (22.2) | 6 (1.7) | 0 | 0 |
| Amylase increased | 55 (15.1) | 26 (7.1) | 4 (1.1) | 0 | 35 (9.8) | 7 (2.0) | 4 (1.1) | 0 |
| Neutrophil count decreased | 27 (7.4) | 39 (10.7) | 13 (3.6) | 0 | 35 (9.8) | 35 (9.8) | 6 (1.7) | 0 |
| Alanine aminotransferase increased | 60 (16.5) | 18 (4.9) | 0 | 0 | 37 (10.4) | 2 (0.6) | 1 (0.3) | 0 |
| Hypokalemia | 44 (12.1) | 25 (6.9) | 6 (1.6) | 0 | 45 (12.6) | 13 (3.7) | 7 (2.0) | 0 |
| Vomiting | 63 (17.3) | 7 (1.9) | 0 | 1 (0.3) | 74 (20.8) | 12 (3.4) | 0 | 0 |
| Odynophagia | 58 (15.9) | 13 (3.6) | 0 | 0 | 59 (16.6) | 18 (5.1) | 0 | 0 |
| Decreased appetite | 51 (14.0) | 18 (4.9) | 0 | 0 | 82 (23.0) | 15 (4.2) | 0 | 0 |
| Thrombocytopenia | 47 (12.9) | 13 (3.6) | 7 (1.9) | 1 (0.3) | 33 (9.3) | 11 (3.1) | 3 (0.8) | 0 |
| Pneumonia | 8 (2.2) | 20 (5.5) | 3 (0.8) | 6 (1.6) | 10 (2.8) | 9 (2.5) | 1 (0.3) | 1 (0.3) |
| General physical health deterioration | 2 (0.5) | 4 (1.1) | 1 (0.3) | 2 (0.5) | 2 (0.6) | 1 (0.3) | 0 | 0 |
| Sepsis | 0 | 2 (0.5) | 4 (1.1) | 2 (0.5) | 1 (0.3) | 1 (0.3) | 0 | 2 (0.6) |
| Tumor hemorrhage | 2 (0.5) | 0 | 2 (0.5) | 0 | 1 (0.3) | 5 (1.4) | 0 | 1 (0.3) |
| Respiratory failure | 3 (0.8) | 1 (0.3) | 0 | 0 | 0 | 0 | 0 | 1 (0.3) |
| Pulmonary edema | 0 | 1 (0.3) | 1 (0.3) | 0 | 0 | 1 (0.3) | 0 | 1 (0.3) |
| Death | 0 | 0 | 0 | 2 (0.5) | 0 | 0 | 0 | 2 (0.6) |
| Pancreatitis | 1 (0.3) | 0 | 0 | 1 (0.3) | 0 | 0 | 0 | 0 |
| Cardiorespiratory arrest | 0 | 0 | 0 | 2 (0.5) | 0 | 0 | 0 | 0 |
| Cardiac failure | 1 (0.3) | 0 | 0 | 0 | 0 | 1 (0.3) | 0 | 1 (0.3) |
| Disease progression | 0 | 0 | 0 | 1 (0.3) | 0 | 1 (0.3) | 0 | 1 (0.3) |
| Pneumothorax | 0 | 1 (0.3) | 0 | 0 | 0 | 0 | 0 | 1 (0.3) |
| Asphyxia | 0 | 0 | 0 | 1 (0.3) | 0 | 0 | 0 | 0 |
| Cardiac arrest | 0 | 0 | 0 | 1 (0.3) | 0 | 0 | 0 | 0 |
| Hepatic failure | 0 | 0 | 0 | 1 (0.3) | 0 | 0 | 0 | 0 |
| Multiple organ dysfunction syndrome | 0 | 0 | 0 | 1 (0.3) | 0 | 0 | 0 | 0 |
| Neurogenic shock | 0 | 0 | 0 | 1 (0.3) | 0 | 0 | 0 | 0 |
| Systemic inflammatory response syndrome | 0 | 0 | 0 | 1 (0.3) | 0 | 0 | 0 | 0 |
| Ischemic cardiomyopathy | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 (0.3) |
| Left ventricular dysfunction | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 (0.3) |
| Tumor rupture | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 (0.3) |
NOTE. Assessed in the safety population (all patients who received at least one dose of study treatment). Patients are counted once for each relevant TEAE.
Abbreviations: CRT, chemoradiotherapy; TEAE, treatment-emergent adverse event.
DISCUSSION
TrilynX did not meet its primary objective of prolonging EFS by BIRC assessment when adding xevinapant to CRT compared with placebo plus CRT in patients with unresected LA SCCHN; in fact, median EFS was shorter with xevinapant. Results were consistent across prespecified subgroups and by investigator assessment. PFS and OS outcomes were also unfavorable with xevinapant plus CRT, suggesting a detrimental effect. Locoregional failure rates were similar across arms, whereas the distant failure rate was higher in the xevinapant arm. The safety profile was worse with xevinapant compared with placebo. Overall, TrilynX did not replicate the positive outcomes of the phase II study of xevinapant plus CRT in unresected LA SCCHN.21,22
An imbalance in grade ≥3 and grade ≥4 TEAEs (including GI disorders, infections [including pneumonia], investigations, and renal and urinary disorders from any cause) as well as serious TEAEs and TEAEs that led to death was observed, which underpinned the observed reduced treatment intensity and completion rates in the xevinapant arm. Xevinapant plus CRT toxicity appeared to be more pronounced and earlier in TrilynX than in the phase II study, resulting in the need for early cisplatin dose modification in the xevinapant arm. An imbalance in cisplatin dose modifications between arms was detectable as early as cycle 1 (data not shown). In comparison, an imbalance in cisplatin dose modification between arms in the phase II study was only detectable in cycle 3 (data on file). Rates of treatment discontinuation were also higher with xevinapant versus placebo, and a high proportion of these discontinuations occurred during the first three cycles while patients were receiving xevinapant plus CRT. In contrast to the phase II study, exposure to both cisplatin (median cumulative dose in the phase II study, 288 mg/m2 in both arms; median cumulative dose in TrilynX, 200 mg/m2 [xevinapant] v 275 mg/m2 [placebo]) and RT (phase II study: proportion of patients who received <66 Gy, 10% v 13%; TrilynX: proportion of patients who received <70 Gy, 11% v 6%, and <50 Gy, 7% v 4%) was lower in the TrilynX xevinapant arm.21 The rate of switching to carboplatin-based CRT and the cumulative carboplatin exposure were similar in both arms of TrilynX, suggesting that carboplatin use did not drive the differences in outcomes. Xevinapant plus CRT in TrilynX was less tolerable than placebo plus CRT, and TEAEs, resulting in dose interruption, modification, or discontinuation of xevinapant and cisplatin occurred earlier and more frequently than in the phase II study. The lower cumulative chemotherapy and RT doses in the xevinapant arm could, in part, explain the unfavorable TrilynX outcomes. However, based on exploratory post hoc analyses, it could not be concluded that this was the main factor explaining our results (data not shown).
Median EFS in the placebo arm (33.1 months) exceeded the assumed value (17.0 months; based on the phase II study), which informed the study design, suggesting that the placebo arm in the phase II study might have underperformed because of possible inclusion of a population with worse outcomes than in TrilynX.21 Notable differences in baseline demographics and clinical characteristics were observed between studies across both arms, particularly in age (higher in TrilynX: 61 v 57 years [xevinapant]; 60 v 59 years [placebo]), ECOG PS (50% [xevinapant] v 42% [placebo] of patients had ECOG PS 1 in TrilynX), tumor location (a higher proportion of patients had larynx tumors in TrilynX in both arms, indicating a better prognosis: 32% v 17% [xevinapant]; 31% v 4% [placebo]), and TNM staging (a lower proportion of patients had stage IVA disease in TrilynX: 54% v 73% [xevinapant]; 56% v 67% [placebo]).21 However, no analyzed subgroups benefited from xevinapant plus CRT in TrilynX. Conversely, all subgroups benefited from xevinapant plus CRT in the phase II study.21,22 Additional differences between TrilynX and the phase II study included a prospective central RT quality assurance review in TrilynX that was not in place and only performed retrospectively in the phase II study, and a treatment regimen of six versus three xevinapant cycles (rationale described in the Data Supplement).21 Whether the three additional xevinapant cycles affected TrilynX outcomes cannot be assessed, as a comparator arm receiving only three xevinapant cycles was not included. The xevinapant formulation differed slightly between studies—the TrilynX formulation contained a low quantity of sodium benzoate (10 mg/dose; ie, 35-fold below the maximum acceptable daily intake based on 70 kg body weight23) and lacked an orange flavoring agent compared with the phase II formulation. However, it is unlikely that these differences affected study outcomes, considering no available data suggest that these excipients were given at sufficient quantities to impact efficacy or safety. Furthermore, exposure to xevinapant 200 mg once daily on Days 1-14 of cycle 1 was generally similar between TrilynX and the phase II study (data not shown); hence, these results provide no explanation for the differing outcomes.
The distant failure rate in the xevinapant arm was higher than that observed in the placebo arm in both TrilynX and a post hoc analysis of the phase II study (data on the file). The high distant failure rate with xevinapant plus CRT and separation of the distant failure curves were evident early in TrilynX. The higher distant failure rates (ie, lack of distant metastasis control) in the xevinapant arm combined with greater risk of some infection types, notably pneumonia, suggest that xevinapant had an immunosuppressive effect that may, in part, explain the unfavorable efficacy outcomes and higher infection rates with xevinapant. If this is true, the higher number of xevinapant cycles in TrilynX (six cycles) compared with the phase II study (three cycles) might have further contributed to this effect. Regarding the higher rate of pneumonias with xevinapant, it cannot be concluded whether these infections were primarily caused by immunosuppression or by aggravation of radiation-induced toxicities (eg, mucositis and dysphagia), which would subsequently increase these infection rates.
To our knowledge, TrilynX was the first randomized phase III study of an IAP inhibitor in any tumor type. Historically, apoptosis has been considered an immune-silent or immunosuppressive form of cell death. Given that xevinapant predominantly rewires cell death toward apoptosis, instead of the more immunogenic necroptosis or pyroptosis,24 xevinapant might have inadvertently reduced the immune-activating CRT effects. It is unknown whether xevinapant would have been better tolerated or resulted in better outcomes if combined with once weekly cisplatin or RT alone. Given the outcomes of this interim analysis, it was determined that xevinapant cannot be recommended for use in this indication, and TrilynX was terminated on June 24, 2024.
Xevinapant plus CRT did not improve EFS versus placebo plus CRT in patients with unresected LA SCCHN. In fact, a detrimental effect was observed, which was, in part, due to the poor tolerability and unfavorable safety profile of xevinapant when added to CRT, particularly early during treatment. This unexpected toxicity also led to earlier and more frequent cisplatin dose reductions, both of which might have negatively affected efficacy. LA SCCHN remains a difficult-to-treat disease with a high unmet need.
ACKNOWLEDGMENT
The authors thank the patients and their families, the investigators, coinvestigators, and study teams at each of the participating centers. Medical writing support was provided by Jamie Ratcliffe of Nucleus Global and funded by Merck (CrossRef Funder ID: 10.13039/100009945), in accordance with Good Publication Practice guidelines (https://www.ismpp.org/gpp-2022).
Jean Bourhis
Consulting or Advisory Role: AstraZeneca, Bristol Myers Squibb, Debiopharm Group, Merck, MSD, Nanobiotix, Roche
Lisa F. Licitra
Honoraria: Merck, MSD, Adlai Nortye, ALTIS Omnia Pharma Service S.r.l., Bristol Myers Squibb
Consulting or Advisory Role: Eisai, Boehringer Ingelheim, AstraZeneca, Merck, MSD, GSK, Roche, Novartis, Seagen, Genmab, Mirati Therapeutics, Janssen Research & Development, AbbVie S.r.l., ALX Oncology, GroupH Ltd
Research Funding: AstraZeneca, Novartis, Roche, MSD, Eisai, Merck, Boehringer Ingelheim, Celgene, Exelixis, IRX Therapeutics, Medpace, Pfizer, Debiopharm Group, Roche
Travel, Accommodations, Expenses: TAE Life Sciences
Barbara Burtness
Consulting or Advisory Role: Merck, CUE Biopharma, MacroGenics, ALX Oncology, IO Biotech, Genentech/Roche, Kura Oncology, MSD, Coherus Biosciences, Arvinas, AbbVie, Vaccinex, Rakuten Medical, Eisai, Mirati Therapeutics, Orphagen Pharmaceuticals, Merus, Seagen, Janssen Oncology
Speakers' Bureau: Clinical Education Alliance, Oncology Education
Research Funding: Merck, MSD, Exelixis, CUE Biopharma, IO Biotech
Expert Testimony: Cel-Sci Corporation
Amanda Psyrri
Honoraria: Merck, MSD, Roche, Bristol Myers Squibb, Genesis Pharmaceuticals, Bayer, AstraZeneca, Pfizer, GSK, Seagen, Merus NV
Consulting or Advisory Role: AstraZeneca, MSD, Pfizer, Bristol Myers Squibb, Amgen, eTheRNA Immunotherapies, GSK, Seagen, Merus NV
Research Funding: Kura Oncology, Bristol Myers Squibb, Roche, Amgen, Boehringer Ingelheim, Pfizer, Demo Pharmaceutical, Pharmathen
Travel, Accommodations, Expenses: Roche, MSD, Ipsen, Bristol Myers Squibb
Uncompensated Relationship: AstraZeneca
Robert Haddad
Employment: Dana-Farber Cancer Institute
Leadership: NCCN
Stock or Other Ownership: Tosk
Consulting or Advisory Role: AstraZeneca, Merck, Eisai, Bristol Myers Squibb, GSK, MSD, Bayer, Coherus Biosciences, Boehringer Ingelheim, Genmab, Galera Therapeutics, Merus NV, ALX Oncology
Research Funding: Merck, MSD, Bristol Myers Squibb, AstraZeneca, Genentech, Pfizer, Kura Oncology, Incyte
Patents, Royalties, Other Intellectual Property: UpToDate
Other Relationship: Nanobiotix, ISA Pharmaceuticals, Boehringer Ingelheim, HOOKIPA Pharma
Kevin Harrington
Honoraria: Arch Oncology, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Merck, MSD, Oncolys BioPharma, Replimune, Inzen Therapeutics, Pfizer, Codiak Biosciences, Scenic Biotech, Johnson & Johnson, Nanobiotix
Consulting or Advisory Role: Arch Oncology, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Merck, MSD, Oncolys BioPharma, Replimune, Inzen Therapeutics, Nanobiotix
Speakers' Bureau: Bristol Myers Squibb, Merck, MSD
Research Funding: AstraZeneca, Replimune, Boehringer Ingelheim
Ezra E.W. Cohen
Leadership: Kura Oncology, Akamis Bio, Kinnate Biopharma, Pangea Bio
Stock or Other Ownership: Kinnate Biopharma, Primmune Therapeutics
Consulting or Advisory Role: Adagene, Astellas Pharma, Cidara, Eisai, Lilly, Genmab, Gilboa Therapeutics, ITeos Therapeutics, Merck, MSD, Nectin Tx, Novartis, Nykode Therapeutics, Pangea Bio, PCI Biotech, Replimune, Roche, SOTERIA Precision Medicine, Viracta Therapeutics
Yungan Tao
Honoraria: Merck, Seagen
Consulting or Advisory Role: MSD
Travel, Accommodations, Expenses: Merck, MSD
Makoto Tahara
Honoraria: Bristol Myers Squibb, Eisai, Ono Pharmaceutical, MSD, Lilly, Bayer, Merck, Novartis
Consulting or Advisory Role: Ono Pharmaceutical, MSD, Pfizer, Bristol Myers Squibb, Rakuten Medical, Bayer, Lilly, Eisai, Boehringer Ingelheim, Genmab, Janssen, Nanobiotix, Astellas Pharma, GlaxoSmithKline, Merck
Research Funding: AstraZeneca, MSD, Merck, Ono Pharmaceutical, Novartis, Pfizer, Bristol Myers Squibb, Rakuten Medical, Bayer, GSK, Lilly
Ammar Sukari
Consulting or Advisory Role: Coherus BioSciences, Merck
Speakers' Bureau: MSD
Tomasz Rutkowski
Speakers' Bureau: Bristol Myers Squibb, MSD
Heidi Nauwelaerts
Employment: Debiopharm International SA
Rudi Scheerlinck
Employment: Ares Trading SA (Eysins, Switzerland) an affiliate of Merck KGaA
Ngoc-Thuy Ha
Employment: Merck Healthcare KGaA (Darmstadt, Germany)
Andreas Schroeder
Employment: Merck Healthcare KGaA (Darmstadt, Germany)
Almudena Rodriguez-Gutierrez
Employment: Merck S.L.U. (Madrid, Spain) an affiliate of Merck KGaA
Jonathan D. Schoenfeld
Leadership: American Society for Radiation Oncology
Stock or Other Ownership: Immunitas, Intragel
Consulting or Advisory Role: Immunitas, Intragel, Merck, SIRPant
Speakers' Bureau: Merck
Research Funding: Bristol Myers Squibb, Merck, Regeneron, MSD, Debiopharm, Siemens
Patents, Royalties, Other Intellectual Property: MAGEA1 IMMUNOGENIC PEPTIDES, BINDING PROTEINS RECOGNIZING MAGEA1 IMMUNOGENIC PEPTIDES, AND USES THEREOF, Nanobody Bioconjugation for Immune Receptor Targeting
Expert Testimony: Burns and White
No other potential conflicts of interest were reported.
See accompanying Understanding the Pathway, p. 3221
DISCLAIMER
The authors are fully responsible for the content of this manuscript, and the views and opinions described in the publication reflect solely those of the authors.
PRIOR PRESENTATION
Presented in part at the 2021 ASCO Annual Meeting, Chicago, IL, June 4-8, 2021.
SUPPORT
Supported by Debiopharm International SA (study conceptualization and sponsorship prior to December 2021) and Merck (CrossRef Funder ID: 10.13039/100009945; sponsorship since December 2021).
CLINICAL TRIAL INFORMATION
DATA SHARING STATEMENT
For all new products or new indications approved in both the EU and the United States after January 1, 2014, Merck will share patient- and study-level data after deidentification, as well as redacted study protocols and clinical study reports from clinical trials in patients. These data will be shared with qualified scientific and medical researchers, upon researcher's request, as necessary for conducting legitimate research. Such requests must be submitted in writing to the company's data sharing portal. More information can be found at https://www.merckgroup.com/en/research/our-approach-to-research-and-development/healthcare/clinical-trials/commitment-responsible-data-sharing.html. Where Merck has a coresearch, codevelopment, or comarketing/copromotion agreement or where the product has been outlicensed, it is recognized that the responsibility for disclosure may be dependent on the agreement between parties. Under these circumstances, Merck will endeavor to gain agreement to share data in response to requests.
AUTHOR CONTRIBUTIONS
Conception and design: Jean Bourhis, Lisa F. Licitra, Barbara Burtness, Ezra E.W. Cohen, Heidi Nauwelaerts, Rudi Scheerlinck, Ngoc-Thuy Ha, Andreas Schroeder, Almudena Rodriguez-Gutierrez, Jonathan D. Schoenfeld
Collection and assembly of data: Jean Bourhis, Lisa F. Licitra, Barbara Burtness, Amanda Psyrri, Robert Haddad, Kevin Harrington, Ezra E.W. Cohen, Yungan Tao, Katsuki Arima Tiscoski, Amiran Matitashvili, Makoto Tahara, Ammar Sukari, Tomasz Rutkowski, Sebastien Salas, Rudi Scheerlinck, Ngoc-Thuy Ha, Andreas Schroeder, Jonathan D. Schoenfeld
Data analysis and interpretation: Jean Bourhis, Lisa F. Licitra, Barbara Burtness, Amanda Psyrri, Robert Haddad, Kevin Harrington, Ezra E.W. Cohen, Heidi Nauwelaerts, Rudi Scheerlinck, Ngoc-Thuy Ha, Andreas Schroeder, Almudena Rodriguez-Gutierrez, Jonathan D. Schoenfeld
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Xevinapant or Placebo Plus Platinum-Based Chemoradiotherapy in Unresected Locally Advanced Squamous Cell Carcinoma of the Head and Neck (TrilynX): A Randomized, Phase III Study
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).
Jean Bourhis
Consulting or Advisory Role: AstraZeneca, Bristol Myers Squibb, Debiopharm Group, Merck, MSD, Nanobiotix, Roche
Lisa F. Licitra
Honoraria: Merck, MSD, Adlai Nortye, ALTIS Omnia Pharma Service S.r.l., Bristol Myers Squibb
Consulting or Advisory Role: Eisai, Boehringer Ingelheim, AstraZeneca, Merck, MSD, GSK, Roche, Novartis, Seagen, Genmab, Mirati Therapeutics, Janssen Research & Development, AbbVie S.r.l., ALX Oncology, GroupH Ltd
Research Funding: AstraZeneca, Novartis, Roche, MSD, Eisai, Merck, Boehringer Ingelheim, Celgene, Exelixis, IRX Therapeutics, Medpace, Pfizer, Debiopharm Group, Roche
Travel, Accommodations, Expenses: TAE Life Sciences
Barbara Burtness
Consulting or Advisory Role: Merck, CUE Biopharma, MacroGenics, ALX Oncology, IO Biotech, Genentech/Roche, Kura Oncology, MSD, Coherus Biosciences, Arvinas, AbbVie, Vaccinex, Rakuten Medical, Eisai, Mirati Therapeutics, Orphagen Pharmaceuticals, Merus, Seagen, Janssen Oncology
Speakers' Bureau: Clinical Education Alliance, Oncology Education
Research Funding: Merck, MSD, Exelixis, CUE Biopharma, IO Biotech
Expert Testimony: Cel-Sci Corporation
Amanda Psyrri
Honoraria: Merck, MSD, Roche, Bristol Myers Squibb, Genesis Pharmaceuticals, Bayer, AstraZeneca, Pfizer, GSK, Seagen, Merus NV
Consulting or Advisory Role: AstraZeneca, MSD, Pfizer, Bristol Myers Squibb, Amgen, eTheRNA Immunotherapies, GSK, Seagen, Merus NV
Research Funding: Kura Oncology, Bristol Myers Squibb, Roche, Amgen, Boehringer Ingelheim, Pfizer, Demo Pharmaceutical, Pharmathen
Travel, Accommodations, Expenses: Roche, MSD, Ipsen, Bristol Myers Squibb
Uncompensated Relationship: AstraZeneca
Robert Haddad
Employment: Dana-Farber Cancer Institute
Leadership: NCCN
Stock or Other Ownership: Tosk
Consulting or Advisory Role: AstraZeneca, Merck, Eisai, Bristol Myers Squibb, GSK, MSD, Bayer, Coherus Biosciences, Boehringer Ingelheim, Genmab, Galera Therapeutics, Merus NV, ALX Oncology
Research Funding: Merck, MSD, Bristol Myers Squibb, AstraZeneca, Genentech, Pfizer, Kura Oncology, Incyte
Patents, Royalties, Other Intellectual Property: UpToDate
Other Relationship: Nanobiotix, ISA Pharmaceuticals, Boehringer Ingelheim, HOOKIPA Pharma
Kevin Harrington
Honoraria: Arch Oncology, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Merck, MSD, Oncolys BioPharma, Replimune, Inzen Therapeutics, Pfizer, Codiak Biosciences, Scenic Biotech, Johnson & Johnson, Nanobiotix
Consulting or Advisory Role: Arch Oncology, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Merck, MSD, Oncolys BioPharma, Replimune, Inzen Therapeutics, Nanobiotix
Speakers' Bureau: Bristol Myers Squibb, Merck, MSD
Research Funding: AstraZeneca, Replimune, Boehringer Ingelheim
Ezra E.W. Cohen
Leadership: Kura Oncology, Akamis Bio, Kinnate Biopharma, Pangea Bio
Stock or Other Ownership: Kinnate Biopharma, Primmune Therapeutics
Consulting or Advisory Role: Adagene, Astellas Pharma, Cidara, Eisai, Lilly, Genmab, Gilboa Therapeutics, ITeos Therapeutics, Merck, MSD, Nectin Tx, Novartis, Nykode Therapeutics, Pangea Bio, PCI Biotech, Replimune, Roche, SOTERIA Precision Medicine, Viracta Therapeutics
Yungan Tao
Honoraria: Merck, Seagen
Consulting or Advisory Role: MSD
Travel, Accommodations, Expenses: Merck, MSD
Makoto Tahara
Honoraria: Bristol Myers Squibb, Eisai, Ono Pharmaceutical, MSD, Lilly, Bayer, Merck, Novartis
Consulting or Advisory Role: Ono Pharmaceutical, MSD, Pfizer, Bristol Myers Squibb, Rakuten Medical, Bayer, Lilly, Eisai, Boehringer Ingelheim, Genmab, Janssen, Nanobiotix, Astellas Pharma, GlaxoSmithKline, Merck
Research Funding: AstraZeneca, MSD, Merck, Ono Pharmaceutical, Novartis, Pfizer, Bristol Myers Squibb, Rakuten Medical, Bayer, GSK, Lilly
Ammar Sukari
Consulting or Advisory Role: Coherus BioSciences, Merck
Speakers' Bureau: MSD
Tomasz Rutkowski
Speakers' Bureau: Bristol Myers Squibb, MSD
Heidi Nauwelaerts
Employment: Debiopharm International SA
Rudi Scheerlinck
Employment: Ares Trading SA (Eysins, Switzerland) an affiliate of Merck KGaA
Ngoc-Thuy Ha
Employment: Merck Healthcare KGaA (Darmstadt, Germany)
Andreas Schroeder
Employment: Merck Healthcare KGaA (Darmstadt, Germany)
Almudena Rodriguez-Gutierrez
Employment: Merck S.L.U. (Madrid, Spain) an affiliate of Merck KGaA
Jonathan D. Schoenfeld
Leadership: American Society for Radiation Oncology
Stock or Other Ownership: Immunitas, Intragel
Consulting or Advisory Role: Immunitas, Intragel, Merck, SIRPant
Speakers' Bureau: Merck
Research Funding: Bristol Myers Squibb, Merck, Regeneron, MSD, Debiopharm, Siemens
Patents, Royalties, Other Intellectual Property: MAGEA1 IMMUNOGENIC PEPTIDES, BINDING PROTEINS RECOGNIZING MAGEA1 IMMUNOGENIC PEPTIDES, AND USES THEREOF, Nanobody Bioconjugation for Immune Receptor Targeting
Expert Testimony: Burns and White
No other potential conflicts of interest were reported.
REFERENCES
- 1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74:229–263. doi: 10.3322/caac.21834. [DOI] [PubMed] [Google Scholar]
- 2. Psyrri A, Rampias T, Vermorken JB. The current and future impact of human papillomavirus on treatment of squamous cell carcinoma of the head and neck. Ann Oncol. 2014;25:2101–2115. doi: 10.1093/annonc/mdu265. [DOI] [PubMed] [Google Scholar]
- 3. NCCN Clinical Practice Guidelines in Oncology Head and neck cancer. v5. 2024 [Google Scholar]
- 4. Ang KK. Multidisciplinary management of locally advanced SCCHN: Optimizing treatment outcomes. Oncologist. 2008;13:899–910. doi: 10.1634/theoncologist.2007-0157. [DOI] [PubMed] [Google Scholar]
- 5. Machiels JP, René Leemans C, Golusinski W, et al. Squamous cell carcinoma of the oral cavity, larynx, oropharynx and hypopharynx: EHNS-ESMO-ESTRO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;31:1462–1475. doi: 10.1016/j.annonc.2020.07.011. [DOI] [PubMed] [Google Scholar]
- 6. Ang KK, Zhang Q, Rosenthal DI, et al. Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma: RTOG 0522. J Clin Oncol. 2014;32:2940–2950. doi: 10.1200/JCO.2013.53.5633. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Lee NY, Ferris RL, Psyrri A, et al. Avelumab plus standard-of-care chemoradiotherapy versus chemoradiotherapy alone in patients with locally advanced squamous cell carcinoma of the head and neck: A randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. Lancet Oncol. 2021;22:450–462. doi: 10.1016/S1470-2045(20)30737-3. [DOI] [PubMed] [Google Scholar]
- 8. Machiels JP, Tao Y, Licitra L, et al. Pembrolizumab plus concurrent chemoradiotherapy versus placebo plus concurrent chemoradiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (KEYNOTE-412): A randomised, double-blind, phase 3 trial. Lancet Oncol. 2024;25:572–587. doi: 10.1016/S1470-2045(24)00100-1. [DOI] [PubMed] [Google Scholar]
- 9. Bourhis J, Tao Y, Sun X, et al. Avelumab-cetuximab-radiotherapy versus standards of care in patients with locally advanced squamous cell carcinoma of head and neck (LA-SCCHN): Randomized phase III GORTEC-REACH trial. Ann Oncol. 2021;32:S1310. (LBA35) [Google Scholar]
- 10. Duckett CS. IAP proteins: Sticking it to Smac. Biochem J. 2005;385:e1–e2. doi: 10.1042/BJ20041800. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Abbas R, Larisch S. Targeting XIAP for promoting cancer cell death-the story of ARTS and SMAC. Cells. 2020;9:663. doi: 10.3390/cells9030663. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Obexer P, Ausserlechner MJ. X-linked inhibitor of apoptosis protein—A critical death resistance regulator and therapeutic target for personalized cancer therapy. Front Oncol. 2014;4:197. doi: 10.3389/fonc.2014.00197. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Zhao XY, Wang XY, Wei QY, et al. Potency and selectivity of SMAC/DIABLO mimetics in solid tumor therapy. Cells. 2020;9:1012. doi: 10.3390/cells9041012. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Vucic D. Targeting IAP (inhibitor of apoptosis) proteins for therapeutic intervention in tumors. Curr Cancer Drug Targets. 2008;8:110–117. doi: 10.2174/156800908783769373. [DOI] [PubMed] [Google Scholar]
- 15. Dubrez L, Berthelet J, Glorian V. IAP proteins as targets for drug development in oncology. Onco Targets Ther. 2013;9:1285–1304. doi: 10.2147/OTT.S33375. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Cetraro P, Plaza-Diaz J, MacKenzie A, et al. A review of the current impact of inhibitors of apoptosis proteins and their repression in cancer. Cancers (Basel) 2022;14:1671. doi: 10.3390/cancers14071671. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Lopes RB, Gangeswaran R, McNeish IA, et al. Expression of the IAP protein family is dysregulated in pancreatic cancer cells and is important for resistance to chemotherapy. Int J Cancer. 2007;120:2344–2352. doi: 10.1002/ijc.22554. [DOI] [PubMed] [Google Scholar]
- 18. Gu L, Zhu N, Zhang H, et al. Regulation of XIAP translation and induction by MDM2 following irradiation. Cancer Cell. 2009;15:363–375. doi: 10.1016/j.ccr.2009.03.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Holcik M, Yeh C, Korneluk RG, et al. Translational upregulation of X-linked inhibitor of apoptosis (XIAP) increases resistance to radiation induced cell death. Oncogene. 2000;19:4174–4177. doi: 10.1038/sj.onc.1203765. [DOI] [PubMed] [Google Scholar]
- 20. Ziegler DS, Keating J, Kesari S, et al. A small-molecule IAP inhibitor overcomes resistance to cytotoxic therapies in malignant gliomas in vitro and in vivo. Neuro Oncol. 2011;13:820–829. doi: 10.1093/neuonc/nor066. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Sun XS, Tao Y, Le Tourneau C, et al. Debio 1143 and high-dose cisplatin chemoradiotherapy in high-risk locoregionally advanced squamous cell carcinoma of the head and neck: A double-blind, multicentre, randomised, phase 2 study. Lancet Oncol. 2020;21:1173–1187. doi: 10.1016/S1470-2045(20)30327-2. [DOI] [PubMed] [Google Scholar]
- 22. Tao Y, Sun XS, Pointreau Y, et al. Extended follow-up of a phase 2 trial of xevinapant plus chemoradiotherapy in high-risk locally advanced squamous cell carcinoma of the head and neck: A randomised clinical trial. Eur J Cancer. 2023;183:24–37. doi: 10.1016/j.ejca.2022.12.015. [DOI] [PubMed] [Google Scholar]
- 23. Walczak-Nowicka ŁM, Herbet M. Sodium benzoate-harmfulness and potential use in therapies for disorders related to the nervous system: A review. Nutrients. 2022;14:1497. doi: 10.3390/nu14071497. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Legrand AJ, Konstantinou M, Goode EF, et al. The diversification of cell death and immunity: Memento mori. Mol Cell. 2019;76:232–242. doi: 10.1016/j.molcel.2019.09.006. [DOI] [PubMed] [Google Scholar]
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