Pembrolizumab plus epacadostat in patients with recurrent/metastatic head and neck squamous cell carcinoma (KEYNOTE-669/ECHO-304): a phase 3, randomized, open-label study.

BACKGROUND: Advanced head and neck squamous cell carcinoma (HNSCC) has a poor prognosis, and new treatment options are needed. Combining immunotherapies with differing mechanisms of action may enhance clinical benefits compared with single-agent immunotherapy. Epacadostat, an indoleamine 2,3 dioxygenase 1 inhibitor, plus pembrolizumab, a PD-1 inhibitor, showed promising activity in advanced HNSCC in the phase 1/2 KEYNOTE-037/ECHO-202 trial. METHODS: KEYNOTE-669/ECHO-304 is a randomized, open-label, phase 3 study evaluating the efficacy and safety of pembrolizumab plus epacadostat, pembrolizumab monotherapy, and the EXTREME regimen (cetuximab with a platinum [carboplatin or cisplatin] and 5-fluorouracil) in recurrent/metastatic (R/M) HNSCC. Participants had no prior systemic therapy for R/M HNSCC and were randomly assigned (2:1:2) to pembrolizumab 200 mg intravenously every 3 weeks plus epacadostat 100 mg orally twice daily, pembrolizumab monotherapy, or EXTREME. The primary endpoint was objective response rate (ORR; investigator assessment). Secondary endpoints were safety and tolerability. Change in serum kynurenine was an exploratory endpoint. Study enrollment was discontinued early as a strategic decision on May 2, 2018, and response assessment was discontinued after first on-study imaging assessment at week 9. Data cut-off was January 17, 2019. RESULTS: Between December 1, 2017, and May 2, 2018, 89 patients were randomly allocated to pembrolizumab plus epacadostat (n = 35), pembrolizumab monotherapy (n = 19), or EXTREME (n = 35). ORR (95% CI) was 31% (17%-49%) for pembrolizumab plus epacadostat, 21% (6%-46%) for pembrolizumab monotherapy, and 34% (19%-52%) for EXTREME. Treatment-related adverse events (TRAEs) occurred in 82% (n = 28) of patients receiving pembrolizumab plus epacadostat, 63% (n = 12) receiving pembrolizumab monotherapy, and 100% (n = 34) receiving EXTREME. Grade 3-4 TRAEs occurred in 24% (n = 8) of patients receiving pembrolizumab plus epacadostat, 16% (n = 3) receiving pembrolizumab monotherapy, and 82% (n = 28) receiving EXTREME. No deaths occurred due to AEs. Pembrolizumab plus epacadostat treatment reduced kynurenine levels but not to that of healthy subjects. CONCLUSIONS: Pembrolizumab plus epacadostat and pembrolizumab monotherapy provided a similar response rate to EXTREME and demonstrated a manageable safety profile in patients with R/M HNSCC. TRIAL REGISTRATION: NCT03358472. Date of trial registration: November 30, 2017.

Sequential multimodal treatments with chemotherapy and surgery for advanced soft tissue sarcoma may be associated with better survival than chemotherapy.

BACKGROUND: In patients with advanced soft tissue sarcoma (STS), surgery had been reported to be associated with superior overall survival (OS). Chemotherapy details for such patients were less reported, and whether multimodal treatment with surgery and chemotherapy provides extra survival benefit remains unclear. METHODS: We retrospectively reviewed patients with newly diagnosed advanced STS treated at National Taiwan University Hospital from January 1, 2011, to December 31, 2017. OS was calculated from the day of diagnosis of advanced STS to the day of death or last follow-up. Baseline patient characteristics and details regarding surgery and chemotherapy were recorded. RESULTS: A total of 545 patients were diagnosed with STS from 2011 to 2017, of which 226 patients had advanced STS. The median age was 54.7 years, and 54% of patients were women. Approximately 38% of patients with advanced STS underwent surgery and exhibited a trend of longer OS compared with who did not (median = 18.6 vs. 11.9 months, p = 0.083). In the chemotherapy subgroup, the benefit of surgery was more prominent (median = 21.9 vs. 16.5 months, p = 0.037). Patients who received chemotherapy prior to surgery exhibited numerically longer OS than those who underwent surgery first (median = 33.9 vs. 18.3 months, p = 0.155). After adjusting other clinical factors, chemotherapy remained an independent factor associated with favourable OS. CONCLUSION: Surgery may be more beneficial for the patients who receive chemotherapy. Our results support evaluation of sequential multimodal treatments strategy including surgery and chemotherapy in patients with advanced STS.

Betel-nut chewing does not influence PD-L1 expression rates in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC): A prospective biomarker prevalence study.

This study explored the relationship between betel-nut chewing and programmed death-ligand 1 (PD-L1) expression in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) patients in Taiwan. A total 280 R/M HNSCC patients, predominantly male, were evaluated; 75.4 % of whom chewed betel-nut. The prevalence of PD-L1 expression (combined positive score ≥1) was 94.3 % with similar PD-L1 expression rates between betel-nut-exposed and non-exposed groups. PD-L1 prevalence did not differ in those who received prior first-or second-line systemic therapy. In summary, betel-nut exposure did not notably affect PD-L1 expression rates in R/M HNSCC patients in Taiwan.

Improved outcomes of localized diffuse large B-cell lymphoma at the Waldeyer ring in comparison to the sinonasal area in the rituximab era.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) of the head-and-neck area primarily involves the Waldeyer ring (WR) and sinonasal area (SN). However, the differential clinical outcomes between patients with WR-DLBCL and those with SN-DLBCL in the rituximab era remain unclear. METHODS: To avoid confounding factors contributed by advanced DLBCL with WR and SN involvement, we assessed the clinical outcomes of patients with stage I/II WR-DLBCL and SN-DLBCL and compared them with those having corresponding stages of DLBCL in the lymph nodes but without other extranodal involvement (LN-DLBCL) in the same period. We compared the patients' clinical characteristics, treatment modalities, event-free survival (EFS), and overall survival (OS) among the three subgroups. RESULTS: We analyzed 67, 15, and 106 patients with WR-DLBCL, SN-DLBCL, and LN-DLBCL, respectively, between January 2000 and December 2019. All patients received front-line rituximab-based regimens, and > 80% received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone-based regimens. More patients with SN-DLBCL had revised International Prognostic Index (R-IPI) score 3 (27%) when compared with those with WR-DLBCL (7%) and those with LN-DLBCL (10%, p = 0.181). Patients with WR-DLBCL, LN-DLBCL, and SN-DLBCL had 5-year EFS and OS rates of 80.7%, 59.5%, and 41.9% (p = 0.021) and 83.7%, 70.8%, and 55.8% (p = 0.032), respectively. Compared to patients with LN-DLBCL, those with WR-DLBCL also had a significantly favorable 5-year EFS rate (p = 0.021) and 5-year OS rate (p = 0.023). Three of the 15 patients with SN-DLBCL experienced lymphoma recurrence in the brain after front-line treatment. In multivariate analyses, R-IPI scores of 1-2 and 3 served as significantly poor prognostic factors for patients with poor EFS and OS. CONCLUSIONS: Compared to patients with LN-DLBCL, patients with WR-DLBCL receiving front-line rituximab-based treatments had favorable clinical outcomes; however, patients with SN-DLBCL had worse clinical outcomes. Further studies on molecular prognostic factors and treatment strategies for SN-DLBCL are warranted.

Clinical decision pathway and management of locally advanced head and neck squamous cell carcinoma: A multidisciplinary consensus in Asia-Pacific.

OBJECTIVES: To develop consensus on patient characteristics and disease-related factors considered in deciding treatment approaches for locally advanced head and neck squamous cell carcinoma (LA-HNSCC) based on real-world treatment patterns in 4 territories in Asia-Pacific. METHODS: A three-round modified Delphi involving a multidisciplinary panel of HN surgeons, medical oncologists, and radiation oncologists was used. Of 41 panelists recruited, responses of 26 from Australia, Japan, Singapore, and Taiwan were analyzed. All panelists had ≥five years' experience managing LA-HNSCC patients and treated ≥15 patients with LA-HNSCC annually. RESULTS: All statements on definitions of LA-HNSCC, treatment intolerance and cisplatin dosing reached consensus. 4 of 7 statements on unresectability, 2 of 4 on adjuvant chemoradiotherapy, 7 of 13 on induction chemotherapy, 1 of 8 on absolute contraindications and 7 of 11 on relative contraindications to high-dose cisplatin did not reach consensus. In all territories except Taiwan, high-dose cisplatin was preferred in definitive and adjuvant settings for patients with no contraindications to cisplatin; weekly cisplatin (40 mg/m2) preferred for patients with relative contraindications to high-dose cisplatin. For Taiwan, the main treatment option was weekly cisplatin. For patients with absolute contraindications to cisplatin, carboplatin ± 5-fluorouracil or radiotherapy alone were preferred alternatives in both definitive and adjuvant settings. CONCLUSION: This multidisciplinary consensus provides insights into management of LA-HNSCC in Asia-Pacific based on patient- and disease-related factors that guide selection of treatment modality and systemic treatment. Despite strong consensus on use of cisplatin-based regimens, areas of non-consensus showed that variability in practice exists where there is limited evidence.