- Solange Peters (Lausanne, CH)
- Josep Tabernero (Barcelona, ES)
LBA8_PR - KEYNOTE-048: Phase 3 study of first-line pembrolizumab (P) for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC)
- Barbara Burtness (New Haven, US)
KEYNOTE-048 was an open-label, randomized phase 3 study of P or P + chemotherapy (C) vs EXTREME (E) as first-line systemic therapy for R/M HNSCC (NCT02358031).
Patients (pts) with R/M HNSCC not curable by local therapy and with no prior systemic therapy (R/M setting) who provided a tumor sample for PD-L1 testing were randomized to P 200 mg Q3W, P + C (cisplatin 100 mg/m2 or carboplatin AUC 5 Q3W + 5-FU 1000 mg/m2/d for 4 d Q3W), or E (cetuximab 400 mg/m2 loading/250 mg/m2 QW + C) given until PD, unacceptable toxicity, 6 cycles (C), or 24 mo (P). Primary end points for P vs E and P + C vs E were PFS and OS in the PD-L1 combined positive score (CPS) ≥20 and ≥1 and total populations (pop). Cutoff date for this final PFS/interim OS analysis was Jun 13, 2018 (minimum follow-up, ~17 mo).
882 pts were randomized: 301 to P, 281 to P + C, 300 to E. P was superior to E for OS in CPS ≥20 (N = 255; median 14.9 vs 10.7 mo; HR 0.61 [95% CI 0.45-0.83]; P = 0.0007) and ≥1 (N = 512; median 12.3 vs 10.3 mo; HR 0.78 [95% CI 0.64-0.96]; P = 0.0086); OS for P was non-inferior to E in the total pop (N = 601). P did not prolong PFS in CPS ≥20 (P = 0.5); per the analysis plan, no further PFS testing was done for P vs E. Confirmed ORR (P vs E) was 23% vs 36% for CPS ≥20, 19% vs 35% for CPS ≥1, and 17% vs 36% for the total pop; median DOR was 20.9 vs 4.2 mo, 20.9 vs 4.5 mo, and 20.9 vs 4.5 mo. Gr 3-5 drug-related AE rates were 17% (P) vs 69% (E). P + C was non-inferior and superior to E for OS in the total pop (N = 559; median 13.0 vs 10.7 mo; HR 0.77 [95% CI 0.63-0.93]; P = 0.0034); OS for P + C was not significantly superior to E in CPS ≥20 and ≥1 at this interim analysis. PFS was not prolonged with P + C (P = 0.2). For P + C vs E, confirmed ORR was 36% vs 36%, median DOR was 6.7 vs 4.3 mo, and gr 3-5 drug-related AE rates were 71% vs 69%.
For first-line R/M HNSCC, P significantly improved OS over E in the PD-L1 CPS ≥20 and ≥1 populations and was noninferior in the total population with favorable safety. P + C significantly improved OS in the total population with safety comparable to E. P and P + C responses were durable. These data support pembrolizumab and pembrolizumab + platinum + 5-FU as new first-line standards of care for R/M HNSCC. The study continues to the final OS analysis.
Clinical trial identification
NCT02358031: Trial initiation, February 6, 2015
Medical writing and editorial assistance was provided by Melanie Leiby, an employee of Merck & Co., Inc., Kenilworth, NJ, USA.
- Jean-Pascal Machiels (Brussels, BE)
LBA9_PR - Cetuximab versus cisplatin in patients with HPV-positive, low risk oropharyngeal cancer, receiving radical radiotherapy
- Hisham Mehanna (Birmingham, GB)
The incidence of Human papillomavirus-positive oropharyngeal cancer (HPV+OPSCC) is rapidly rising. It is a distinct disease entity, affecting younger patients, with much better outcomes. However, standard treatment (cisplatin+radiotherapy) causes significant toxicity, which these young patients have to endure for decades.
Cetuximab, an epidermal growth factor receptor inhibitor, has been proposed for treatment de-escalation to reduce toxicity of standard (cisplatin) treatment, but no randomised trials exist.
In this international, multi-centre, randomised, controlled trial, patients with low-risk HPV+OPSCC were randomised to receive radiotherapy (70G in 35F) and either cisplatin (3 doses of 100 mg/m2) or cetuximab (400 mg/m2 loading dose followed by weekly 250 mg/m2). Outcomes were total number of severe (Grades 3-5) toxicity events, overall survival, and quality of life.
We recruited 334 patients (166 in cisplatin arm and 168 in cetuximab arm) between November 2012 through October 2016 at 32 head and neck treatment centres in 3 countries: UK, Ireland and the Netherlands. Of patients randomised, 80% are male, mean age 57 years. The arms were well balanced.
There were 10 recurrences and 6 deaths in cisplatin arm, compared to 29 recurrences and 20 deaths in cetuximab arm. There was a significant difference in the 2-year overall survival between cisplatin and cetuximab (97.5% vs 89.4% respectively, p=0.001, HR=4.99, 95% CI 1.70-14.67) and in 2-year recurrence rate (6.0% vs 16.1% respectively, p=0.0007, HR=3.39, 95% CI 1.61-7.19).
There were no differences between the cisplatin and cetuximab arms in the reported mean number of overall (5.37 vs 5.45 events per patient respectively), acute or late severe (grade 3-5) toxicity events per patient or all grade toxicity (overall 29.15 vs 30.05 event per patients respectively). There were significantly more serious adverse events (162 vs 95) in the cisplatin arm compared to the cetuximab arm.
There was significant detriment from the use of cetuximab instead of cisplatin in terms of tumour control, and no benefit in terms of reduced toxicity. Cisplatin and radiotherapy remains the standard of care in this setting.
Clinical trial identification
- Amanda Psyrri (Athens, GR)
LBA10 - Primary results of ALESIA: A randomised, phase III, open-label study of alectinib vs crizotinib in Asian patients with treatment-naïve ALK+ advanced NSCLC
- Caicun Zhou (Shanghai, CN)
The highly selective, central nervous system (CNS)-active, ALK inhibitor alectinib, showed superior efficacy and lower toxicity than crizotinib in patients with treatment-naïve ALK+ NSCLC in the global phase III ALEX study (NCT02075840; PFS hazard ratio [HR] 0.47, 95% CI 0.34–0.65, p<0.001): median PFS not estimable alectinib vs 11.1 months crizotinib. Updated data from ALEX (cut-off date Dec 1, 2017), revealed a PFS HR of 0.43, 95% CI 0.32–0.58, with a median PFS of 34.8 months alectinib vs 10.9 months crizotinib [Camidge et al. ASCO 2018]. We will present primary results from the randomised, open-label, phase III ALESIA study comparing the efficacy and safety of first-line alectinib versus crizotinib in Asian patients with advanced ALK+ NSCLC (NCT02838420). The objective of the study is to determine whether the PFS benefit of alectinib in Asian patients is consistent with the benefit observed in the global ALEX study.
Alectinib (ALC), a highly selective CNS-active ALK inhibitor, showed superior efficacy vs crizotinib (CRZ) in treatment-naïve ALK+ NSCLC in the global phase III ALEX study (PFS HR 0.47, 95% CI 0.34–0.65, p<0.001). At an updated data cutoff, the PFS HR was 0.43, 95% CI 0.32–0.58, median PFS 34.8 months ALC vs 10.9 months CRZ. We report primary results from the phase III ALESIA study of first-line ALC vs CRZ in Asian patients with advanced ALK+ NSCLC using the global ALC dose (NCT02838420).
Patients had ALK+ stage IIIB/IV NSCLC (by central IHC testing) and ECOG PS 0–2. Asymptomatic CNS metastases were allowed. Patients were randomised 2:1 to receive ALC 600mg BID (n=125) or CRZ 250mg BID (n=62). Regular tumour/CNS imaging was performed. Primary endpoint: PFS by INV (RECIST v1.1). Primary objective: consistency with the PFS benefit seen in ALEX. Secondary endpoints: PFS by IRC, time to CNS progression, ORR, DOR, OS, CNS ORR, QoL and safety.
Median duration of follow-up was 16.2 months ALC vs 15.0 months CRZ. At the primary data cutoff (May 31, 2018), ALC significantly reduced the risk of progression/death (INV PFS) vs CRZ: HR 0.22, 95% CI 0.13–0.38, p<0.0001; median PFS not estimable (NE) ALC vs 11.1 months CRZ. Secondary endpoints supported the primary endpoint: IRC PFS, HR 0.37 (95% CI 0.22–0.61; p<0.0001); median PFS NE ALC vs 10.7 months CRZ; time to CNS progression (IRC) cause-specific HR 0.14 (95% CI 0.06–0.30; p<0.0001); ORR (INV), 91.2% ALC vs 77.4% CRZ, p=0.0095; DOR (INV), HR 0.22 (95% CI 0.12–0.40), p<0.0001; median DOR NE ALC vs 9.3 months CRZ; OS data immature: HR 0.28 (95% CI 0.12–0.68), p=0.0027, event rate ALC 6.4% vs CRZ 21.0%; median OS NE both arms; CNS ORR (IRC) in patients with measurable/non-measurable CNS baseline lesions, 72.7% ALC vs 21.7% CRZ (50.0% vs 13.0% complete response). Despite longer treatment duration (14.7 ALC vs 12.6 months CRZ), fewer ALC patients had grade 3–5 AEs (29% vs 48% CRZ), serious AEs (15% vs 26%) or AEs leading to treatment discontinuation (7% vs 10%).
ALESIA study results are consistent with the global ALEX study and confirm the clinical benefit of ALC in Asian patients with advanced ALK+ NSCLC.
Clinical trial identification
- Tony S.K. Mok (Shatin, HK)