In FLAURA2 (NCT04035486), 1L osi + platinum-pemetrexed (pem) chemotherapy (CTx) (n=279) significantly improved PFS vs osi alone (n=278) in EGFRm advanced NSCLC (HR 0.62; 95% CI 0.49, 0.79; p<0.0001 per investigator). Safety of osi + CTx was consistent with individual Tx profiles and was associated with higher incidence of G≥3 AEs vs osi. Most G≥3 AEs occurred during platinum-based CTx induction phase (pem + platinum CTx, 4 cycles Q3W) but reduced during maintenance. We report FLAURA2 PROs. Symptoms, function and HRQoL were measured using EORTC QLQ-C30/LC13 questionnaires (Table). Score (range 0–100) changes from baseline (BL) to progression/19 mos were analysed by a mixed-effects model. A clinically meaningful within-pt change was defined as ≥10 point change from BL. Tolerability was assessed with PRO-CTCAE items. EORTC questionnaire completion/PRO-CTCAE visit compliance was ≥80/≥75% to Wk 82. Non-clinically meaningful improvements in global health status/quality of life (GHS/QoL) and physical function were seen in both arms: average least-squares mean (LSM) change in GHS/QoL from BL (95% CI) over all visits was 3.32 (1.67, 4.98) with osi + CTx and 7.38 (5.70, 9.07) with osi. Non-clinically meaningful worsening of fatigue/appetite loss (LSM change from BL [95% CI]) was seen with osi + CTx in induction (10 wks: 2.98 [0.65, 5.32]/9.30 [6.13, 12.46]), but improved during maintenance (28 wks: -0.33 [-2.66, 2.00]/5.52 [2.60, 8.44]). A trend to improvement in dyspnoea, chest pain and cough was seen in both arms; clinically meaningful improvement for cough from Wks 5 (osi + CTx) and 6 (osi). PRO-CTCAE results showed osi + CTx and osi were similarly well tolerated except nausea/vomiting (more common with osi + CTx). A trend to improved HRQoL and several symptoms was seen after induction CTx. Negative changes in HRQoL from adding CTx to osi were not clinically meaningful and were mostly transient (trended back to BL post-induction CTx).Table: 9PMedian total study drug exposure, mos (range) at data cut-off 3 Apr 2023Osi + CTx: Platinum CTx, 2.8 (0.7, 4.1); Pem, 8.3 (0.7, 33.8); Osi, 22.3 (0.1, 33.8)Osi alone: 19.3 (0.1, 33.8)PRO toolPrespecified primary scalesScheduleEORTC QLQ-C30GHS/QoL, physical function, fatigue, appetite lossBL, Q3W to Wk 10 & Q6W to second-PFS (PFS2)EORTC QLQ-LC13Cough, dyspnoea, chest painBL, QW to Wk 10 & Q3W to PFS2PRO-CTCAE (exploratory endpoint)Mouth/throat sores, nausea, vomiting, diarrhoea, abdominal pain, loss of bowel movement control, dry skin, hair loss, numbness/tingling in hands/feetChange from BL: increased GHS/QoL = improved GHS/QoL & function; decreased symptom score = improved symptom burden Open table in a new tab

Based on the phase 3 KEYNOTE-048 trial, 1L SOC treatment (tx) for R/M HNSCC, regardless of PD-L1 status, is pembro + platinum + 5-FU. 5-FU alternatives are needed because of associated cardiovascular, dihydropyrimidine dehydrogenase deficiency–related toxicities and patient (pt) inconvenience, costs, and complications associated with continuous 4-day infusion. In clinical studies, platinum + pacli was no less efficacious than platinum + 5-FU in R/M HNSCC. We present initial results of the first global prospective trial of pembro + carbo + pacli in 1L R/M HNSCC. In the ongoing phase 4 KEYNOTE-B10 trial (NCT04489888), pts with previously untreated, R/M HNSCC regardless of tumor PD-L1 status and ECOG PS 0/1 received pembro 200 mg IV Q3W, carbo AUC 5 mg/mL/min IV Q3W, and pacli 175 mg/m2 IV Q3W or 100 mg/m2 IV Q1W on days 1 and 8. Tx continued for ≤35 cycles of pembro, ≤6 cycles of carbo and pacli, or until PD, unacceptable toxicity, or pt withdrawal. Primary end point: ORR per RECIST v1.1 by BICR. Secondary end points: DOR and PFS by BICR, OS, safety and tolerability. Efficacy analysis was based on first 82 treated pts to ensure sufficient follow-up. Safety was analyzed in all treated pts. At March 16, 2022, data cutoff, 92 of 100 planned pts were enrolled; 41 remained on tx and 51 discontinued, most because of PD (31 of 51 pts). Median follow-up was 8.2 mo (range, 0.3-15.8). Confirmed ORR was 43% (95% CI, 32-54). Median OS was 12.1 mo (95% CI, 10-NR). For all treated pts (n = 92), any-grade TRAEs occurred in 96%, most commonly decreased neutrophil count (57%), anemia (43%), and fatigue (40%). Grade 3-5 TRAEs occurred in 71% of pts; 2 were grade 5 (sepsis; hypersensitivity reaction).Table: 651Opembro + carbo + pacliTotal N = 82ORR per BICR, % (n) [95%% CI]43 (35) [32-54]CR per BICR, % (n)5 (4)PR per BICR, % (n)38 (31)PD-L1 CPS ≥1, n68ORR in PD-L1 CPS ≥1 per BICR, % (95% CI)38 (27-51)PD-L1 CPS ≥20, n35ORR in PD-L1 CPS ≥20 per BICR, % (95% CI)34 (19-52)DOR, median, (range), months5.5 (1.1+ - 9.8+)PFS, median, months (95% CI)5.6 (4-7)OS, median, months (95% CI)12.1 (10-NR)6-month OS rate, % (95% CI)73 (61-82)12-month OS rate, % (95% CI)58 (42-71)BICR, blinded independent central review; NR, not reached."+" indicates there is no progressive disease by the time of last disease assessment Open table in a new tab BICR, blinded independent central review; NR, not reached. "+" indicates there is no progressive disease by the time of last disease assessment Pembro + carbo + pacli showed antitumor activity with a manageable safety profile, suggesting this 5-FU-free regimen may be comparable to historical 1L SOC and may expand tx options for 1L R/M HNSCC.

Advanced BTC is a rare, heterogenous cancer with poor prognosis. At the preplanned interim analysis (data cutoff 11 August 2021) of TOPAZ-1 (NCT03875235), D + GC significantly improved OS versus PBO + GC in pts with advanced BTC (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.66–0.97; p=0.021). We report an updated OS and safety analysis for TOPAZ-1. Pts previously untreated for unresectable locally advanced, recurrent, or metastatic BTC were randomised 1:1 to receive D (1500 mg every 3 weeks [Q3W]) or PBO, + G (1000 mg/m2) and C (25 mg/m2) on days 1 and 8 Q3W, for up to 8 cycles, followed by D (1500 mg Q4W) or PBO monotherapy until disease progression or unacceptable toxicity. The primary objective was to assess OS. This OS and safety analysis was conducted after 6 months (mo) of additional follow-up with 76.9% overall OS event maturity. At data cutoff (25 February 2022), 685 pts were randomised to D + GC (n=341) or PBO + GC (n=344); median (95% CI) follow-up time was 23.4 (20.6–25.2) mo and 22.4 (21.4–23.8) mo, respectively. Median (95% CI) OS was 12.9 (11.6–14.1) mo with D + GC and 11.3 (10.1–12.5) mo with PBO + GC (HR, 0.76; 95% CI, 0.64–0.91). OS HRs (95% CI) favoured D + GC in all prespecified subgroups, including disease status (initially unresectable, 0.79 [0.65–0.95]; recurrent, 0.76 [0.49–1.20]), primary tumour location (intrahepatic cholangiocarcinoma, 0.78 [0.62–0.99]; extrahepatic cholangiocarcinoma, 0.61 [0.41–0.91]; gallbladder cancer, 0.90 [0.64–1.25]) and PD-L1 (tumour area positivity [TAP] ≥1%, 0.75 [0.60–0.93]; TAP <1%, 0.79 [0.58–1.09]). OS rates (D + GC vs PBO + GC) at 12 mo, 18 mo and 24 mo were 54.3% vs 47.1%, 34.8% vs 24.1% and 23.6% vs 11.5%, respectively. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 60.9% of pts receiving D and 63.5% of pts receiving PBO; TRAEs leading to discontinuation of any study medication occurred in 8.9% and 11.4% of pts, respectively. D + GC continues to demonstrate clinically meaningful benefit vs PBO, that is consistent among subgroups, and manageable safety with longer follow-up, further supporting D + GC as a new first-line standard of care regimen for pts with advanced BTC.

TOPAZ-1 (NCT03875235) is a double-blind, Phase 3 study of durvalumab (D) + gemcitabine and cisplatin (GemCis) in patients (pts) with advanced biliary tract cancer (BTC). D + GemCis improved overall survival (OS) vs placebo (PBO) + GemCis, and is a potential new treatment option (Oh et al. NEJM Evid 2022; https://doi.org/10.1056/EVIDoa2200015). In BTC, primary tumour location may impact risk factors, prognoses and treatment response.

In TOPAZ-1 (NCT03875235), D + GC significantly improved overall survival (OS) vs PBO + GC for patients (pts) with advanced BTC (Oh et al. NEJM Evid 2022; https://doi.org/10.1056/EVIDoa2200015). D (immune checkpoint inhibitor) may cause imAEs; imAEs have been associated with improved OS (Zhou et al. BMC Med 2020;18:87).

Advanced BTC is a rare, heterogenous cancer with poor prognosis. At the preplanned interim analysis (data cutoff 11 August 2021) of TOPAZ-1 (NCT03875235), D + GC significantly improved OS versus PBO + GC in pts with advanced BTC (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.66–0.97; p=0.021). We report an updated OS and safety analysis for TOPAZ-1.

In TOPAZ-1 (NCT03875235), D + GC significantly improved overall survival (OS) vs PBO + GC for patients (pts) with advanced BTC (Oh et al. J Clin Oncol 2022;40(suppl. 4): Abs 378). D (immune checkpoint inhibitor) may cause imAEs; imAEs have been associated with improved OS (Zhou et al. BMC Med 2020;18:87).