Q-TWiST analysis of pembrolizumab or placebo plus chemotherapy for patients with advanced HER2-negative gastric or gastroesophageal junction (G/GEJ) cancer in KEYNOTE-859.
Authors: Wyrwicz Lucjan , Kalampoki Vasiliki , Valderrama Adriana , Ramakrishnan Karthik , Young Kate 
Published: January 2025

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Background:
In the phase 3 KEYNOTE-859 study (NCT03675737; N = 1579), patients (pts) with locally advanced or metastatic HER2-negative G/GEJ cancer treated with first-line pembrolizumab (pembro) plus chemotherapy (chemo) had a significant and clinically meaningful improvement in OS with manageable toxicity vs placebo (pbo) plus chemo while maintaining HRQoL in the intention-to-treat and prespecified PD-L1 combined positive score (CPS) populations. We report data from an analysis of quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST).
Methods:
Q-TWiST is a measure of survival weighted by health states utility values. The analysis categorized survival time into 3 health states: time with grade ≥3 AEs (toxicity [TOX]) and time without symptoms or toxicities (TWiST)—both before disease progression or death—and relapse (REL), defined as time from disease progression to death. Q-TWiST was calculated as the restricted mean survival time (RMST) spent in each state, with a weighted health state utility for that state. Average utility weights were derived based on pooled EQ-5D-5L scores using the US mapping algorithm and standardized base case utility weights. Relative gains in Q-TWiST of ≥10% and ≥15% were “clinically important” and “clearly clinically important,” respectively, as reported in the literature. Treatment difference 95% CIs were generated using the nonparametric bootstrapping method. Data are reported for all randomly assigned pts and pts with PD-L1 CPS ≥1 and CPS ≥10 tumors. The data cutoff date was August 22, 2023.
Results:
At the maximum follow-up of 56 mo for pembro plus chemo vs pbo plus chemo, RMST was 5.16 vs 2.86 mo for TOX, 7.77 vs 5.87 mo for TWiST, and 6.85 vs 7.12 mo for REL. Between-treatment differences are shown in the table. The difference in restricted mean Q-TWiST and relative gain favored pembro plus chemo.
Conclusions:
A clearly clinically important Q-TWiST gain was observed for pembro plus chemo vs pbo plus chemo in all pts with advanced HER2-negative G/GEJ cancer and pts with PD-L1 CPS ≥1 and CPS ≥10 tumors.
Clinical trial information: NCT03675737
.

All ptsN = 1579
PD-L1 CPS ≥1n = 1235
PD-L1 CPS ≥10n = 553

RMST in TOX, mo (95% CI)
2.30(1.28 to 3.44)
2.65(1.46 to 3.99)
4.28(2.08 to 6.41)

RMST in TWiST, mo (95% CI)
1.90(−0.02 to 3.79)
2.28(0.07 to 4.49)
3.72(0.43 to 7.19)

RMST in REL, mo (95% CI)
−0.28(−2.43 to 2.01)
−0.22(−2.88 to 2.39)
−0.45(−4.52 to 3.71)

Restricted meanQ-TWiST, mo (95% CI)
a

3.31(2.10 to 4.59)
3.98(2.60 to 5.43)
6.45(4.26 to 8.74)

Relative Q-TWiST gain, % (95% CI)
a

20.90(12.49 to 30.56)
25.34(16.04 to 36.26)
38.05(23.21 to 56.59)

Restricted meanQ-TWiST, mo (95% CI)
b

2.91(1.58 to 4.14)
3.50(2.02 to 4.88)
5.63(3.31 to 7.99)

Relative Q-TWiST gain, % (95% CI)
b

18.38(9.78 to 27.46)
22.27(12.65 to 32.52)
33.19(18.76 to 49.97)

a
Based on US mapping algorithm.

b
Based on standardized base case utility weights.