TAP Score and CPS May Be Viable for PD-L1 Expression Measurement in Advanced Gastric Cancers

Overall survival (OS) and progression-free survival (PFS) outcomes with tislelizumab-jsgr (Tevimbra) plus chemotherapy, as defined by tumor area positivity (TAP) score and combined positive score (CPS), were comparable at matched PD-L1 positivity thresholds, suggesting that both TAP score and CPS are viable measurements of PD-L1 expression in gastric cancer/gastroesophageal junction (GEJ) cancer.¹

Findings from a post-hoc analysis of the phase 3 RATIONALE-305 trial (NCT03777657) presented at the 2024 ESMO Gastrointestinal Cancers Congress showed that TAP score and CPS at matched thresholds of 10% or greater, 1% or greater, and 5% or greater displayed notable concordance among patients enrolled in RATIONALE-305. Moreover, improvements in OS and PFS with tislelizumab plus chemotherapy according to TAP score and CPS were similar to previously reported results in patients with a PD-L1 TAP score of 5% or greater.

The median OS for patients with a TAP score of 1% or greater, 5% or greater, and 10% or greater was 15.0 months (95% CI, 13.3-16.7), 16.4 months (95% CI, 13.6-19.1), and 22.5 months (95% CI, 16.4-26.4) with the tislelizumab combination; corresponding median OS outcomes in the placebo arm were 12.8 (95% CI, 12.1-14.1), 12.8 (95% CI, 12.0-14.5), and 12.3 (95% CI, 11.3-14.9). This translated to HRs of 0.78 (95% CI, 0.67-0.90), 0.72 (95% CI, 0.59-0.88), and 0.57 (95% CI, 0.43-0.76).

For patients with a CPS of 1 or greater, 5 or greater, and 10 or greater, the median OS in the experimental arm was 15.1 months (95% CI, 13.6-17.2), 17.8 months (95% CI, 14.8-20.8), and 18.0 months (95% CI, 13.6-23.2). In the placebo arm, respective median OS outcomes were 12.9 months (95% CI, 12.1-14.1), 13.2 months (95% CI, 12.1-12.6), and 12.9 months (95% CI, 11.5-15.5). This translated to HRs of 0.78 (95% CI, 0.67-0.91), 0.73 (95% CI, 0.60-0.89), and 0.68 (95% CI, 0.52-0.90).

“These PD-L1 subgroup results, along with previous results from the RATIONALE-305 primary analysis in all randomized patients, support tislelizumab plus chemotherapy as a new first-line treatment option for advanced HER2-negative gastric cancer/GEJ cancer,” Markus Moehler, MD, PhD, head of Gastrointestinal Oncology at the Mainz University Clinic in Germany, stated in a presentation of the data.

Regarding PFS, patients with a TAP score of 1% or greater, 5% or greater, and 10% or greater had HRs of 0.78 (95% CI, 0.67-0.91), 0.69 (95% CI, 0.57-0.84), and 0.56 (95% CI, 0.42-0.74); respective PFS HRs for a CPS of 1 or greater, 5 or greater, and 10 or greater were 0.77 (95% CI, 0.66-0.90), 0.73 (95% CI, 0.60-0.90), 0.69 (95% CI, 0.53-0.91).

“Tislelizumab added to chemotherapy as first-line treatment for gastric cancer/GEJ cancer improved PFS in patients with PD-L1 TAP scores of 10% or greater and 1% or greater,” Moehler stated.

The PD-L1 TAP score evaluates both immune and tumor cells for advanced gastric/GEJ cancer and was both analytically developed and validated in the RATIONALE-305 study. Previously reported data from this study demonstrated a significant OS benefit with first-line tislelizumab plus chemotherapy vs chemotherapy alone in all patients, including those with a TAP score of 5% or greater (HR, 0.71; 95% CI, 0.58-0.86).²

RATIONALE-305 enrolled patients with histologically confirmed gastric or GEJ cancer who had not previously received treatment for unresectable, locally advanced or metastatic disease and whose tumors did not display HER2 positivity.

Upon enrollment, patients were randomly assigned 1:1 to receive 200 mg of intravenous tislelizumab every 3 weeks with chemotherapy or placebo with chemotherapy. Chemotherapy regimens consisted of oxaliplatin at 130 mg/m2 on day 1 plus capecitabine 1000 mg/m2 twice daily for days 1 to 14 every 3 weeks or cisplatin at 80 mg/m2 on day 1 plus 5-fluororacil at 800 mg/m2 daily on days 1 to 5 every 3 weeks. Maintenance therapy was administered until unacceptable toxicity or progressive disease.

Patients were stratified according to region of enrollment, PD-L1 score (5% or greater vs less than 5%), the presence or absence of peritoneal metastasis, and investigator’s choice of chemotherapy regimen.

The primary end points of the analysis were OS in the PD-L1–positive population (PD-L1 TAP score of 5% or greater) and intention-to-treat populations. Key secondary end points comprised of subgroup analysis of OS and PFS utilizing exploratory PD-L1 TAP score and CPS, as well as TAP score vs CPS concordance.

TAP score was calculated by assessing the space occupied by PD-L1 staining tumor and immune cells in a given tumor area and was scored by visual-based estimation. CPS was defined as the number of PD-L1 staining tumor and immune cells out of the total number of viable tumor cells and was scored by cell count.

Of the randomized patients (n = 997), all had an evaluable TAP score, while 974 had evaluable post-hoc CPS results. Among those with an evaluable TAP score (tislelizumab arm, n = 501; placebo arm, n = 496), patients had a PD-L1 status TAP score of 1% or greater (86.2%; 91.3%), less than 1% (13.8%; 8.7%), 5% or greater (54.7%; 54.8%), less than 5% (45.3%; 45.2%), 10% or greater (27.1%; 29.2%), and less than 10% (72.9%; 70.8%).

Among participants with an evaluable CPS score, patients had a score of 1 or greater (tislelizumab arm, 85.5%; placebo arm, 89.9%), less than 1 (14.5%; 10.1%), 5 or greater (51.7%; 55.7%), less than 5 (48.3%; 44.3%), 10 or greater (30.8%; 28.6%), and less than 10 (69.2%; 71.4%).

“Prevalence was comparable across arms by TAP score or CPS under different thresholds,” Moehler reported in the presentation.

In the remaining patients with TAP scores of less than 10%, less than 5%, and less than 1%, unstratified HRs for OS were 0.91 (95% CI, 0.77-1.07), 0.91 (95% CI, 0.74-1.12), and 0.98 (95% CI, 0.64-1.50), respectively. For patients with CPS at matched thresholds, unstratified HRs for OS were 0.87 (95% CI, 0.73-1.03), 0.89 (95% CI, 0.72- 1.09), and 1.01 (95% CI, 0.66-1.52), respectively.

Unstratified PFS HRs for patients in these 3 PD-L1 subgroups according to TAP score, respectively, were 0.90 (95% CI, 0.76-1.06), 0.92 (95% CI, 0.75-1.14), and 0.87 (95% CI, 0.54-1.41). Patients in at matched thresholds by CPS had PFS HRs of 0.82 (95% CI, 0.69-0.97), 0.82 (95% CI, 0.67-1.02), and 0.80 (95% CI, 0.52-1.23).

Considerable correlation was observed between the TAP score and CPS in advanced gastric/GEJ cancer, with an interclass correlation coefficient (ICC) of 0.81 (95% CI, 0.79, 0.83). The TAP score and CPS showed concordance in terms of overall percent agreement (OPA) and Cohen’s Kappa at matched thresholds for each score. The OPA was 95% (95% CI, 94%-97%) at the 1% threshold, 82% (95% CI, 80%-85%) at the 5% threshold, and 85% (95% CI, 83%-87%) at the 10% threshold, respectively.

Disclosures: Professor Moehler reports serving in a consultancy/advisory role for Bayer, Merck Sharp & Dohme (MSD), Merck Serono, Amgen, Taiho Pharmaceutical, Pfizer, Roche, Lilly, Servier Laboratories, BeiGene, Bristol Myers Squibb (BMS), AstraZeneca, Astellas, Dragonfly, and Novartis; receiving honoraria from Amgen, Roche/Genentech, Merck Serono, MSD Oncology, BMS, AstraZeneca/MedImmune, Servier Laboratories, Pierre Fabre, Sanofi, Falk Foundation, Transcenta Holding, Daiichi Sankyo, Astellas Pharma, and Nordic Pharma; receiving grant/research funding from Amgen, Leap Therapeutics, Merck Serono, and MSD; other remuneration from Amgen, Merck Serono, Roche, Bayer, American Society for Clinical Oncology (ASCO), German Cancer Society, MSD, European Society for Medical Oncology (ESMO), BeiGene, and the European Organisation for Research and Treatment (EORTC).

References

1. Moehler M, Oh D, Kato K, et al. Tislelizumab (TIS) plus chemotherapy (CT) vs placebo (PBO) plus CT in HER2-negative advanced or metastatic gastric or gastro-esophageal junction adenocarcinoma (GC/GEJC): PD-L1 biomarker analysis from RATIONALE-305. Ann Oncol. 2024;35(suppl 1):S162-S204.Doi: 10.1016/annonc/annonc1482
2. Qiu MZ, Oh DY, Kato K, et al. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma: RATIONALE-305 randomised, double blind, phase 3 trial. BMJ. 2024;385:e078876. Published 2024 May 28. doi:10.1136/bmj-2023-078876