Tislelizumab-chemo sustains PFS advantage over chemo alone at 3 years in recurrent/metastatic NPC

With the follow-up extended for an additional year, the RATIONALE-309 trial demonstrates a continued progression-free survival (PFS) advantage following the addition of tislelizumab to chemotherapy for the first-line (1L) treatment of recurrent or metastatic (R/M) nasopharyngeal cancer (NPC), as shown in the 3-year follow-up results presented at ESMO Asia 2024.

At a median follow-up of 27.5 months, the median PFS per independent review committee (IRC) assessment for both arms remained unchanged from a previous analysis (median follow-up 15.5 months): 9.6 months in patients treated with tislelizumab plus gemcitabine-cisplatin (GC) vs 7.4 months with placebo plus GC (stratified hazard ratio [HR], 0.53, 95 percent confidence interval [CI], 0.39–0.71). [ESMO Asia 2024, abstract 403O]

The current HR was consistent with that in the prior analysis (stratified HR, 0.50, 95 percent CI, 0.37–0.68; nominal p<0.0001), and the magnitude of PFS improvement with tislelizumab has been sustained since the interim analysis (stratified HR, 0.52; p<0.0001). [Cancer Cell 2023;41:1061-1072.e4]

A trend towards prolonged overall survival (OS) was observed, favouring the arm incorporating the PD-1 inhibitor (median 45.3 vs 31.8 months; stratified HR, 0.73, 95 percent CI, 0.51–1.05). Whilst the 13.5-month improvement was considered clinically meaningful, the significance of the OS benefit was limited by the considerable crossover from the placebo plus GC arm to receive tislelizumab alone upon IRC-confirmed disease progression (52.3 percent), as permitted by the protocol.

“At 3-year follow-up, the RATIONALE-309 study demonstrated sustained benefits of tislelizumab plus chemotherapy over placebo plus chemotherapy,” said Dr Wen-Feng Fang from the Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China. “The results support tislelizumab plus chemotherapy as an effective 1L treatment option for patients with R/M NPC.”

More indications of an OS benefit

To adjust for the impact of crossover, additional analyses were conducted to estimate the OS that would have been observed in the placebo plus GC arm in the absence of crossover. A consistent OS improvement in favour of tislelizumab plus GC was observed in both a rank-preserving structural failure time model without multivariate adjustments and a two-stage estimation, with a significant OS benefit noted in the latter method (median 45.3 vs 27 months; HR, 0.62, 95 percent CI, 0.40–0.97).

Secondly, the median time to progression on next-line treatment or death (PFS2) was longer with tislelizumab plus GC vs placebo plus GC (45.3 vs 20.5 months). The risk of a PFS2 event was 49 percent lower with the inclusion of tislelizumab upfront (HR, 0.51, 95 percent CI, 0.34–0.75).

“PFS2 is usually used as a surrogate for OS in some trials,” said abstract discussant Dr Darren Wan-Teck Lim from the Department of Medical Oncology, National Cancer Centre Singapore, a point that was reflected in the identical median survival time for OS and PFS2 with tislelizumab. “Again, there is a sustained OS benefit.”

“The PFS2 data, first to be evaluated in a phase III trial in 1L R/M NPC, supported the observed OS benefit of tislelizumab plus chemotherapy vs placebo plus chemotherapy,” said Fang.

1L tislelizumab-chemo vs 1L chemo followed by salvage tislelizumab

Patients in RATIONALE-309 (n=263) received GC for 4–6 cycles, along with the randomized treatment of tislelizumab or matching placebo every 3 weeks.

Because crossover to receive tislelizumab after first progression was permitted, unlike in other phase III trials of immunotherapy for R/M NPC, the implications of RATIONALE-309 encompassed the comparison of tislelizumab-chemotherapy as 1L therapy vs chemotherapy as 1L therapy followed by salvage single-agent tislelizumab. [Lancet Oncol 2021;22:1162-1174; JAMA 2023;330:1961-1970]