Add-on toripalimab yields survival benefit in advanced, metastatic ESCC with manageable toxicity

In the first-line treatment of locally advanced or metastatic esophageal squamous cell carcinoma (ESCC), adding the anti-PD-1 monoclonal antibody toripalimab to a standard chemotherapy regimen can significantly cut the risk of progression or death without an increase in adverse events, according to the prespecified analysis of the phase III JUPITER-06 trial.

Compared with placebo, the toripalimab produced a clinically meaningful improvement in progression-free survival (PFS; hazard ratio [HR], 0.58, 95 percent confidence interval [CI], 0.46–0.74; p<0.0001) and overall survival (OS; HR, 0.58, 95 percent CI, 0.43–0.78; p=0.0004). The median follow-up time was 7.1 months in both the toripalimab and placebo arms. [Cancer Cell 2022;40:277-288.E3]

“Although the PFS curves were relatively close at the 50-percent PFS probability (median, 5.7 vs 5.5 months for the toripalimab vs placebo arms), the curves separate early, and the curve of the toripalimab arm is above that of the placebo arm over the entire period, resulting in a … clinically significant improvement in the 1-year PFS rate (27.8 percent vs 6.1 percent),” according to the investigators.

In terms of safety, the incidence of grade ≥3 treatment-emergent adverse events (TEAEs) was similar in the toripalimab and placebo arms (73.2 percent vs 70.0 percent), as was that of fatal TEAEs (8.2 percent for both) and serious AEs (36.2 percent vs 28.8 percent). The most common TEAES were anaemia, leukopenia, neutropenia, nausea, fatigue, peripheral neuropathy, vomiting, decreased appetite, and alopecia. TEAEs led to treatment discontinuation in 11.7 percent of patients in the toripalimab arm and 6.2 percent in the placebo arm.

“The toxicity profile observed in JUPITER-06 was consistent with those previously observed in other PD-1 blockers in combination with chemotherapy, as well as those in toripalimab plus chemotherapy in gastric cancer and nasopharyngeal carcinoma, with no new safety signal identified,” the investigators noted. [JAMA 2021;326:916-925; Ann Oncol 2019;30:1479-1486; Nat Med 2021;27:1536-1543]

Independent of PD-L1 tumour expression

JUPITER-06 randomized 514 patients with locally advanced or metastatic ESCC to receive toripalimab (n=257) or placebo (n=257) in the first-line setting. Treatment was given in combination with paclitaxel plus cisplatin (TP) every 3 weeks for up to 6 cycles, followed by toripalimab or placebo maintenance.

Baseline demographic and disease characteristics were generally comparable between the two treatment arms. PD-L1-positive expression (CPS ≥1) was detected in 201 (78.2 percent) patients in the toripalimab arm and 200 (77.8 percent) in the placebo arm; 115 (44.7 percent) and 97 (37.7 percent) patients in the respective arms had high PD-L1-high expression (CPS ≥10).

The role of PD-1 blockade plus chemotherapy has been previously explored in the first-line treatment of advanced ESCC. Trials such as the KEYNOTE-590, CheckMate 648, and ESCORT-1st all showed a positive correlation between the PD-L1 expression level (either on tumour cells or both tumour and immune cells) and the efficacy of PD-1 blockade plus chemotherapy. [J Clin Oncol 2021;39:LBA4001; JAMA 2021;326:916-925; Lancet 2021;398:759-771]

Interestingly, the PFS and OS benefits of the toripalimab–chemotherapy combination were independent of the PD-L1 expression level. The investigators pointed out that the lack of correlation between treatment effects and different PD-L1 expression levels was unlikely explained by the usage of a different PD-L1 staining assay in JUPITER-06.

“The reasons for the differences in the correlation of PD-L1 expression and efficacy between JUPITER-06 and the previous phase III trials remain unclear. However, similar to KENOTE-590, CheckMate 648, and ESCORT-1st, the JUPITER-06 study also demonstrates statistically significant PFS and OS benefits of the toripalimab–TP combination among the intention-to-treat population, hence supporting the use of this regimen in advanced ESCC irrespective of PD-L1 expression,” they added.

Benefit unclear in Caucasians

The population of JUPITER-06 comprised Chinese patients with 100 percent squamous histology—a subtype predominant in Asia but accounts for only 30 percent of esophageal cancer in the West. As such, the investigators identified a need to explore the efficacy of the toripalimab–TP combination in esophageal adenocarcinoma and/or in the White population. [Gastroenterology 2018;154:360-373; Cureus 2018;10:e3709]

“However, we speculate that the findings from JUPITER-06 might be extrapolated to western ESCC patients, as the efficacy and survival of the immuno-chemotherapy combination did not differ by race in the CheckMate 648 study, which enrolled both White and Asian ESCC patients,” the investigators pointed out. [J Clin Oncol 2021;39:LBA4001]

“In addition, the current treatment guidelines regarding the management of advanced ESCC are similar in the West and East,” they continued. [J Natl Compr Canc Netw 2019;17:855-883; Ann Oncol 2019;30:34-43; Chin J Cancer Res 2019;31:223-258]

Taken together, JUPITER-06 provides a new front-line treatment option for managing advanced ESCC, according to the investigators, adding that they have been continuously collecting long-term OS data to be presented for information only as the current OS result is considered definitive.