News in oncology

Toripalimab plus chemotherapy in recurrent metastatic nasopharyngeal carcinoma. The JUPITER-02 Randomized clinical trial. Current standard of care for recurrent metastatic nasopharyngeal carcinoma (RM-NPC) is Gemcitabine-Cisplatin, based on GEM20110714 trial with median OS of 22.1 months. However, 5-year overall survival rate is still 49% in this setting. There has been a growing interest in addition of a programmed cell death protein 1 (PD-1)–blocking antibody to the Gemcitabine-Cisplatin backbone for the first-line treatment of RM-NPC with three RCTs JUPITER-02, CAPTAIN-1st, and RATIONALE-309—having reported similar significant improvements in progression-free survival. However, due to the immaturity of survival data, a definitive analysis of survival benefit has not yet been reported. JUPITER-02 trial (JAMA 2023 Nov 28;330(20):1961-1970. doi:10.1001/jama.2023.20181) has reported on the Overall survival data along with the PFS benefit. This was a phase 3 international multicentre randomized trial that looked forward to determine the effect of addition of Toripalimab, an immune checkpoint inhibitor with Gemcitabine-Cisplatin on progression free and overall survival in recurrent metastatic setting. Crossovers were allowed. 289 patients were randomized (1:1) to receive Toripalimab 240 mg or placebo given 3 weekly with 6 cycles of Gemcitabine-Cisplatin followed by Toripalimab or placebo maintenance till progression of disease, unacceptable toxicity or completion of 2 years of treatment. 58% were recurrent disease and 42% were primary metastatic patients. PD-L1 expression was evaluated by IHC staining with JS311 assay on Ventana platform. Progression free survival, the primary end point, was significantly longer in Toripalimab arm against placebo (21.7 months vs 8.1 months with HR-0.52).The median overall survival was not reached against 33.7 months in placebo (HR-0.63). The benefit was seen in both PD-L1 high and low subgroup. The median overall survival was not reached in the Toripalimab group, while it was 33.7 months in the placebo group. A significant improvement in overall survival was detected for Toripalimab over placebo (HR, 0.63 [95% CI, 0.45-0.89]; 2-sided P = .008, crossing the prespecified efficacy boundary). The overall survival treatment effects were generally consistent across major subgroups, with the exception of patients with primary metastatic disease at baseline. Notably, the treatment effects on overall survival favoured Toripalimab in all PD-L1 expression subgroups and EBV DNA copy number subgroups. Treatment emergent adverse events (TEAE) were similar in 2 groups. Hypothyroidism (36.3%), upper respiratory tract infection (25.3%), pneumonia (17.8%) were more common in Toripalimab arm. Immune related adverse events (54.1 % vs 21.7%) were higher in Toripalimab arm. The demonstrated progression-free survival and overall survival benefits support the use of Toripalimab in combination with Gemcitabine-Cisplatin as the new standard first-line treatment for patients with recurrent or metastatic nasopharyngeal carcinoma. Perioperative Chemotherapy or Preoperative Chemoradiotherapy in Esophageal Cancer. Surgery is the primary treatment for resectable cases of esophageal adenocarcinoma, but has poor survival rates. Preoperative chemoradiotherapy (CROSS trial) and perioperative chemotherapy (MAGIC and FLOT4-AIO trials) have shown to improve outcomes. CROSS uses carboplatin, paclitaxel, and radiotherapy, while FLOT involves fluorouracil, leucovorin, oxaliplatin, and docetaxel. Trials like TOPGEAR and Neo-AEGIS show clinical equipoise between these approaches. Despite advancements, concerns remain over systemic disease control with chemoradiotherapy and toxicity with FLOT regimen, prompting a study like ESOPEC (N Engl J Med. 2025 Jan 23;392(4):323-335. doi: 10.1056/NEJMoa2409408). to compare survival outcomes. The ESOPEC trial was a phase 3, investigator initiated, multicentre, unblinded, randomized,controlled trial conducted at 25 centres in Germany. They recruited adult patients with histologically confirmed Esophageal adenocarcinoma (cT1 cN+, cT2–4a cN+, or cT2–4a cN0). Patients were randomized 1:1 to FLOT peri-operative chemotherapy or preoperative chemo-radiotherapy in the CROSS protocol. FLOT was administered as four cycles of fluorouracil, leucovorin, oxaliplatin, and docetaxel before and after surgery. CROSS involved carboplatin, paclitaxel, and 41.4 Gy radiotherapy. Surgery with lymph-node dissection followed treatment. Follow-ups included clinical visits and CT scans for up to three years. The primary endpoint was overall survival, with secondary endpoints including progression-free survival and adverse events. The trial intended to demonstrate the superiority of FLOT over preoperative chemo-radiotherapy. Survival differences were assessed by Cox regression and Kaplan-Meier methods. With 438 patients, statistical analyses ensured 90% power for the primary outcome in an intention-to-treat approach. The 438 enrolled patients included 221 in the FLOT group and 217 in the preoperative-chemoradiotherapy group. Median follow-up was 55 months. This trial showed that perioperative FLOT chemotherapy significantly improved overall survival compared to preoperative chemoradiotherapy in patients with resectable esophageal adenocarcinoma, with median survival of 66 months vs. 37 months, respectively. The FLOT regimen addressed the higher risk of distant progression, a key determinant of survival. Pathological complete response rates were higher with FLOT (16.7%) compared to preoperative chemoradiotherapy (10.1%). Although tumor characteristics differed slightly between groups, findings were consistent with those of other international studies, such as MATTERHORN. Serious adverse events were controllable, but questions persist regarding strategies for the treatment of patients who are unable to tolerate FLOT. Findings indicate that the preoperative chemoradiotherapy previously employed is no longer considered the best available therapy for this population of patients.