Switch Maintenance Paclitaxel/Ramucirumab Prolongs Survival in Gastric Cancer

Microscopic image of gastric tumor cells - Generated with Google Gemini AI

Switch maintenance therapy with paclitaxel (Taxol) plus ramucirumab (Cyramza) consistently prolonged survival regardless of clinical or molecular subgroups in HER2-negative disease controlled, metastatic gastric cancer. These findings from the phase 3 ARMANI trial (NCT02934464) were presented by Giovanni Randon, MD, during the European Society for Medical Oncology Gastrointestinal (ESMO GI) Cancer Congress 2024.

“The primary end point [of] progression free survival [PFS] was significantly improved; the median PFS was 6.6 vs 3.5 months corresponding to an HR of 0.64 [95% CI, 0.49%-0.81%; P = .001] in favor of paclitaxel plus ramucirumab. Importantly, the overall survival [OS] was also significantly improved. In fact, the median OS was 12.6 vs 10.4 months corresponding to an HR of 0.75 [95% CI, 0.58%-0.97%; P = .028] in favor of the experimental arm [arm A],” Randon stated in the presentation of the data. Randon is an oncologist in the Department of Medical Oncology at the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy.

Patients with HER2-negative advanced gastric or gastroesophageal junction (GEJ) cancer, who showed no disease progression after 3 months of initial oxaliplatin-based chemotherapy, were randomly assigned into 2 groups. One group received ramucirumab plus paclitaxel (arm A; n=144). The other group received an additional 3 months of CAPOX (capecitabine [Xeloda] and oxaliplatin [Eloxatin])/FOLFOX (folinic acid [leucovorin], 5-fluorouracil [5-FU], and oxaliplatin) chemotherapy followed by maintenance therapy with fluoropyrimidine (arm B; n =136).

At the median follow-up of 43.7 months (IQR: 24.0 – 57.9), data from the randomized, open-label, multicenter trial demonstrated significant improvements in PFS and OS for patients in arm A compared with arm B as mentioned. The data cutoff was March 8, 2024, and the PFS and OS results were observed across all clinical subgroups.

In arm A, patients received paclitaxel at a dose of 80 mg on days 1, 8, and 15 and received ramucirumab at a dose of 8mg on days 1 and 15 every 4 weeks.

Patient characteristics included a median age of 64 years in arm A and 66 years in arm B. The majority of patients were male across both arms (67% vs 61%, respectively). Patients in arm A had an ECOG performance status of 0 (74%) or 1 (26%) vs arm B (64% or 36%, respectively), and patients with a site of origin in the gastric region or GEJ also accounted for 74% in each treatment arm. There were 28% vs 23% of patients, respectively, who received a prior gastrectomy.

Regarding metastases, in arm A there were 53% who had peritoneal metastases vs 43% of patients in arm B. Liver metastases were observed in 24% vs 30% of patients, respectively, and the number of metastatic sites (0-1/>1) were observed in 48% of patients in arm A and 42% of patients in arm B.

The secondary end points of the trial were OS, safety, quality of life, overall survival, and duration of response.

As part of the exploratory analysis, several biomarkers including PD-L1 combined positive score (CPS), Claudin 18.2 (CLDN18), and mismatch repair (MMR) status were assessed using immunohistochemistry to better understand their potential role in predicting treatment response and outcomes.

Biomarker evaluations included 179 patients (64%) for CLDN18, 189 patients (67%) for PD-L1 CPS, and 214 patients (76%) for MMR/microsatellite instability (MSI) status. Positive CLDN18 expression was detected in 39% of patients, and PD-L1 CPS scores of 5 or greater were found in 41%. Deficient (dMMR) and/or MSI-high status was observed in 5% of patients.

“Up to one-third of the trial population had a triple negative tumor and would not have been eligible to PD-1 or CLDN18 inhibitors,” Randon stated.

The study also examined the interaction between biomarker status and treatment efficacy. The median PFS for PD-L1 CPS 5 or greater was 6.1 in arm A vs 2.6 months in arm B (HR 0.72; 95% CI, 0.44-1.17; P =.413). The median OS was 12.2 vs 7.7 months, respectively (HR 0.64; 95% CI, 0.39-1.06; P =.408).

In those with a PD-L1 CPS of less than 5, the median PFS was 6.6 in arm A vs 4.1 months in arm B (HR 0.78, 95% CI, 0.52-1.15) and the OS was 12.8 vs 13.7 months, respectively (HR, 0.94; 95% CI, 0.62-1.42).

Regarding CLDN18.2 positive status the median PFS was 5.5 in arm A vs 3.2 months in arm B, with an HR of 0.94 (95% CI 0.55-1.61; P = .237), and the OS was 10.6 vs 12.3 months, respectively, with an HR of 0.97 (95% CI, 0.56-1.68; P = .259). For those with CLDN18.2 negative status the results deferred more showing a median PFS of 7.4 in arm A vs 3.9 months in arm B and with an HR of 0.70 (95% CI, 0.48-1.03). The OS for this same subpopulation was 14.4 vs 10.9, respectively, with an HR of 0.72 (95% CI, 0.48-1.09).

Lastly, for MMR/MSI status the data were organized by proficient (pMMR)/MSS or dMMR/MSI -high status. The median PFS for dMMR/MSI -high was 13.1 in arm A vs 2.5 months in arm B and with an HR of 0.75 (95% CI, 0.25-2.26; P =.013). The median OS was 18.2 vs 7.2, respectively, and with an HR of 0.60 (95% CI, 0.17-1.74; P = .295). For those with a status of pMMR/MSS, the median PFS was 6.6 in arm A vs 3.5 months in arm B and with an HR of 0.66 (95% CI, 0.50-0.89) and the median OS was 12.8 vs 11.4 months, respectively, and with an HR of 0.81 (95% CI, 0.60-1.10).

“Treatment with paclitaxel plus ramucirumab was associated with a greater and meaningful survival gain in this small subset of patients with dMMR, as compared with the pMMR counterpart. The interaction test of the P value was statistically significant in terms of PFS, and a similar trend was observed also for OS,” Randon explained.

With a sample size of 280 patients, the study was designed to have a 90% power to detect a significant difference at the 5% level, and investigators expected to see a median PFS increase from 4 to 6 months (target HR = 0.67).

Before immunotherapy, the standard first-line treatment for patients with HER2-negative metastatic gastric or GEJ cancer was a combination of platinum and fluoropyrimidine, though survival rates were low. For these patients, paclitaxel combined with ramucirumab is the standard second-line therapy. To guide first-line treatment decisions, initial biomarker testing for PD-L1, MMR, and soon CLDN18.2, is necessary, according to investigators.

“The ARMANI strategy may represent a novel post induction therapy for patients not eligible for targeted agents,” Randon concluded.

REFERENCE:

Randon G, Nappo F, Fassan M, et al. Switch maintenance with ramucirumab plus paclitaxel versus continuation of oxaliplatin-based chemotherapy in advanced HER2-negative gastric or gastroesophageal junction (GEJ) cancer: final results and key biomarkers of the ARMANI phase 3 trial. Presented at: ESMO Gastrointestinal Cancers Annual Congress. LBA4; June 26-29, 2024. Accessed June 28, 2024.