Switch Ramucirumab/Paclitaxel Maintenance Yields Favorable Outcomes in HER2– Gastric Cancer

Switch maintenance therapy with ramucirumab (Cyramza) plus paclitaxel improved progression-free survival (PFS) and overall survival (OS) outcomes vs continuation of FOLFOX (folinic acid, fluorouracil, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin) in patients with advanced HER2-negative gastric or gastroesophageal junction (GEJ) cancer who achieved disease control after 3 months of induction FOLFOX or CAPOX, according to the final results of the ARMANI trial (NCT02934464), which were presented at the 2024 ESMO Gastrointestinal Cancers Congress.¹

Ramucirumab plus paclitaxel maintenance therapy (n = 144) led to a median PFS of 6.6 months (95% CI, 6.0-7.8) vs 3.5 months (95% CI, 2.8-4.2) with FOLFOX/CAPOX continuation (n = 136; HR, 0.64 [95% CI, 0.49-0.81; 2-sided P < .001]).

“The benefit of paclitaxel plus ramucirumab was confirmed irrespective of the main clinical and molecular subgroups,” lead study author Giovanni Randon, MD, of the Fondazione IRCCS Istituto Nazionale dei Tumori di Milano in Italy, said in the presentation.

Ramucirumab plus paclitaxel is the second-line standard of care for patients with previously treated advanced gastric or GEJ adenocarcinoma based on data from the pivotal phase 3 RAINBOW trial (NCT01170663), in which treatment with the combination (n = 330) resulted in a median OS of 9.6 months (95% CI, 8.5-10.8) vs 7.4 months (95% CI, 6.3-8.4) with placebo plus paclitaxel (n = 335) in this patient population (HR, 0.807; 95% CI, 0.678-0.962; P = .017).²

ARMANI evaluated the efficacy of switch maintenance therapy with ramucirumab plus paclitaxel after 3 months of out-of-trial induction FOLFOX or CAPOX in patients with HER2-negative gastric or GEJ cancers.¹ A total of 280 patients in the intention-to-treat population were randomly assigned 1:1 to receive paclitaxel at 80 mg/m² on days 1, 8, and 15 plus ramucirumab at 8 mg/kg on days 1 and 15 every 4 weeks (arm A) or continuation of FOLFOX or CAPOX for 3 months followed by fluoropyrimidine maintenance therapy (arm B). Treatment was continued in both arms until progressive disease, unacceptable toxicity, or withdrawal of patient consent. Patients were stratified by prior gastrectomy (yes vs no), the presence of peritoneal disease (yes vs no), and site of disease origin (gastric vs GEJ).

PFS served as the primary end point. Secondary end points included OS, safety, quality of life, overall response rate, and duration of response. Exploratory biomarkers included PD-L1 combined positive score (CPS), claudin 18.2 (CLDN18.2), and mismatch repair (MMR) by immunohistochemistry.

In arm A, patients had a median age of 64 years (range, 57-71), most were male (67%), and most had an ECOG performance status (PS) of 0 (74%), gastric cancer (74%), no prior gastrectomy (72%), peritoneal metastases (53%), no liver metastases (76%), more than 1 metastatic site (62%), and synchronous metastases (76%). Regarding histotype, 41%, 40%, and 19% of patients had intestinal, diffuse, and not otherwise specified (NOS) disease, respectively. Overall, 81.2% and 18.8% of patients had received frontline FOLFOX and CAPOX, respectively. Twenty-nine percent of patients had a PD-L1 CPS of at least 5, and 22% of patients had a PD-L1 CPS of at least 10. In total, 24% and 39% of patients had CLDN18.2-positive and -negative disease, respectively, and 37% of patients had no available CLDN18.2 data. Furthermore, 5% and 71% of patients had MMR-deficient (dMMR) and MMR-proficient (pMMR) disease, respectively, and 24% of patients had no available MMR data.

In arm B, patients had a median age of 66 years (range, 57-72), most were male (61%), and most had an ECOG PS of 0 (64%), gastric cancer (74%), no prior gastrectomy (77%), no peritoneal metastases (57%), no liver metastases (70%), more than 1 metastatic site (68%), and synchronous metastases (81%). Regarding histotype, 34%, 43%, and 23% of patients had intestinal, diffuse, and NOS disease, respectively. Overall, 86.8% and 13.2% of patients had received frontline FOLFOX and CAPOX, respectively. Twenty-five percent of patients had a PD-L1 CPS of at least 5, and 18% of patients had a PD-L1 CPS of at least 10. In total, 23% and 42% of patients had CLDN18.2-positive and -negative disease, respectively, and 35% of patients had no available CLDN18.2 data. Furthermore, 5% and 72% of patients had dMMR and pMMR disease, respectively, and 23% of patients had no available MMR data.

The median OS was 12.6 months (95% CI, 11.5-15.0) with ramucirumab plus paclitaxel vs 10.4 months (95% CI, 8.0-13.1) with FOLFOX/CAPOX continuation (HR, 0.75; 95% CI, 0.58-0.97; 2-sided P = .028).

Paired tissue biomarker data were evaluable in 113 patients. In total, 41% and 59% of patients had a PD-L1 CPS of at least 5% and less than 5%, respectively. Furthermore, 39% and 61% of patients had CLDN18.2-positive and -negative disease, respectively, and 5% and 95% of patients had dMMR and pMMR disease, respectively. Overall, 34% of patients had triple-negative disease.

Among patients in arms B and A with a PD-L1 CPS of less than 5, the median PFS was 4.1 months (95% CI, 3.3-6.9) and 6.6 months (95% CI, 5.4-8.8) months, respectively (HR, 0.78; 0.52-1.15). Among patients in these respective populations with a PD-L1 CPS of 5 or greater, the median PFS was 2.6 months (95% CI, 2.3-5.8) and 6.1 months (95% CI, 4.9-9.7) months, respectively (HR, 0.72; 0.44-1.17; P = .413).

Among patients in arms B and A with a PD-L1 CPS of less than 5, the median OS was 13.7 months (95% CI, 10.4-17.6) and 12.8 months (95% CI, 10.8-15.8) months, respectively (HR, 0.94; 0.62-1.42). Among patients in these respective populations with a PD-L1 CPS of 5 or greater, the median OS was 7.7 months (95% CI, 7.20-14.20) and 12.2 months (95% CI, 10.6-17.8) months, respectively (HR, 0.64; 0.39-1.06; P = .408).

Among patients in arms B and A with CLDN18.2-negative disease, the median PFS was 3.9 months (95% CI, 2.8-5.5) and 7.4 months (95% CI, 5.7-11.2) months, respectively (HR, 0.70; 0.48-1.03). Among patients in these respective populations with CLDN18.2-positive disease, the median PFS was 3.2 months (95% CI, 2.6-12.2) and 5.5 months (95% CI, 4.1-9.7) months, respectively (HR, 0.94; 0.55-1.61; P = .237).

Among patients in arms B and A with CLDN18.2-negative disease, the median OS was 10.9 months (95% CI, 8.8-16.5) and 14.4 months (95% CI, 11.8-22.0) months, respectively (HR, 0.72; 0.48-1.09). Among patients in these respective populations with CLDN18.2-positive disease, the median OS was 12.3 months (95% CI, 7.2-20.5) and 10.6 months (95% CI, 9.6-18.2) months, respectively (HR, 0.97; 0.56-1.68; P = .259).

Among patients in arms B and A with pMMR/microsatellite stable (MSS) disease, the median PFS was 3.5 months (95% CI, 2.8-4.4) and 6.6 months (95% CI, 5.6-7.7) months, respectively (HR, 0.66; 0.50-0.89). Among patients in these respective populations with dMMR/microsatellite instability–high (MSI-H) disease, the median PFS was 2.5 months (95% CI, 1.6-NA) and 13.1 months (95% CI, 4.9-not available [NA]) months, respectively (HR, 0.75; 0.25-2.26; P = .013).

Among patients in arms B and A with pMMR/MSS disease, the median OS was 11.4 months (95% CI, 8.8-15.6) and 12.6 months (95% CI, 11.7-15.6) months, respectively (HR, 0.81; 0.60-1.10). Among patients in these respective populations with dMMR/MSI-H disease, the median OS was 7.2 months (95% CI, 2.8-NA) and 18.2 months (95% CI, 8.6-NA) months, respectively (HR, 0.60; 0.17-1.74; P = .295).

“Up-front biomarker testing, including PD-L1, MMR, and, in the next future, CLDN18.2, is needed to drive first-line treatment choices,” Randon emphasized. “The ARMANI strategy may represent a novel post-induction therapy for patients not eligible for targeted agents,” he concluded.

Disclosures: Dr Randon reports no conflicts of interest.

References

1. 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 III trial. Presented at: 2024 ESMO Gastrointestinal Cancers Congress; June 26-29, 2024; Munich, Germany. Abstract LBA4.
2. Wilke H, Muro K, Van Cutsem E, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15(11):1224-1235. doi:10.1016/S1470-2045(14)70420-6