Oxaliplatin Plus Fluoropyrimidine/Bevacizumab Does Not Improve Survival in Older Patients With mCRC

The addition of oxaliplatin to fluoropyrimidine and bevacizumab (Avastin) did not significantly improve progression-free survival (PFS) vs fluoropyrimidine/bevacizumab alone when used as first-line treatment in older Japanese patients with unresectable metastatic colorectal cancer (mCRC), according to data from the phase 3 JCOG1018 study (jRCTs031190145).¹

The findings, which were published in the Journal of Clinical Oncology, indicated that the oxaliplatin-containing regimen (n = 126) led to a median PFS of 10.0 months (95% CI, 9.0-11.2) vs 9.4 months (95% CI, 8.3-10.3) with fluoropyrimidine/bevacizumab alone (n = 125; HR, 0.837; 90.5% CI, 0.673-1.042; 1-sided P = .086), missing the primary end point of the study. Moreover, the median overall survival (OS) with oxaliplatin was 19.7 months (95% CI, 15.5-25.5) vs 21.3 months (95% CI, 18.7-24.3) without oxaliplatin (HR, 1.058; 95% CI, 0.808-1.386).

“In conclusion, in this randomized phase III trial, superiority of first-line treatment with OX added to fluoropyrimidine plus bevacizumab was not shown in PFS in older patients with unresectable mCRC,” lead study author Atsuo Takashima, MD, of the Department of Gastrointestinal Oncology at National Cancer Center Hospital in Tokyo, Japan, and colleagues, wrote in the paper. “OS also did not significantly differ between the two arms, with a higher incidence of toxicities in the fluoropyrimidine plus bevacizumab plus oxaliplatin arm. On the basis of the results of this trial, fluoropyrimidine plus bevacizumab is still considered the standard and is recommended as first-line treatment in older patients with mCRC.”

The open-label, randomized, phase 3 trial enrolled patients with colorectal adenocarcinoma, unresectable stage IV, or recurrent CRC who were between the ages of 70 years and 74 years and had an ECOG performance status of 2 or were 75 years or older and had a status ranging from 0 to 2. They were required to have adequate major organ function and be eligible to receive bevacizumab. Although RAS, BRAF, and microsatellite instability status was not originally specified in the inclusion criteria, trial protocol was later revised so that these data were collected.

Prior to randomization, physicians selected a fluoropyrimidine regimen, which was either 5-fluorouracil (5-FU) plus calcium levofolinate (LV) or capecitabine. Those who received the former regimen were given 5-FU at 2400 mg/m2, LV at 200 mg/m2 and bevacizumab at 5 mg/kg every 2 weeks. The latter regimen was comprised of 1250 mg/m2 or 1000 mg/m2 of capecitabine based on creatinine clearance (≥50 mL/min vs <50 mL/min, respectively) twice daily on days 1 through 14 and bevacizumab at 7.5 mg/kg every 3 weeks.

For FOLFOX, 5-FU/LV plus bevacizumab was the same as in the fluoropyrimidine/bevacizumab arm, and 85 mg/m2 of oxaliplatin was given. For CAPOX, 1000 mg/m2 or 750 mg/m2 of capecitabine was given based on creatinine clearance (<50 mL/min vs ≥30 mL/min) twice daily on days 1 to 14 plus 130 mg/m2 of oxaliplatin every 3 weeks.

Participants were randomly assigned to fluoropyrimidine/bevacizumab or oxaliplatin plus fluoropyrimidine and bevacizumab via a minimization method with a random component to balance age, performance status, number of metastatic sites, and institution.

In addition to investigator-assessed PFS serving as the trial’s primary end point, secondary end points included OS, objective response rate (ORR) by RECIST 1.1 criteria, safety, and quality of life per EuroQol 5 dimensions.

Baseline characteristics were well balanced between the treatment arms. The median patient age was 79 years (interquartile range [IQR], 77-82) in the oxaliplatin arm vs 80 years (IQR, 77-82) in the non-oxaliplatin arm; 13% of patients in each arm were aged 85 years or older and 4.8% in each arm were between the ages of 70 years and 74 years. The majority of patients in both arms had an ECOG performance status of 0 or 1; only 6% of those in the oxaliplatin arm and 9% of those in the non-oxaliplatin arm had a status of 2. More than half of patients in the triplet and doublet arms had comorbidities (60% vs 64%), and approximately half of patients in each arm had a VES-13 score of 1 or 2 (48% vs 46%).

Additional data showed that the ORR was significantly higher with oxaliplatin vs without, at 47.7% (95% CI, 38.1%-57.5%) and 29.5% (95% CI, 21.2%-38.8%), respectively (P = .0059). The ORR proved to be higher with the oxaliplatin-containing regimens, irrespective of if 5-FU/LV or capecitabine were utilized. Among those who responded to the oxaliplatin-containing regimen (n = 109), 0.9% achieved a complete response, 47% experienced a partial response, and 39% had stable disease; 6% experienced disease progression and 8% were not evaluable.

Regarding safety, a higher proportion of any grade 3 or higher toxicities was reported in the oxaliplatin arm (n = 123) vs the non-oxaliplatin arm (n = 124), at 69% and 52%, respectively. Specifically, there was a higher incidence of neutropenia, nausea, vomiting, anorexia, diarrhea, sensory neuropathy, and fatigue with the oxaliplatin-containing regimen vs without oxaliplatin.

More patients in the oxaliplatin arm required treatment changes (79% vs 69%) and experienced toxicities that resulted in discontinuation (45% vs 27%) than those in the non-oxaliplatin arm.

The most common adverse effects reported in the oxaliplatin arm included leukopenia (grade 1-2, 32%; grade 3, 1%; grade 4, 0%), anemia (84%; 2%; 0%), sensory neuropathy (77%; 11%; 0%)l, thrombocytopenia (74%; 3%; 1%), neutropenia (53%; 19%; 5%), fatigue (48%; 10%; N/A) increased aspartate aminotransferase (47%; 1%; 0%), anorexia (44%; 15%; 0%), nausea (41%; 8%; 0%), stomatitis (40%; 2%; 0%), diarrhea (37%; 4%; 0%), Palmar-plantar erythrodysesthesia syndrome (33%; 2%; 0%), increased alanine aminotransferase (32%; 1%; 0%), hypertension (28%; 20%; 0%), increased creatinine (26%; 0%; 0%), vomiting (16%; 2%; 0%), hyperbilirubinemia (5%; 0%; 0%), bleeding (2%; 2%; 1%), and thromboembolism (1%; 2%; 1%).

“This study, in concert with other clinical trials, offers further evidence that the addition of oxaliplatin to fluoropyrimidine-based chemotherapy confers little therapeutic benefit to older patients with mCRC,” Andrew H. Ko, MD, FASCO, associate editor of the journal, wrote.

Reference

Takashima A, Hamaguchi T, Mizusawa J, et al. Oxaliplatin added to fluoropyrimidine/bevacizumab as initial therapy for unresectable metastatic colorectal cancer in older patients: a multicenter, randomized, open-label phase III trial (JCOG1018). J Clin Oncol. Published online August 26, 2024. doi:10.1200/JCO.23.02722