PARADIGM Researchers Pit Anti-EGFR Against Anti-VEGF for Metastatic Colorectal Cancer

Adding panitumumab to first-line chemo led to significantly improved OS vs bevacizumab in RAS wild-type metastatic CRC

04/18/2023
Liz Meszaros, Deputy Managing Editor, BreakingMED™
Vandana G. Abramson, MD, Associate Professor of Medicine, Vanderbilt University Medical Center
Take Away

  1. In patients with RAS wild-type metastatic colorectal cancer, the addition of panitumumab, an anti-EGFR monoclonal antibody, to standard first-line chemotherapy, significantly improved overall survival (OS) in patients with left-sided tumors and in the overall population, compared with the addition of bevacizumab, and anti-VEGF antibody.

  2. Similar rates of progression-free survival (PFS) were seen in both treatment groups after a median follow-up of roughly 5 years.

The addition of panitumumab—an anti-EGFR monoclonal antibody—to standard first-line chemotherapy led to significantly improved overall survival (OS) compared with addition of bevacizumab—an anti-VEGF antibody—in patients with RAS wild-type metastatic colorectal cancer who had left-sided tumors, as well as in the overall study population, according to results from the PARADIGM clinical trial, published in JAMA.

Progression-free survival (PFS), however, was not improved with the addition of panitumumab compared with bevacizumab, researchers found.

"Colorectal cancer was the second most common cause of cancer death worldwide in 2020. An estimated 20% to 30% of patients with colorectal cancer have metastatic tumors at diagnosis. Following surgery with curative intent, approximately 10% to 25% of patients develop metachronous metastases in studies of patients treated between 2000 and 2015. Systemic chemotherapy is standard treatment for patients with unresectable metastatic or recurrent disease. Combining chemotherapy with either anti–epidermal growth factor receptor (anti-EGFR) monoclonal antibodies, such as cetuximab or panitumumab, or the anti–vascular endothelial growth factor (anti-VEGF) antibody bevacizumab prolonged median overall survival up to approximately 30 months," explained researchers led by Takayuki Yoshino, MD, PhD, of the Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.

Thus, they undertook this phase III, randomized, open-label clinical trial, enrolling 802 patients with chemotherapy-naïve RAS wild-type, unresectable metastatic colorectal cancer from 197 sites in Japan from May 2015 through January 2022.

"KRAS/NRAS tests were performed using approved in vitro diagnostic tests, and all of the following exons/codons for both KRAS and NRAS were required to be wild type: exon 2, codons 12, 13; exon 3, codons 59, 61; and exon 4, codons 117, 146," explained researchers.

Patients were randomized to treatment with either panitumumab or bevacizumab plus modified fluorouracil, I-leucovorin, and oxaliplatin (mFOLFOX6) every 14 days. The primary endpoint of the study was overall survival (OS), which was first tested in patients with left-sided tumors (n=604; 75.3%), and then in the overall study population. Secondary endpoints included progression-free survival (PFS), response rate, duration of response, and the curative resection rate, which researchers defined as R0 status.

After a median follow-up of 61 months, patients treated with panitumumab had a median OS of 37.9 months, compared with 34.3 months in those treated with bevacizumab (hazard ratio [HR] for death, 0.82; 95.798% CI, 0.68-0.99; P=0.03) in patients with left-sided tumors. In the overall population, median OS was 36.2 versus 31.3 months, respectively (HR, 0.84; 95% CI, 0.72-0.98; P=0.03). Finally, median PFS was not significantly different between the two treatment groups, at 13.1 versus 11.9 months, respectively, in patients with left-sided tumors (HR, 1.00; 95% CI, 0.83-1.2), and 12.2 versus 11.4 months in the overall population (HR, 1.05; 95% CI, 0.90-1.24).

In patients with left-sided tumors, response rates were 80.2% with panitumumab versus 68.6% with bevacizumab, for a difference of 11.2% (95% CI, 4.4%-17.9%). In the overall population, response rates were 74.9% versus 67.3%, respectively, for a difference of 7.7% (95% CI, 1.5%-13.8%).

Median duration of response was 13.1 months in patients treated with panitumumab with let-sided tumors, compared with 11.2 months for those treated with bevacizumab (HR, 0.86; 95% CI, 0.70-1.10), and curative resection rates were 18.3% versus 11.6%, respectively, for a difference of 6.6% (95% CI, 1.0%-12.3%). In the overall population, median durations of response were 11.9 versus 10.7, respectively (HR, 089; 95% CI, 0.74-1.06), and curative resection rats, 16.5% versus 10.9%, for an overall between-group difference of 5.6% (95% CI, 1.0%-10.3%).

Common treatment-emergent adverse events included acneiform rash—which occurred in 74.8% of patients treated with panitumumab versus 3.2% of those treated with bevacizumab—peripheral sensory neuropathy (70.8% versus 73.7%, respectively), and stomatitis (61.6% versus 40.5%).

That these results from PARADIGM showed no significant difference in PFS between panitumumab and bevacizumab was cited as one of the limitations of this study by Hannah R. Robinson, MD, and Christopher H. Lieu, MD, both of the Division of Medical Oncology of the University of Colorado Anschutz Medical Campus, Aurora, Colorado, as was the exclusion of other biomarkers relevant to frontline anti-EGFR therapy, such as microsatellite instability high cancer, ERBB2, and BRAF.

Further, Yoshino et al also did not address the effects of chemotherapy selection and sequencing in combination with these biologic treatments or the effects of treatment on quality of life, wrote Robinson and Lieu in their accompanying editorial.

Nevertheless, they concluded with a commendation for these results with an anti-EGFR agent as front-line therapy in patients with metastatic colorectal cancer, and a call for further studies.

"The PARADIGM trial offers the first prospective evidence, to our knowledge, to support the use of anti-EGFR therapy over bevacizumab in combination with chemotherapy in the frontline treatment of RAS WT, left-sided mCRC. These results strengthen prior evidence from post hoc analyses, establishing chemotherapy plus anti-EGFR therapy as the standard of care in this setting. Outcomes for patients with right-sided mCRC remain poor regardless of treatment approach, and additional research and treatment strategies focused on this population are needed," wrote Robinson and Lieu.

Other study limitations cited by Yoshino and colleagues included that randomization stratification factors did not include the location of primary tumors, that the primary analysis did not include all randomized patients, the lack of a strict definition on when to proceed to curative-intent resection, the uncertainty that these results could apply to patients with previously resected colon cancer treated with adjuvant FOLFOX due to their exclusion from the study, and that only patients from Japan were enrolled in this study.

Disclosures

This study was funded by Takeda Pharmaceutical Company Limited.

Yoshino reported receipt of grants (Ono Pharmaceutical, Sanofi, Daiichi Sankyo, Parexel International, Pfizer Japan, Taiho Pharmaceutical, Merck Sharp & Dohme, Amgen, Genomedia Inc, Sysmex Corp, Chugai Pharmaceutical, Nippon Boehringer Ingelheim) and honoraria (Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly Japan KK, Merck Biopharma, Bayer Yakuhin, Ono Pharmaceutical, Merck Sharp & Dohme).

Robinson and Lieu reported no disclosures.

Sources

Watanabe J, et al "Panitumumab vs bevacizumab added to standard first-line chemotherapy and overall survival among patients with RAS wild-type, left-sided metastatic colorectal cancer: A randomized clinical trial" JAMA 2023; DOI: 10.1001/jama.2023.4428.

Robinson HR and Lieu CH "Anti-EGFR therapy for left-sided RAS wild-type colorectal cancer—PARADIGM shift" JAMA 2023; DOI: 10.1001/jamaoncol.2023.1088.