Takayuki Yoshino, MD, PhD, Illuminates Research Supporting Panitumumab Over Bevacizumab Plus mFOLFOX6 for Metastatic CRC

Takayuki Yoshino, MD, PhD
Director, Department of Gastroenterology and Gastrointestinal Oncology
Deputy Director, National Cancer Center Hospital East
Kashiwa, Japan

Modified oxaliplatin, levofolinate calcium, fluorouracil (mFOLFOX6) in combination with panitumumab (Vectibix) outperformed bevacizumab (Avastin) in patients with RAS wild-type metastatic colorectal cancer (mCRC), according to findings from the phase 3 PARADIGM trial (NCT02394795)presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.

Lead investigator Takayuki Yoshino, MD, PhD, director for the Department of Gastroenterology and Gastrointestinal Oncology and deputy director of the National Cancer Center Hospital East in Kashiwa, Japan, spoke with CancerNetwork^® about how these findings reflect a need for a paradigm shift in the United States in the frontline setting for this patient population.

In particular, Yoshino highlighted the overall survival (OS) observed in patients with left-sided tumors who were treated with the panitumumab regimen (HR 0.82; 95.798% CI, 0.68-0.99, P = .031) in addition to the overall population (HR 0.84; 95% CI, 0.72-0.98; P = .030). Additionally, those treated with panitumumab had higher response and R0 resection rates. The overall response rate was 80.2% (95% CI, 75.3%-84.5%) higher with panitumumab in the left-sided population and 74.9% (95% CI, 70.3%-79.1%) higher in the overall population vs 68.6% (95% CI, 62.9%-74.0%) and 67.3% (95% CI, 62.4%-71.9%) in the bevacizumab arm, respectively.

CancerNetwork^®: What was the rationale for combining panitumumab with mFOLFOX6 for the treatment of RAS wild-type mCRC?

Yoshino: In the first-line setting [for mCRC], there are a lot of global trials. The [current] standard of care [involves] a choice between [a few] biologics—either anti-EGFR monoclonal antibodies, such as cetuximab or panitumumab, or the anti-VEGFR monoclonal antibody bevacizumab. However, the optimal treatment has not yet been determined in terms of the molecular biologics. The cytotoxic chemotherapy regimen mFOLFOX6 is the current standard of care.

In this study, we examined 2 cohorts: panitumumab plus mFOLFOX6 vs bevacizumab plus mFOLFOX6 in the first-line treatment setting of mCRC.

What were the key findings of this trial?

The first key finding was that OS in the left-sided population—defined as those patients whose primary tumors are located in the descending colon, sigmoid colon, rectosigmoid, and/or rectum—was superior in those treated with panitumumab over bevacizumab in combination with mFOLFOX6. The median OS difference was 3.6 months, which is clinically meaningful.

Did anything stand out regarding the safety profile of these regimens?

There were no new or unexpected safety signals observed in this study. The most common toxicities were higher in the panitumumab group compared with the bevacizumab group and included acne-like dermatitis, stomatitis, paronychia, dry skin, and hypomagnesemia. Those toxicities were a little higher in the panitumumab group vs the bevacizumab group. However, keep in mind, when balancing efficacy against toxicity, it’s important to consider that the OS benefit with panitumumab was bigger. This combination of panitumumab plus mFOLFOX6 should be established as the new standard of care.

Are there any plans for future analyses based on this research?

Yes, in this trial we are also conducting translational research. We collected pre-treatment tissue and plasma from [roughly] 92% of patients. Additionally, at the time of progressive disease, plasma was collected from 75% of patients. In addition to that, some patients received curative intent surgery after randomization based on treatment effect. Of the 161 patients who underwent surgical resection, 100% contributed surgical specimens. An analysis of these samples is still ongoing but nearing completion. Our translational research data on clinical outcomes will be presented at a future international conference.

What do you hope your colleagues took away from this research?

In the clinical practice setting—especially in the United States—bevacizumab in combination with chemotherapy is still the mainstay treatment in the frontline setting. However, our data show a [clear] OS benefit with the panitumumab/mFOLFOX6 regimen. Our American colleagues and physicians should consider a first-line therapy paradigm shift from bevacizumab to panitumumab.

Additionally, in the United States, RAS testing is not usually conducted before the initiation of chemotherapy in the first- and second- line settings. RAS testing before the initiation of any chemotherapy is necessary for optimal treatment selection for patients with mCRC.

Reference

Yoshino T, Watanabe J, Shitara K, et al. Panitumumab (PAN) plus mFOLFOX6 versus bevacizumab (BEV) plus mFOLFOX6 as first-line treatment in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC): results from the phase 3 PARADIGM trial. J Clin Oncol. 2022;40(suppl 17):LBA1. doi:10.1200/JCO.2022.40.17_suppl.LBA1