Panitumumab Beats Bevacizumab in Left-Sided mCRC

Liam Davenport

June 05, 2022

A suspicion from retrospective data has now been confirmed by a prospective clinical trial: adding panitumumab (Vectibix) to standard chemotherapy in left-sided RAS wild-type metastatic colorectal cancer (mCRC) is more effective than adding bevacizumab (Avastin).

Patients treated with panitumumab alongside chemotherapy saw a 16% improvement in overall survival versus those given bevacizumab after a median follow-up of over 5 years.

The overall survival benefit rose to 18% in those with left-sided tumors.

However, there was no difference in overall survival between the two treatment groups in the small subgroup of patients with right-sided primary tumors.

These findings come from the PARADIGM trial conducted in Japan.

The results were presented during a plenary session at the American Society of Clinical Oncology (ASCO) 2022 annual meeting.

"If gene testing shows that a tumor is RAS wild-type, the choice of initial treatment with panitumumab plus mFOLFOX6 chemotherapy is superior...for those people with left-sided tumors," said lead researcher Takayuki Yoshino, MD, PhD, department of gastrointestinal oncology, National Cancer Center Hospital East, Chiba, Japan, in an ASCO press release.

"It has long been believed that the sequence of metastatic colorectal cancer treatment does not matter as long as patients had access to the drugs at some point, which has now been disproven," he noted.

Yoshino added in a press conference about the trial that the results establish "a standard first-line combination regimen for patients with RAS wild-type, left-sided mCRC."

This is the "longest survival ever reported in a first-line unresectable metastatic colorectal cancer prospective phase 3 trial," commented Cathy Eng, MD, ASCO Expert in gastrointestinal cancers.

The findings "emphasize the importance of taking into account sidedness, as well as including comprehensive biomarker testing," she said.

Eng underlined that this is especially the case for RAS gene status testing, "which is critical for all colorectal cancer patients at the time of diagnosis of metastatic disease."

These results are of particular relevance in the United States, where the choice between an anti-EGFR or anti-VEGF antibody for the treatment of mCRC has been an area of "controversy" due to the lack of supporting data.

Panitumumab is a human monoclonal antibody that targets EGFR. It was approved in 2006 for use in mCRC by the US Food and Drug Administration (FDA) and also approved in 2014 for use in combination with FOLFOX for the first-line treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) mCRC, having previously been shown to be equally effective as cetuximab (another EGFR inhibitor) in this population.

In contrast, bevacizumab is a monoclonal antibody that targets the VEGF receptor. It was approved by the FDA for use in mCRC in 2004 in combination with intravenous 5-fluorouracil-based chemotherapy.

Yoshino explained that around 36% of patients with CRC have metastatic tumors at diagnosis and that adding an anti-EGFR or anti-VEGF antibody to chemotherapy improves overall survival in these patients by up to 30 months.

There has been "accumulating" evidence from retrospective studies suggesting that patients with RAS wild-type mCRC whose primary tumor is on the left side, which accounts for approximately 35% of mCRC cases, have a longer survival benefit with an anti-EGFR antibody, he commented.

Despite this, both antibody types continue to be used in these patients, he added.

PARADIGM was the first prospective trial to compare the two antibody types. Patients were randomized to receive either panitumumab or bevacizumab plus the combination chemotherapy regimen modified FOLFOX6 (mFOLFOX6).

The trial involved 823 Japanese patients with previously untreated wild-type mCRC with unresectable disease. Most patients had left-sided primary tumors (312 of 400 patients in the panitumumab group, and 292 of 402 patients in the bevacizumab group).  

After a median follow-up of 61 months, panitumumab was associated with a significant improvement in overall survival in the overall study population, at a hazard ratio of 0.84 (P = .030, with the boundary of significance set at P < .05).

In addition, panitumumab was associated with a significant improvement in overall survival in the large subgroup of patients with left-sided primary tumors, at 37.9 versus 34.3 months, or a hazard ratio of 0.82 (P = .031).

However, there was no significant difference in overall survival between the two treatment groups in the smaller subgroup of patients with right-sided tumors, at a hazard ratio of 1.09.

Median progression-free survival was no different between the panitumumab and bevacizumab groups, at 13.7 versus 13.2 months in patients with a left-sided tumor and 12.9 versus 12.0 months in the overall cohort.

There was, however, a difference in response rates in left-sided patients between those receiving the two antibodies, at 80.2% with panitumumab versus 68.6% with bevacizumab, and in curative resection rates, at 18.3% and 11.6%, respectively.

These results demonstrate the "superiority of first-line panitumumab versus bevacizumab in combination with mFOLFOX6 in the left-sided and overall populations," Yoshino concluded.

He also highlighted that the team has undertaken a large-scale biomarker analysis of pre- and post-treatment plasma and tissue samples from patients in the PARADIGM study to identify potential biomarkers of treatment response.

At the plenary session, discussant for this abstract Chiara Cremolini, MD, PhD, professor of medical oncology, Pisa University Hospital, Italy, commented that "location matters" when it comes to mCRC tumors.

Cremolini pointed out that the separation of the survival curves at 28 months suggests that the 40% of patients with left-sided tumors who survived only up until that time point receive an equal benefit from panitumumab and bevacizumab.

In contrast, the remainder who survived for longer showed better outcomes with panitumumab.

Overall, she said, in her opinion and based on the findings from other studies, the current results support the use of panitumumab plus mFOLFOX6 as first-line therapy in patients with microsatellite stable RAS wild-type and with BRAF wild-type left-sided mCRC.

Cremolini emphasized that patients should be warned that, if they opt for doublet chemotherapy plus bevacizumab, they could face a median 3.6-month loss in overall survival, as well as poorer treatment activity.

However, patients with high microsatellite instability should receive immunotherapy up front, she added, while those with BRAF mutations should be given FOLFOX upfront plus bevacizumab, followed by encorafenib plus cetuximab in the case of progression.

Cremolini ended by noting that there has, as yet, been no prospective comparison of doublet chemotherapy plus an anti-EGFR antibody with triplet chemotherapy plus bevacizumab in this population.

The study was funded by Takeda. Yoshino has reported relationships with Bayer Yakuhin, Chugai Pharmaceutical, Merck, and MSD. Eng has reported relationships with Bayer Health, Gilead/Forty Seven, GlaxoSmithKline, Hookipa Biotech, Mirati Therapeutics, Natera, Pfizer, Elevar, Fruquitinib, Merck, and Pfizer.

ASCO 2022 Annual Meeting. Presented June 5, 2022. Abstract LBA1.

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