Chiara Cremolini, MD, PhD, Comments on Findings From the PARADIGM Trial

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The invited discussant of PARADIGM, Chiara Cremolini, MD, PhD, Professor of Medical Oncology at the University of Pisa, Italy, said the findings prospectively confirm the superior benefit of FOLFOX (fluorouracil, leucovorin, oxaliplatin) paired with panitumumab rather than bevacizumab in RAS wild-type left-sided primary tumors. The higher response rates in that arm also translated into a higher chance of curative-intent resections, she noted.

For patients with RAS wild-type disease, the two epidermal growth factor receptor (EGFR) inhibitors panitumumab and cetuximab and the vascular endothelial growth factor (VEGF) inhibitor bevacizumab are all recommended options for pairing with doublet chemotherapy in the first-line setting. Older studies have compared these targeted drugs, but none have clearly defined the best approach according to tumor sidedness—now recognized as an important factor. Prior to this study, out of almost 3,000 patients pooled from the FIRE-3, CALGB/SWOG 80405, and PEAK trials, only about 700 were RAS wild-type and left-sided. A prospective trial in this unique population was needed.

Chiara Cremolini, MD, PhD

Chiara Cremolini, MD, PhD

Tumor sidedness can strongly influence treatment response based on various clinicopathologic features. “Genomic and phenotypic features potentially associated with intrinsic resistance to anti-EGFR agents are much more prevalent among right-sided tumors,” Dr. Cremolini explained.

These features include BRAF and PIK3CA/AKT mutations, mismatch repair deficiency, low AREG-EREG expression, MET amplification, ALK/ROS1/NTRK/RET fusions, PRESSING-2 alterations, and CMS1 (immune) subtype. Left-sided tumors, on the other hand, have EGFR amplification, high AREG-EREG expression, miR-31-3p low expression, and CMS2 (canonical) subtype—rendering them sensitive to anti-EGFR agents such as panitumumab.

“The poor prognosis of right-sided tumors is not counteracted by conventional upfront treatments among patients with RAS wild-type tumors. Both FOLFOX plus panitumumab and FOLFOX plus bevacizumab provided quite disappointing results in terms of overall survival,” she noted.

Study Implications

“My conclusion, in the context of first-line therapy of metastatic colorectal cancer, is that these results support panitumumab plus modified FOLFOX6 as a first-line therapy for patients with microsatellite-stable, wild-type RAS, and left-sided disease, independent of treatment intent,” Dr. Cremolini said.

“Based on the PARADIGM trial, when our patients are worried about anti-EGFR–related adverse events—mainly skin rash—we can share that the choice of a doublet plus bevacizumab would be associated with a 3.6-month median loss of overall survival and a disadvantage in treatment activity,” she said.

Dr. Cremolini emphasized this upfront therapy is not for all left-sided tumors: patients whose tumors are mismatch repair–deficient/microsatellite instability–high should receive immunotherapy, and those with BRAF-mutated tumors should receive chemotherapy plus bevacizu­mab, followed by encorafenib plus cetuximab upon disease progression. 

It remains unclear whether a chemotherapy doublet plus an anti-EGFR agent maintains an advantage over a chemotherapy triplet (ie, fluorouracil, leucovorin, oxaliplatin, irinotecan [FOLFOXIRI]) plus bevacizumab. For right-sided tumors, FOLFOXIRI plus bevacizumab is currently the preferred first-line regimen, when feasible, she said.

“I am convinced that more precise selection of patients with anti-­EGFR–sensitive tumors is possible based on this comprehensive molecular profiling,” Dr. Cremolini said. “This may lead to an earlier and clearer separation of the overall survival curves than what we observe in the left-sided RAS wild-type subgroup.”

DISCLOSURE: Dr. Cremolini reported financial relationships with Amgen, Bayer, Merck, MSD, Organon, Pierre Fabre, Roche, and Servier.


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