Diagnosis and Treatment of mCRC With a Focus on HER2-Positive Disease: Year in Review 2022 - Episode 3

PARADIGM Trial: Panitumumab in RAS Wild-Type and Left-Sided Metastatic CRC

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Expert perspectives on the PARADIGM study, which highlighted the role of panitumumab in combination with frontline chemotherapy in patients with left-sided, RAS wild-type metastatic colorectal cancer.


Cathy Eng, MD: Let's focus now more on the treatment for our patient population. Currently, the majority of our patients at least here in the United States there are MSI stable patients. We commonly heard obviously FOLFOX plus bevacizumab, FOLFIRI plus bevacizumab and then the most recently we have the adoption of FOLFOXIRI plus bevacizumab. And that's a common approach to our metastatic colorectal cancer patient population, and we all know that obviously with prolonged oxaliplatin platinum-base therapy we run into issues with neuropathy, and we must consider maintenance chemotherapy. But this year's ASCO [American Society of Clinical Oncology] the plenary discussion was focused on a phase 3 trial that was very specific for a left-sided all RAS wild-type patient population. And we know now that patients that are treatment naive and that are RAS wild-type in right-sided tumors should not receive anti-EGFR therapy in combination. But Dr Saab or Tony, could you comment, what was the highlight of this year's plenary discussion? And what were your thoughts on it? I know it wasn't necessarily new in some respects, but it was new in the sense it was a prospective trial. Can you please comment on the PARADIGM trial?

Tanios S. Bekaii-Saab, MD: Yes. Cathy, thank you. Yes, indeed. This is knowledge that is not new. In fact, even when the data with CALGB 80405 and others were discussedit wasn't technically new because we knew that there was a prognostic element to the right versus left. The new finding was mostly around the EGFR inhibitors and whether they realize the maximum benefit. Also, in view of the other genomic markers that exclude or include or tend to for us to include those agents, specifically cetuximab and panitumumab. The PARADIGM study as you said, was a study that was large and powered enough to prospectively asked if EGFR inhibitors is preferred and specifically in the study, panitumumab preferred over bevacizumab in an agent of FOLFOX-6 in patients with left-sided RAS wild-type tumors and they had a BRAF analysis. And I know we'll talk a little bit about HER2, but I would include HER2 amplifications as a potential exclusionary factor for these EGFR inhibitors on the left side. Interestingly, we’re seeing the same trends on the study. There is a survival benefit for panitumumab and for the EGFR inhibitor versus bevacizumab. This becomes more apparent after a couple of years down the line. We want to look at the PFS, PFS hasn't again changed much between panitumumab and bevacizumab. The same trends that we've been seeing. A bit intriguing because we do expect some level of PFS effect if you want to see that survival benefit, especially, that survival benefit happening at least a year maybe up to two years. At least when we look at the curves. So that to me says that there is even in that patient population, most patients still do not see a significantly better benefit from pani versus beva except for those few that end up being – driving the bottom of the curve rather than the top of the curve, and we still need to identify those patients. But from a practical standpoint in the clinic, it tells us that if we have all the right elements in a left-sided tumor that EGFR inhibitors should be considered in first line. Now why I would not get to the point where I would say, they need to be 100% in. The reason is, one for many of our patients younger and relatively younger patients meaning 60 even up to 70 and below. FOLFOXIRI may be an option and this really hasn't been tested in versus full FOLFOXIRI, which we know outperforms FOLFOX and bevacizumab even in a worse prognostic patient population. It's a preferred option but it's not the only option for left-sided tumors that are RAS wild-type, BRAF wild-type, and I would add also HER2 non-amplified.

Cathy Eng, MD: I'm glad that you mentioned that obviously the trial is specifically EGFR versus anti-VEGF therapy with a FOLFOX backbone, but a lot of us are also aware of the data from TRIBE with FOLFOXIRI, and I agree with you. There's never been a head-to-head comparison thus far. I do want to comment, you mentioned there wasn't a difference in progression-free survival but an improvement in overall survival notably after 2 years. Yet they showed these curves but depth of response, higher response rate overall as well. We know some people went on to resection, about 16%, but we don't have any of the data yet. We still don't have the final publication. Do you just want to comment very briefly about that aspect?

Tanios S. Bekaii-Saab, MD: Yes. I'm always very cautious about the subgroup analyses and what they mean. Maybe the depth of response means something. I know our European colleagues love it. They stand by it. I'm not sure what frankly it means. We know that we have patients who have stable disease that are progression-free and do great for it. Biologies beyond just the depth of response. The other thing is resection is always that unicorn. Unless the question is specifically geared towards patients with potential resectable disease, then we're introducing a lot of valuables including the fact that this is a non-unblinded study, which you can blind that EGFR versus VEGF and that has been that bias that always leads us to think that EGFR inhibitors may induce a better opportunity to get resection and you're not blinded to it. There is that bias. There's also the bias of looking at a scan in a patient who received an agent that may likely get you a better response versus not so there are a lot of biases that get introduced especially with very small numbers of patients. At this point of time I would say, that again, that this is a great option. A preferred option perhaps, but we've seen good numbers in similar underpowered studies for the question of liver resection with FOLFOXIRI.

Transcript edited for clarity.