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ESMO WCGIC 2023 | Colorectal trials at WCGIC 2023: VELO, DEEPER, IMPROVE and AVETRIC

Shouki Bazarbashi, MBBS, King Faisal Specialist Hospital and Research Center-Riyadh, Riyadh, Saudi Arabia, provides an overview of several metastatic colorectal cancer (mCRC) trials presented that the World Congress on Gastrointestinal Cancer (WCGIC). Addition of panitumumab with trifluridine and tipiracil in patients with pre-treated RAS-wild type mCRC resulted in enhanced progression-free survival (PFS) but not overall survival (OS) in the Phase II VELO trial (NCT05468892). The Phase II DEEPER trial (NCT02515734) assessed first-line FOLFOXIRI plus cetuximab or bevacizumab in RAS-wild type mCRC, and addition of cetuximab resulted in enhanced depth of response. Whilst the primary endpoint of progression-free survival on treatment (PFSOT) was met in the IMPROVE study (NCT04425239) of panitumumab plus FOLFIRI in RAS/BRAF wild-type mCRC, more research is needed to assess responses in patients who progress on treatment. The AVETRIC trial (NCT04513951) of modified FOLFOXIRI with cetuximab and avelumab in mCRC failed to show clinical benefit in patients. This interview took place at the ESMO WCGIC 2023 in Barcelona, Spain.

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Transcript (edited for clarity)

Okay, so I’ll be discussing four abstracts. The first one is the VELO trial and this trial is discussing patients who failed two lines of therapy with metastatic colorectal cancer. They have multiple options. One of the option is the Trifluridine Tipiracil and we know that it actually improves survival compared to best supportive care...

Okay, so I’ll be discussing four abstracts. The first one is the VELO trial and this trial is discussing patients who failed two lines of therapy with metastatic colorectal cancer. They have multiple options. One of the option is the Trifluridine Tipiracil and we know that it actually improves survival compared to best supportive care. Recent data have shown that patients when you add bevacizumab to those patients, they actually have a better survival. This is the SUNLIGHT trial. So now the VELO trial is actually addressing whether in those patients who are Ras-wildtype, whether by adding anti-EGFR in this case it was panitumumab, it actually improved the result. And the idea is actually very interesting and the background is is very reasonable. I think the the only the trial actually it was a randomized Phase II trial and it actually met its primary endpoint by improvement in the progression free survival. However, unfortunately there was no overall survival. So it’s a small trial when you compare those data to if you have somebody whom you want to give them a Trifluridine Tipiracil and whether you actually would add the Mab or anti-EGFR, I think at the present time I would probably go with a bevacizumab especially that the subgroup analysis for the SUNLIGHT trial showed a similar hazard ratio in patients who are wild type and in patients who are Ras mutant. So this is the VELO trial.

The second trial was the DEEPER trial and that trial looked at a actually the primary endpoint was the depth of response. And this is first line therapy in patients with metastatic colorectal cancer who are wild type and they were randomized to triplet therapy. In this case it was FOLFOXIRI with either bevacizumab or anti-EGFRcetuximab. In this case and this trial we know from previous presentation that it actually met the primary endpoint. There was an increase in the depth of response for the cetuximab arm as compared to the bevacizumab arm. However, when they looked at overall survival, there was the they had to go to the subgroup of patient with left sided colon cancer and BRAF wild type to get a survival advantage. There are too few things here. Number one is the number of the number of patients is small with the subgroup analysis and accordingly you don’t get a positive P value. However, if you look at the numerical difference between the group who received a bevacizumab versus cetuximab, the cetuximab arm had numerically much higher survival up to 12 or 13 months in those subgroups. I think my only concern is we do have a previous trial. It’s called the TRIPLET trial which discussed the value of a triplet chemotherapy with anti EGFR versus doublet chemotherapy with anti-EGFR for patients who are wild type. And in that Phase IIItrial, I think it was either Phase III, Phase II, there was no difference in PFS, no difference in response rate and no difference in overall survival between triplet and EGFR versus Doublet and EGFR in patients with wild type. So the whole point is do you really need a triplet plus anti-EGFR? I think that’s my only take on this trial, but we’ll wait and see.

And the third trial is the IMPROVE trial. So the IMPROVE trial is actually looking at a very interesting point which is trying to delay the emergence of resistance in the two anti-EGFR therapy in patients with wild type metastatic colorectal cancer. Similarly, it was a randomized trial first line setting patient who. Wild type and those patients were randomized to standard of care, which is. FOLFIRI plus cetuximab given continuously until disease progression versus the investigational arm which was FOLFIRI plus cetuximab but given only for eight cycles. And then patients were where treatment free until they progressed and they are reintroduced to the same regimen upon progression. My only problem with this trial was the primary endpoint. The primary endpoint was progression free survival on treatment. So it’s not looking at progression free survival in general, but only on treatment. And with this, of course the trial was positive, so there was an improvement in PFS, really. There was significant improvement in the progression free survival on treatment for the investigational arm as compared to the standard arm. But I think this is partly because of the primary endpoint that was chosen did not take into account patients who progressed in the treatment free interval. So I think the investigators are looking at, you know, going into a phase three trial and I would rather see the data for just PFS alone.

And the last trial was the AVETRIC trial and that was based that was investigating the effect of triple therapy plus anti-EGRF plus anti PD-L1. In this case it was a avelumab. And the idea behind this and the authors have looked at a doublet chemotherapy with anti-EGFR in patients who are wild type and and avelumab and they actually had good results. Although the previous Phase II trial did not meet its primary endpoint, but the results were encouraging. The idea behind this is the more killer cells will actually release more antigen or tumor antigen that actually will be picked up by the phagocytes or phagocytes and actually will be delivered to the T cells. So it will stimulate the immune cycle in the body. So the trial was positive. It was a Phase II trial single arm and actually met the primary endpoint with an improvement in the PFS, which was the primary endpoint and the PFS was 14 months. This is very encouraging for a Phase II trial with the PFS in patient with metastatic colorectal cancer. We’re actually waiting to see if the Phase III trial will actually shows a significant improvement.


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