At the 2023 ASCO Gastrointestinal Cancers Symposium, Sebastian Stintzing, MD, Charité – Berlin University of Medicine, Germany, presented an analysis from the phase 3 FIRE-4 study, evaluating the efficacy of standard therapy (FOLFIRI plus cetuximab) compared with switch maintenance (induction on FOLFIRI plus cetuximab followed by maintenance on fluorouracil-5 plus bevacizumab) during first-line treatment for patients with RAS wild-type colorectal cancer.

In this trial, patients were allowed to receive 1 cycle of FOLFIRI alone prior to randomization, to account for the possibility of RAS mutational analysis not being available in a timely manner. Dr Stintzing concluded that 1 initial cycle of chemotherapy alone “did not affect response rates or progression-free survival within a first-line treatment regimen of FOLFIRI plus cetuximab.”

Transcript:

Dear colleagues, it's a pleasure to show you the data, and to talk to you about the data we have presented at the 2023 ASCO Gastrointestinal Cancers Symposium. My name is Sebastian Stintzing. I'm heading the Department of Hematology, Oncology and Cancer Immunology here in Berlin at Charité Berlin.

The poster I had presented at ASCO GI this year was about the FIRE-4 study, a randomized study to investigate a switch maintenance concept with 5FU [fluorouracil-5] plus bevacizumab after FOLFIRI plus cetuximab induction treatment versus the continuation of FOLFIRI plus cetuximab. And here we report the first-line efficacy, as it was allowed per protocol, to have 1 cycle of FOLFIRI without a monoclonal antibody. I here want to present the data examining what the influence was of 1 previous cycle of FOLFIRI before starting an induction treatment using FOLFIRI plus cetuximab on the treatment efficacy.

First, as I said, 1 cycle of FOLFIRI alone was allowed. Why did we allow this? Well, RAS testing takes time, and sometimes the patient wants to start treatment early and we have this delay due to RAS testing and to basically bridge this delay, we allowed this 1 cycle of FOLFIRI, and overall, around 30% of our patients, exactly 205 patients, got 1 cycle of FORFIRI before FOLFIRI-cetuximab was used within the trial.

There was no difference when it came to response rate. In the whole [intention-to-treat] ITT population, the response rates were 62.1% and 59.4%. Those who got 1 previous cycle of chemotherapy before the addition of cetuximab had an overall survival rate of 67% and 57.4%. There was no obvious difference when it comes to tumor response.

What about survival, progression-free survival and overall survival? We used all patients within this trial, a total of 673 patients were randomized. Those 205 got 1 previous cycle of FOLFIRI and the others started with FOLFIRI plus cetuximab right away. There was no difference when it came to PFS. The median PFS that was reached was 11.0 and 11.2 months, totally comparable between both treatment modalities. What about overall survival? There was a small difference in overall survival, favoring the start with cetuximab right from the beginning. The median overall survival times were 28.1 months and 33.4 months. But this difference was mainly due to the different sites those patients were treated in. If this was a site in an outpatient private oncology group, usually it takes longer to get the RAS testing than if you are treated within a larger institution such as a university hospital. Those differences in overall survival were probably more due to the fact of where those patients were actually treated.

We also looked into the survival effect within the 2 specific arms, and it was quite interesting to see that in the standard arm of cetuximab plus FOLFIRI until progression or intolerable toxicity, there was no significant difference between both treatment modalities. One cycle without cetuximab did not affect PFS and did not affect OS. OS reached 28.5 months and 33.4. PFS was 10.6 and 10.9 months.

But in the experimental arm with an induction treatment of FOLFIRI/cetuximab and an early switch after 4 to 6 cycles toward 5-FU plus bevacizumab, there was no difference seen when it comes to PFS. Both reached 11.2 and 11.4 months. So totally comparable, but there was a significant difference when it came to overall survival. 28 and 32 months of median overall survival were reached. Probably due to the fact that if I don't have a cetuximab cycle in the beginning and then stop cetuximab, the anti-EGFR early, obviously the time on treatment with the anti-EGFR was too short and this translates into a difference in overall survival. Basically, when we talk about FOLFIRI plus cetuximab, we can start FOLFIRI without cetuximab in the beginning, but we should go on with cetuximab and FOLFIRI for as long as possible, until progression or until the occurrence of intolerable toxicity.

To sum it up, the omission of cetuximab in the first cycle of chemotherapy did not affect response rate or PFS within a first-line strategy of FOLFIRI plus cetuximab. If RAS mutation analysis is not timely available, a start of FOLFIRI then adding cetuximab in cycle 2 seems therefore to be safe with respect to efficacy.

Thank you so much for your attention.

Source:

Stintzing S, von Weikersthal LF, Fuchs M, et al. Phase III FIRE-4 study (AIO KRK-0114): Evaluation of first-line treatment efficacy of FOLFIRI/cetuximab in patients with RAS-WT mCRC receiving the first cycle of treatment with chemotherapy only. Presented at 2023 ASCO Gastrointestinal Symposium; January 19 – 21, 2023; San Francisco, California. Abstract LBA49