Encorafenib-Centuximab Plus Chemotherapy Tolerable for BRAFV600E Metastatic Colorectal Cancer: BREAKWATER Trial

Josep Tabernero, MD, Vall d’Hebron University Hospital, Barcelona, Spain, reviews updated safety data from an analysis of the phase 3 BREAKWATER trial, evaluating encorafenib plus cetuximab plus chemotherapy for BRAFV600E metastatic colorectal cancer.

These results were first presented at the 2022 European Society for Medical Oncology Congress in Paris, France.

Transcript: 

Hello, my name is Josep Tabernero. I'm a medical oncologist based at the Vall d'Hebron Institute of Oncology in Barcelona, Spain and on behalf of all of us I'm very glad to present and discuss the BREAKWATER safety lead-in data that we have just presented at the ESMO Congress in Paris.

The BREAKWATER is a study evaluating the combination of encorafenib, cetuximab, with chemotherapy for the population of BRAFV600E metastatic colorectal cancer. As a background, it is well known that patients with metastatic colorectal cancer that have the BRAFV600E mutation account for between 8% to 12% of the patients, but they have a poor prognosis compared to other populations.

 In fact, chemotherapy in the first line has limited efficacy, with an overall response rate that ranges around 35%, and usually the median progression-free survival is shorter than 6 months. The BEACON study met the primary endpoint to demonstrate that the combination of encorafenib, a BRAF inhibitor, and cetuximab, an EGFR inhibitor, as a targeted regional approach, increased overall survival in the population of patients with metastic BRAFV600E colorectal cancer in the second line and in the third line setting.

Moreover, the single-arm ANCHOR study in the first-line setting combining encorafenib and cetuximab plus a MEK inhibitor, in this case binimetinib, achieved an overall response rate around 50% with a median progression-free survival of 6 months.

Building on all these data, the ongoing open-label, global, multicenter, randomized phase 3 BREAKWATER study is evaluating encorafenib, cetuximab, plus or minus chemotherapy, compared to the standard-of-care chemotherapy alone in the first-line setting in patients with BRAFV600E metastatic colorectal cancer. What we presented to ESMO is an updated analysis of the BREAKWATER safety lead-in part, and this includes safety, pharmacokinetic results, but also new anti-tumor activity.

In the safety lead-in part, we had 2 cohorts. The first cohort combined encorafenib, cetuximab, and FOLFIRI as a chemotherapy backbone, and the second cohort combined encorafenib, cetuximab, and modified FOLFOX6 as a chemotherapy backbone. In this study, in this part, we included patients both in the first-line and in the second-line setting with metastatic colorectal cancer, the BRAFV600E mutation in the BRAF gene. Patients could have received chemotherapy before, but they could not have received the chemotherapy backbone that was for the cohort that they were allocated.

We included a total of 57 patients that were distributed in the 2 different cohorts, a little bit more female in the FOLFOX cohort and more presence with liver metastasis in the FOLFIRI cohort, but there were no major differences. The first thing that we evaluated was the safety profile of this combination, and I have to say that the tolerability of the combinations of both FOLFIRI and FOLFOX with encorafenib and cetuximab was very acceptable.

There were no new findings in the safety profile. Only 1 patient out of the total that we included had a dose limiting toxicity, consisting of grade 4 neutropenia lasting more than 7 days in the cohort of FOLFIRI, and less than 70% of the patients actually had to permanently discontinue any drug due to treatment-emergent adverse events.

As mentioned, avoiding potential interactions of the targeted therapy of encorafenib with chemotherapy was an important point of this study, and we compared the pharmacokinetic profile, especially the exposure in the 2 first cycles. In the case of oxaliplatin, there was no kind of interaction in the expression of this compound between the second cycle and the first cycle when encorafenib was administered. For FOLFIRI, we knew that encorafenib was a CYP3A inducer, and we also know that irinotecan, and also SN-38, the metabolite of irinotecan, are substrates of CYP3A. So it was anticipated that there could be a potential interaction.

When we look at the data, we did see that the exposure of irinotecan and SN-38, the metabolite, after the second administration of irinotecan was approximately 25% lower than the original one in the first cycle. And this is consistent with the predicted CYP3A-mediated interaction between encorafenib and irinotecan. Important data, perhaps the most important data on efficacy, actually was very reinforcing. Globally, we could say that the overall respond rate of either modified FOLFOX6 plus encorafenib, cetuximab or FOLFIRI, encorafenib, and cetuximab in the first-line setting exceeded 65%. In fact, for FOLFOX, it was 68.4% and for FOLFIRI was 66.7%.

The same data were very encouraging in those patients that were treated in the second-line setting because again, the response rate, the overall response rate in both cohorts was 50%, but actually very important. And even when we can look at the waterfall plot of all the patients included in the study, both in the first line and in the second line, is really very reinforcing that almost all patients benefit from the treatment. Indeed, only 1 patient had progressive disease as the best response, so all the other patients did benefit from the treatment.

Progression-free survival is still immature because the follow-up is short, but we can say that for both FOLFOX, the combination of FOLFOX, encorafenib, cetuximab, and FOLFIRI, encorafenib, cetuximab in the first-line setting, the median progression-free survival exceeds 10 months. And the same for those patients that were treated in the second-line setting with either FOLFOX or FOLFIRI combined with encorafenib, cetuximab. Again the median progression-free survival exceeding the figure of 10 months.

To conclude about this data that we presented, this important data, is that the combination of encorafenib and cetuximab was generally tolerable without any new safety signals. For the combination of FOLFOX6 plus encorafenib, cetuximab, at the steady-state encorafenib, there was no alteration, difference, in oxaliplatin exposures. However, for FOLFIRI, in the presence of a steady-state encorafenib, the exposures of irinotecan and also SN-38, the metabolite of irinotecan, decreased by approximately 25%. And actually this was consistent with the predicted CYP3A-mediated interaction between encorafenib and irinotecan.

The data shows preliminary promising anti-tumor activity, and this was seen for all patients, either receiving FOLFOX or FOLFIRI with encorafenib and cetuximab, either in the first-line or in the second-line setting in this population of patients with BRAFV600E metastatic colorectal cancer. And actually, this supports the ongoing phase 3 study with this combination. I have to say that these results are particularly encouraging when we compare this with historical results of first-line chemotherapy that I mentioned at the beginning of my presentation.

Finally, all the data that we presented support the ongoing phase 3 BREAKWATER study in which encorafenib and cetuximab is combined with modified FOLFOX6. And modified FOLFOX6 was chosen in part based on the lack of this PK interaction between encorafenib and oxaliplatin. I think I do have very important data that supports the ongoing study that we are doing in the firstline setting of patients with metastatic BRAFV600E colorectal cancer, and I think that this is a real hope for patients.

We are awaiting the results of the randomized BREAKWATER study that will define whether the combination is a real opportunity for patients in this combination.

Of course, I would like to thank all the patients that were included in the study, also the families, all the investigators, and the staff at participating sites. And of course, this study couldn't be done if it was not sponsored by Pfizer, and also the support of Merck KGaA in Darmstadt, Ono Pharmaceuticals, and Eli Lilly. Thank you very much for your attention.