Safety Lead-In Data Show Survival Improvement With Triplet Combination in BRAF V600E-Mutant mCRC

Axel Grothey, MD

Axel Grothey, MD

At the 2019 Gastrointestinal Cancers Symposium,findings from the safety lead-in cohort of the phase III randomized BEACON CRC trialshowed a promising improvement in survival for patients withBRAFV600E-mutant metastatic colorectal cancer (mCRC).

This patient population only makes up about 10% to 15% of patients with advanced CRC. These patients generally have a poor prognosis, and based on recent data, the overall survival (OS) in these patients is less than 12 months.

Patients withBRAFV600E-mutant mCRC represent an unmet need where new treatment options are necessary. BEACON CRC aims to investigate the triplet regimen of the BRAF inhibitor encorafenib (Braftovi), the MEK inhibitor binimetinib (Mektovi), and the anti-EGFR antibody cetuximab (Erbitux) in this setting.

In an interview withTargeted Oncology,Axel Grothey, MD, medical oncologist at West Cancer Center, discussed the results from a safety lead-in cohort to the BEACON CRC trial and highlighted the significance of these data.

TARGETED ONCOLOGY:What was the rationale for the BEACON trial?

Patients withBRAFV600E-mutant mCRC are patients with very poor prognosis. We know in the advanced setting, about 10% to 15% of patients have this alteration, thisBRAFV600E mutation. OS in these patients, even from first-line, is very poor. We saw recently in actual modern data that the OS is below 12 months compared to, say, more than 3 years that we expect from a RAS and RAS wild-type advanced disease.

For patients withBRAFV600E-mutant CRC, they are representing an unmet need. We need new treatment approaches. We know combination chemotherapy like triplet chemotherapy with fluorouracil (5-FU), oxaliplatin, irinotecan (Camptosar) plus bevacizumab (Avastin) might be a standard of care, but not a lot of patients can tolerate a triplet, and even if they respond to first-line treatment. OS is still very poor, so these patients represent an unmet need.

TARGETED ONCOLOGY:How was this study designed?

The BEACON study tried to address these specific molecular alterations of the patients withBRAFV600E tumors. We have known for some time that we have BRAF inhibitors which can inhibit the BRAF activity quite well. BRAF is one of those components of the so-called MAP kinase pathway, which is really EGFR receptor, RAS, RAF, MEK, and ERK. That’s the kinase components that we have that we try to inhibit. We have BRAF inhibitors like regorafenib (Stivarga), dabrafenib (Tafinlar), and encorafenib, but by themselves, they have very limited activity in mCRC.

The BEACON study was actually built on the results from a lot of translational studies that showed we do much better in patients when we not only inhibit BRAF but also the feedback mechanisms that activate EGFR receptors in CRC. So we combine the BRAF inhibitor with an EGFR inhibitor such as cetuximab or panitumumab, and, in order to finish the blockade of this pathway, we might add in a MEK inhibitor, which is binimetinib.

The BEACON study really tests a biologic triplet of encorafenib, binimetinib, and cetuximab, 3 ways to inhibit this MAP kinase pathway including feedback groups, compared to a biologic doublet of encorafenib and cetuximab and standard chemotherapy which is irinotecan plus cetuximab, which we know from a lot of data is not very effective. BEACON is a phase III study interrogating exactly this combination in 3 arms: triplet biologic therapy, doublet biologic therapy, compared to standard chemotherapy.

The BEACON study had a safety lead-in phase. In the safety lead-in phase, the triplet combination, encorafenib, binimetinib, and cetuximab, was tested in 30 patients withBRAFV600E-mutant mCRC in the second- and third-line setting. Now we actually have efficacy data from this safety lead-in cohort of this triplet.

TARGETED ONCOLOGY:What were the results from the lead-in phase?

The data that we have from the safety lead-in phase are 30 patients eligible for safety and 29 patients eligible for efficacy because 1 patient in this cohort had a non-BRAFV600E-mutant mCRC which cannot respond, so 29 patients were available for efficacy and activity.

Very intriguingly, we have a response rate of 48% and not a single patient had progression of disease by RECIST criteria in the first analysis. The median progression-free survival (PFS) is 8 months, which by far beats the historical control of about 2 to 4 months depending on what kind of regimen you look at. At this conference, we hear the OS data from a poster presentation, which is 15.3 months, almost 3 times as long as the standard treatment approach that is FDA approved. [This is] very much longer than what we have seen even with biologic combinations in this setting.

TARGETED ONCOLOGY:What is the significance of these data?

First of all, the results are important because these patients normally have a very poor prognosis. As I mention, they have an unmet need with very limited response to standard therapies. The best response we have seen so far in a clinical study is about 16%, not necessarily confirmed responses, but all responses. Here we have 48% responses, which is a significant leap in terms of efficacy. It seems to be that we are hitting the biology that drives these cancers perfectly well.

Duration of response is interesting. There were 6 patients that are still on the study drug more than 12 months after initiation of therapy. This is, again, a treatment that does not include chemotherapy. It’s just biologic agents. We are really targeting the biology that drives these cancers. An OS of 15 or more months with solid data because we passed the median is very impressive, so the durability of response, response rate itself, and the overall response rate in second- and third-line population of a poor prognostic patient group is impressive.

In addition, another thing that is interesting is the safety profile was actually quite benign. There were some toxicities, but low grade 3 or 4 toxicities. In particular, the potentially dreaded skin toxicity was not as apparent as we thought. It actually seems to be that when you combine the BRAF and MEK inhibitor with an EGFR inhibitor that the toxicity from EGFR inhibitor, the EGFR receptor-based rash was actually less than if you had a single-agent cetuximab in a tumor. We have a well-tolerated regimen hitting biology with good efficacy. That is impressive.

TARGETED ONCOLOGY:What is important to take away from these data?

I think the BEACON safety lead-in phase is really only the lead-in to the larger randomized trial. The randomized trial, which will include more than 600 patients with 3 arms, the biologic triplet, the biologic doublet, and chemotherapy plus a VEGF antibody, has completed accrual in December of 2018. Hopefully, we will see the efficacy data very soon. We will probably have response rate data before we have PFS or OS data, but I hope that if the data holds up in the larger randomized BEACON study component that we will identify a new standard of care.

TARGETED ONCOLOGY:How does this trial compare to other data we are seeing in advanced CRC?

The BEACON study targeting theBRAF-mutant tumor is probably the most interesting or promising approach right now in the advanced setting. We have some ongoing studies with napabucasin in the second-line setting which was a stemness inhibitor that might have different mechanisms of action than a stem cell inhibitor, so there is a phase III trial ongoing. We had several approaches toward immunotherapy in primarily non-immunogenic tumors, meaning microsatellite stable tumors, which have recently failed, so we are back to the drawing board of designing trials that might activate the immune system and make tumors more immunogenic in these primarily non-immunogenic cancers.

So far, I think the most promising data in this subgroup of patients is really the BEACON data ofBRAFV600E tumors. There’s some efforts in earlier stage colon cancer utilizing circulating tumor DNA to assign treatments to patients to have a better understanding of risk of recurrence and potentially influence choice of therapy. But in the advanced setting right now at this point in time, as we just discussed in an expert group, it’s not easy to see where we are going. There’s not just this 1 new drug out there beyond targetingBRAFmutations.