Combination Regimens Induce Promising Survival Benefit in BRAF-Mutant Colon Cancer

Richard Kim, MD

Richard Kim, MD

Patients withBRAF-mutant colorectal cancer (CRC) tend to have a poorer prognosis than others with CRC. Prior data has demonstrated that by using BRAF inhibitors, however, the EGFR pathway is stimulated, which makes the BRAF inhibitor single-agent therapy not work. Many studies are now confirming the role of combination and triplet regimens of the BRAF and EGFR inhibitors, particularly in combination with MEK inhibitor, according to Richard Kim, MD.

The triplet combination of BRAF inhibitor encorafenib (Braftovi), MEK inhibitor binimetinib (Mektovi), and EGFR inhibitor cetuximab (Erbitux) demonstrated significant improvement in overall survival (OS) in patients with previously treatedBRAFV600E-mutant metastatic CRC compared with the standard of care, cetuximab plus irinotecan-based chemotherapy, according to data from the phase III BEACON CRC trial. Improvements in progression-free survival (PFS) and objective response rate (ORR) also favored the triplet regimen.

The median OS was 9.0 months versus 5.4 months with the triplet versus the standard of care regimen, respectively (HR, 0.52; 95% CI, 0.39-0.70;P<.0001). The median PFS was 4.3 months with the triplet compared with 1.5 months with the standard of care (HR, 0.38; 95% CI, 0.29-0.49;P<.0001), and the ORR was 26.1% with the triplet compared with 1.9% (P<.0001).

The combination of encorafenib plus cetuximab was also evaluated and compared with the control arm. The median OS was 8.4 months in this subset of patients versus 5.4 months in the control arm (HR, 0.60; 95% CI, 0.45-0.79;P<.0003). The median PFS was 4.2 months versus 1.5 months (HR, 0.40; 95% CI, 0.31-0.52;P<.0001). The ORR was 20.4% with the doublet versus 1.9% (P<.0001).&nbsp;

This triplet regimen also did not lead to any unexpected toxicities. Fifty-eight percent of patients experienced grade 3 or greater adverse events (AEs) with the triplet regimen and 50% with the doublet versus 61% with the standard of care regimen. AEs led to discontinuation in 7% of patients with the triplet regimen and 8% in the doublet arm versus 11% with the standard of care. Investigators determined that the safety profile was consistent with prior experiences with each drug and the effects were standard for MEK, RAF, and EGFR-directed therapies.

Encorafenib plus binimetinib and cetuximab previously receiveda breakthrough therapy designation from the FDA in August 2018for the treatment of patients with BRAF V600E-mutant metastatic CRC based on the results of the BEACON CRC trial. In December 2019, the FDA accepted&nbsp;a supplemental new drug application for the combination of encorafenib and cetuximabfor the treatment of these patients as well, based on these data.

In an interview withTargeted Oncology, Kim, associate professor at H. Lee Moffit Cancer Center, discussed the research from several trials that support the use of doublet and triplet regimens as treatment of patients with metastatic CRC harboring aBRAFmutation. He highlighted the rationale for using the combination of BRAF and EGFR inhibitors in this patient population.

TARGETED ONCOLOGY: Could you provide an overview of the expanding options for patients with metastaticBRAF-mutant CRC?

Kim:BRAF-mutant tumors in colon cancer is a subset patient population of about 5% to 10%. We know that patients withBRAF-mutant CRC tend to have a poor prognosis, right-sided with more pertinent involvement, female, and are older in age. We also know that, most commonly, theBRAFV600E mutation occurs about 90% of the time.

So far from the data, we know that patients with theBRAF-mutant tumor tend to have a poor prognosis. Unlike patients withBRAFwild-type, their life expectancy is only anywhere from 9 to 14 months versus patients with wild-type where they live up to 2 or 3 years. These are the patients that we don&rsquo;t have a lot of time to give them fourth- or fifth-line therapy. You usually get a second shot after the first-line in the beginning, so we need to come up with a more aggressive approach to treat those patients.

In 2019, we have targeted drugs that target the BRAF pathway. In the past, there has been a lot of robust data in melanoma and other diseases in patients withBRAF-mutant tumors, where if you give a BRAF inhibitor by itself, it seems to have a very strong efficacy, ORR, OS, and PFS. However, in CRC, when they tried to study this with a single-agent BRAF inhibitor such as vemurafenib (Zelboraf), the response rate was very low, less than 5%, with a modest PFS and OS. The reason for that is that in patients with CRC if you block the BRAF inhibitor, there is a loop that stimulates the EGFR pathway. Therefore, by doing that, you are reactivating the MAP kinase pathway and making the single-agent BRAF inhibitor not work. In CRC, you have to block not only the BRAF pathway but also the EGFR pathway as well for that pathway to work. We could take this 1 step further by blocking another pathway, the MEK pathway, to see if the triplet combination has more efficacy in CRC.

TARGETED ONCOLOGY: What data have we seen so far surrounding the triplet regimen inBRAF-mutant CRC?

Kim:There are 2 studies done using the combination of BRAF and EGFR inhibitors in&nbsp;BRAF-mutant CRC. The first was the SWOG study. It was a randomized phase II study which randomized the standard of care, cetuximab plus irinotecan, to BRAF inhibitor vemurafenib plus irinotecan and rituximab (Rituxan). The primary end point was PFS, and the triplet regimen doubled the PFS from 2 months in the control arm to 4 months. There was a trend towards OS, and the ORR was much higher in the triplet arm. Based on that, it is currently on the NCCN listing as 1 of the options for the treatment of patients withBRAF-mutant CRC.

Most recently, the BEACON CRC study was presented at the 2019 ESMO Annual Meeting and has also been published. This was a randomized phase III trial comparing the triplet arm of a BRAF inhibitor plus binimetinib, a MEK inhibitor, plus an EGFR inhibitor versus the standard of care, which is irinotecan or fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) plus cetuximab. The primary end point was trying to demonstrate the OS of the triplet versus the control. However, they had a third arm of doublets, where they just had a BRAF inhibitor plus an EGFR inhibitor. The doublet was compared to the control arm.

When that trial was published and presented, the combination of the triplet regimen was superior to the control arm with the improvement in OS close to 4 months&rsquo; benefit. The response rate was much higher around 35% versus the control arm. The secondary end point was comparing the doublet to the control arm. Similarly, there seemed to be a benefit in not only OS but also ORR and PFS compared to the control arm. The trial was not designed to compare the doublets versus triplets, so at this moment, we don&rsquo;t know if the triplet is better than the doublet. However, we do know, at least from the toxicity perspective, overall grade 3 or higher AEs seem to be similar in the doublet and triplet arm. However, by adding a MEK inhibitor, you will get more side effects from the MEK inhibitor, which is the eye or heart/cardiac issues. One has to be concerned about that when you add a third drug. However, most commonly based on the data presented in the BEACON study, patients withBRAF-mutant tumors should get at least the triplet regimen to start off at the beginning in the second-line setting. If there is toxicity from the MEK inhibitor, I would just drop the MEK inhibitor and continue the doublet knowing it still shows an OS benefit compared with the control arm.

TARGETED ONCOLOGY: How are biomarkers being used in the treatment of CRC?

Kim:In CRC, there are currently many biomarkers available, including&nbsp;BRAF,KRAS, mismatch repair (MMR) status, TRK fusion, and HER2 status. I think it is important, at least in metastatic CRC, that as soon as they are diagnosed with stage IV, it is important to test for all this molecular profiling because we need an optimal treatment plan for this patient. For example, if you know the patient has aBRAF-mutant tumor at the beginning, we know the patient has a very poor prognosis, and they do not have the luxury of time to receive a third- or fourth-line therapy. These are the patients that typically, based on the TRIBE study, we would use the FOLFIRINOX regimen with bevacizumab in the first-line setting knowing we don&rsquo;t have a lot of time. We know from the subset analysis from the TRIBE study that the median OS with FOLFIRINOX plus bevacizumab inBRAF-mutant tumors was up to 19 months compared to the historical OS of 9 to 14 months. Nineteen months is more encouraging, so knowing the molecular profile at the beginning is a very important step for the treatment of the patient.

TARGETED ONCOLOGY: How is immunotherapy being used for the treatment of patients with CRC?

Kim:Currently, immunotherapy is only used for patients who are MMR deficient or microsatellite instability-high (MSI-H). There are plenty of data out there suggesting the single-agent or doublet regimen of PD-L1 and CTLA4 inhibitors have excellent efficacy and durability of response in patients who are MSI-H. However, only 5% of patients are stage IV. There is a lot of research going on right now trying to target those patients who are microsatellite stable (MSS) with immunotherapy to convert the cold tumor to a hot tumor. Data from the 2019 ASCO Annual Meeting looked at the combination of regorafenib and nivolumab (Opdivo). Regorafenib changes the microenvironment so that it becomes more sensitive to the immunotherapy. At least the data by the Japanese group showed that in patients who were MSS, the combination induced a response rate of around 25% to 30%. Compared to single-agent checkpoint inhibitor, the response rate is closer to 0%. Those are the combinations we will be looking at in the future to help those patients who are not MSI-high.

TARGETED ONCOLOGY: What do you hope oncologists take away from this?

Kim:In patients with&nbsp;BRAF-mutant tumors, it is very important that we know at the time of diagnosis of the status so we can develop an optimal treatment. First-line therapy should be the combination of chemotherapy, most likely FOLFIRINOX plus bevacizumab based on the TRIBE study, but as soon as they progress, there is now clear evidence that the triplet regimen of the BRAF, MEK, and EGFR inhibitors is the way to go in the second-line setting. If there is a doubt about toxicity, we can drop the MEK inhibitor and continue with the BRAF and EGFR inhibitors in that setting.