Evolution of Predictive Biomarkers for Metastatic CRC - Episode 4
Transcript:Richard Kim, MD: It is very important to know the molecular profiling status at the beginning of treatment, especially in patients with stage IV disease because we want to know how to personalize the management depending on the molecular profiling. For example, if we know that a patient has a BRAF mutation at the beginning of treatment, those are the patients who have very poor prognoses. Those patients don’t have the luxury of waiting for third- or fourth-line therapy. So, if I know the patient is BRAF-mutated, I will start the patient off by giving a FOLFOXIRI [folinic acid, fluorouracil, oxaliplatin, irinotecan]-based regimen based on the TRIBE study showing there’s a small overall survival [OS] benefit. So that’s the importance of the BRAF status.
On the other hand, the RAS status is something we really want to know at the beginning because that will dictate whether we use an antiangiogenic agent versus an anti-EGFR agent. I think the biggest dilemma right now in first-line therapy is that we know the backbone—typically we use FOLFOX [folinic acid, fluorouracil, oxaliplatin] here in the United States—but what kind of biologics do you add to it? Now, if you know the patient is RAS mutant, it’s pretty easy. You start with usually FOLFOX plus bevacizumab. Once they progress on FOLFOX plus bevacizumab, in the second line typically we change the backbone to FOLFIRI [folinic acid fluorouracil, irinotecan] and we continue antiangiogenic therapy beyond progression. Usually, it could be the bevacizumab. There are data with ramucirumab, and there are data with aflibercept. So these are 2 or 3 anti-VEGF drugs that you could use in second-line therapy once patients progress.
However, if you know the patient has a RAS wild-type tumor and it’s a left-sided tumor, based on the post hoc analysis of a couple large phase III studies, we know that there seems to be an overall survival [OS] benefit favoring the EGFR arm in the left-sided tumor. Therefore, if you have a left-sided tumor, RAS wild type, I think you would have a discussion with the patient to see whether the patient would like to have an EGFR drug plus bevacizumab. Now the downside of the EGFR drug is that we get rashes, and patients are on first-line therapy for a long time, so they suffer with a rash and paronychia issue. However, there seems to be an OS benefit. Therefore, that would be the discussion that I would have with the patient at the beginning to see if the patient would like to have an anti-EGFR versus anti-VEGF drug in the first-line setting in left-sided RAS wild-type disease.
Scott Kopetz, MD, PhD: Our understanding of how best to utilize biologic therapy in combination with cytotoxic chemotherapy for first-line treatment is really guided by some studies that, while older now, really still inform our best practices in this population. And that’s the CALGB/SWOG 80405 and the FIRE-3 studies.
The CALGB/SWOG 80405 is a study that was completed in the United States where patients were treated with a cytotoxic backbone of either FOLFOX or FOLFIRI—in the United States population practice, that was predominantly FOLFOX-based—and then randomized to either cetuximab or bevacizumab in the key analysis. These were RAS/RAF wild-type patients, and the question was really about the overall survival of this population.
In unplanned analysis it was identified that tumor sidedness was a major factor impacting the overall survival of these patients where the EGFR-based therapies had best outcomes in patients who were wild type for RAS/RAF and had left-sided disease. Conversely, the bevacizumab arms performed best in the right-sided tumors. And these data are consistent with the FIRE-3 study, a European study, that, while smaller, provided complementary information. The backbone here was FOLFIRI, and again, cetuximab or bevacizumab. The primary end point for this study was response rate, but overall survival data likewise showed a similar benefit favoring an EGFR inhibitor for a left-sided RAS/RAF wild-type tumor, and bevacizumab for the right-sided tumors.
Richard Kim, MD: FIRE-3 was a randomized phase III study in the first-line setting in patients with KRAS wild-type disease. It was a study looking at FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab. And the primary endpoint was response rate. Overall, the trial was negative as there was no difference in response rate. Now, last year they had a final analysis, the final results of the FIRE-3 study. And, in that study, they looked at what we called a per-protocol analysis. And those are the patients who actually got at least three cycles of chemotherapy or had more than one baseline CT [computed tomography] scan done.
In those patients, there was a significant improvement in response rates. Response rates were close to 77%, 78% versus 65%, favoring the arm of cetuximab. And that translated into a median overall survival difference about seven months. Even the PFS [progression-free survival] was very similar. So there was always a question about why the arm of an EGFR inhibitor against cetuximab had the same PFS, but there was as difference in overall survival.
And one of the hypotheses is that because of this high response rate, there is what we call early tumor responses, and also there’s a depth of response you see with the EGFR inhibitor. And we think that that correlates with possibly overall survival benefit. So, in patients who are RAS wild type and have a left-sided tumor—where you’re looking for a shrinkage of the tumor, downstaging it, or possibly an OS benefit—I think it’s definitely reasonable to use an EGFR inhibitor in the first-line setting in combination with chemotherapy in all RAS wild-type patients.
Scott Kopetz, MD, PhD: As a result of these studies, and our improved understanding of the biologic underpinning of these results, this has now changed practice and guidelines. While the guidelines differ between the United States and Europe, I think it’s fair to say that consideration of an anti-EGFR therapy is strongly encouraged in a left-sided RAS/RAF wild-type patient as part of the first-line chemotherapy regimen. This information is being used in my clinical practice where the default discussion with the patient is really about an EGFR-containing first-line treatment because of the suggestion of an overall survival benefit. Now practically, this has to be weighed with the adverse effects and discussion of the potential impact of that treatment. But overall, this approach I think provides the best outcome for our patients based on our available data.
Transcript Edited for Clarity