Bevacizumab and Chemotherapy Remains Standard of Care in RAS/RAF Mutated mCRC

In an interview with Targeted Oncology, Christopher Nevala-Plagemann, MD, discussed the key takeaways of his research on the best treatment strategies for patients with left sided RAS or RAF wild-type metastatic colorectal cancer.

Chemotherapy in addition to bevacizumab (Avastin) remains the most widely used first-line treatment strategy for patients with left-sided RAS/RAF wild-type metastatic colorectal cancer (mCRC). Despite this preference, treatment with an anti-EGFR agent was associated with improved overall survival (OS).1

In a post hoc analysis of the CALGB/SWOG 80405 trial (NCT00265850), it was suggested that anti-EGFR therapy may be superior to bevacizumab when added to first-line chemotherapy in this patient population.2 However, research published in the Official Journal of the National Comprehensive Cancer Network showed no significant increase in the relative percentage of patients with left-sided RAS/RAF wild-type mCRC being treated with anti-EGFR agents from 2013 to 2018.1

In the analysis, experts examined the trends in use of anti-EGFR agents in patients with left-sided RAS/RAF wild-type mCRC compared with the clinical outcomes among the most used treatment strategies. A nationwide electronic health record (EHR)–derived deidentified database was reviewed for these patients and treatment trends over time were assessed by fitting a linear model to the percentage of patients receiving anti-EGFR therapy.

There were 20,333 patients with mCRC included in the EHR-derived dataset. Among those enrolled, 9,753 received a standard chemotherapy doublet with or without targeted therapy, and 5,876 were available for additional analysis. Of those eligible for another analysis, 2,449 (41%) had a tumor sidedness–specific ICD code, and 1,607 (65%) were documented as having an LSPT. Then, 456 patients (28%) in this cohort received first-line chemotherapy alone, while 965 (60%) received chemotherapy plus bevacizumab, and 186 (12%) received chemotherapy plus an anti-EGFR agent.

Findings revealed that the percentage of patients who received an anti-EGFR drug increased from 9% to 16% between 2013 and 2018. Additionally, the median OS for patients treated with chemotherapy alone was 27.3 months (95% CI, 24.8-32.3), 27.5 months with bevacizumab (HR 0.88; 95% CI, 25.8-28.9; P =.33), and 42.9 months with an anti-EGFR agent (HR 0.52; 95% CI, 36.0 to not reached; P =.005).

Overall, this analysis did not reveal any significant increase in the percentage of patients with left-sided RAS/RAF wild-type mCRC being treated with anti-EGFR, showing the continued benefit of chemotherapy plus bevacizumab as a first-line treatment strategy for these patients in the United States. However, findings did reveal that survival outcomes may be superior with the addition of a first-line anti-EGFR agent in this patient population.

In an interview with Targeted OncologyTM, Christopher Nevala-Plagemann, MD, Huntsman Cancer Institute at the University of Utah, further discussed the key takeaways of his research on the best treatment strategies for patients with left sided RAS or RAF wild-type mCRC.

Targeted Oncology: How has the therapeutic landscape for frontline left sided RAS or RAF wild-type mCRC evolved over the past 10 years?

Nevala-Plagemann: Over the last decade or so, we have identified several cytotoxic therapies that are active in our colorectal cancer patients. We know that CAPOX, FOLFOX, FOLFIRI, and potential the triplet therapy of FOLFOXIRI are all active in our patients with metastatic disease. The landscape of targeted therapies that we can add on to a cytotoxic chemotherapy backbone has also evolved quite a bit in the last decade or 2. We know that anti VEGF targeting therapies like bevacizumab as well as the anti-EGFR therapy, cetuximab [Erbitux], and panitumumab [Vectibix] also have activity in our patients with metastatic colon cancer.

Over the last decade, we've started to understand that not all patients are going to benefit from these drugs. There are certain subsets who are more likely to respond to anti-EGFR targeted therapies, specifically patients with left sided primary tumors and who have RAS/RAF wild-type disease. Our paper was looking at and expanding upon some of the data that we have from large clinical trials that were published in the 2010s. The CALGB/SWOG 80405 trial, as well as the FIRE-3 trial [NCT00433927], attempted to answer the question of how we should be managing these patients in the first-line setting with RAS/RAF wild-type disease. What we found based on some post hoc analyses of these trials was that it seems that anti-EGFR therapies are superior to bevacizumab in this specific population with left sided RAS/RAF wild-type tumors.

What do outcomes look like with the available therapies?

We know that prognosis varies based on where a patient's primary tumor is and what their mutational status is. For that select group of patients who have RAS/RAF wild-type disease with the left side of primary tumor, we think that they have a better prognosis than patients who either have a RAS/RAF mutation or right side of primary tumor depending on what trial you're looking at. [This means] overall survival is ranging from somewhere between 2 to 3 years for these patients who have left side a RAS/RAF wild-type tumors.

Can you discuss the results of the CALGB/SWOG 80405 trial and how it has impacted the landscape?

The CALGB/SWOG 80405 trial was trying to determine whether an upfront therapy with a cytotoxic backbone of FOLFOXIRI or CAPOX with the addition of either bevacizumab or anti-EGFR therapy was superior. It did not demonstrate a significant difference in overall survival with the addition of anti-EGFR targeted therapy compared to a bevacizumab.

However, this trial included patients with both left and right sided primary tumors. Post hoc analyses of this trial that were published a few years later did show potential superiority of an anti-EGFR therapy compared to bevacizumab in these left sided primary tumor patients. This fits with another trial that was published around the same time, the FIRE-3 trial, which also showed in post hoc analyses that these patients who have left sided primary tumors with RAS/RAF wild-type disease seem to benefit more with the addition of an anti-EGFR targeted therapy.

Can you provide some background and explain the purpose of your EHR derived database study?

Because of some of these discrepant results between CALGB/SWOG 80405 and FIRE-3, and because of these post hoc analyses suggesting a benefit in a very specific population, we wanted to look at some real-world data and see how physicians in the United States are practicing. Are they incorporating anti-EGFR targeted therapies into the first-line setting? If they are, how do the outcomes of those patients compare with patients who receive bevacizumab in the first-line setting? That was the purpose of our study here.

What were the key findings?

There were a couple key findings that we took from our study. The main one was that in this population of patients included in this EHR derived database that we used, we did see what appeared to be a clinically significant improvement in first-line overall survival of patients who received cetuximab and panitumumab compared to bevacizumab. In our study, the median overall survival for patients who got into EGFR therapy was 42.9 months, compared to only 27.5 months for the patients who got bevacizumab. This finding held up when controlling for potential confounding factors and a propensity score-based analysis with the hazard ratio of around 0.52. This seemed like good evidence that using an anti-EGFR therapy in the first-line setting is something that you should be offering your patients.

What should oncologists take away from this research?

One of the exciting things is to see some of the recent results of other prospective studies that were recently presented at ASCO. We had the paradigm trial which looked at a very similar question to what we were trying to answer in our retrospective study. In that trial, they saw that there was a trend towards benefit with anti-EGFR targeted therapy compared to bevacizumab in this very specific left sided RAS/RAF wild-type population. When we combine some of this real-world retrospective data with some of this prospective data that's coming out, I think all practicing oncologists need to at least present first-line anti-EGFR targeted therapy as an option for our metastatic colorectal cancer patients.

There are certainly some specific side effects that come with anti-EGFR targeted therapy, things that can impact the patient's quality of life, with skin toxicity like rash, and so all these things need to be discussed with patients. Given the potential for it to improve overall survival, I think we should at least be offering it to all the patients we see.

What barriers may be keeping community oncologists from using anti-EGFR therapy over chemotherapy or bevacizumab in the front-line setting?

In our study, we also looked at the uptake of these drugs in the community since the publication of the FIRE-3 and CALGB/SWOG 80405and post hoc analyses and how have patients been being treated in the United States. what we saw was that despite potential for improved overall survival with an anti-EGFR front-line strategy, that's not what the majority of oncologists are using in the US, at least not at the time of our study.

I think there's several potential reasons for this. One is that bevacizumab has just been around a bit more. We're more comfortable with the toxicity profile of it. Also, I think, oncologists, are aware of the skin toxicity of anti-EGFR therapies. Patients don't like having a skin toxicity as it is something that people will notice. I think that's something that oncologist tried to avoid. I think that's been 1 of the major limitations to uptake of these therapies in the community.

That being said, we do know now that there are ways we can mitigate these toxicities that impact a patient's quality of life, using things like prophylactic antibiotics or steroid creams. Things like that can allow patients that tolerate these medications better and are something that we need to make sure everybody understands.

What are your recommendations for providing access to better therapies in the future?

I think the key is to keep an open mind with all our patients, no matter where we're practicing, and to be enrolling as many of our patients as we can in clinical trials so that we can keep identifying new novel treatment strategies and novel therapies. Getting next generation sequencing on all our colorectal cancer patients with metastatic disease is going to be really important. There are new therapies coming out all the time, and we need to be making sure our patients have access to all the new therapies that are available.

References:
Nevala-Plagemann C, Iyengar S, Trunk AD, Pappas L, Haaland B, Garrido-Laguna I. Treatment Trends and Clinical Outcomes of Left-Sided RAS/RAF Wild-Type Metastatic Colorectal Cancer in the United States. J Natl Compr Canc Netw. 2022;20(3):268-275. doi:10.6004/jnccn.2021.7079
Cetuximab and/or bevacizumab combined with combination chemotherapy in treating patients with metastatic colorectal cancer. ClinicalTrials.gov. Updated May 7, 2020. Accessed August 4, 2022. https://clinicaltrials.gov/ct2/show/NCT00265850