An interview with Dr. Van Morris from The University of Texas MD Anderson Cancer Center in Houston, TX and Dr. Cathy Eng from Vanderbilt-Ingram Cancer Center in Nashville, TN, co-chairs on "Treatment of Metastatic Colorectal Cancer: ASCO Guideline." Dr. Morris and Dr. Eng review the evidence-based recommendations from the guideline, focusing on areas of uncertainty in the treatment of metastatic colorectal cancer, and highlighting the importance of multidisciplinary collaboration and shared decision-making between patients and clinicians. Read the full guideline at www.asco.org/gastrointestinal-cancer-guidelines. TRANSCRIPT Brittany Harvey: Hello, and welcome to the ASCO Guidelines Podcast series, brought to you by the ASCO Podcast Network; a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at: asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Van Morris, from The University of Texas MD Anderson Cancer Center in Houston, Texas, and Dr. Cathy Eng from Vanderbilt-Ingram Cancer Center in Nashville, Tennessee - co-chairs on, 'Treatment of Metastatic Colorectal Cancer, ASCO Guideline.' Thank you for being here, Dr. Morris, and Dr. Eng. Dr. Cathy Eng: Thank you. Dr. Van Morris: Thank you. Brittany Harvey: First. I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The full Conflict of Interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Morris, do you have any relevant disclosures that are directly related to the guideline topic? Dr. Van Morris: Not personally, but I do have research support to my institution from Pfizer and Bristol Myers Squibb who have products that I'll be discussing on this podcast. Brittany Harvey: Thank you, Dr. Morris. And Dr. Eng, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Cathy Eng: Also, not personally associated with any honorarium specific to this topic. Brittany Harvey: Great. Thank you both. So then, let's talk about the content of this guideline. So first, Dr. Morris, can you provide an overview of the scope of this guideline? Dr. Van Morris: Sure. So colorectal cancer is the second-leading cause of cancer-related death in the United States. And especially in the time of the recent COVID-19 pandemic with people less likely to go for screening colonoscopies, there's great concern that more and more patients will be presenting at the time of their initial diagnosis with later-stage, more advanced colorectal cancer. So with that said, research is moving very quickly for the benefit of patients with colorectal cancer, and we were interested in assembling a multidisciplinary team that consisted of medical oncologists, surgical oncologists, radiation oncologists, pathologists, and radiologists as well, to help us make guidelines that really summarize the most relevant up-to-date practices, based on rigorous literature review for treatment recommendations for advanced metastatic colorectal cancer. Brittany Harvey: Great. And then as you just mentioned, this guideline provides recommendations, and a lot of those focus on areas of uncertainty in the treatment of metastatic colorectal cancer. And I'd like to review those key recommendations that you mentioned for our listeners. So, Dr. Eng, starting with - for patients with previously untreated, initially unresectable metastatic colorectal cancer, who are candidates for chemotherapy plus bevacizumab, is doublet or triplet cytotoxic chemotherapy recommended? Dr. Cathy Eng: For treatment-naive patients, bevacizumab has been approved, and we do agree that it's a very reasonable treatment option with doublet or triplet therapy for our patient population. Obviously, these are guidelines, and it's extremely important to keep in mind that as a provider, you need to discuss the potential side effects with the patient. With bevacizumab, you know, standard concerns must be discussed with the patient, especially in regards to wound healing, if they've had recent surgery or any potential risk factors for a recent cardiac event from a recent thrombosis. So, those things obviously, would preclude the patient from initiating treatment with bevacizumab. But currently, doublet therapy or triplet therapy could be a potential option for patients. Brittany Harvey: Great. And yes, as you mentioned, shared decision-making is paramount to these decisions. So then following that recommendation, Dr. Morris, which patients should be offered pembrolizumab in the first-line setting? Dr. Van Morris: Yeah. So, I think that this represents really one of the exciting advances in the treatment of metastatic colorectal cancer over the past several years. We have great data now that suggests for patients with microsatellite instability-high metastatic colorectal cancer, especially who have not had any prior treatment, we would recommend use of immune checkpoint blockade therapies, really coming from the seminal KEYNOTE-177 trial. This was a phase III international trial that looked at patients with advanced unresectable or metastatic colorectal cancer. And patients were either randomized to pembrolizumab monotherapy, or cytotoxic chemotherapy with FOLFOX, with or without bevacizumab. And this trial did meet its primary endpoint and showed an improvement in progression-free survival, with use of pembrolizumab as a single agent relative to cytotoxic chemotherapy. And based on this trial and the clear benefit that we see in patients with pembrolizumab, the FDA has approved this as an option for patients with MSI-high untreated metastatic colorectal cancer. There are other trials which have looked at use of immunotherapy; the CheckMate 142 trial looked at combination PD-1 CTLA-4 therapy as a single-arm study. And, you know, there's another trial, the CheckMate 8HW, which is looking at one versus two immunotherapy agents in this setting as well. But really, as it stands for now, patients with MSI-high untreated metastatic colorectal cancer are the ones who benefit from the use of immunotherapy. One of the questions that we often get in talking with other clinical oncologists is the FDA approval for pembrolizumab in any cancer type for a TMB, tumor mutation burden, greater than 10. And, we talked about this with our panel in this context, and we don't see that patients with microsatellite-stable metastatic colorectal cancer, who have a tumor mutation burden over 10 benefit from use of immunotherapy. There is one exception to this for patients who harbor pathogenic POLE or POLD1 mutations, these patients oftentimes do experience sustained clinical benefit with immunotherapy. But in general, patients with microsatellite-stable metastatic colorectal cancer, who don't have POLE/POLD1 mutations, we don't favor use of immunotherapy in that context at this point in time. Brittany Harvey: Great. Thank you for reviewing that recommendation and the data behind who benefits and who doesn't benefit from immunotherapy in this setting. So then following that, the next question that this guideline addressed is for treatment-naive RAS-wild type metastatic colorectal cancer. So, for these patients, Dr. Eng, is anti-EGFR therapy recommended for patients with right or left sided primary tumors? Dr. Cathy Eng: That is such an important question, and thank you for asking this. We know based upon pivotal data from CALGB/SWOG 80405, that right-sided tumors treatment-naive, even if they're RAS-wild type, these patients should not receive anti-EGFR therapy. But also, we've learned from 80405, FIRE-3, and PEAK, which was a phase two study, that there appeared to be some benefit versus anti-VEGF therapy for left-sided tumors based upon studies that have been conducted. So, at this year's ASCO, actually, the PARADIGM trial was specifically a phase III trial, more focused on left-sided tumors. It was amended twice before it decided to focus on the left-sided patient population. And it was a phase III study where patients were randomized to FOLFOX plus panitumumab versus FOLFOX and bevacizumab. And the primary endpoint was overall survival. And we added this data to our guidelines. This data just came out, hot off the presses in June, at this year's ASCO. And the primary endpoint was fulfilled. And basically, it prospectively demonstrated that the data from the other three trials, based upon a pooled analysis, suggested left-sided tumors fare better with anti-EGFR therapy. And in fact, the PARADIGM trial basically validated those findings. Obviously, the PARADIGM trial just recently presented, we have not seen the final publication, we do not know much about the maintenance setting, but specifically, when thinking about anti-EGFR therapy, it is very reasonable to consider it in a left-sided tumor, all RAS-wild type patient population. I would like to mention though, and we do highlight this also in the guidelines, which is critically important, is that there was another study, which is a phase III trial called, TRIPLETE, that was presented as well, looking at FOLFOXIRI plus panitumumab versus basically, standard treatment. And what it noted is that there is no additional benefit for FOLFOXIRI plus panitumumab in left-sided tumors in regards to response or progression-free survival, there was no additional benefit. So, FOLFOX plus panitumumab seems very reasonable, FOLFOXIRI plus panitumumab is not necessarily needed in left-sided tumors. Brittany Harvey: Great. Thank you for that explanation, and also for the work of the panel to rapidly include this new information recently presented at ASCO. So then following those recommendations, Dr. Morris, what recommen
