Translating Outcomes in Metastatic Colorectal Cancer (mCRC)

In this Precision Medicine Perspectives series, Translating Real-World Outcomes to Clinical Practice in mCRC, Tanios Bekaii-Saab, MD, Leader of the Gastrointestinal Cancer Program at the Mayo Clinic Comprehensive Cancer Center in Phoenix, AZ, outlines the therapeutic landscape of metastatic colorectal cancer and explores how recent real-world data will impact treatment paradigms.

Targeted Oncology™: Could you provide a brief overview of available treatment options in the mCRC space?

Dr Bekaii-Saab: The treatment landscape for patients with mCRC has evolved quite a bit over the last couple of decades. We went from having a single-agent modality to having several chemotherapeutic options, a number of biologics, and more and more precise targeted options. Also, the introduction of multiple oral agents, including chemotherapeutic and multi-kinase inhibitors, has expanded the likelihood of our patients [being able] to go through multiple lines of therapy and, ultimately, improve their outcomes. In the earlier lines, we have FOLFOX, FOLFIRI, or FOLFOXIRI with or without bevacizumab, with or without EGFR inhibitors, such as the cetuximab or panitumumab, using factors like KRAS and HER2 amplification to select patients who may not respond to EGFR inhibitors. More recently, [we’ve moved] into positive predictive biomarkers, picking patients based on MSI-high for immune therapy, BRAF V600E mutations, for BRAF-targeted therapies, HER2 amplifications for HER2-targeted strategies, such as to tucatinib, trastuzumab, and trastuzumab deruxtecan. Also, [there is an] emerging field [to target] KRAS G12C, with the availability of 2 agents, adagrasib and sotorasib, preferentially given with cetuximab or panitumumab in patients with mCRC. There are also small subsets [of patients] with NTRK fusions, RAS fusions, and other rare abnormalities [who] also have some...agents that are available [to treat them].

Before starting any treatment, [I order] a liquid biopsy circulating tumor DNA (ctDNA) assessment. Usually, within a week we will get results, with a caveat [that] this has high sensitivity and specificity, but you may still miss some targets. If it’s present in blood, it’s likely present in the tumor. If it’s not present in blood, it can still be present in the tumor. The liquid biopsy ctDNA gives me assurance that it [has] hit 80% to 90% of the targets, and then we await the tissue results. That usually takes 2 to 3 weeks.

Targeted Oncology: Regarding clinical progression and later lines of therapy, where does [the multi-kinase inhibitor] regorafenib fit into your treatment paradigm?

Dr Bekaii-Saab: We think about 15% to 20% of patients [with mCRC] have some targetable alterations. Those are the patients who would...receive a targeted therapy from the get-go, depending on availability of treatment or standard-of-care [treatment]. A patient with a BRAF V600E mutation or HER2 amplification, following failure of chemotherapy, would go [on] to either encorafenib plus cetuximab or tucatinib plus trastuzumab based on what alteration or amplification they have. For 80% to 85% of the patients, that is not an option. Unfortunately, for those patients [whose] primary chemotherapy [fails] in the first or second line, they will be unable to receive any further targeted option because there’s no target. Those are the patients who ultimately will go on 1 of 3 options. We have regorafenib, which is a multi-kinase inhibitor. We have TAS-102 and TAS-102 plus bevacizumab, [which] is approved for treating patients in the refractory setting. And fruquintinib was recently approved. Fruquintinib is another multi-kinase inhibitor, [but it is] a little bit different than regorafenib. It’s very potent for targeting VEGF and tends to be less toxic in that sense.

So overall, the landscape has become richer. These agents are all relevant options. Regorafenib was the first to be approved, close to a decade ago, in refractory mCRC [based on] the phase 3 CORRECT (NCT01103323) study that [evaluated] regorafenib at a dose of 160 mg daily, 3 weeks on and 1 week off, versus placebo. It was positive for all its primary end points. The problem was that the level of toxicity was significant at that 160-mg dose, significant enough to limit its use when this agent made it to the clinic.

We essentially looked at different dosing strategies. The phase 2, randomized [ReDOS] study (NCT02368886), [evaluated] regorafenib with a dose-escalation strategy, starting at 80 mg going to 120 mg then 160 mg, as tolerated, compared with the 160-mg dose. The primary end point was what percent of patients could [complete] 2 cycles and then move on to the third cycle, a measure that looked at efficacy and toxicity. The ReDOS strategy was superior to the standard strategy. Survival was improved, time to progression was a little bit better, and the quality of life of the patients was better. Toxicities were better with the dose-escalation strategy, and that [dose] was integrated in[to] the NCCN (National Comprehensive Cancer Network) guidelines.

Targeted Oncology: Looking at real-world outcomes recently presented at [the] European Society for Medical Oncology Congress 2023 (ESMO 2023), which data were most notable to you?

Dr Bekaii-Saab: The PROMETCO trial (NCT03935763), a real-world perspective, longitudinal cohort on the continuum of care, included about 738 patients from 18 countries and nearly half of those patients had RAS mutations. This study looked at what patients received in the first line, second line, and then beyond. As you would expect, almost 100% received fluoropyrimidine, nearly 80% received a VEGF inhibitor, and 40% an anti-EGFR. In this study, 75% of the patients received TAS-102 and 25% received regorafenib. Overall, [the study observed] survival [rates for] these patients after exposure to multiple lines of therapy. Previously, the survival was [about] 20-plus months. This study [found that] the survival for those patients who were evaluable for survival was 35.4 months. That tells us that in a real-world setting, exposing patients to all standard treatment options significantly improves their outcome.

There was another real-world, multicenter, retrospective analysis [that] looked at a sequential treatment of regorafenib and TAS-102 in [the] third line and beyond. It included a large number of patients (n=866) and, of those [patients], about 17% started with TAS-102 followed by regorafenib. Another 13% [of patients] were [given] the reverse sequence. About 37% of the patients had TAS-102 alone and 32% [had] regorafenib alone. This is a real-world analysis so it’s very difficult to control for all parameters that could be confounding, but this study showed [that] regorafenib followed by TAS-102 may be a better strategy in terms of survival and PFS [progression-free survival]. There were also some advantages in terms of the toxicities that you typically see by giving patients a break from a cytotoxic agent, such as [fewer instances of] neutropenia and less [frequent] use of G-CSF [granulocyte colony-stimulating factor].

[Another] study presented at ESMO 2023 looked at the impact of sequencing from the US perspective. This study [assessed] regorafenib and TAS-102, with a small proportion of patients actually being exposed to TAS-102 and bevacizumab, which is relevant today where we’re shifting from TAS-102 to TAS-102 with bevacizumab. This retrospective analysis [of] the Flatiron Health electronic health record–derived database, [included] 818 patients. [About half of the patients were treated with] regorafenib followed by TAS-102. [The other half] started with TAS-102 followed by regorafenib. Patient characteristics [were] relatively well balanced [in the cohorts]. There appeared to be, at least numerically, a little bit better [survival] with regorafenib followed by TAS-102 [versus] TAS-102 followed by regorafenib. It is important to note that these differences were not statistically significant, and the hazard ratio was 0.94. The time to discontinuation, which is a surrogate of time to tumor progression or time to treatment failure, was slightly longer. If you start with regorafenib followed by TAS-102 versus TAS-102 followed by regorafenib, it was 8.7 months versus 8.1 months. Again, this was not statistically significant.

Also, the frequency of neutropenia and use of GCSF were lower [in patients treated with] regorafenib followed by TAS-102 versus the opposite. The frequency of neutropenia was less than 40% with regorafenib followed by TAS-102 [versus] 50% with TAS-102 followed by regorafenib. GCSF use was about 14% with regorafenib followed by TAS-102 [versus] 18% with TAS-102 first then regorafenib. The hypothesis is that perhaps patients who are given a break from a cytotoxic agent like TAS-102 before initiating it, will have less need to use GCSF and [fewer instances of] neutropenia.

Another paper at ESMO looked at the prior use of anti-VEGF agents on overall survival in patients with refractory mCRC [who] ultimately went on to receive TAS-102 with or without bevacizumab. This paper was a post hoc analysis [of the phase 3 SUNLIGHT trial (NCT04737187)], [that analyzed] subgroups [of patients who] did not receive anti-VEGF [therapy or] who received anti-VEGF in the first line, in the second line, [or] in the first and the second line[s]. Although the study did not mandate prior anti-VEGF therapy, there were many patients who did not even receive it in the first line. [The study found that] the benefits of TAS-102 plus bevacizumab versus TAS-102 [monotherapy depends on] whether patients were exposed to prior anti-VEGF or not. However, the benefit seems to be highest if patients were not exposed to prior bevacizumab.

When we look at all these studies and the approvals in later lines of therapy, a theme continues to emerge that targeting VEGF is very important, even when patients are exposed to prior anti-VEGF therapy. So, whether it’s regorafenib, fruquintinib, or TAS-102 plus bevacizumab, all these options include VEGF inhibition.

Targeted Oncology: Could you speak to your recent publication [that discusses the] clinical effectiveness of treatment selection for mCRC?

Dr Bekaii-Saab: In [a] study recently published in Clinical Colorectal Cancer, [we] looked at a Markov model to estimate total cost and quality-adjusted life-years (QALYs). This study [evaluated] strategies in later lines of therapy, including regorafenib with the dose-optimization strategy, regorafenib at 160 mg, TAS-102, and TAS-102 with bevacizumab. There were [several] end points, including health-state utility values and incremental cost-effectiveness ratios (ICERs) to compare treatment outcomes. There were elements that clearly favored regorafenib with the dose-optimization strategy when looking at the benefit-to-toxicity ratio and relative cost-effectiveness measures. I think that’s very important in [the] world we live in where elements of cost-effectiveness [and] benefit-to-toxicity ratios are very important, especially when looking at strategies that appear to offer very similar outcomes when patients are exposed to the various treatment options.

Targeted Oncology: Looking at the FRESCO (NCT02314819) and FRESCO-2 (NCT04322539) trials, how do they differ in terms of US versus non-US patient populations?

Dr Bekaii-Saab: Fruquintinib is extremely interesting, and worthy of exploring in patients with mCRC who are refractory to other options. This agent is a highly selective and potent oral inhibitor of VEGF receptors 1, 2, and 3. The FRESCO [study], which was [done in] China, [evaluated] fruquintinib versus placebo, and led to the approval of fruquintinib in China. The confirmatory FRESCO-2 study [evaluated] fruquintinib versus placebo. FRESCO-2 was a very well-controlled study that [included] patients exposed to all standard therapies, including...TAS-102 and regorafenib. In fact, 100% of the patients received TAS-102 or regorafenib, and about 40% of the patients received both sequentially. Fruquintinib outperformed placebo, both for overall survival and PFS. The hazard ratio for PFS is one of the most significant I’ve seen across all the refractory studies in the setting. [The] toxicities of fruquintinib appear to be a little bit different than regorafenib. It [causes] more hypertension, because it’s much more of a potent VEGF inhibitor, but [fewer] hand-and-foot syndrome reactions due to less targeting [outside] VEGF.

The FRESCO study was interesting [in that] in China, there is less [agent] availability. As a result, there was less [frequent] pre-exposure to VEGF and EGFR inhibitors. And overall, at least with the survival rates, the numbers look a little bit better. In the patient population [in the western hemisphere], more patients were pretreated, and more [were] pre-exposed to biologics, such as anti-VEGF and anti-EGFR [agents]. And similar to what we’ve seen with the SUNLIGHT [trial],...patients who have less exposure to prior biologics, less exposure to prior anti-VEGF therapies, [and] less pre-exposure to anti-EGFR inhibitors tend to do better than those who have been exposed to all these agents before receiving these multi-kinase inhibitors. Realistically, in our practices in the US, [most] patients will be pre-exposed to all these biologics and chemotherapeutics before consideration of regorafenib or TAS-102, so the focus [will be]: How [will] we end up sequencing these agents? And again, this is where a lot of these real-world studies are helping us understand a little bit more [about] how to prioritize the different options in a way that essentially optimizes patients’ outcomes.