FDA Approval of Fruquintinib Expands Later-Line Treatment Options in mCRC


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John Lindsay Marshall, MD, sheds light on the significance of the FDA approval of fruquintinib for patients with heavily pretreated metastatic colorectal cancer and discusses the efficacy and safety data from the FRESCO and FRESCO-2 trials that supported the decision in this population.

John Lindsay Marshall, MD

John Lindsay Marshall, MD

The recent FDA approval of fruquintinib (Fruzaqla) in patients with metastatic colorectal cancer (CRC) provides those who have exhausted many other prior therapies with an effective and safe treatment option in the third or fourth line, according to John Lindsay Marshall, MD. He added that next steps will likely consist of exploring this agent in combination regimens within this highly heterogeneous disease.

On November 8, 2023, fruquintinib received approval from the FDA for the treatment of adult patients with mCRCwho were previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; a VEGF inhibitor; and an EGFR inhibitor if deemed medically appropriate for those with RAS wild-type disease.1 The regulatory decision was based on findings from the phase 3 FRESCO-2 (NCT04322539) and Chinese FRESCO (NCT02314819) trials.2

In FRESCO-2, patients who received fruquintinib plus best supportive care (BSC; n = 461) experienced a median overall survival (OS) of 7.4 months (95% CI, 6.7-8.2) compared with 4.8 months (95% CI, 4.0-5.8) with placebo plus BSC (n = 230; HR, 0.66; 95% CI, 0.55-0.80; P < .001). Additionally, the median progression-free survival (PFS) was 3.7 months (95% CI, 3.5-3.8) with the fruquintinib regimen vs 1.8 months (95% CI, 1.8-1.9) with the placebo regimen (HR, 0.32; 95% CI, 0.27-0.39; P < .001).

These data confirmed the clinical activity seen with fruquintinib in the original FRESCO trial. Here, patients who received fruquintinib plus BSC (n = 278) had a median OS of 9.3 months (95% CI, 8.2-10.5) and a median PFS of 3.7 months (95% CI, 3.7-4.6) vs a median OS of 6.6 months (95% CI, 5.9-8.1) and a median PFS of 1.8 months (95% CI, 1.8-1.8), respectively, with placebo plus BSC (n = 138).

“[Overall], we’re excited to hear about fruquintinib’s approval, and we think it’s going to play an important role in the management of patients with mCRC,” said Marshall, who is chief of Hematology and Oncology, professor of medicine and oncology, and director of the Otto J. Ruesch Center for the Cure of Gastrointestinal Cancers at the Lombardi Comprehensive Cancer Center of Georgetown University in Washington, D.C.

In an interview with OncLive®, Marshall shed light on the significance of the fruquintinib approval for patients with heavily pretreated mCRC, reported the efficacy and safety data from the FRESCO and FRESCO-2 trials that supported the decision in this population, and described the potential role for this agent as a bridging therapy in later lines and as a second maintenance therapy.

OncLive: What is the significance of the FDA approval of fruquintinib for the treatment of patients with mCRC?

Marshall: We’ve had many therapies come forward and attempt to move the bar in CRC in this “refractory” setting. We have had trifluridine/tipiracil [TAS-102; Lonsurf] and we have had regorafenib [Stivarga]. The newer data from the phase 3 SUNLIGHT trial [NCT04737187] of TAS-102 plus bevacizumab [Avastin] was positive. Right on the heels of that, we have this new VEGF inhibitor called fruquintinib. Compared with a placebo control, [fruquintinib] demonstrated a significant improvement in OS, and [its approval] has a major positive impact for our patients with metastatic disease.

What is unique about the mechanism of action of fruquintinib?

Fruquintinib is a novel oral TKI; it targets and blocks all 3 VEGF receptors. If you think about all the VEGF inhibition we give in CRC, we mostly use bevacizumab, which is binding to the ligand to prevent the [cell from] signaling to the receptor. [Fruquintinib] works through a different mechanism. It proves that VEGF inhibition is a critical pathway in CRC, because almost all patients on this clinical trial had received prior bevacizumab. [This is] showing that VEGF inhibition beyond progression [has] a positive impact.

What key efficacy findings reported from the FRESCO and FRESCO-2 trials supported the approval of the agent?

The FRESCO-2 trial shows us a couple of important things. One, VEGF inhibition by itself doesn’t [elicit] many responses; that’s not what we’re going for here. We’re looking for stable disease bridging to the next therapy and adding time. We saw a lot of patients with disease control. What was impressive about the data, and what I always look at, is where that PFS curve came off. [According to] the clinical trial results, it came off above 50%, so more than half of the patients who received this drug had some element of disease control that lasted a clinically significant amount of time. Those 2 key elements, OS and PFS, were significantly positive in this patient population.

The original [FRESCO] study was done exclusively in China. For all of us, we like to see that sort of confirmatory trial. FRESCO and FRESCO-2 go together in many ways, and they demonstrate very similar outcomes. However, the one done in China is more representative of our kind of patient population. The reality is that they look very similar. To me, [the FRESCO-2 study] is validating the data that were initially shown in the Chinese population.

What should be known about the safety profile of fruquintinib according to these studies?

The drug’s [safety profile is] what you would expect from a VEGF inhibitor. You have the hypertension, some fatigue, and some hand-foot syndrome that goes along with it. Even though it’s an oral [agent involving] VEGF inhibition, you need to know about the adverse effects [AEs]. I have yet to give a dose of this medicine, as it has just become FDA approved. We’ll all be learning how best to manage the toxicities. [The drug has] acceptable toxicities, but still ones that we will need to manage.

Going forward, how might fruquintinib fit into the current CRC treatment paradigm?

When looking at the strategy of treating CRC, I like to [conceptualize] it is less about lines of therapy and more about the chess game, because you don’t always move the pieces in chess the same [way] every time. I think of a drug like fruquintinib as being a nice bridge or a stabilization factor. You could use this for patients in the third or fourth line, and that would be its sweet spot. However, you could also [potentially] use it as a second maintenance approach. [If] somebody received capecitabine and bevacizumab for maintenance in the first line, maybe TAS-102 and bevacizumab or fruquintinib could be maintenance in a later line of therapy.

I caution us all to avoid thinking that this medicine is going to catch somebody who is having a hard time with rapidly progressing cancer. This is directed more [toward patients] with a good performance status [who are] still doing their daily thing. We want something that’s going to be easy to administer and that will stabilize their cancer for a meaningful period.

As with any new medicine, we’re going to learn how to better use it and what the right scenarios are to use it in. We’ll also begin learning about combinations and other strategies with the medicine in other disease states.


  1. Takeda receives US FDA approval of FRUZAQLA™ (fruquintinib) for previously treated metastatic colorectal cancer. Takeda. News release. November 8, 2023. Accessed November 13, 2023. https://www.takeda.com/newsroom/newsreleases/2023/Takeda-Receives-US-FDA-Approval-of-FRUZAQLA-fruquintinib-for-Previously-Treated-Metastatic-Colorectal-Cancer/
  2. Fruquintinib (Fruzaqla). Prescribing information; Takeda Pharmaceuticals America, Inc.; Updated November 2023. Accessed November 13, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217564s000lbl.pdf
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