Big potential for small molecule drugs in cancer treatment

With recent recommendation of Takeda’s fruquintinib by the European Medicines Agency (EMA), EPR spoke to Dr Sebastian Stintzing, Professor of Medicine, Head of the Department of Hematology, Oncology, and Tumor Immunology (CCM) of The Charité University Hospital in Berlin and investigator on the FRESCO-2 trial, to find out more about the potential of small molecule drugs in shaping future cancer treatment.

Small molecule drugs fruquintinib

Small molecule drugs have been a critical part of the pharmaceutical toolbox for over a century. Most can be taken orally and pass through cell membranes to reach intercellular targets, however, recent advancements in areas such as AI and machine learning have seen the potential for new small molecule-based therapeutics grow exponentially. One example of this is Takeda’s small molecule drug, fruquintinib, which has been shown to be an effective treatment for heavily pretreated metastatic colorectal cancer (mCRC).1

The highly selective tyrosine kinase inhibitor is taken orally and works on all three vascular endothelial growth factors – VEGFR 1-2-3, blocking the angiogenesis process to slow tumour growth.

Two Phase III trials, FRESCO and FRESCO-2, have studied fruquintinib. Results of the FRESCO-2 trial showed that median overall survival was 7.4 months in the fruquintinib group versus 4.8 months in the placebo group.2

Potential of fruquintinib in colorectal cancer 

Thanks to these positive results in May this year, the treatment was recommended for marketing authorisation by European Medicines Agency (EMA) for mCRC,3 which subject to approval, would add a new line in treatment for patients who have exhausted other options.

“One big difference to many other treatment options in colorectal cancer is that fruqintinib is a small molecule and… it is a non-chemotherapeutic treatment option… It increases our options in the treatment of metastatic colorectal cancer”

“One big difference to many other treatment options in colorectal cancer is that fruqintinib is a small molecule and, as a pure anti-angiogenic substance, it is a non-chemotherapeutic treatment option. [This is] important for patients that have been treated for a longer time with chemotherapeutic substances. It is well tolerated and…increases our options in the treatment of metastatic colorectal cancer”, explained Stintzing.

The potential of combining fruquintinib with other treatments is also being explored for other types of cancer. “There’s already a Phase III study for gastric cancer showing positive results for the combination of paclitaxel and fruqintinib. Other tumours such as lung cancer are already explored, but results are pending. With the good toxicity profile of fruqintinib [and] the easy oral administration [in the future we could] see…combinations of fruquintinib, plus either chemotherapeutic substances, target treatment options [or] immunoncology”, Stintzing continued.

Investigating the potential of small molecule drugs

Fruquintinib and other immunoncology therapies

However, results are not clear cut as there is still need for more research into the exact mechanism and interaction of small molecule drugs and the immune system. Stintzing pointed out that the anti-angiogenic drug bevacizumab in combination with immunoncology has shown efficacy, while immune checkpoint inhibition, plus small molecules such as cabozantinib, have not been so successful. He emphasised that “we need to have a more in depth understanding on what is actually done by those small molecules with respect to the…immunogenic pattern of a tumour.”

Stintzing believed that small molecule drugs in combination with other treatments give us real hope. We could see a more precise and personalised approach to cancer treatment”

Looking to the future, Stintzing believed that small molecule drugs in combination with other treatments give us real hope. We could see a more precise and personalised approach to cancer treatment. “In an ideal world, we would be able to not only treat entities like colorectal or lung cancer, but also have a deeper look into the individual cancer of our patients. [Giving us an understanding of] what are the key compounds that need to be inhibited by a combined approach to really have a high efficacy with less toxicity”, he anticipated.

An example of this is the KRAS-G12C inhibitors for G12 mutant colorectal cancer. “[This] is very efficacious in combination with an anti-EGFR antibody and panitumumab or cetuximab. I think this is something that gives us hope and…in the future we will see more of those,” theorised Stintzing. This is particularly exciting as there has not been much progress made on KRAS-mutant mCRC in decades, but with the advent of new small molecule drugs to use in combination with a range of other therapies there could be a brighter future ahead for many hard-to-treat cancers.

About the interviewee

Dr Sebastian Stintzing (Charité University Hospital)Dr Sebastian Stintzing is Professor of Medicine and Head of the Division of Haematology, Oncology, and Cancer Immunology (CCM), Department of Medicine, at The Charité University Hospital in Berlin.  He is an investigator on the FRESCO-2 trial. Professor Stintzing is a member of several national and international cancer associations and is a member of the steering committee of the working group ‘Colorectal Carcinoma’ of the German AIO (Arbeitsgemeinschaft Internistische Onkologie). He coordinates several multicentre and international investigator-initiated studies.

Sebastian Stintzing received his medical degree from the Friedrich–Alexander University Erlangen– Nürnberg, Germany. He earned his postdoctoral lecture qualification with a thesis on prognostic and predictive factors in the treatment of metastatic colorectal cancer.



  1. Stucchi E, Bartolini M, Airoldi M, et al. Fruquintinib as new treatment option in metastatic colorectal cancer patients: is there an optimal sequence? Expert Opinion on Pharmacotherapy. 2024; 25(4), 371–382.
  2. Arvind Dasari, Sara Lonardi, Rocio Garcia-Carbonero, et al. Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 study. The Lancet. 2023; 402(10395), 41-53.
  3. EMA Recommends Granting a Marketing Authorisation for Fruquintinib [Internet]. [cited 2024June]. Available from:

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