Basilea reports interim results from phase 1/2 study FIDES-02 exploring derazantinib in patients with advanced urothelial cancer

• Successful completion of phase 1b part of FIDES-02 exploring the safety and tolerability of combining derazantinib with PD-L1 checkpoint inhibitor atezolizumab
• Recommended phase 2 dose for the combination established at full standard doses of derazantinib and atezolizumab
• Phase 2 expansion substudies exploring derazantinib and atezolizumab combination in urothelial cancer patients now open for enrolment

Basel, Switzerland, October 13, 2020

Basilea Pharmaceutica Ltd. (SIX: BSLN) announced today interim results from the phase 1b part of the ongoing phase 1/2 study FIDES-02. The study is evaluating its fibroblast growth factor receptor (FGFR) inhibitor, derazantinib, as single agent and in combination with Roche’s PD-L1 checkpoint inhibitor, atezolizumab, in patients with advanced urothelial cancer and FGFR genetic aberrations.¹ The Recommended Phase 2 Dose (RP2D) for the combination has been determined and phase 2 expansion substudies are now open for enrolment. The phase 2 substudies include patients with FGFR-positive advanced urothelial cancer receiving treatment with derazantinib alone or in combination with atezolizumab as first-line therapy or after progression on prior FGFR-inhibitor therapy.

Based on a safety analysis conducted for 26 patients who received increasing doses of derazantinib and atezolizumab, the Independent Data Monitoring Committee for the study determined that derazantinib and atezolizumab can be safely combined at doses of 300 mg of daily oral derazantinib and 1200 mg atezolizumab, administered intravenously once every three weeks. This RP2D corresponds to the derazantinib monotherapy dose used in the phase 2 study FIDES-01 and the standard dose for atezolizumab as a single agent in urothelial cancer. There were no dose-limiting toxicities observed. The most frequent reported adverse events were asthenia (weakness) or fatigue, nausea and diarrhoea.

Derazantinib inhibits FGFR1-3 kinases, which are key drivers of cell proliferation, differentiation and migration. In-vitro data show that it also inhibits the colony-stimulating-factor-1-receptor (CSF1R) kinase and thus has the potential to enhance the response to atezolizumab’s PD-L1 checkpoint inhibition, as CSF1R-inhibition has been shown to improve the susceptibility to PD-1/PD-L1 inhibitors, in preclinical models.²

Dr. Marc Engelhardt, Basilea’s Chief Medical Officer, said: “Our development strategy for derazantinib is focused on strengthening the clinical evidence on its differentiation versus other FGFR inhibitors, based on its unique kinase inhibition spectrum and safety and tolerability profile. The interim results from the FIDES-02 study support the safety profile of derazantinib in combination with atezolizumab, and the ability to combine the two treatments at full standard doses is particularly encouraging. We have now moved to the next important step in the development of derazantinib, by exploring potential synergies of derazantinib and atezolizumab in our ongoing clinical study in patients with advanced urothelial cancer.”

About derazantinib

Derazantinib is an investigational orally administered small-molecule FGFR inhibitor with strong activity against FGFR1, 2, and 3.³ FGFR kinases are key drivers of cell proliferation, differentiation and migration. FGFR genetic aberrations, e.g. gene fusions, mutations or amplifications, have been identified as potentially important therapeutic targets for various cancers, including intrahepatic cholangiocarcinoma (iCCA), urothelial, breast, gastric and lung cancers.⁴ In these cancers, FGFR genetic aberrations are found in a range of 5% to 30%.⁵
Derazantinib also inhibits the colony-stimulating-factor-1-receptor (CSF1R) kinase.^{3, 6} CSF1R-mediated signaling is important for the maintenance of tumor-promoting macrophages and therefore has been identified as a potential target for anti-cancer drugs.⁷ Preclinical data has shown that tumor macrophage depletion through CSF1R blockade renders tumors more responsive to T-cell checkpoint immunotherapy, including approaches targeting PD-1/PD-L1.^8, 9
Derazantinib has demonstrated antitumor activity and a manageable safety profile in a previous biomarker-driven phase 1/2 study in iCCA patients,¹⁰ and has received U.S. and EU orphan drug designation for iCCA. Basilea is currently conducting three clinical studies with derazantinib. The first study, FIDES-01, is a registrational phase 2 study in patients with inoperable or advanced iCCA. It comprises one cohort of patients with FGFR2 gene fusions and another cohort of patients with mutations or amplifications.¹¹ The second study, FIDES-02, is a phase 1/2 study evaluating derazantinib alone and in combination with Roche's PD-L1-blocking immune-checkpoint inhibitor, atezolizumab, in patients with advanced urothelial cancer, including metastatic, or recurrent surgically unresectable disease, expressing FGFR genetic aberrations.¹ The third study, FIDES-03, is a phase 1/2 study evaluating derazantinib alone and in combination with other cancer treatments, for instance with Roche’s PD-L1 checkpoint inhibitor, atezolizumab, in patients with advanced gastric cancer with FGFR genetic aberrations. Basilea in-licensed derazantinib from ArQule Inc., a wholly-owned subsidiary of Merck & Co., Inc., Kenilworth, N.J., U.S.A.

About Basilea

Basilea Pharmaceutica Ltd. is a commercial-stage biopharmaceutical company, focused on the development of products that address the medical challenges in the therapeutic areas of oncology and infectious diseases. With two commercialized drugs, the company is committed to discovering, developing and commercializing innovative pharmaceutical products to meet the medical needs of patients with serious and life-threatening conditions. Basilea Pharmaceutica Ltd. is headquartered in Basel, Switzerland and listed on the SIX Swiss Exchange (SIX: BSLN). Additional information can be found at Basilea's website www.basilea.com.

Disclaimer

This communication expressly or implicitly contains certain forward-looking statements, such as "believe", "assume", "expect", "forecast", "project", "may", "could", "might", "will" or similar expressions concerning Basilea Pharmaceutica Ltd. and its business, including with respect to the progress, timing and completion of research, development and clinical studies for product candidates. Such statements involve certain known and unknown risks, uncertainties and other factors, which could cause the actual results, financial condition, performance or achievements of Basilea Pharmaceutica Ltd. to be materially different from any future results, performance or achievements expressed or implied by such forward-looking statements. Basilea Pharmaceutica Ltd. is providing this communication as of this date and does not undertake to update any forward-looking statements contained herein as a result of new information, future events or otherwise. Derazantinib and its uses are investigational and have not been approved by a regulatory authority for any use. Efficacy and safety have not been established. The information presented should not be construed as a recommendation for use. The relevance of findings in nonclinical/preclinical studies to humans is currently being evaluated.

For further information, please contact:

Peer Nils Schröder, PhD Head of Corporate Communications & Investor Relations
Phone	+41 61 606 1102
E-mail	media_relations@basilea.com investor_relations@basilea.com

This press release can be downloaded from www.basilea.com.

References

1. A. Chaudhry, C.N. Sternberg, M. de Santis et al. FIDES-02: a phase 1b/2 study of derazantinib as monotherapy and combination therapy with atezolizumab in patients with surgically unresectable or metastatic urothelial cancer and FGFR genetic aberrations Journal of Clinical Oncology 2020; 38, no. 6_suppl. TPS590. ClinicalTrials.gov identifier: NCT04045613
2. X. Zheng, K. Turkowski, J. Mora et al. Redirecting tumor-associated macrophages to become tumoricidal effectors as a novel strategy for cancer therapy. Oncotarget. 2017;8(29):48436-48452
3. T. G. Hall, Y. Yu, S. Eathiraj et al. Preclinical activity of ARQ 087, a novel inhibitor targeting FGFR dysregulation. PLoS ONE 2016, 11 (9), e0162594
4. R. Porta, R. Borea, A. Coelho et al. FGFR a promising druggable target in cancer: Molecular biology and new drugs. Critical Reviews in Oncology/Hematology 2017 (113), 256-267
5. T. Helsten, S. Elkin, E. Arthur et al. The FGFR landscape in cancer: Analysis of 4,853 tumors by next-generation sequencing. Clinical Cancer Research 2016 (22), 259-267
6. P. McSheehy, F. Bachmann, N. Forster-Gross et al. Derazantinib (DZB): A dual FGFR/CSF1R-inhibitor active in PDX-models of urothelial cancer. Molecular Cancer Therapeutics 2019 (18), 12 supplement, pp. LB-C12
7. M. A. Cannarile, M. Weisser, W. Jacob et al. Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy. Journal for ImmunoTherapy of Cancer 2017, 5:53
8. Y. Zhu, B. L. Knolhoff, M. A. Meyer et al. CSF1/CSF1R Blockade reprograms tumor-infiltrating macrophages and improves response to T cell checkpoint immunotherapy in pancreatic cancer models. Cancer Research 2014 (74), 5057-5069
9. E. Peranzoni, J. Lemoine, L. Vimeux et al. Macrophages impede CD8 T cells from reaching tumor cells and limit the efficacy of anti–PD-1 treatment. Proceedings of the National Academy of Science of the United States of America 2018 (115), E4041-E4050
10. V. Mazzaferro, B. F. El-Rayes, M. Droz dit Busset et al. Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma. British Journal of Cancer 2019 (120), 165-171. ClinicalTrials.gov identifier: NCT01752920
11. FIDES-01: ClinicalTrials.gov identifier: NCT03230318

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