New, highly selective inhibitor of FGFR2 driver alterations and resistance mutations

RLY-4008 is a highly selective, irreversible inhibitor targeting oncogenic FGFR2 driver alterations and showing clinical activity in patients with FGFR inhibitor-naïve cholangiocarcinoma (CCA) harbouring an FGFR2 fusion or rearrangement, results from REFOCUS showed.

CCA is a rare malignancy with a dismal prognosis; the median overall survival with first-line chemotherapy is approximately 1 year [1]. FGFR2 fusions or rearrangements drive 10–15% of intrahepatic CCR [2]. RLY-4008 is a highly selective FGFR2 inhibitor (FGFR2i) and has potent in-vivo activity against FGFR2 inhibitor-sensitive and resistant CCR [3]. The phase 1/2 REFOCUS trial (NCT04526106) enrolled patients with advanced solid tumours harbouring an FGFR2 alteration who received RLY-4008. Prof. Antoine Hollebecque (Institut Gustave Roussy, France) reported the results [4].

The successful phase 1 of the REFOCUS trial resulted in a recommended phase 2 dose of 70 mg every day. 38 patients with FGFR inhibitor-naïve CCA were treated with RLY-4008 in phase 1 (n=21) or phase 2 (n=17). Key objectives were investigator-assessed overall response rate (ORR) per RECIST v1.1, duration of response (DOR), and safety. The radiographic ORR was 63.2% (all partial responses). The radiographic ORR in patients treated with 70 mg was 88.2% (all partial responses; see Figure). The median time to response was 1.8 months.

The most common treatment-related adverse events (all grades) were stomatitis (42%), nail toxicities (43%), palmar-plantar erythrodysesthesia syndrome (35%), and alopecia (26%). The most common grade ≥3 treatment-related adverse event was stomatitis (8%). Interruption of treatment occurred in 42% of patients, reduction in 27% of patients, and discontinuation in 1% of patients.

Based on these results, Prof. Hollebecque resolved that “RLY-4008 is the first highly selective, irreversible inhibitor designed to target oncogenic FGFR2 driver alterations and resistance mutations. REFOCUS validates this novel mode of action and supports expedited development for treating patients with FGFR inhibitor-naïve CCA harbouring an FGFR2 fusion or rearrangement.”

1. Valle J, et al. N Engl J Med. 2010;362:1273–1281.
2. Jusakul A, et al. Cancer Discov. 2017;7(10):1116–1135.
3. Casalleto J, et al. Cancer Res. 2021;81(13_Supplement):1455.
4. Hollebecque A, et al. Efficacy of RLY-4008, a highly selective FGFR2 inhibitor in patients (pts) with an FGFR2-fusion or rearrangement (f/r), FGFR inhibitor (FGFRi)-naïve cholangiocarcinoma (CCA): ReFocus trial. Abstract LBA12, ESMO Congress 2022, 09–13 September, Paris, France.

Figure: Radiographic tumour regression and response upon RLY-4008 administration to patients with advanced solid tumours harbouring an FGFR2 alteration [4].



RPD2, recommended phase 2 dose. QD, once daily dosing. BOR, best overall response. PR, partial response. PD, progressive disease. SD, stable disease. uPR, unconfirmed partial response.

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Posted on 16 November 202222 February 2024