Summary: expected outcomes and the benchmarks they are measured against

In the 116 FGFR inhibitor-naive participants of the REFOCUS pivotal cohort, the FDA reports an objective response rate of 46% (95% CI 36 to 55) by independent review and a median duration of response of 11.8 months (95% CI 7.5 to 13.0). The manufacturer reports median progression-free survival of 11.3 months (95% CI 9.2 to 14.8) with a 12-month rate of 49.2%, and the congress report of the same cohort gives median overall survival of 22.8 months (95% CI 17.3 to 27.2) with a 12-month rate of 74.6%, responses lasting more than 6 months in 76.2% of responders, treatment-related dose reductions in 75.9%, and discontinuation for treatment-related adverse events in 4.3%.

These values come from a single-arm trial and are read against cross-trial benchmarks: pemigatinib, objective response rate 37.0%, median progression-free survival 7.0 months, and median overall survival 17.5 months (FIGHT-202 final analysis); futibatinib, 42%, 9.0 months, and 21.7 months (FOENIX-CCA2); and FOLFOX in unselected second-line biliary tract cancer, 5%, 4.0 months, and 6.2 months (ABC-06). In routine care, median overall survival among 221 United States participants who initiated pemigatinib was 15.9 months, and in a Canadian patient support program median real-world progression-free survival with pemigatinib was 12.1 months. Quality of life was stable over 9.0 months of futibatinib in FOENIX-CCA2; no quality-of-life result for lirafugratinib was identified in the cited sources.

Response, duration of response, and progression-free survival supporting approval

“The major efficacy outcome measures were objective response rate (ORR) and duration of response (DOR) as determined by an independent review committee according to RECIST v1.1. ORR was 46% (95% CI: 36, 55) and median DOR was 11.8 months (95% CI: 7.5, 13.0).” (opens the source at this quote in a new tab)

“Median progression-free survival was 11.3 months (95% CI, 9.2, 14.8), with a 12-month rate of 49.2%.” (opens the source at this quote in a new tab)
“Its safety profile in the clinical data was shown to be predictable and manageable through dose adjustments.” (opens the source at this quote in a new tab)

Lirafugratinib: ReFocus pivotal cohort in FGFR inhibitor-naive cholangiocarcinoma

“Pivotal cohort of patients (n=116) with advanced/metastatic CCA harboring FGFR2 f/r previously treated with ≥1 systemic therapy and FGFRi-naive were treated with oral lirafugratinib 70 mg once daily until disease progression or unacceptable toxicity.” (opens the source at this quote in a new tab)
“Median age 57 years with 61.4% female.” (opens the source at this quote in a new tab)
“IRC-assessed ORR was 47%, and median DOR was 11.8 months (mos) (95% CI, 7.5-13.0), where 76.2% of responses lasted >6 mos. Median PFS was 11.3 mos (95% CI, 9.2, 14.8), with 12-month rate of 49.2%. Median OS was 22.8 mos (95% CI, 17.3-27.2), with 12-month rate of 74.6%.” (opens the source at this quote in a new tab)
“Common grade ≥3 on-target, off-tumor treatment-related adverse events (TRAEs) included palmar-plantar erythrodysesthesia (32.8%) and stomatitis (12.1%). TRAEs led to dose reductions of 75.9%, dose interruption of 82.8%, and treatment discontinuation of 4.3%.” (opens the source at this quote in a new tab)

Real-world pemigatinib outcomes: US claims analysis

“Overall, 221 patients with CCA were included (median age 57 years); 90.5% had iCCA, and the population was racially diverse. The most common baseline regimen was gemcitabine + cisplatin (34.4%). Most patients (86.9%) initiated pemigatinib at the recommended dose (13.5 mg). During observation, 47.1% of patients discontinued pemigatinib; median [95% confidence interval (CI)] time to discontinuation was 7.0 (6.1-9.7) months. During 6-month follow-up, 68.4% of patients had a medication possession ratio ≥0.8. Median (95% CI) OS was 15.9 (13.4-23.2) months.” (opens the source at this quote in a new tab)

Real-world pemigatinib outcomes: Canadian patient support program

“The median follow-up time on pemigatinib was 12.6 (range: 2.3–28.4) months, and their median real-world progression-free survival (rwPFS) was 12.1 months (95% CI 7.2-NR). The physician-assessed objective response and disease control rates were 56% and 89%, respectively. For the nine patients who discontinued pemigatinib, the median treatment duration was 10.6 months (range: 0.8–21.7). Disease progression was the most common reason for discontinuation (89%). None discontinued due to adverse events.” (opens the source at this quote in a new tab)

Benchmarks for response and survival with second-line chemotherapy

“The combinations of therapeutics used in this setting, which are not labeled for this indication, generally have an ORR of ~5% or less and patients face a median overall survival of approximately six months.” (opens the source at this quote in a new tab)

“Overall survival was significantly longer in the ASC plus FOLFOX group than in the ASC alone group, with a median overall survival of 6·2 months (95% CI 5·4–7·6) in the ASC plus FOLFOX group versus 5·3 months (4·1–5·8) in the ASC alone group (adjusted hazard ratio 0·69 [95% CI 0·50–0·97]; p=0·031).” (opens the source at this quote in a new tab)
“Objective response was observed in four (5%) of 81 patients in the ASC plus FOLFOX group: one (1%) patient had a complete response and three (4%) patients had a partial response.” (opens the source at this quote in a new tab)

“second-line FOLFOX resulted in a median progression-free survival of 4·0 months (95% CI 3·2–5·0), a median overall survival of 6·2 months (95% CI 5·4–7·6), and an objective response rate of 5%.” (opens the source at this quote in a new tab)

Lirafugratinib (Lyrfigtu)

Expected outcomes of therapy