Summary: modifiers of FGFR inhibitor treatment effect

Prior FGFR inhibitor exposure is the largest reported modifier of lirafugratinib activity. In the ReFocus dose-escalation analysis, the objective response rate among participants with FGFR2 fusion or rearrangement-positive cholangiocarcinoma was 52% (13 of 25) without and 14% (7 of 50) with prior FGFR inhibitor therapy, with median duration of response of 8.2 and 5.6 months. Resistance mutations explain part of the difference: 28 of 46 pretreated participants evaluable by circulating tumour DNA had at least one baseline FGFR2 resistance mutation, and the proportion with such mutations rose from 1 of 6 without prior FGFR inhibitor to 5 of 12 after one and 6 of 7 after two or more. Acquired resistance to lirafugratinib differs from that to pan-FGFR inhibitors, with FGFR2 M538 or L618 mutations in 11 of 16 cases and receptor tyrosine kinase or MAPK bypass alterations in 9 of 16.

Co-occurring alterations modify outcome with approved FGFR inhibitors. In a real-world pemigatinib cohort, median progression-free survival was 4.79 versus 8.66 months with and without CDKN2A mutations and 5.97 versus 8.52 months with and without BAP1 mutations, without a difference in overall survival. With futibatinib, progression-free survival was shorter with CDKN2B alterations (4.8 versus 11.0 months), responses did not correlate with fusion partner, and response rates did not differ by TP53 status. With pemigatinib in FIGHT-202, participants with TP53 alterations (n = 9) had no objective responses and a median progression-free survival of 2.8 months vs 9.0 months, CDKN2A/B alterations were associated with shorter median progression-free survival (6.4 months vs 9.0 months), and response did not differ between rearrangements and predicted fusions (40.0% vs 34.8%) or between BICC1 and other partners. In an institutional series, TP53 and CDKN2A/B alterations were associated with shorter overall survival and BAP1 had no prognostic effect. By alteration type, FGFR fusions were associated with the most favourable FGFR inhibitor outcomes (objective response rate 45.9%), with median progression-free survival of 7.3 months, against 4.1 months for mutations and 2.1 months for amplifications. Within second-line chemotherapy, FOLFOX benefit in ABC-06 was independent of platinum sensitivity and the number of elevated tumour markers stratified survival. In first-line chemoimmunotherapy, the survival benefits of durvalumab in TOPAZ-1 were generally consistent across the subgroups analysed, including PD-L1 tumour area positivity of 1% or greater and of less than 1%.

Molecular covariates of response to futibatinib in FGFR2-altered disease

“Analysis of the molecular profile of the tumors in the 103 patients in the efficacy population indicated that responses did not correlate with FGFR2 fusion-partner status or co-occurring alterations in tumor-suppressor genes or oncogenes (Fig. 2).” (opens the source at this quote in a new tab)
“Numerical differences were noted with respect to median progression-free survival between patients with and those without CDKN2A (4.9 months and 9.7 months, respectively) and those with and those without CDKN2B alterations (4.8 months and 11.0 months).” (opens the source at this quote in a new tab)

Lirafugratinib: ReFocus dose escalation in FGFR inhibitor-naive and FGFR inhibitor-pretreated cholangiocarcinoma

“As of 30 Jan 23, 116 pts (82 f/r, 27 mutation, 6 amplification) received RLY-4008 at doses of 20-200 mg/day, including 91 with CCA. 50% had prior FGFRi, and median lines of prior therapies was 3 (1-15).” (opens the source at this quote in a new tab)
“28/46 ct-DNA-evaluable pts with CCA with prior FGFRi had ≥1 baseline resistance mutation, most commonly at FGFR2 N549X (23/46) or V564X (17/46).” (opens the source at this quote in a new tab)

Lirafugratinib: ReFocus dose escalation outcomes by prior FGFR inhibitor exposure

Outcome	FGFR inhibitor-naive cholangiocarcinoma with FGFR2 fusion or rearrangement (N = 25)	Prior FGFR inhibitor cholangiocarcinoma with FGFR2 fusion or rearrangement (N = 50)
Objective response rate, n (%) [95% CI]	“13 (52% [31.3%-72.2%])”	“7 (14% [5.8%-26.7%])”
Median duration of response, months (range)	“8.2 (1.9-18.6)”	“5.6 (1.9-7.4)”
Duration of response longer than 24 weeks	“10/13 (77%)”	“4/7 (57%)”
Response ongoing	“6/13 (46%)”	“2/7 (29%)”
Disease control rate, n (%)	“22 (88%)”	“40 (80%)”

Lirafugratinib: clinical activity after prior FGFR inhibitor therapy

“Importantly, lirafugratinib demonstrated clinical efficacy in the FGFR inhibitor-refractory setting, with ctDNA dynamics showing resolution of multiple FGFR2 mutations and persistence or emergence of others.” (opens the source at this quote in a new tab)

“In the pan-FGFRi–resistant setting, patient B had a confirmed PR to RLY-4008 following progression on infigratinib.” (opens the source at this quote in a new tab)

FGFR inhibitor-pretreated participants with baseline FGFR2 resistance mutations

“Of 25 FGFR2 fusion/rearrangement–positive cholangiocarcinoma patients evaluable by circulating tumor DNA (ctDNA), one of six (17%) FGFRi-naive patients, five of 12 (42%) patients with one previous line of pan-FGFRi therapy, and six of seven (86%) patients with two or more previous lines of pan-FGFRi therapy at their approved doses had FGFR2 kinase domain resistance mutations at baseline” (opens the source at this quote in a new tab)

Resistance mechanisms to lirafugratinib

“Polyclonal FGFR2 kinase domain mutations and receptor tyrosine kinase-mitogen activated protein kinase (RTK-MAPK) bypass alterations emerged as common lirafugratinib resistance mechanisms in the FGFR inhibitor-naive context (8/16 and 9/16 patients, respectively). Resistance profiles differed markedly from pan-FGFR inhibitors, with decreased FGFR2 V565F/L and N550H/K mutations, increased M538I and L618F mutations, and more frequent RTK-MAPK bypass alterations.” (opens the source at this quote in a new tab)

“Patients with acquired lirafugratinib resistance manifested an unprecedented emergence of FGFR2 mutations in the M538 and/or L618 residues of the kinase domain, documented in 11 of 16 cases (69%). Compared with futibatinib resistance, FGFR2 molecular brake (N550) and gatekeeper (V565) mutations were rare.” (opens the source at this quote in a new tab)

Co-occurring BAP1 and CDKN2A alterations and progression-free survival with pemigatinib

“Of 72 patients of PEMIREAL‐PEMIBIL, 63 patients had evaluable NGS data, with concomitant GAs identified in 28 patients (44.4%). The most frequently observed concomitant GAs involved BAP1 (7/63, 11.1%), CDKN2A (7/63, 11.1%), TP53 (6/63, 9.5%), CDKN2B (5/63, 7.9%), PTEN (3/63, 4.7%) and IDH1 (1/63, 1.5%). A significantly shorter PFS was observed in patients with CDKN2A mutations compared to CDKN2A wild‐type tumours (4.79 vs. 8.66 months, p = 0.0011, HR: 3.48 95% CI: 0.91–13.24), and similarly in patients with BAP1 mutations compared to BAP1 wild‐type tumours (5.97 vs. 8.52 months, p = 0.025, HR:2.55 95% CI: 0.72–9.00). No significant differences in OS were observed.” (opens the source at this quote in a new tab)

Co-occurring CDKN2B and TP53 alterations and outcomes with futibatinib

“Objective response rates on futibatinib were not significantly different between patients with TP53-altered versus -unaltered solid tumors; progression-free survival was reduced in patients with CDKN2B-altered versus -unaltered cholangiocarcinoma (median 4.8 versus 11.0 months; P = 0.03).” (opens the source at this quote in a new tab)

Futibatinib outcomes by baseline ctDNA co-alteration in FOENIX-CCA2

“In total, 93 patients from FOENIX-CCA2 with baseline ctDNA samples were included in this analysis. No individual gene alterations or lack of alterations correlated significantly with ORR (Table 2).” (opens the source at this quote in a new tab)

Molecular subgroup (n)	Objective response, n (%, 95% CI)	P value for objective response	Median PFS, months (95% CI)	P value for PFS
FGFR2 fusion/rearrangement (93)	“40 (43%, 33-53)”		“8.9 (6.6-13.1)”
BAP1 unaltered (53)	“26 (49%, 35-63)”	“0.2”	“8.0 (4.9-13.8)”	“0.7”
BAP1 altered (40)	“14 (35%, 21-52)”		“9.0 (5.1-13.3)”
CDKN2A unaltered (73)	“32 (44%, 32-56)”	“0.8”	“9.7 (6.9-13.8)”	“0.2”
CDKN2A altered (20)	“8 (40%, 19-64)”		“4.9 (3.4-13.3)”
CDKN2B unaltered (77)	“33 (43%, 32-55)”	“1.0”	“11.0 (7.2-15.1)”	“0.03”
CDKN2B altered (16)	“7 (44%, 20-70)”		“4.8 (3.4-4.9)”
TP53 unaltered (80)	“35 (44%, 33-55)”	“0.8”	“9.0 (6.6-13.3)”	“0.2”
TP53 altered (13)	“5 (39%, 14-68)”		“7.0 (1.4-13.8)”
PBRM1 unaltered (84)	“38 (45%, 34-56)”	“0.3”	“9.0 (6.7-13.1)”	“0.2”
PBRM1 altered (9)	“2 (22%, 2.8-60)”		“4.8 (1.2-NC)”

“Limitations of this exploratory analysis included differences between the phase Ib and II patient populations and the sample size of tumor type subgroups.” (opens the source at this quote in a new tab)
“Data from various tumor types were included from the phase Ib portion of the study, and individual subgroups were too small to make clinically meaningful inferences, thereby making any statistically significant findings hypothesis-generating only.” (opens the source at this quote in a new tab)

Prognostic co-alterations in FGFR-altered cholangiocarcinoma

“BAP1 mutation was the most common coexisting mutation without prognostic impact, whereas TP53 (P = .04) and CDKN2A/B (P = .04) were correlated with a shorter OS.” (opens the source at this quote in a new tab)

“About 15% of intrahepatic cholangiocarcinomas (iCCAs) express fibroblast growth factor receptor 2 (FGFR2) fusion proteins (FFs), usually alongside mutational inactivation of TP53, CDKN2A or BAP1.” (opens the source at this quote in a new tab)

Preclinical determinants of FGFR2 fusion dependence: fusion identity, tumour suppressor background, and gatekeeper-resistant mutants

“Clinical responses to FGFR kinase inhibitors in CCA are often of modest durability.” (opens the source at this quote in a new tab)
“a number of mutations causing single amino acid substitutions in the FF TKD were found to be a genetic determinant of secondary resistance, due to their ability to impair drug-target interactions.” (opens the source at this quote in a new tab)
“The penetrance of this tumorigenic phenotype was influenced by FF identity.” (opens the source at this quote in a new tab)
“We observed that structurally different FFs diverged in terms of oncogenic potential.” (opens the source at this quote in a new tab)
“A recent study reported that FGFR2-AHCYL1 was tumorigenic when expressed in Cdkn2a-null mouse liver organoids” (opens the source at this quote in a new tab)
“Therefore, it is possible that FF-driven iCCA pathogenesis might be influenced by the genetic background generated by loss of a specific tumor suppressor gene on one side and still unclear biological properties intrinsic to individual FFs on the other.” (opens the source at this quote in a new tab)
“We also generated an iCCA model driven by the BGJ398-resistant FGFR2-TACC3 V565F mutant (Fig. 2C and S11A-D) and determined that the resulting F-TKI-resistant tumoroids (Fig. S11E, F) were also dependent on Erk1/2 signaling (Fig. S11G).” (opens the source at this quote in a new tab)
“The advantage offered by the B+T combo in our experiments must also be considered in light of the finding that TP53 mutations are associated with an aggressive disease course and less favorable responses to single agent FGFR TKIs in iCCA with FGFR2 rearrangements.” (opens the source at this quote in a new tab)

FGFR inhibitor outcomes by FGFR alteration type

“FGFR fusions, most common in cholangiocarcinoma, were associated with the most favorable outcomes with an overall response rate (ORR) of 45.9%, median progression free survival (PFS) and overall survival (OS) of 7.3 and 19.7 months, respectively.” (opens the source at this quote in a new tab)

FGFR inhibitor survival by alteration type, FGFR gene, and tumor type in an institutional cohort

“By FGFR alteration type, PFS was longer in the fusion group with 7.3 months 95%CI[5.6–8.5]), compared to 4.1 months 95%CI [2.7–5.6] for mutations, and 2.1 months 95%CI[1.6–3.0] for amplifications (p < 0.001).” (opens the source at this quote in a new tab)
“Compared to other patients, FGFR fusion was associated with a significantly reduced risk of death (HR=0.633, 95%CI[0.449–0.894], p = 0.009), while amplifications and mutations did not reach statistical significance (Fig. 3, supplementary data Table 2).” (opens the source at this quote in a new tab)
“FGFR3 was associated with a shorter PFS at 3.4 months 95%CI[1.5–7.4] vs 7.9 months 95%CI[6.1–9.3] for FGFR2 (HR=1.940, 95%CI[1.120–3.360], p = 0.020).” (opens the source at this quote in a new tab)
“Regarding survival for most frequent tumor types, cholangiocarcinoma had a median PFS/OS of 8.4/49.6 months, breast cancer 2.4/20.2, urothelial carcinoma 4.6/18.4 and CNS tumor 3.0/14.3.” (opens the source at this quote in a new tab)
“As a retrospective analysis, it is susceptible to selection and reporting biases.” (opens the source at this quote in a new tab)
“However, no multivariate analysis was performed to explore the impact of these variables due to the insufficient number of patients for each subgroup.” (opens the source at this quote in a new tab)

Primary and acquired resistance identified by clinicogenomic analysis of pemigatinib-treated participants

“Clinicogenomic analysis of pemigatinib-treated patients identified mechanisms of primary and acquired resistance.” (opens the source at this quote in a new tab)

“Among those experiencing primary resistance to lirafugratinib, we identified potential resistance mechanisms in five of six pretreatment samples.” (opens the source at this quote in a new tab)

Co-occurring tumor suppressor alterations and fusion partner and outcomes with pemigatinib in FIGHT-202

“Among FGFR2-rearranged versus non-FGFR2-rearranged patients, the most frequent co-alterations were BAP1 (38.4% vs 8.2%), CDKN2A (21.7% vs 30.0%), CDKN2B (15.2% vs 20.2%), and PBRM1 (9.4% vs 10.7%) (Fig. 2D).” (opens the source at this quote in a new tab)
“ORR was higher in BAP1 altered versus unaltered patients but did not reach statistical significance (43.6% vs 30.9%, P = 0.19).” (opens the source at this quote in a new tab)
“Patients with GAs in CDKN2A/B or PBRM1 alterations trended toward a lower ORR (CDKN2A/B, 23.8% vs 38.4%, P = 0.22; PBRM1, 30.0% vs 36.1%; P = 0.70), although not statistically significant, and significantly shorter median PFS (CDKN2A/B, 6.4 months vs 9.0 months, P = 0.03; PBRM1, 4.7 months vs 7.0 months, P = 0.05).” (opens the source at this quote in a new tab)
“Of note, patients with TP53 alterations (n = 9) had no objective responses and significantly shorter median PFS (2.8 months vs 9.0 months, P = 0.0003) (Table 1 and Fig. 4B).” (opens the source at this quote in a new tab)
“This group of patients, accounting for 63% of all patients, had significantly shorter median PFS although ORR was similar between the two groups.” (opens the source at this quote in a new tab)
“No significant difference in ORR was observed for patients with FGFR2 alterations classified as rearrangements versus for patients with predicted fusions (40.0% vs 34.8%, P = 0.70).” (opens the source at this quote in a new tab)
“Importantly, we saw no differences in clinical response to pemigatinib in patients with BICC1 versus other partners.” (opens the source at this quote in a new tab)
“However, the small number of patients, particularly with TP53 or PBRM1 alterations, must be acknowledged as a limitation.” (opens the source at this quote in a new tab)

Subgroup findings in the second-line chemotherapy comparator

“The ABC-06 study showed how the overall survival and progression-free survival benefit was independent of whether patients were classed as being platinum sensitive or platinum refractory or resistant. In fact, subgroups with suspected poorer prognosis seemed to benefit most from FOLFOX.” (opens the source at this quote in a new tab)
“Our subgroup analysis also showed a weaker overall survival benefit from treatment with FOLFOX in the extrahepatic cholangiocarcinoma subgroup; however, this observation should be viewed with caution owing to insufficient statistical power.” (opens the source at this quote in a new tab)
“The insufficient power for subgroup analyses, which challenges some interpretations, is an acknowledged limitation, especially in such a heterogeneous disease.” (opens the source at this quote in a new tab)

Subgroup findings in the first-line chemoimmunotherapy comparator

“The overall and progression-free survival benefits observed with durvalumab in combination with gemcitabine and cisplatin were generally consistent across the clinically relevant subgroups analyzed (Fig. 2A and 2B).” (opens the source at this quote in a new tab)
“Although the Asia subgroup appeared to have a relatively larger improvement in survival compared with the rest-of-the-world subgroup, the study was not sized for any individual subgroup evaluations, and no adjustments were made for multiplicity.” (opens the source at this quote in a new tab)
“The addition of durvalumab to chemotherapy benefited patients with tumors characterized by a PD-L1 TAP of 1% or greater and a TAP of less than 1%, indicating that PD-L1 status may have limited value in predicting clinical benefit with durvalumab plus chemotherapy in this patient population.” (opens the source at this quote in a new tab)
“Exploratory analyses using tumor tissue samples are needed to assess potential survival and response correlations to biomarkers, including driver mutations and tumor mutational burden.” (opens the source at this quote in a new tab)

Tumor markers as prognostic stratifiers in second-line treatment

“In addition, median OS decreased from 8.9 months (no markers elevated) to 3.2 months (all three elevated).” (opens the source at this quote in a new tab)

Lirafugratinib (Lyrfigtu)

Heterogeneity of treatment effect