Infigratinib (Truseltiq): A Comprehensive Oncological and Regulatory Review

1. Infigratinib: Overview and Physicochemical Properties

1.1. Introduction to Infigratinib (Truseltiq)

Infigratinib, which was marketed under the brand name Truseltiq, is an orally bioavailable small-molecule kinase inhibitor.[1] It was developed as a targeted therapeutic agent for cancers characterized by aberrations in the fibroblast growth factor receptor (FGFR) signaling pathway, with a primary focus on cholangiocarcinoma (CCA).[1] The development and initial approval of Infigratinib represent the broader shift in oncology towards precision medicine, where treatments are increasingly tailored to specific genetic alterations within a patient's tumor. This paradigm necessitates molecular profiling of tumors to identify eligible patients, moving away from a one-size-fits-all approach.[1] The trajectory of Infigratinib, from its development through to accelerated and conditional approvals for a rare cancer indication, was notably rapid, reflecting the urgent unmet medical need in this patient population.[1] However, this expedited pathway also imposed obligations for post-marketing confirmatory studies, which ultimately presented significant challenges.[7]

1.2. Chemical Identity

The precise chemical identification of a drug substance is paramount for scientific discourse, regulatory documentation, and intellectual property protection.

• Generic Name: Infigratinib [1]
• DrugBank ID: DB11886 [User Query]
• CAS Number: 872511-34-7 (for the free base form).[9] Other CAS numbers exist for different salt forms and hydrates, such as 1310746-10-1 (phosphate), 1310746-11-2 (monohydrate), and 1310746-12-3 (mesylate).[9] The existence of multiple salt forms is a common aspect of pharmaceutical development, aimed at optimizing properties like solubility, stability, and bioavailability. The form marketed as Truseltiq was infigratinib phosphate.[10]
• Synonyms/Alternate Names: The compound has been known by several identifiers throughout its development, including BGJ398, NVP-BGJ398, BGJ-398, NVPBGJ398, Infigratinib free base, and WHO 10032.[1] These synonyms reflect its progression from an investigational chemical entity to a recognized pharmaceutical agent.
• Chemical Formula: C26​H31​Cl2​N7​O3​ [9]
• Molecular Weight: 560.470 g/mol [9]
• IUPAC Name: 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(6-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)-1-methylurea [9]

1.3. Drug Class and Type

Infigratinib is classified as a Small Molecule drug.1

Pharmacologically, it is a pan-fibroblast growth factor receptor (FGFR) kinase inhibitor, acting as an ATP-competitive inhibitor of FGFR subtypes 1, 2, 3, and 4.1 Its broader classifications include antineoplastic agent, enzyme inhibitor, protein kinase inhibitor, and specifically an FGFR tyrosine kinase inhibitor.2

Chemically, Infigratinib belongs to several classes, including being an aminopyrimidine, a N-arylpiperazine, a N-alkylpiperazine, a dichlorobenzene, and a member of phenylureas.11

While described as a "pan-FGFR inhibitor," its affinity is highest for FGFR1, FGFR2, and FGFR3.1 This nuanced specificity is important. The "pan-inhibitor" characteristic, targeting multiple members of a receptor family, inherently raises considerations regarding the balance between achieving broad efficacy against diverse FGFR alterations and the potential for increased on-target toxicities due to the inhibition of multiple physiologically important receptor subtypes.

2. Mechanism of Action

2.1. Target: Fibroblast Growth Factor Receptors (FGFRs)

Infigratinib exerts its therapeutic effects by targeting fibroblast growth factor receptors (FGFRs), a family of four structurally related receptor tyrosine kinases (FGFR1, FGFR2, FGFR3, and FGFR4).1 These receptors are integral to a multitude of cellular processes, including proliferation, differentiation, migration, survival, and angiogenesis.1 Aberrant FGFR signaling, often resulting from gene fusions, rearrangements, amplifications, or activating mutations, is implicated in the pathogenesis of various human cancers, including cholangiocarcinoma.1

The drug's development for cholangiocarcinoma was strongly driven by the significant role of FGFR2 alterations in this malignancy. Specifically, FGFR2 fusions or rearrangements are frequently observed in intrahepatic cholangiocarcinoma (iCCA), with studies indicating that up to 45% of iCCA patients may exhibit such genetic alterations, leading to constitutively active FGFR2 signaling that promotes tumor growth and survival.1 This high prevalence established FGFR2 as a critical therapeutic target in this specific cancer subtype.

2.2. Molecular Interactions

Infigratinib functions as a reversible, ATP-competitive inhibitor of the kinase activity of FGFR1, FGFR2, and FGFR3, and to a lesser extent FGFR4.[1] It binds to the ATP-binding pocket within the catalytic domain of these receptors, thereby preventing the binding of ATP and subsequent receptor autophosphorylation and activation.[1] This competitive and reversible mode of inhibition dictates its pharmacological profile and differentiates it from irreversible or covalent inhibitors. As an ATP-competitive inhibitor, its efficacy can be influenced by intracellular ATP concentrations, and tumors may develop resistance through mutations in the ATP-binding pocket that reduce drug affinity or through the upregulation of alternative signaling pathways.

2.3. Downstream Signaling Pathways Affected

By inhibiting FGFR kinase activity, Infigratinib effectively blocks the phosphorylation of downstream signaling molecules and the subsequent activation of intracellular signaling cascades.1 The primary pathway affected is the Ras-mitogen-activated protein kinase (MAPK) pathway, which is a critical regulator of cell proliferation and survival.1 Preclinical studies have demonstrated that Infigratinib inhibits FGF-induced phosphorylation of key downstream effectors such as Fibroblast growth factor Receptor Substrate 2-alpha (FRS2-α) and Extracellular signal-Regulated Kinases 1/2 (ERK1/2).9

The specificity of this pathway inhibition is an important characteristic. Infigratinib's inhibitory action was shown to be selective for the FGF/FGFR signaling pathway, as evidenced by its lack of effect on Hepatocyte Growth Factor (HGF)-induced phosphorylation of ERK1/2.9 This suggests a targeted mechanism of action rather than broad, non-specific kinase inhibition, which could theoretically contribute to a more manageable side effect profile compared to less selective kinase inhibitors.

2.4. Impact on Cancer Cell Proliferation and Survival

The inhibition of FGFR signaling by Infigratinib translates into potent anti-cancer effects. In vitro, Infigratinib has been shown to inhibit cell proliferation in cancer cell lines that harbor activating FGFR amplifications, mutations, or fusions.1 Mechanistically, this involves the induction of G1 cell cycle arrest, thereby halting cell division, and ultimately promoting tumor cell death.9

In vivo, Infigratinib has demonstrated anti-tumor activity in mouse and rat xenograft models of human tumors characterized by activating alterations in FGFR2 or FGFR3, including patient-derived xenograft models of cholangiocarcinoma expressing FGFR2 fusion proteins.1 This anti-tumor activity is consistently linked to the presence of these specific FGFR alterations, reinforcing its designation and utility as a biomarker-driven, targeted therapy.1

3. Pharmacokinetics (Absorption, Distribution, Metabolism, Excretion - ADME)

3.1. Absorption and Bioavailability

Infigratinib is administered orally.2 Following oral administration, at steady state (presumably at the 125 mg daily dose for 21 days), the mean maximum plasma concentration (Cmax) is 282.5 ng/mL with a coefficient of variation (CV) of 54%, and the mean area under the plasma concentration-time curve from 0 to 24 hours (AUC0-24h) is 3780 ngxh/mL with a CV of 59%.1 Steady state is typically achieved within 15 days of initiating the 21-days-on/7-days-off dosing regimen.1 The median time to achieve peak plasma concentration (Tmax) at steady state is approximately six hours, with a range of two to seven hours.1

Pharmacokinetic studies have shown that Infigratinib Cmax and AUC increase more than proportionally across a dose range of 5 to 150 mg.1 This non-linear pharmacokinetic behavior suggests that clearance mechanisms (likely metabolism) may become saturated at higher doses, leading to a greater than expected increase in drug exposure with dose escalation. Such non-linearity underscores the importance of precise dosing and heightened awareness of factors that could further impair clearance, such as drug interactions or organ dysfunction, as these could lead to disproportionately large increases in exposure and potential toxicity.

A significant food effect has been noted; Infigratinib should be taken on an empty stomach, at least 1 hour before or 2 hours after eating.4 This instruction is critical for ensuring consistent absorption. The high inter-patient variability in exposure, as indicated by the CVs for Cmax (54%) and AUC (59%), further highlights the importance of standardized administration conditions relative to meals to minimize this variability and achieve more predictable therapeutic drug levels.1

3.2. Distribution

Specific quantitative data regarding the volume of distribution and plasma protein binding of Infigratinib are not detailed in the provided information. These parameters are important components of a complete pharmacokinetic profile, influencing the extent of drug distribution into tissues and the fraction of unbound, pharmacologically active drug in circulation.

3.3. Metabolism

Infigratinib is primarily metabolized in the liver.[2] The major enzyme responsible for its metabolism is Cytochrome P450 3A4 (CYP3A4).[2] This reliance on CYP3A4 for clearance makes Infigratinib susceptible to clinically significant drug-drug interactions with agents that inhibit or induce CYP3A4 activity.[15] Hepatic metabolism via CYP3A4 can also lead to the formation of various metabolites, which could potentially be active or contribute to toxicity. While not definitively established for Infigratinib from the available data, it has been speculated that liver injury, though rare, could theoretically be caused by a toxic or immunogenic intermediate metabolite formed during this process.[2]

3.4. Excretion

Detailed information on the routes and extent of excretion of Infigratinib and its metabolites (e.g., renal vs. fecal elimination) and its elimination half-life are not provided in the available documentation. These parameters are essential for a comprehensive understanding of the drug's disposition and for guiding dose adjustments in patients with impaired elimination pathways.

4. Clinical Efficacy in Cholangiocarcinoma

4.1. Therapeutic Indication

Infigratinib (Truseltiq) initially received accelerated approval for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma (CCA) harboring a fibroblast growth factor receptor 2 (FGFR2) fusion or another rearrangement, as detected by an FDA-approved test.[1] This specific indication underscored its role as a targeted therapy, necessitating genetic testing of the tumor to identify eligible patients, and positioned it as a second-line or subsequent therapeutic option for this molecularly defined subgroup. The requirement for an "FDA-approved test" highlights the integral role of companion diagnostics in personalized oncology. The FoundationOne CDx test was approved concurrently by the FDA as a companion diagnostic to select patients for Infigratinib treatment.[5]

4.2. Pivotal Clinical Trial (CBGJ398X2204; NCT02150967)

The regulatory approval of Infigratinib for CCA was primarily based on the results of the CBGJ398X2204 study, a multicenter, open-label, single-arm Phase 2 clinical trial.[4] This trial enrolled 108 patients with previously treated, unresectable locally advanced or metastatic CCA who had centrally confirmed FGFR2 gene fusions or other rearrangements.[5] The patient population was heavily pretreated, with the majority having received at least one prior line of systemic therapy, and a significant proportion having received two or more lines.[18] Nearly all (99%) patients had metastatic (Stage IV) disease, and 99% had previously received gemcitabine-based chemotherapy.[4] Patients received Infigratinib at a dose of 125 mg orally once daily for 21 consecutive days, followed by a 7-day rest period, in 28-day cycles, until disease progression or unacceptable toxicity occurred.[2] Single-arm Phase 2 trial designs are often employed for accelerated approvals in rare diseases with high unmet medical needs, although the absence of a direct comparator arm makes relative efficacy assessments more challenging.

An important observation from the trial data suggested that the extent of prior treatment may influence response rates. Patients who had received fewer prior lines of therapy (specifically, those treated in the second-line setting) appeared to achieve a better objective response rate (ORR 34.0%) compared to those who had received more than one prior line of therapy (ORR 13.8%).[18] This pattern, commonly observed with targeted agents in oncology, suggests that earlier introduction of Infigratinib in eligible patients might yield greater clinical benefit, potentially due to less acquired resistance or better patient performance status earlier in the disease trajectory.

4.3. Key Efficacy Outcomes (from CBGJ398X2204 trial)

The primary efficacy endpoints in the CBGJ398X2204 trial were overall response rate (ORR) and duration of response (DOR), as assessed by a blinded independent central review (BICR) according to RECIST v1.1 criteria.[7]

Table 4.1: Summary of Efficacy Results from CBGJ398X2204 Trial in Previously Treated FGFR2-Altered Cholangiocarcinoma

Efficacy Endpoint	Result (Value, 95% CI if available)	Source Snippet(s)
Overall Response Rate (ORR) - BICR	23% (95% CI: 16-32) or 23.1% (95% CI: 15.6-32.2)	3
Complete Response (CR) - BICR	1 patient (approx. 0.9%)	3
Partial Response (PR) - BICR	24 patients (approx. 22.2%)	3
Median Duration of Response (DOR)	5.0 months (95% CI: 3.7-9.3)	3
Patients with DOR $\geq$6 months	8 patients (32% or 35% of responders)	3
Median Progression-Free Survival (PFS)	7.3 months	19
Median Overall Survival (OS)	12.2 months (general); 14.5 months (second-line)	18

The investigator-assessed ORR was reported to be higher, at 34%.[19] Such discrepancies between investigator assessment and BICR are not uncommon in oncology trials and underscore the value of independent review for maintaining objectivity in regulatory evaluations. These efficacy outcomes, particularly the ORR and DOR achieved in a refractory patient population with limited therapeutic alternatives, were considered clinically meaningful and formed the basis for the accelerated approval granted by the FDA.[4] While an ORR of 23% is noteworthy, the median DOR of 5 months indicates that for a substantial portion of responders, the clinical benefit was not sustained long-term. This is a frequent challenge in the treatment of advanced cancers and points to the ongoing need for strategies to overcome therapeutic resistance and enhance the durability of response. The observation that 32% of responders maintained their response for at least 6 months offers a more encouraging signal for a subset of patients.

5. Safety Profile and Tolerability

5.1. Common Adverse Events

Treatment with Infigratinib is associated with a range of adverse events (AEs). The most commonly reported AEs (occurring in $\geq$20% of patients in clinical trials) included hyperphosphatemia (approximately 74-77%), stomatitis (51-56%), fatigue (29-40%), alopecia (32-38%), dry eye (29-31%), palmar-plantar erythrodysesthesia syndrome (PPES) (32%), arthralgia (32%), dysgeusia (26-40%), constipation, abdominal pain, dry mouth, eyelash changes, diarrhea, dry skin, decreased appetite, blurred vision, nail toxicity, and increased serum creatinine.5

Many of these common AEs, particularly hyperphosphatemia, ocular toxicities (such as dry eye and blurred vision, often related to retinal changes), and various dermatological manifestations (skin dryness, nail toxicity, alopecia), are considered on-target effects. These arise from the inhibition of FGFR signaling in normal tissues where these receptors play physiological roles, for example, in phosphate homeostasis, ocular tissue maintenance, and skin and appendage integrity.2 Proactive monitoring and management of these anticipated toxicities are crucial for patient tolerability and adherence to therapy.

5.2. Serious Adverse Events and Grade 3/4 Toxicities

Serious risks associated with Infigratinib therapy include severe hyperphosphatemia and ocular toxicity, most notably retinal pigment epithelial detachment (RPED).2 Grade 3 or 4 AEs reported in clinical trials included hyperphosphatemia, stomatitis, hyponatremia, and hypophosphatemia.5

The adverse event profile often necessitated modifications to treatment. In the pivotal CBGJ398X2204 trial, AEs led to dose interruptions in 64% of patients, dose reductions in 60%, and permanent discontinuation of Infigratinib in 15%.2 While many of these toxicities are described as "manageable" through dose adjustments and standard supportive care measures 3, the high frequency of such interventions indicates a substantial treatment burden. This burden can significantly impact patient quality of life and adherence, and may have factored into the overall risk-benefit assessment and commercial viability of the drug.

5.3. Hepatotoxicity

Infigratinib has been associated with transient and generally mild elevations in serum aminotransferase levels during therapy.2 In preregistration clinical trials involving 108 patients, alanine aminotransferase (ALT) elevations were observed in 51% of patients, with 6% experiencing elevations greater than 5 times the upper limit of normal (ULN).2 These elevations were typically self-limited and resolved with or without dose adjustments.2 Importantly, no patients in these trials developed clinically apparent liver injury or jaundice.2 The likelihood score for Infigratinib as a cause of clinically apparent liver injury has been rated as E* (unproven but possible, rare cause).2

Given that Infigratinib is primarily metabolized in the liver by CYP3A4, there is a theoretical possibility that a toxic or immunogenic metabolite could contribute to liver injury, although this has not been proven.2 While routine intensive liver function test monitoring was not specifically mandated in some guidance, a cautious approach involving careful follow-up of confirmed elevations is advised. Dose reduction or temporary cessation of therapy is recommended for ALT/AST elevations exceeding 5 times ULN, or for any elevations accompanied by jaundice or symptoms of liver dysfunction.2

5.4. Management of Key Toxicities

Specific management strategies are outlined for the characteristic on-target toxicities of Infigratinib:

• Ocular Toxicity (RPED and Dry Eye): Patients should undergo comprehensive ophthalmic examinations, including optical coherence tomography (OCT), prior to starting Infigratinib, then at 1 month, 3 months, and every 3 months thereafter during treatment. If visual symptoms suggestive of RPED occur, urgent ophthalmic evaluation is necessary, with follow-up every 3 weeks until resolution or discontinuation. Dose withholding, reduction, or permanent discontinuation is recommended based on the severity and persistence of RPED. Dry eye, a common related symptom, should be managed with ocular demulcents as needed.[15]
• Hyperphosphatemia: Serum phosphate levels must be monitored throughout treatment. Management involves initiation or adjustment of phosphate binder therapy (e.g., sevelamer). Phosphate binders should be held during the 7-day off-therapy period of each Infigratinib cycle and during other treatment interruptions not related to hyperphosphatemia. Infigratinib dosing should be withheld, reduced, or permanently discontinued based on the severity (serum phosphate levels) and duration of hyperphosphatemia, with specific thresholds provided for these actions.[15] The detailed and proactive monitoring schedules for RPED and hyperphosphatemia underscore a strategy aimed at early detection and intervention to mitigate these potentially serious toxicities.

Table 5.1: Common and Serious Adverse Events Associated with Infigratinib

Adverse Event	Frequency (Any Grade, %)	Grade $\geq$3 Frequency (%)	Management Notes (if specified)	Source Snippet(s)
Hyperphosphatemia	74-89	~15 5	Monitor serum phosphate; phosphate binders; dose modification/interruption based on levels.	2
Stomatitis	51-56	Common 22	Supportive care; dose modification.	5
Dry Eye	29-31	Infrequent Grade $\geq$3	Ocular demulcents.	5
Retinal Pigment Epithelial Detachment (RPED)	11-17	Part of serious risk	Ophthalmic exams (OCT); dose modification/interruption/discontinuation based on severity.	2
Fatigue	29-40	Variable	Supportive care.	5
Alopecia	32-49	Not typically Grade $\geq$3	-	5
Nail Toxicity	$\geq$20 5	Variable	-	5
Palmar-Plantar Erythrodysesthesia (PPES)	32	Variable	Supportive care; dose modification.	5
Arthralgia	25-32	Variable	Supportive care.	5
Dysgeusia	26-40	Not typically Grade $\geq$3	-	5
Increased Creatinine	$\geq$20 (lab abnormality)	Variable	Monitor renal function.	5
ALT/AST Elevations	51 (ALT any grade)	6 (ALT >5xULN)	Monitor liver enzymes; dose modification if significant.	2

6. Dosage, Administration, and Special Populations

6.1. Recommended Dosage and Schedule

The recommended dosage of Infigratinib for its approved indication in cholangiocarcinoma was 125 mg administered orally once daily for 21 consecutive days, followed by a 7-day off-therapy period, constituting a 28-day cycle.[2] This cyclic regimen is a common strategy for oral anticancer drugs, allowing for patient recovery from cumulative toxicities during the off-therapy week. Treatment was to be continued until evidence of disease progression or the development of unacceptable toxicity.[2] The 125 mg dose is achieved by combining two different capsule strengths: one 100 mg capsule and one 25 mg capsule.[4] This requirement for multiple capsules of different strengths to achieve the daily dose could have minor implications for prescription clarity and patient adherence if not properly communicated and managed.

6.2. Administration Instructions

For optimal and consistent absorption, Infigratinib should be taken on an empty stomach, defined as at least 1 hour before or 2 hours after food consumption.[4] It should be administered at approximately the same time each day.[4] The capsules must be swallowed whole with a glass of water and should not be crushed, chewed, or dissolved.[4] If a dose is missed by 4 hours or more, or if vomiting occurs after taking a dose, the patient should not take an additional dose on that day but should resume the regular daily dosing schedule on the following day.[15]

6.3. Dosage Adjustments for Adverse Reactions

The Infigratinib prescribing information provides detailed guidelines for dose modifications in the event of adverse reactions. Recommended dose reductions are sequential: the first reduction is to 100 mg daily, the second to 75 mg daily, and the third to 50 mg daily (maintaining the 21 days on/7 days off schedule).[15] Specific criteria and actions are outlined for managing key toxicities such as RPED and hyperphosphatemia, as well as other Grade 3 or 4 adverse reactions. These actions may include withholding therapy, resuming at the same or a reduced dose level once toxicity improves to Grade $\leq$1 or baseline, or permanent discontinuation if the adverse effect is severe, life-threatening, or does not resolve within a specified timeframe (e.g., $\leq$14 days for other Grade 3 AEs).[15]

Table 6.1: Recommended Dosage Modifications for Infigratinib Adverse Reactions

Toxicity	Severity/Criteria	Recommended Action	Source Snippet(s)
Retinal Pigment Epithelial Detachment (RPED)	Any RPED	Continue Infigratinib at current dose; periodic ophthalmic exams. If improves within 14 days, continue current dose. If no improvement in 14 days, withhold; resume at previous or lower dose once condition improves.	15
Hyperphosphatemia	Serum phosphate >5.5 – $\leq$7.5 mg/dL	Continue Infigratinib at current dose; initiate/adjust phosphate binder. Monitor serum phosphate weekly.	15
Hyperphosphatemia	Serum phosphate >7.5 mg/dL OR one-time serum phosphate >9 mg/dL	Withhold Infigratinib until serum phosphate $\leq$5.5 mg/dL. Resume with max dose phosphate binder. Resume at same dose if >7.5 mg/dL for <7 days; resume at next lower dose if >7.5 mg/dL for >7 days or one-time >9 mg/dL.	15
Hyperphosphatemia	Life-threatening consequences (e.g., dialysis needed)	Permanently discontinue Infigratinib.	15
Other Grade 3 Adverse Reactions	Grade 3	Withhold therapy; may resume at next lower dosage level once toxicity improves to Grade $\leq$1. Permanently discontinue if adverse effect does not resolve within $\leq$14 days.	15
Other Grade 4 Adverse Reactions	Grade 4	Permanently discontinue Infigratinib.	15

6.4. Dosage in Special Populations

Dose adjustments for Infigratinib are recommended for patients with certain degrees of organ impairment:

• Renal Impairment:
• For patients with mild to moderate renal impairment (Creatinine Clearance [Clcr] 30–89 mL/minute), the Infigratinib dose should be reduced to 100 mg orally once daily for 21 consecutive days, followed by 7 days off therapy.[4]
• The dosage has not been established for patients with severe renal impairment (Clcr <30 mL/minute) or those with end-stage renal disease (ESRD) receiving intermittent dialysis, indicating a lack of sufficient data in these populations.[23]
• Hepatic Impairment:
• For patients with mild hepatic impairment (total bilirubin >1 to 1.5 times ULN, or AST >ULN with normal total bilirubin), the Infigratinib dose should be reduced to 100 mg orally once daily (21 days on/7 days off).[4]
• For patients with moderate hepatic impairment (total bilirubin >1.5 to 3 times ULN with any AST value), the recommended reduced dose is 75 mg orally once daily (21 days on/7 days off).[4]
• The dosage has not been established for patients with severe hepatic impairment (total bilirubin >3 times ULN with any AST value).[23] The nuanced dose adjustments for varying degrees of renal and hepatic impairment reflect a considered approach to manage potential pharmacokinetic alterations in these patient groups. However, the absence of established dosages for severe renal or hepatic impairment signifies important data gaps where the drug's safety and efficacy have not been adequately characterized.
• Pregnancy and Lactation: Infigratinib can cause fetal harm based on findings in animal studies and its mechanism of action.[15] The pregnancy status of females of reproductive potential must be verified before initiating treatment. Effective contraception is required for both females of reproductive potential and males with female partners of reproductive potential during treatment and for 1 month after the final dose of Infigratinib.[15] Due to the potential for serious adverse reactions in breastfed children, women should be advised not to breastfeed during treatment with Infigratinib and for 1 month after the final dose.[15]

7. Drug Interactions

Infigratinib is susceptible to several clinically significant drug interactions, primarily related to its metabolism by CYP3A4 and its pH-dependent solubility.

7.1. Interactions with CYP3A4 Modulators

• Strong or Moderate CYP3A Inhibitors: Coadministration of Infigratinib with strong or moderate inhibitors of CYP3A4 (e.g., itraconazole, ketoconazole, clarithromycin, grapefruit juice) should be avoided.[15] These inhibitors can significantly increase plasma concentrations of Infigratinib. For example, coadministration with the strong CYP3A inhibitor itraconazole was shown to increase Infigratinib AUC0-inf by 622% and Cmax by 164%.[15] Such a substantial increase in exposure markedly elevates the risk of adverse reactions. The magnitude of this interaction makes empirical dose adjustment of Infigratinib impractical and potentially unsafe, thus warranting the strong recommendation to avoid concurrent use.
• Strong or Moderate CYP3A Inducers: Similarly, coadministration of Infigratinib with strong or moderate inducers of CYP3A4 (e.g., rifampin, carbamazepine, phenytoin, St. John's Wort) should be avoided.[15] These inducers can significantly decrease Infigratinib plasma concentrations, potentially compromising its therapeutic efficacy. For instance, coadministration with the strong CYP3A inducer rifampin decreased Infigratinib AUC0-inf by 56% and Cmax by 44%.[15] A reduction in exposure of this magnitude would likely lead to sub-therapeutic drug levels and diminished anti-tumor activity.

7.2. Interactions with Gastric Acid-Reducing Agents

Coadministration of Infigratinib with gastric acid-reducing agents, including proton pump inhibitors (PPIs), histamine-2 (H2) receptor antagonists, and locally-acting antacids, should generally be avoided.15 These agents increase gastric pH, which may decrease the solubility and subsequent absorption of Infigratinib, leading to reduced plasma concentrations and potentially diminished efficacy. For example, coadministration with the PPI lansoprazole decreased Infigratinib AUC0-inf by 45% and Cmax by 49%.15

If coadministration with certain acid reducers cannot be avoided, specific staggering of administration is recommended:

• H2-receptor antagonist: Administer Infigratinib 2 hours before or 10 hours after the H2-antagonist.[15]
• Locally-acting antacid: Administer Infigratinib 2 hours before or 2 hours after the antacid.[15] The guidance implies a hierarchy of concern, with PPIs (which cause profound and prolonged acid suppression) being generally advised against without specific staggering alternatives, suggesting their impact is more difficult to manage by timing alone compared to H2-antagonists or antacids.

7.3. Other Interactions

Infigratinib is reported to have severe interactions with idelalisib (a PI3K inhibitor also used in oncology) and isoniazid (an antibiotic).[16] Furthermore, it is listed as having serious interactions with at least 119 other drugs.[16] While the specific details of these numerous interactions are not provided in the summarized data, this large number underscores the critical need for a thorough review of all concomitant medications by healthcare providers before initiating Infigratinib therapy, likely involving consultation of comprehensive drug interaction databases.

Table 7.1: Clinically Significant Drug Interactions with Infigratinib

Interacting Drug/Class	Effect on Infigratinib (Exposure/Efficacy)	Mechanism	Management Recommendation	Source Snippet(s)
Strong or Moderate CYP3A Inhibitors (e.g., itraconazole)	Significantly increased plasma concentrations (AUC ↑ 622%, Cmax ↑ 164% with itraconazole); increased risk of adverse reactions.	Inhibition of CYP3A4 metabolism.	Avoid coadministration.	15
Strong or Moderate CYP3A Inducers (e.g., rifampin)	Significantly decreased plasma concentrations (AUC ↓ 56%, Cmax ↓ 44% with rifampin); potential loss of efficacy.	Induction of CYP3A4 metabolism.	Avoid coadministration.	15
Proton Pump Inhibitors (PPIs) (e.g., lansoprazole)	Decreased plasma concentrations (AUC ↓ 45%, Cmax ↓ 49% with lansoprazole); potential loss of efficacy.	Increased gastric pH, reduced solubility/absorption.	Avoid coadministration.	15
H2-Receptor Antagonists	Potential decrease in plasma concentrations and efficacy.	Increased gastric pH, reduced solubility/absorption.	Avoid coadministration. If unavoidable, separate Infigratinib by 2 hrs before or 10 hrs after H2-antagonist.	15
Locally-acting Antacids	Potential decrease in plasma concentrations and efficacy.	Increased gastric pH, reduced solubility/absorption.	Avoid coadministration. If unavoidable, separate Infigratinib by 2 hrs before or 2 hrs after antacid.	15
Idelalisib	Severe interaction (details not specified).	Not specified (likely CYP3A modulation or other).	Avoid coadministration (inferred from "severe interaction").	16
Isoniazid	Severe interaction (details not specified).	Not specified (isoniazid is a CYP modulator).	Avoid coadministration (inferred from "severe interaction").	16

8. Regulatory History and Current Global Status

The regulatory journey of Infigratinib for cholangiocarcinoma has been complex, marked by initial accelerated approvals in some regions followed by subsequent withdrawals.

8.1. FDA (United States)

The U.S. Food and Drug Administration (FDA) granted accelerated approval to Infigratinib (Truseltiq, QED Therapeutics, Inc., later Helsinn Healthcare SA) on May 28, 2021.1 The indication was for adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or other rearrangement, detected by an FDA-approved test.1 This approval was supported by special designations including priority review, fast-track designation, and orphan drug designation.4 Concurrently, the FoundationOne CDx test was approved as a companion diagnostic.5

However, on May 16, 2024, the FDA announced the withdrawal of this approval.7 This action was taken at the voluntary request of the NDA holder, Helsinn Healthcare SA.7 The primary reasons cited were significant difficulties in recruiting and enrolling study subjects for the required post-marketing confirmatory clinical trial (the PROOF trial, NCT03773302), which was investigating Infigratinib in first-line CCA.7 Consequently, the sponsor determined that continued distribution of Infigratinib for the second-line CCA indication was no longer commercially reasonable.7 It is important to note that this discontinuation was not primarily driven by new safety or efficacy concerns related to the initially approved indication itself.26 Helsinn had already decided to cease distribution of Truseltiq in the first quarter of 2023.26

This sequence of events illustrates a challenge sometimes referred to as the "accelerated approval paradox" in rare cancers. Accelerated approval is granted based on promising early data in small patient populations with high unmet need, often contingent upon successful completion of larger confirmatory trials. However, the very rarity of the disease and the specificity of the required biomarker (like FGFR2 fusions in CCA) can render recruitment for these confirmatory trials exceptionally difficult. This logistical hurdle can lead to withdrawal not necessarily because the drug lacks efficacy in its approved niche, but because the post-marketing requirements become practically or commercially insurmountable.

8.2. EMA (Europe)

Infigratinib received Orphan Drug Designation from the European Medicines Agency (EMA) in August 2020 for advanced or metastatic CCA.3 However, in December 2022, Helsinn Birex Pharmaceuticals withdrew its Marketing Authorization Application (MAA) for Infigratinib (then proposed as Febseltiq) in Europe.22

The withdrawal occurred after the EMA's Committee for Medicinal Products for Human Use (CHMP) had expressed concerns during the review of the Phase 2 data that supported the application. The EMA's provisional opinion was that Infigratinib could not have been authorized for the treatment of cholangiocarcinoma.22 The agency cited insufficient evidence that Infigratinib was effective against tumors and noted concerns regarding a number of severe adverse effects.22 The company, in its notification letter, stated the decision to withdraw was based on a reassessment of its regulatory and business strategy and the decision to stop the development of the medicine.22 This divergence in early assessment between the FDA (which granted accelerated approval) and the EMA (which expressed early reservations) highlights that regulatory agencies can arrive at different interpretations of the same benefit-risk profile from early-phase data, particularly for conditional approval pathways.

8.3. Health Canada

Health Canada granted conditional approval (Notice of Compliance with Conditions, NOC/c) for Infigratinib on September 27, 2021, for the same indication as the FDA, under the framework of Project Orbis.6 This approval was contingent upon the sponsor conducting confirmatory trials to verify the clinical benefit.6

While the provided information does not contain a formal withdrawal notice from Health Canada, the global discontinuation of Infigratinib for CCA by Helsinn and the termination of the PROOF confirmatory trial effectively render the conditions of the NOC/c unfulfillable.25 Health Canada's own guidance states that an NOC/c can be withdrawn if confirmatory trials do not demonstrate the anticipated benefit.30 Given the sponsor's actions, the Canadian conditional approval is, for practical purposes, obsolete.

8.4. TGA (Australia)

The Therapeutic Goods Administration (TGA) of Australia granted provisional approval for Infigratinib on November 2, 2021, also under Project Orbis and for the same indication.14 Similar to Health Canada, this approval was conditional upon the verification and description of clinical benefit in confirmatory trials, and the product was included in the Black Triangle Scheme for enhanced safety monitoring.14

As with Canada, there is no explicit TGA withdrawal notice in the provided data. However, the global cessation of the confirmatory trial and the sponsor's decision to discontinue commercialization for CCA make the continuation of its provisional registration in Australia unsustainable under the original terms.

8.5. PMDA (Japan)

The available information does not indicate that Infigratinib (Truseltiq) was submitted for approval or approved by the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan for the treatment of cholangiocarcinoma.[32] Reports concerning PMDA approvals for FGFR inhibitors in CCA within the provided documents primarily discuss futibatinib (Lytgobi) and pemigatinib (Pemazyre).[33] LianBio, which held rights for Infigratinib development in Mainland China, Hong Kong, and Macau, did not explicitly have rights for Japan concerning CCA.[27]

Table 8.1: Summary of Infigratinib Regulatory Status for Cholangiocarcinoma by Agency

Regulatory Agency (Country/Region)	Initial Action (Date)	Companion Diagnostic (if any)	Subsequent Action (Date)	Reason for Subsequent Action	Source Snippet(s)
FDA (USA)	Accelerated Approval (May 28, 2021)	FoundationOne CDx	Approval Withdrawn (May 16, 2024)	Difficulties in recruiting for confirmatory trial (PROOF); commercial non-viability.	1
EMA (Europe)	Orphan Drug Designation (Aug 2020)	N/A	MAA Withdrawn by applicant (Dec 2022)	EMA concerns on benefit-risk from Phase 2 data; sponsor's strategic reassessment.	3
Health Canada (Canada)	Conditional Approval (NOC/c) (Sep 27, 2021)	N/A (requires FGFR2 testing)	Effectively Obsolete (no formal withdrawal date in snippets)	Global termination of confirmatory trial & discontinuation by sponsor.	6
TGA (Australia)	Provisional Approval (Nov 2, 2021)	N/A (requires FGFR2 testing)	Effectively Obsolete (no formal withdrawal date in snippets)	Global termination of confirmatory trial & discontinuation by sponsor.	14
PMDA (Japan)	No approval or submission for CCA found.	N/A	N/A	N/A	32

9. Other Investigational Uses and Discontinued Development

9.1. First-line Cholangiocarcinoma (PROOF trial - NCT03773302)

The PROOF-301 trial was a Phase 3, randomized, controlled study designed to evaluate Infigratinib versus standard-of-care gemcitabine plus cisplatin as a first-line treatment for patients with advanced/metastatic or inoperable cholangiocarcinoma harboring FGFR2 gene fusions or translocations.18 Initiated in February 2019 with a planned enrollment of 350 patients, this trial was intended to serve as the confirmatory study for Infigratinib's accelerated approval.36

However, the PROOF trial was terminated early, not due to safety concerns, but because of persistent difficulties in patient recruitment and the sponsor's subsequent decision to discontinue the development of Infigratinib in oncology within their territories.25 Only 48 patients were enrolled out of the planned 350 over approximately 40 months.37

Preliminary results from the 48 enrolled patients (29 Infigratinib, 19 chemotherapy) showed a median PFS by BICR of 7.4 months for Infigratinib versus 8.0 months for chemotherapy. The ORR by BICR was 37.9% for Infigratinib compared to 15.8% for chemotherapy. Grade 3–4 adverse events were more frequent with Infigratinib (79.3%) than with chemotherapy (58.8%).37 Due to the very small sample size and early termination, these results are insufficient to draw definitive conclusions regarding Infigratinib's efficacy or safety relative to standard chemotherapy in the first-line setting.37 The failure of the PROOF trial to adequately recruit underscores the immense challenges in conducting front-line, biomarker-selected trials in rare cancer subpopulations. Factors such as patient reluctance to be randomized against an established standard of care, even if modestly effective, and the logistical complexities of screening for rare biomarkers across numerous sites can significantly impede trial completion.

9.2. Urothelial Carcinoma (Bladder Cancer)

Infigratinib has also been investigated for the treatment of advanced urothelial carcinoma harboring FGFR3 genomic alterations.[3] FGFR3 alterations are known oncogenic drivers in a subset of urothelial cancers, making this a rational therapeutic target. Erdafitinib, another FGFR inhibitor, has received FDA approval for this indication.[38] While Infigratinib showed clinical activity in this setting, the overall discontinuation of its development in oncology by the original sponsors (Helsinn/BridgeBio) casts doubt on its future advancement for urothelial carcinoma under their direction [25], unless pursued by other partners or under a different strategic framework.

9.3. Gastric Cancer / Gastroesophageal Junction Adenocarcinoma

Despite the discontinuation of Infigratinib for cholangiocarcinoma in Western markets, regional development for other oncology indications has continued. LianBio, holding rights for Infigratinib in Mainland China, Hong Kong, and Macau, is conducting a Phase 2a clinical trial evaluating the drug in patients with locally advanced or metastatic gastric cancer or gastroesophageal junction (GEJ) adenocarcinoma with FGFR2 gene amplification, as well as other advanced solid tumors with FGFR alterations.[27] Topline results from a cohort of 20 pretreated patients in this trial demonstrated an ORR of 25.0%.[28] Based on these findings, Infigratinib received a Breakthrough Therapy Designation from China's National Medical Products Administration (NMPA) for this indication.[28] This ongoing development by LianBio illustrates how regional partnerships can sustain a compound's exploration, particularly if there is a significant local unmet medical need or differing commercial and regulatory landscapes.

9.4. Achondroplasia

Beyond oncology, Infigratinib is being investigated for achondroplasia, the most common form of dwarfism, which is caused by activating mutations in FGFR3 that impair normal bone growth.[3] BridgeBio Pharma has stated that its development program for Infigratinib in achondroplasia is not affected by the withdrawal and discontinuation in oncology.[27] Furthering this non-oncology pursuit, BridgeBio granted exclusive rights to Kyowa Kirin for the development and commercialization of Infigratinib for achondroplasia in Japan, a deal involving a $100 million upfront payment.[39] This pursuit of Infigratinib for a skeletal dysplasia highlights a strategy of portfolio diversification and drug repurposing. The compound's failure in one therapeutic area (oncology, under its original sponsors) does not preclude its potential success in an entirely different indication driven by a distinct aspect of its mechanism of action (FGFR3 inhibition relevant to chondrocyte function).

9.5. Reasons for Discontinuation in Oncology by Original Sponsors (Helsinn/BridgeBio)

The decision by Helsinn and BridgeBio to discontinue the development and marketing of Infigratinib for cholangiocarcinoma in their territories was multifactorial.[7] The central issue was the insurmountable difficulty in recruiting patients for the PROOF-301 confirmatory trial in first-line CCA.[7] This failure to progress with the required post-marketing study led to a commercial reassessment, wherein continued distribution for the second-line accelerated approval indication was deemed not viable.[7] The EMA's earlier skepticism regarding the benefit-risk profile based on the Phase 2 data may also have influenced the overall strategic decision.[22] This sequence—promising Phase 2 results leading to accelerated approval, followed by challenges in confirmatory trial execution, coupled with commercial and potentially differing regulatory assessments—ultimately led to the voluntary withdrawal for the oncology indication.

10. Comparative Context

10.1. Comparison with Pemigatinib (another FGFR inhibitor for CCA)

Pemigatinib (Pemazyre) was the first FGFR inhibitor to receive FDA approval (April 2020) and subsequently EMA approval (March 2021) for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or other rearrangement.4 This established a benchmark in this therapeutic space before Infigratinib's approval.

Comparing data from their respective pivotal Phase 2 trials (Infigratinib: CBGJ398X2204; Pemigatinib: FIGHT-202), though direct cross-trial comparisons have limitations:

• Efficacy: Infigratinib demonstrated an ORR of approximately 23%, a median DOR of 5.0 months, and a median PFS of 7.3 months.[5] Pemigatinib, in the FIGHT-202 trial (n=107 with FGFR2 fusions/rearrangements), showed an ORR of 35.5%, a median DOR of 7.5 months, and a median PFS of 6.9 months.[31]
• Adverse Event Profile: The types of adverse events were generally comparable, reflecting class effects of FGFR inhibitors, including hyperphosphatemia, alopecia, stomatitis, dysgeusia, and diarrhea.[3] However, reported frequencies for some AEs differed: for instance, stomatitis was reported at 51-56% for Infigratinib versus 35% for Pemigatinib, while hyperphosphatemia was 74% for Infigratinib versus 55-60% for Pemigatinib (all grades).[20]
• Dosing Schedule: Infigratinib was dosed at 125 mg once daily for 21 days on, followed by 7 days off.[2] Pemigatinib is dosed at 13.5 mg once daily for 14 days on, followed by 7 days off.[20] The earlier approval of Pemigatinib and its numerically higher ORR and longer DOR observed in its Phase 2 trial may have influenced the competitive landscape and potentially contributed to the commercial challenges faced by Infigratinib. In a niche market for a rare disease, being a second-to-market drug with Phase 2 efficacy data that, on face value, did not appear superior to the established first-in-class agent could have made it more difficult to gain market traction and justify continued investment, especially when confirmatory trial recruitment proved arduous. Notably, Pemigatinib's own first-line confirmatory trial (FIGHT-302) was also reportedly terminated due to poor accrual, underscoring the pervasive difficulties in this specific research area.[37]

10.2. Other FGFR Inhibitors

The landscape of FGFR inhibitors is dynamic, with several agents approved or in development. Futibatinib (Lytgobi) has also received EMA approval for FGFR2-altered cholangiocarcinoma.31 Other inhibitors like erdafitinib (approved for urothelial cancer) and derazantinib have also been investigated in cholangiocarcinoma.20

An interesting area of ongoing research is the potential for sequential FGFR inhibitor therapy. Preliminary data have suggested that some patients who progress on one FGFR inhibitor might still respond to another, such as futibatinib after prior FGFR inhibitor treatment.20 This observation hints at potentially non-overlapping resistance mechanisms or different drug-target interaction profiles among various FGFR inhibitors, which could open avenues for sequencing these agents. However, this concept requires substantial further investigation to be validated and clinically implemented.

11. Expert Summary and Conclusion

11.1. Recap of Infigratinib's Profile and Clinical Utility in CCA

Infigratinib, a pan-FGFR kinase inhibitor, demonstrated clinically meaningful activity in a heavily pretreated population of patients with unresectable or metastatic cholangiocarcinoma harboring FGFR2 gene fusions or rearrangements. The pivotal Phase 2 CBGJ398X2204 trial reported an objective response rate of approximately 23% (BICR), a median duration of response of 5.0 months, and a median progression-free survival of 7.3 months. Its safety profile was characterized by common on-target FGFR inhibitor class effects, notably hyperphosphatemia and ocular toxicities (including RPED), which required careful monitoring and management through dose modifications and supportive care.

11.2. Factors Leading to Market Withdrawal for Cholangiocarcinoma

Despite its initial accelerated approval by the FDA and conditional approvals in other regions like Canada and Australia, Infigratinib's journey for the cholangiocarcinoma indication was cut short. The primary catalyst for its withdrawal was the insurmountable difficulty encountered in recruiting patients for the PROOF-301 confirmatory trial, which was designed to verify its clinical benefit in the first-line setting. This recruitment failure, coupled with the EMA's earlier expressed skepticism regarding the benefit-risk balance based on the Phase 2 data, led the sponsor (Helsinn Healthcare SA/BridgeBio Pharma) to a strategic business decision that continued commercialization for the second-line indication was not viable. The withdrawal was formally requested by the sponsor and was not primarily due to newly identified safety or efficacy issues with the drug in its approved setting.

11.3. Lessons Learned from Infigratinib's Development and Regulatory Pathway

The trajectory of Infigratinib serves as an important case study in the complexities of drug development for rare, biomarker-defined cancers. It highlights the "valley of death" that can exist for conditionally approved drugs: initial promise in early-phase trials can lead to expedited regulatory pathways, but the stringent requirements for robust post-marketing confirmation can be exceedingly challenging to meet. The rarity of the target population, the logistical hurdles of global trial conduct, and the competitive landscape can all conspire to make confirmatory studies difficult to complete, potentially leading to withdrawal irrespective of the drug's utility in its niche.

Furthermore, Infigratinib's story underscores the significance of diversified global and therapeutic area strategies in pharmaceutical development. While its path in cholangiocarcinoma in major Western markets has ended, its continued investigation for gastric cancer in China by LianBio and for the non-oncological indication of achondroplasia by BridgeBio and Kyowa Kirin demonstrates that a compound's value proposition can differ across geographical regions and medical conditions. This allows for potential repurposing and regional lifelines that can salvage a drug's overall development program even if one indication falters.

11.4. Future Perspectives

For cholangiocarcinoma, Infigratinib (Truseltiq) is no longer a therapeutic option in regions where its approval was withdrawn or development ceased by the original sponsors. The focus for FGFR2-altered CCA will remain on other approved FGFR inhibitors like pemigatinib and futibatinib, and on novel agents in development.

However, Infigratinib as a chemical entity may still hold promise in other areas. The ongoing development for achondroplasia, a genetically defined skeletal dysplasia driven by FGFR3 mutations, represents a distinct opportunity. Similarly, the investigation in FGFR2-amplified gastric cancer by LianBio in China could pave a new path for the drug in a different oncologic setting and geographical region. The success of these endeavors will depend on the outcomes of ongoing and future clinical trials and the specific regulatory and commercial environments pertinent to those indications and regions. The challenges faced in the cholangiocarcinoma setting provide valuable lessons for the strategic planning and execution of future targeted therapy development programs, particularly in rare diseases.

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