Global Expanded Access Program for Pemigatinib in Patients with Previously Treated Locally Advanced or Metastatic Cholangiocarcinoma and Fibroblast Growth Factor Receptor Gene Alterations.

PURPOSE: Pemigatinib is a fibroblast growth factor receptor-2 (FGFR2) inhibitor approved for use in patients with previously treated cholangiocarcinoma (CCA) and FGFR2 fusions or rearrangements. This ongoing global Expanded Access Program (EAP) allows physicians in regions where pemigatinib is not commercially available to request pemigatinib for patients with locally advanced or metastatic CCA who, in the physician's opinion, could benefit from pemigatinib treatment. MATERIALS AND METHODS: Eighty-nine patients from Europe, North America, and Israel were treated from January 2020 through September 2021. RESULTS: Patients had FGFR gene fusions (68.5%), rearrangements (12.4%), translocations (5.6%), amplifications (2.2%), and other alterations (11.2%). Median duration of treatment in the EAP was 4.0 months (range, 0.1 to 13.6 months). The most frequently reported adverse event (AE) was hyperphosphatemia (22.5%); the most common serious AE was cholangitis (3.4%). Treatment discontinuation was associated with reports of AEs for seven patients (7.9%). AEs associated with pemigatinib were consistent with those observed in clinical trials. CONCLUSION: Efficacy was not assessed in this EAP. However, some patients remained on treatment for up to a year, suggesting that they observed a benefit from treatment. Patients with CCA should undergo molecular testing to identify those who could benefit from targeted treatments such as pemigatinib.

FIGHT-102: A phase 1 study of pemigatinib in Japanese patients with advanced malignancies.

BACKGROUND: FIGHT-102 was a phase 1, dose-escalation, dose-expansion study of pemigatinib in Japanese patients with advanced solid tumors. Here, we report safety, tolerability, and preliminary efficacy of pemigatinib from FIGHT-102. METHODS: Patients (≥20 years old) self-administered oral pemigatinib 9, 13.5, or 18 mg QD on intermittent dosing (Part 1) or 13.5 mg QD intermittent or continuous dosing (Part 2). A dosing cycle was 21 days (2 weeks on/1 week off or 21 continuous days). Primary endpoint was safety. Secondary endpoints were pharmacokinetics, pharmacodynamics, and preliminary efficacy. RESULTS: Forty-four patients (Part 1, n = 14; Part 2, n = 30) were enrolled; most common tumors, cholangiocarcinoma, n = 8; esophageal, n = 6; 26 patients had confirmed FGF/FGFR alterations (Part 1, n = 3; Part 2, n = 23); 70.5% had ≥3 prior systemic therapies. Maximum tolerated dose was not identified. The recommended phase 2 dosage was determined to be 13.5 mg QD. Most common treatment-emergent adverse events (TEAEs) were hyperphosphatemia (81.8%), dysgeusia (45.5%), stomatitis (43.2%), and alopecia (38.6%); most frequent Grade ≥3 TEAEs were anemia and decreased appetite (9.1% each). In Part 1, no patient achieved partial response (PR) or complete response, and 7 (50.0%) patients had stable disease (SD). In Part 2, 5 (16.7%) patients achieved PR (one each with cholangiocarcinoma, gall bladder cancer, breast cancer, urothelial tract/bladder cancer, and sweat gland carcinoma) and 6 (20%) had SD. Median duration of response was 9.56 months (95% CI: 4.17, 14.95). CONCLUSIONS: Pemigatinib demonstrated manageable adverse events, consistent pharmacokinetics and pharmacodynamics profiles, and preliminary efficacy in Japanese patients with advanced solid tumors.

Progression-Free Survival in Patients With Cholangiocarcinoma With or Without FGF/FGFR Alterations: A FIGHT-202 Post Hoc Analysis of Prior Systemic Therapy Response.

PURPOSE: Oncogenic fibroblast growth factor receptor (FGFR) gene alterations have been described in patients with cholangiocarcinoma (CCA). This post hoc analysis assessed progression-free survival (PFS) in patients who had received first- or second-line systemic therapy for advanced/metastatic CCA before enrollment in the phase II FIGHT-202 study (ClinicalTrials.gov identifier: NCT02924376). PATIENTS AND METHODS: Patients with locally advanced or metastatic CCA with FGFR2 fusions/rearrangements (n = 107), other FGF/FGFR alterations (n = 20), or no FGF/FGFR alterations (n = 18) and documented disease progression after at least one systemic cancer therapy before enrollment in FIGHT-202 were assessed. Prior therapy and disease response data were collated from electronic case report forms. PFS was calculated for each prior line of systemic cancer therapy. RESULTS: Among patients with FGFR2 fusions/rearrangements, other FGF/FGFR alterations, and no FGF/FGFR alterations, respectively, the median PFS with prior first-line systemic therapy was 5.5 months (95% CI, 4.0 to 8.0; n = 102), 4.4 months (2.7 to 7.1; n = 19), and 2.8 months (1.6 to 11.3; n = 16); the median PFS with prior second-line systemic therapy was 4.2 months (3.0 to 5.3; n = 39), 3.0 months (1.1 to 9.9; n = 8), and 5.9 months (2.4 to 12.5; n = 6). The median PFS was 7.0 months (4.9 to 11.1) for patients with FGFR2 fusions/rearrangements (n = 65) with second-line pemigatinib received during the FIGHT-202 trial. CONCLUSION: In patients with CCA and FGFR2 fusions or rearrangements, second-line treatment with pemigatinib may be associated with longer PFS compared with second-line treatment with systemic therapy received before study enrollment; however, a prospective controlled trial is required to confirm this. The results support the therapeutic potential of pemigatinib previously demonstrated in FIGHT-202.

FIGHT-302: first-line pemigatinib vs gemcitabine plus cisplatin for advanced cholangiocarcinoma with FGFR2 rearrangements.

FGFR2 rearrangements resulting in dysregulated signaling are drivers of cholangiocarcinoma (CCA) tumorigenesis, and occur almost exclusively in intrahepatic CCA. Pemigatinib, a selective, potent, oral inhibitor of FGFR1-3, has demonstrated efficacy and safety in a Phase II study of patients with previously treated locally advanced/metastatic CCA harboring FGFR2 fusions/rearrangements. We describe the study design of FIGHT-302, an open-label, randomized, active-controlled, multicenter, global, Phase III study comparing the efficacy and safety of first-line pemigatinib versus gemcitabine plus cisplatin in patients with advanced CCA with FGFR2 rearrangements (NCT03656536). The primary end point is progression-free survival; secondary end points are objective response rate, overall survival, duration of response, disease control rate, safety and quality of life. Clinical Trial Registration: NCT03656536 (ClinicalTrials.gov).

Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study.

BACKGROUND: Fibroblast growth factor receptor (FGFR) 2 gene alterations are involved in the pathogenesis of cholangiocarcinoma. Pemigatinib is a selective, potent, oral inhibitor of FGFR1, 2, and 3. This study evaluated the safety and antitumour activity of pemigatinib in patients with previously treated, locally advanced or metastatic cholangiocarcinoma with and without FGFR2 fusions or rearrangements. METHODS: In this multicentre, open-label, single-arm, multicohort, phase 2 study (FIGHT-202), patients aged 18 years or older with disease progression following at least one previous treatment and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 recruited from 146 academic or community-based sites in the USA, Europe, the Middle East, and Asia were assigned to one of three cohorts: patients with FGFR2 fusions or rearrangements, patients with other FGF/FGFR alterations, or patients with no FGF/FGFR alterations. All enrolled patients received a starting dose of 13·5 mg oral pemigatinib once daily (21-day cycle; 2 weeks on, 1 week off) until disease progression, unacceptable toxicity, withdrawal of consent, or physician decision. The primary endpoint was the proportion of patients who achieved an objective response among those with FGFR2 fusions or rearrangements, assessed centrally in all patients who received at least one dose of pemigatinib. This study is registered with ClinicalTrials.gov, NCT02924376, and enrolment is completed. FINDINGS: Between Jan 17, 2017, and March 22, 2019, 146 patients were enrolled: 107 with FGFR2 fusions or rearrangements, 20 with other FGF/FGFR alterations, 18 with no FGF/FGFR alterations, and one with an undetermined FGF/FGFR alteration. The median follow-up was 17·8 months (IQR 11·6-21·3). 38 (35·5% [95% CI 26·5-45·4]) patients with FGFR2 fusions or rearrangements achieved an objective response (three complete responses and 35 partial responses). Overall, hyperphosphataemia was the most common all-grade adverse event irrespective of cause (88 [60%] of 146 patients). 93 (64%) patients had a grade 3 or worse adverse event (irrespective of cause); the most frequent were hypophosphataemia (18 [12%]), arthralgia (nine [6%]), stomatitis (eight [5%]), hyponatraemia (eight [5%]), abdominal pain (seven [5%]), and fatigue (seven [5%]). 65 (45%) patients had serious adverse events; the most frequent were abdominal pain (seven [5%]), pyrexia (seven [5%]), cholangitis (five [3%]), and pleural effusion (five [3%]). Overall, 71 (49%) patients died during the study, most frequently because of disease progression (61 [42%]); no deaths were deemed to be treatment related. INTERPRETATION: These data support the therapeutic potential of pemigatinib in previously treated patients with cholangiocarcinoma who have FGFR2 fusions or rearrangements. FUNDING: Incyte Corporation.

Use of intravesical valrubicin in clinical practice for treatment of nonmuscle-invasive bladder cancer, including carcinoma in situ of the bladder.

OBJECTIVES: The objective was to conduct a US multicenter, retrospective medical record study examining the effectiveness, safety, and patterns of use of valrubicin for treatment of nonmuscle-invasive bladder cancer (NMIBC) by clinicians since the 2009 reintroduction of valrubicin. METHODS: Patients ≥ 18 years with NMIBC who received had one or more instillations of valrubicin (October 2009- September 2011) were eligible. The primary endpoint was event-free survival (EFS). Safety and tolerability were also assessed. RESULTS: The medical records of 113 patients met the inclusion criteria; 100 patients (88.5%) completed valrubicin treatment. The median age was 75 years (range 42-95 years). The median NMIBC duration was 31 months since diagnosis: 51.3% (58/113) had carcinoma in situ (CIS) alone, and 31.9% (36/113) had unspecified NMIBC. Most patients, 94.7% (107/113), had more than three valrubicin instillations and 70.8% (80/113) completed a full course. The EFS rate (95% confidence interval) was 51.6% (40.9-61.3%), 30.4% (20.4-41.1%), and 16.4% (7.9-27.5%) at 3, 6, and 12 months, respectively. Median time to an event was 3.5 (2.5-4.0) months after the first valrubicin instillation. Local adverse reactions (LARs) were experienced by 49.6% (56/113) of patients; most LARs were mild (93.6%). The most frequent LARs were hematuria, pollakiuria, micturition urgency, bladder spasm, and dysuria. In total, 4.4% (5/113) of patients discontinued valrubicin because of adverse events or LARs. CONCLUSIONS: Data from the present retrospective study are consistent with previous prospective clinical trials that demonstrated valrubicin effectiveness and tolerability for select patients with CIS, before considering cystectomy. Additional prospective studies are warranted to evaluate valrubicin safety and efficacy in the broader patient population with NMIBC.

Single-dose, sustained-release epidural morphine in the management of postoperative pain after elective cesarean delivery: results of a multicenter randomized controlled study.

In this multicenter, randomized, controlled study, we compared the analgesic efficacy and safety profile of a new single-dose extended-release epidural morphine (EREM) formulation (DepoDur) with that of epidural morphine sulfate for the management of postoperative pain for up to 48 h after elective cesarean delivery. ASA physical status I or II parturients (n = 75) were anesthetized with a combined spinal/epidural technique. Parturients received intrathecal bupivacaine 12-15 mg and fentanyl 10 mug for spinal anesthesia and a single epidural injection of either 5 mg of standard (conventional preservative-free) morphine or 5, 10, or 15 mg of extended-release morphine after cord clamping for postoperative pain control. Single-dose EREM 10 and 15 mg groups significantly decreased total supplemental opioid medication use and improved functional ability scores for 48 h after surgery compared with those receiving 5 mg of standard morphine. Visual analog scale pain scores at rest and with activity at 24 to 48 h after dosing were significantly better in the 10- and 15-mg single-dose EREM groups versus the standard morphine group. There were no significant differences between the two 5 mg (single-dose EREM and standard morphine) groups. Single-dose EREM was well tolerated, and most adverse events were mild to moderate in severity. Single-dose EREM is a potentially beneficial epidural analgesic for the management of post-cesarean delivery pain and has particular advantages over standard morphine for the period from 24 to 48 h after surgery.