Open-label, dose-escalation FIGHT-101 study of pemigatinib combined with targeted therapy, chemotherapy, or immunotherapy in patients with advanced malignancies.

BACKGROUND: Pemigatinib is an oral, potent, selective fibroblast growth factor receptor (FGFR) 1-3 inhibitor. FIGHT-101, a three-part, open-label, first-in-human, phase I/II study (NCT02393248), evaluated pemigatinib in patients with advanced solid tumors. In parts 1 and 2, pemigatinib monotherapy had a manageable safety profile and antitumor activity in FGFR-altered tumors. Part 3 (pemigatinib combination therapies) results are presented here. PATIENTS AND METHODS: Patients received 9, 13.5, or 20 mg oral once-daily pemigatinib on continuous or intermittent schedules with gemcitabine and cisplatin (pemi/gem/cis), docetaxel (pemi/doc), trastuzumab (pemi/tras), pembrolizumab (pemi/pembro), or retifanlimab (pemi/reti) irrespective of whether the tumor was confirmed as FGFR altered. Primary endpoints were safety and pharmacodynamics. Secondary endpoints were investigator-assessed tumor objective response rates (ORRs) and pharmacokinetics (PK). RESULTS: Of 65 enrolled patients (pemi/gem/cis, n = 8; pemi/doc, n = 7; pemi/tras, n = 6; pemi/pembro, n = 26; pemi/reti, n = 18), all discontinued. Treatment-emergent adverse events (TEAEs) were generally consistent with individual drug AEs. Serious and grade ≥3 TEAEs occurred in 0%-85.7% and 33.3%-100.0% of patients across treatment groups, respectively. All pemigatinib combinations demonstrated steady-state PK comparable to monotherapy. Pharmacodynamic effects in all pemigatinib combinations, except pemi/gem/cis, were consistent with monotherapy. Less inhibition of FGFR2α phosphorylation was observed with this combination. ORRs (95% confidence interval) were 37.5% [8.5% to 75.5% (pemi/gem/cis)], 14.3% [0.4% to 57.9% (pemi/doc)], 0% (pemi/tras), 26.9% [11.6% to 47.8% (pemi/pembro)], and 11.1% [1.4% to 34.7% (pemi/reti)]. All groups had instances of tumor shrinkage. ORRs in assessable patients with FGFR rearrangements and mutations were 50% and 33%, respectively. CONCLUSIONS: Pemigatinib combination therapy showed no unexpected toxicities. PK and pharmacodynamics were mostly consistent with pemigatinib monotherapy. Pemi/gem/cis (37.5%) and pemi/pembro (26.9%) had the highest ORR; most responders had FGFR alterations.

Pan-tumor landscape of fibroblast growth factor receptor 1-4 genomic alterations.

BACKGROUND: Selective tyrosine kinase inhibitors targeting fibroblast growth factor receptor (FGFR) 1-4 genomic alterations are in development or have been approved for FGFR-altered cancers (e.g. bladder cancer and advanced intrahepatic cholangiocarcinoma). Understanding FGFR inhibitor-resistance mechanisms is increasingly relevant; we surveyed the pan-tumor landscape of FGFR1-4 genomic alterations [short variants (SVs), gene rearrangements (REs), and copy number alterations (CNAs)], including their association with tumor mutational burden (TMB) and the genomic comutational landscape. PATIENTS AND METHODS: Comprehensive genomic profiling of 355 813 solid tumor clinical cases was performed using the FoundationOne and FoundationOne CDx assays (Foundation Medicine, Inc.) to identify genomic alterations in >300 cancer-associated genes and TMB (determined on ≤1.1 megabases of sequenced DNA). RESULTS: FGFR1-4 SVs and REs occurred in 9603/355 813 (2.7%), and CNAs in 15 078/355 813 (4.2%) samples. Most common FGFR alterations for bladder cancer, intrahepatic cholangiocarcinoma, and glioma were FGFR3 SVs (1051/7739, 13.6%), FGFR2 REs (618/6641, 9.3%), and FGFR1 SVs (239/11 550, 2.1%), respectively. We found several, potentially clinically relevant, tumor-specific associations between FGFR1-4 genomic alterations and other genomic markers. FGFR3 SV-altered bladder cancers and FGFR1 SV-altered gliomas were significantly less likely to be TMB-high versus unaltered samples. FGFR3 SVs in bladder cancer significantly co-occurred with TERT and CDKN2A/B alterations; TP53 and RB1 alterations were mutually exclusive. In intrahepatic cholangiocarcinoma, FGFR2 REs significantly co-occurred with BAP1 alterations, whereas KRAS, TP53, IDH1, and ARID1A alterations were mutually exclusive. FGFR1 SVs in gliomas significantly co-occurred with H3-3A and PTPN11 alterations, but were mutually exclusive with TERT, EGFR, TP53, and CDKN2A/B alterations. CONCLUSIONS: Overall, our hypothesis-generating findings may help to stratify patients in clinical trials and guide optimal targeted therapy in those with FGFR alterations.

FIGHT-101, a first-in-human study of potent and selective FGFR 1-3 inhibitor pemigatinib in pan-cancer patients with FGF/FGFR alterations and advanced malignancies.

BACKGROUND: The phase I/II FIGHT-101 study (NCT02393248) evaluated safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of pemigatinib, a potent and selective fibroblast growth factor receptor (FGFR) 1-3 inhibitor, as monotherapy or in combination therapy, for refractory advanced malignancies, with and without fibroblast growth factor (FGF) and receptor (FGFR) gene alterations. PATIENTS AND METHODS: Eligible, molecularly unselected patients with advanced malignancies were included in part 1 (dose escalation; 3 + 3 design) to determine the maximum tolerated dose. Part 2 (dose expansion) evaluated the recommended phase II dose in tumors with or where FGF/FGFR activity is relevant. RESULTS: Patients (N = 128) received pemigatinib 1-20 mg once daily intermittently (2 weeks on/1 week off; n = 70) or continuously (n = 58). No dose-limiting toxicities were reported. Doses ≥4 mg were pharmacologically active (maximum tolerated dose not reached; recommended phase II dose 13.5 mg once daily). The most common treatment-emergent adverse event (TEAE) was hyperphosphatemia (75.0%; grade ≥3, 2.3%); the most common grade ≥3 TEAE was fatigue (10.2%). Dose interruption, dose reduction, and TEAE-related treatment discontinuation occurred in 66 (51.6%), 14 (10.9%), and 13 (10.2%) patients, respectively. Overall, 12 partial responses were achieved, most commonly in cholangiocarcinoma (n = 5) as well as in a broad spectrum of tumors including head and neck, pancreatic, gallbladder, uterine, urothelial carcinoma, recurrent pilocytic astrocytoma, and non-small-cell lung cancer (each n = 1); median duration of response was 7.3 months [95% confidence interval (CI) 3.3-14.5 months]. Overall response rate was highest for patients with FGFR fusions/rearrangements [n = 5; 25.0% (95% CI 8.7% to 49.1%)], followed by those with FGFR mutations [n = 3; 23.1% (95% CI 5.0% to 53.8%)]. CONCLUSIONS: Pemigatinib was associated with a manageable safety profile and pharmacodynamic and clinical activity, with responses seen across tumors and driven by FGFR fusions/rearrangements and mutations. These results prompted a registrational study in cholangiocarcinoma and phase II/III trials in multiple tumor types demonstrating the benefit of precision therapy, even in early phase trials.

Myocardial infarction with angiographically normal coronary arteries.

To determine the prevalence rate and clinical and hemodynamic profile of patients with myocardial infarction (MI) with angiographically normal coronary arteries, we analyzed 3,403 consecutive angiograms performed within a 4.5-year period. Of these studies, 1,124 were performed following an acute MI. Through a computerized search, 12 patients were identified who had documented MI with normal or insignificant (< 30% stenosis in one epicardial vessel only) coronary disease. Q-wave MI developed in five patients (group A) and non-Q-wave MI developed in seven patients (group B). Group A patients were all men whereas group B patients were all women. Overall, group A patients were younger (p = 0.003), had a longer smoking history (p = 0.008), and a higher cardiac index (p = 0.005). In ten patients, areas of localized dyskinesia or hypokinesia were shown on left ventricular cineangiography. Mitral valve prolapse was present in four of the patients and varying degrees of mitral regurgitation were identified in another six. The prevalence rate of MI with angiographically normal coronary arteries was 1% in this study. This entity had a bimodal age and sex distribution: a younger age group, all men, with a stronger cigarette smoking history who had Q-wave MI vs an older age group, all women, and no significant association with cigarette smoking who developed non-Q-wave MI. A mean follow-up of 4 years demonstrated a favorable prognosis in both groups.

Prospective study comparing different echocardiographic measurements of pulmonary capillary wedge pressure in patients with organic heart disease other than mitral stenosis.

In 25 patients with cardiac disease, but free of left ventricular inflow obstruction, the electrocardiogram and M-mode echocardiogram of the aortic root, left atrium and both the mitral and the aortic valves were obtained simultaneously with the pulmonary artery wedge pressure (PAWP) during right heart catheterization. The echocardiographic measurements of the left atrial size, PR-AC interval, left atrial emptying index and the ratio between the electrocardiographic Q wave to mitral valve closure (Q-MVC) and between aortic valve closure to the mitral E point (AVC-E) were correlated to the pulmonary artery wedge pressure by means of linear regression analysis. A formula in which PAWP = 36.6 (Q-MVC/AVC-E)-- 2 was prospectively used to study the measured pressure in the current group of patients. The pulmonary artery wedge pressure derived from these latter measurements correlated well with the invasive measurement of this pressure (r = 0.91). The pulmonary artery wedge pressure calculated by echocardiography differed from the pulmonary artery wedge pressure measured by catheterization by 3 mm Hg or less in 19 of the 25 patients, by 4 mm Hg or less in 22 patients and by 6 mm Hg or less in 24 patients. Although the correlation between the (Q-MVC/AVC-E) ratio and measured pulmonary artery wedge pressure was highly significant (r = 0.91, probability [p] less than 0.001, n = 25), the left atrial emptying index, PR-AC and left atrial size revealed poor correlation coefficients (r = 0.45, r = 0.45 and r = 0.56 [p less than 0.05]), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)