Truncated FGFR2 is a clinically actionable oncogene in multiple cancers.

Somatic hotspot mutations and structural amplifications and fusions that affect fibroblast growth factor receptor 2 (encoded by FGFR2) occur in multiple types of cancer1. However, clinical responses to FGFR inhibitors have remained variable1-9, emphasizing the need to better understand which FGFR2 alterations are oncogenic and therapeutically targetable. Here we apply transposon-based screening10,11 and tumour modelling in mice12,13, and find that the truncation of exon 18 (E18) of Fgfr2 is a potent driver mutation. Human oncogenomic datasets revealed a diverse set of FGFR2 alterations, including rearrangements, E1-E17 partial amplifications, and E18 nonsense and frameshift mutations, each causing the transcription of E18-truncated FGFR2 (FGFR2ΔE18). Functional in vitro and in vivo examination of a compendium of FGFR2ΔE18 and full-length variants pinpointed FGFR2-E18 truncation as single-driver alteration in cancer. By contrast, the oncogenic competence of FGFR2 full-length amplifications depended on a distinct landscape of cooperating driver genes. This suggests that genomic alterations that generate stable FGFR2ΔE18 variants are actionable therapeutic targets, which we confirmed in preclinical mouse and human tumour models, and in a clinical trial. We propose that cancers containing any FGFR2 variant with a truncated E18 should be considered for FGFR-targeted therapies.

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.

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).

Outcome of patients treated with palliative weekly paclitaxel plus cetuximab in recurrent head and neck cancer after failure of platinum-based therapy.

Few therapeutic options are available for recurrent/metastatic head and neck cancer when progression occurs after initial chemotherapy. We analyzed retrospectively the efficacy of weekly Paclitaxel plus Cetuximab as second line of palliative chemotherapy. Patients with squamous carcinoma of head and neck with documented progression after initial treatment were enrolled. Tumor response was evaluated through the response evaluation criteria in solid tumor criteria. The retrospective analysis focused on overall survival (OS) and progression-free survival (PFS). Between 2008 and 2011, 33 consecutive patients were treated. A response rate of 55% was observed, with median response duration of 5.0 months (95% CI 3.3-11.1). The median PFS was 4.0 months (95% CI 2.9-5.0) and the median OS time was 10.0 months (95% CI 7.9-12.0). Acne-like rash/Folliculitis and chronic anemia were the most common adverse events. A weekly schedule of Paclitaxel plus Cetuximab is a promising regimen for patients with advanced head and neck cancer after failure of platinum-based therapy. Good tolerance of this treatment suggests that would be used in fragile patients.

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.

Effect of FGFR2 Alterations on Overall and Progression-Free Survival in Patients Receiving Systemic Therapy for Intrahepatic Cholangiocarcinoma.

BACKGROUND: First-line standard-of-care therapy for advanced cholangiocarcinoma is gemcitabine plus cisplatin; there is no established second-line systemic therapy. Fibroblast growth factor receptor (FGFR)-2 fusions/rearrangements can be oncogenic drivers, occurring almost exclusively in intrahepatic cholangiocarcinoma, but little is known about whether FGFR2 status affects the response to systemic chemotherapy. OBJECTIVE: We aimed to evaluate the effects of FGFR2 status on survival outcomes in patients receiving systemic therapy for intrahepatic cholangiocarcinoma. METHODS: In this retrospective analysis, patients treated with systemic therapy at Memorial Sloan Kettering Cancer Center for intrahepatic cholangiocarcinoma were categorized into three cohorts: FGFR2 fusions; other FGFR2 alterations; no FGFR2 alterations. Endpoints were overall survival and progression-free survival per therapy line. RESULTS: In total, 132 patients with intrahepatic cholangiocarcinoma were included (FGFR2 fusions, n = 15; other FGFR2 alterations, n = 2 [data not reported]; no FGFR2 alterations, n = 115). First-line therapy was platinum based in 93% of patients; 80% received platinum/pyrimidine-based second-line therapy. For patients with FGFR2 fusions and no FGFR2 alterations, respectively, median overall survival from diagnosis was 31.3 months (95% confidence interval [CI] 5.8-not estimable months) [n = 9] and 21.7 months (95% CI 16.1-26.6) [n = 109]; median progression-free survival in first-line therapy was 6.2 months (95% CI 2.0-16.8) [n = 15] and 7.2 months (95% CI 5.0-8.3) [n = 107], and median progression-free survival in second-line therapy was 5.6 months (95% CI 2.8-10.3) [n = 8] and 3.7 months (95% CI 2.6-5.6) [n = 81]. CONCLUSIONS: Patients with intrahepatic cholangiocarcinoma and FGFR2 fusions may have a better prognosis than those without FGFR2 alterations in terms of overall survival, and progression-free survival on second-line, but not first-line systemic therapy. Progression-free survival improvement on second-line chemotherapy may imply an important impact of prior chemotherapy as first line.

Intrahepatic cholangiocarcinoma (iCCA) can be caused by changes in many different genes. One type of change in iCCA is a fibroblast growth factor receptor 2 gene (FGFR2) fusion. In fusions, the FGFR2 gene has fused to another gene. Our study examined people with iCCA to compare the overall survival following diagnosis for people with FGFR2 changes and people without. We also measured progression-free survival, which is the time from their first chemotherapy dose until their cancer got worse. All participants had iCCA and their first or second treatment was chemotherapy. Fifteen participants had FGFR2 fusions and 115 had no FGFR2 changes. We found that participants with FGFR2 fusions lived longer (median 31 months) than those without these fusions (median 22 months). During their first treatment, median progression-free survival was similar for participants with and without FGFR2 fusions. After the second chemotherapy, median progression-free survival was about 2 months longer for participants with FGFR2 fusions than those without. Results will vary from person to person and will depend on other factors. However, people with iCCA with FGFR2 fusions may stay slightly longer on their second treatment without their cancer getting worse. With chemotherapy, they may also live somewhat longer than those without FGFR2 fusions.

Validation and Characterization of FGFR2 Rearrangements in Cholangiocarcinoma with Comprehensive Genomic Profiling.

Cholangiocarcinoma (CCA) is a heterogeneous biliary tract cancer with a poor prognosis. Approximately 30% to 50% of patients harbor actionable alterations, including FGFR2 rearrangements. Pemigatinib, a potent, selective fibroblast growth factor receptor (FGFR) FGFR1-3 inhibitor, is approved for previously treated, unresectable, locally advanced or metastatic CCA harboring FGFR2 fusions/rearrangements, as detected by a US Food and Drug Administration-approved test. The next-generation sequencing (NGS)-based FoundationOneCDx (F1CDx) was US Food and Drug Administration approved for detecting FGFR2 fusions or rearrangements. The precision and reproducibility of F1CDx in detecting FGFR2 rearrangements in CCA were examined. Analytical concordance between F1CDx and an externally validated RNA-based NGS (evNGS) test was performed. Identification of FGFR2 rearrangements in the screening population from the pivotal FIGHT-202 study (NCT02924376) was compared with F1CDx. The reproducibility and repeatability of F1CDx were 90% to 100%. Adjusted positive, negative, and overall percentage agreements were 87.1%, 99.6%, and 98.3%, respectively, between F1CDx and evNGS. Compared with evNGS, F1CDx had a positive predictive value of 96.2% and a negative predictive value of 98.5%. The positive percentage agreement, negative percentage agreement, overall percentage agreement, positive predictive value, and negative predictive value were 100% for F1CDx versus the FIbroblast Growth factor receptor inhibitor in oncology and Hematology Trial-202 (FIGHT-202) clinical trial assay. Of 6802 CCA samples interrogated, 9.2% had FGFR2 rearrangements. Cell lines expressing diverse FGFR2 fusions were sensitive to pemigatinib. F1CDx demonstrated sensitivity, reproducibility, and high concordance with clinical utility in identifying patients with FGFR2 rearrangements who may benefit from pemigatinib treatment.

Clinicogenomic Analysis of FGFR2-Rearranged Cholangiocarcinoma Identifies Correlates of Response and Mechanisms of Resistance to Pemigatinib.

Pemigatinib, a selective FGFR1-3 inhibitor, has demonstrated antitumor activity in FIGHT-202, a phase II study in patients with cholangiocarcinoma harboring FGFR2 fusions/rearrangements, and has gained regulatory approval in the United States. Eligibility for FIGHT-202 was assessed using genomic profiling; here, these data were utilized to characterize the genomic landscape of cholangiocarcinoma and to uncover unique molecular features of patients harboring FGFR2 rearrangements. The results highlight the high percentage of patients with cholangiocarcinoma harboring potentially actionable genomic alterations and the diversity in gene partners that rearrange with FGFR2. Clinicogenomic analysis of pemigatinib-treated patients identified mechanisms of primary and acquired resistance. Genomic subsets of patients with other potentially actionable FGF/FGFR alterations were also identified. Our study provides a framework for molecularly guided clinical trials and underscores the importance of genomic profiling to enable a deeper understanding of the molecular basis for response and nonresponse to targeted therapy. SIGNIFICANCE: We utilized genomic profiling data from FIGHT-202 to gain insights into the genomic landscape of cholangiocarcinoma, to understand the molecular diversity of patients with FGFR2 fusions or rearrangements, and to interrogate the clinicogenomics of patients treated with pemigatinib. Our study highlights the utility of genomic profiling in clinical trials.This article is highlighted in the In This Issue feature, p. 211.

Comparative study on the use of three different near infrared spectroscopy recording methodologies for varietal discrimination of walnuts.

Walnut fruit (Juglans regia L.) is an internationally well-known product with an important tradition of consumption. Its health benefits and economic importance in the food industry make this nut an interesting research topic. In this feasibility study, 200 walnut samples of 5 different varieties were collected and their near infrared (NIR) spectra were recorded with 3 different devices: a benchtop Fourier transform near infrared (FT-NIR) spectrograph, a dispersive hyperspectral imaging camera and a portable NIR dispersive spectrograph. Discriminant analyses were applied and different methods for the varietal discrimination of walnuts were obtained and compared. Up to 96 and 84% of correct identification were respectively obtained in internal (training set) and external validations. Better results were obtained covering the entire shell surface than collecting a unique random spectrum per sample. Moreover, FT-NIR and hyperspectral tools produced classification models with a lower classification error in internal and external validations than the portable NIR one.

Adjuvant therapy sparing in rectal cancer achieving complete response after chemoradiation.

AIM: To evaluate the long-term results of conventional chemoradiotherapy and laparoscopic mesorectal excision in rectal adenocarcinoma patients without adjuvant therapy. METHODS: Patients with biopsy-proven adenocarcinoma of the rectum staged cT3-T4 by endoscopic ultrasound or magnetic resonance imaging received neoadjuvant continuous infusion of 5-fluorouracil for five weeks and concomitant radiotherapy. Laparoscopic surgery was planned after 5-8 wk. Patients diagnosed with ypT0N0 stage cancer were not treated with adjuvant therapy according to the protocol. Patients with ypT1-2N0 or ypT3-4 or N+ were offered 5-fluorouracil-based adjuvant treatment on an individual basis. An external cohort was used as a reference for the findings. RESULTS: One hundred and seventy six patients were treated with induction chemoradiotherapy and 170 underwent total mesorectal excision. Cancer staging of ypT0N0 was achieved in 26/170 (15.3%) patients. After a median follow-up of 58.3 mo, patients with ypT0N0 had five-year disease-free and overall survival rates of 96% (95%CI: 77-99) and 100%, respectively. We provide evidence about the natural history of patients with localized rectal cancer achieving a complete response after preoperative chemoradiation. The inherent good prognosis of these patients will have implications for clinical trial design and care of patients. CONCLUSION: Withholding adjuvant chemotherapy after complete response following standard neoadjuvant chemoradiotherapy and laparoscopic mesorectal excision might be safe within an experienced multidisciplinary team.

Anti-vascular endothelial growth factor therapy in the era of personalized medicine.

PURPOSE: To review the role of anti-vascular endothelial growth factor (anti-VEGF) therapies in the personalized medicine era. METHODS: We searched PubMed for prospective clinical trials published through October 2012 of anti-VEGF agents approved by the U.S. Food and Drug Administration or the European Medicines Agency. RESULTS: The use of anti-VEGF drugs as single agents or in combination with other targeted or cytotoxic agents was associated with improved response rates and progression-free survival. Anti-VEGF therapy exerts its action by blocking tumor vessel formation and, thus, proliferation. Some investigators demonstrated modest to no improvement in overall survival, although the maintenance of anti-VEGF therapy beyond progression was shown to result in longer overall survival. The use of anti-VEGF therapy was associated with adverse events (i.e., thromboembolism, hemorrhage, myocardial infarction, and hypertension) and transformation to a more invasive phenotype. CONCLUSIONS: The development of multikinase targeting agents that include anti-VEGF properties warrants further investigation. The role of anti-VEGF therapy is evolving in the era of personalized medicine, and its use needs to be reassessed in tumor types with effective FDA-approved targeted agents, especially in light of its relatively high cost.