{"id":46633,"date":"2024-05-17T07:00:00","date_gmt":"2024-05-17T07:00:00","guid":{"rendered":"http:\/\/2e5f2084610546fa35c25f5b22a9f24b"},"modified":"2024-11-03T15:11:50","modified_gmt":"2024-11-03T15:11:50","slug":"evaluation-of-pemigatinib-efficacy-in-fgfr-altered-advanced-solid-tumours-led-to-identification-of-new-therapeutic-areas-for-fgfr-inhibition-and-drug-failure-mechanisms","status":"publish","type":"post","link":"https:\/\/ogkologos.com\/en\/evaluation-of-pemigatinib-efficacy-in-fgfr-altered-advanced-solid-tumours-led-to-identification-of-new-therapeutic-areas-for-fgfr-inhibition-and-drug-failure-mechanisms\/","title":{"rendered":"Evaluation of Pemigatinib Efficacy in FGFR-Altered Advanced Solid Tumours Led to Identification of New Therapeutic Areas for FGFR Inhibition and Drug Failure Mechanisms"},"content":{"rendered":"

In an exploratory phase II FIGHT-207 basket study, the investigators observed antitumour activity in cancers beyond cholangiocarcinoma and bladder cancer, as pemigatinib demonstrated also activity in patients with central nervous system tumours, pancreatic cancer (all KRAS<\/em> wild-type) and cervical cancer. The findings suggest that FGFR inhibitors may be effective in cholangiocarcinoma with FGFR2<\/em> alterations other than fusions and rearrangements. Dedicated cohort for activating FGFR2<\/em> mutations allowed to explore the sensitivity of previously clinically unvalidated classes of mutations.<\/p>\n

Study of potential mechanisms of primary resistance to pemigatinib revealed that baseline TP53<\/em> co-mutations were associated with lack of response and BAP1<\/em> alterations with higher response rates. Serial circulating tumour DNA (ctDNA) analysis revealed mechanisms of acquired resistance to pemigatinib in a variety of tumour types. FGFR1<\/em>\u2013FGFR3<\/em> gatekeeper and molecular brake mutations led to acquired resistance. The findings are published by Drs. Jordi Rod\u00f3n of The University of Texas MD Anderson Cancer Center in Houston, TX, US, Lipika Goyal of the Mass General Cancer Center, Harvard Medical School in Boston, MA, US and Stanford Cancer Center, Stanford School of Medicine in Stanford, CA, US and colleagues on 6 May 2024 in the Nature Medicine<\/em>.<\/p>\n

The authors wrote in the background that mutations, fusions and amplifications involving FGFR1\u2013FGFR3<\/em> occur in up to 7% of cancers with selective FGFR inhibitors gaining regulatory approval in disease-specific contexts. In advanced refractory urothelial tract and bladder cancers, where FGFR3<\/em> mutations are frequent, erdafitinib is approved for tumours harbouring FGFR2<\/em> or FGFR3<\/em> point mutations or fusions. In advanced refractory cholangiocarcinoma, where FGFR2<\/em> fusions predominate, pemigatinib and futibatinib are approved for tumours with FGFR2<\/em> fusions or other rearrangements. In relapsed or refractory myeloid and lymphoid neoplasms, pemigatinib gained approval for patients with FGFR1<\/em> rearrangements.<\/p>\n

Evidence of other potentially oncogenic and actionable FGFR<\/em> alterations and potentially responsive tumours are emerging, providing rationale for evaluating FGFR inhibition in a tumour-agnostic trial. FGFR1\u2013FGFR3<\/em> fusions and point mutations in tumours of different histologies have demonstrated sensitivity to FGFR inhibition in early phase studies, including FIGHT-101, the first-in-human, phase I study of pemigatinib.<\/p>\n

FGFR<\/em> alterations, including in-frame insertions and truncating deletions, have been described as potential oncogenic drivers but have not been clinically established as actionable. Essential questions remain about the sensitivity of these rarer gene alterations to FGFR inhibition, the sensitivity of different FGFR<\/em>-altered tumour histologies, the impact of specific gene co-alterations on response to FGFR inhibitors and mechanisms of drug failure across histologies.<\/p>\n

Given the diversity of FGFR<\/em> alterations and the variety of histologic contexts in which they appear, the FIGHT-207 study investigators sought to evaluate the therapeutic importance of FGFR<\/em> alterations in multiple tumour types. The phase II FIGHT-207 basket study was designed to evaluate a selective, potent, oral FGFR1\u2013FGFR3 inhibitor, pemigatinib in patients with previously treated unresectable or metastatic solid tumours with FGFR1\u2013FGFR3<\/em> fusions\/rearrangements or mutations.<\/p>\n

Primary endpoints were objective response rate (ORR) in cohorts A (fusions\/rearrangements) and B (activating non-kinase domain mutations). Secondary endpoints were progression-free survival (PFS), duration of response (DoR) and overall survival (OS) in cohorts A and B, and safety. Exploratory endpoints included ORR of cohort C (kinase domain mutations, potentially pathogenic variants of unknown significance) and analysis of co-alterations associated with resistance and response.<\/p>\n

In the article published in the Nature Medicine<\/em>, the authors reported the clinical outcomes of the study and the biological correlates of intrinsic and acquired resistance from analysis of tissue and ctDNA samples. The study investigators reported ORRs for cohorts A, B and C as following: 26.5%, 9.4% and 3.8%. Tumours with no approved FGFR inhibitors or those with alterations not previously confirmed to be sensitive to FGFR inhibition had objective responses. In cohorts A and B, the median PFS was 4.5 and 3.7 months, median DoR was 7.8 and 6.9 months and median OS was 17.5 and 11.4 months.<\/p>\n

Safety was consistent with previous reports. The most common any-grade treatment-emergent adverse events (TEAEs) were hyperphosphatemia (84%) and stomatitis (53%). Eight patients (7.2%) discontinued pemigatinib due to TEAEs. Nail toxicities and serous retinal detachment occurred in 45% and 14% of patients.<\/p>\n

The authors underlined that benefit of FGFR inhibition seen in this study highlights the value of routine comprehensive molecular screening in solid tumours. In addition to confirming previous reports that FGFR2<\/em> fusions and other rearrangements in cholangiocarcinoma are sensitive to FGFR inhibition, the FIGHT-207 study showed in a dedicated cohort of FGFR<\/em>-mutated tumours that specific FGFR2<\/em> single nucleotide variants (SNVs), namely C382R and in-frame deletions, are associated with response to pemigatinib, suggesting that FGFR inhibitors may be effective in cholangiocarcinoma with FGFR2<\/em> alterations other than fusions and rearrangements.<\/p>\n

In-frame deletions are consistently associated with objective responses. Exon 18 truncating mutations are associated with prolonged stable disease in some instances. De novo FGFR<\/em> kinase domain mutations showed low response to pemigatinib; however, the study team noted that exceptional cases of clinical benefit did occur. To systematically characterise the sensitivity of a diverse array of FGFR1\u2013FGFR3<\/em> SNVs to FGFR inhibition in the clinic, the study team additionally compiled available data from these patients from multiple FGFR inhibitor trials and reviewed response data for 254 patients with FGFR1\u2013FGFR3<\/em> SNVs treated with at least one of five FGFR inhibitors. The resulting maps indicate that certain activating FGFR1\u2013FGFR3<\/em> SNVs show repeated evidence of clinical benefit in response to FGFR inhibition, providing a rationale for clinical development for these patients.<\/p>\n

Study of potential mechanisms of primary resistance to pemigatinib revealed that baseline co-alterations in tumour suppressors, particularly TP53<\/em> and ARID1A<\/em>, and oncogenic co-alterations in the MAPK pathway were associated with shorter PFS compared to those without alterations. A positive correlation was seen between alterations in BAP1<\/em> and both clinical benefit from and response to pemigatinib. Further prospective studies are needed to validate the correlations seen in this study to assess whether co-mutation status can inform patient selection.<\/p>\n

Consistent with laboratory characterisation of acquired FGFR2<\/em> and FGFR3<\/em> resistance mutations in patients with cholangiocarcinoma and urothelial carcinoma, the study also revealed that across FGFR1\u2013FGFR3<\/em>, the most common sites for progression-emergent kinase domain mutations are the gatekeeper residues and the molecular brake residues. In addition to patients with cholangiocarcinoma, polyclonal acquired resistance was seen in patients with FGFR2<\/em>-altered gastro-oesophageal\/gastro-oesophageal junction cancer and cancer of unknown primary origin, FGFR3-<\/em>altered non-small cell lung cancer and FGFR1-<\/em>altered pancreatic cancer.<\/p>\n

Besides the observed secondary mutations in FGFRs<\/em>, molecular analysis of ctDNA at the time of progression identified other emergent gene variants that may contribute to acquired resistance. Genes with emergent variants were PIK3CA<\/em> and RAS family genes (KRAS<\/em>, NRAS<\/em> and HRAS<\/em>). The interplay between oncogenic FGFR1\u2013FGFR3<\/em> alterations, acquired on-target resistance mutations and emergent co-alterations compensating for FGFR inhibition requires further study and clinical validation.<\/p>\n

The authors commented that inherent limitation of the basket study design is that heterogeneous tumours and genetic alterations were included, some of which were not well represented. The study was terminated early by the sponsor for business reasons and some tumour and molecular cohorts, cohorts A and B, specifically, were underpowered to definitively conclude questions of FGFR dependency for specific alterations and tumour types. However, the observations of response in this study are valuable as indicators for potentially actionable FGFR<\/em> alterations and tumours that warrant deeper investigation.<\/p>\n

The study was funded by Incyte.<\/p>\n

Reference<\/h3>\n

Rod\u00f3n J, Damian S, Furqan M, et al. <\/em>Pemigatinib in previously treated solid tumors with activating FGFR1\u2013FGFR3<\/em><\/a> alterations: phase 2 FIGHT-207 basket trial<\/a>. Nature Medicine<\/em>; Published online 6 May 2024. DOI: https:\/\/doi.org\/10.1038\/s41591-024-02934-7<\/a><\/p>\n

Source<\/a><\/p>","protected":false},"excerpt":{"rendered":"

In an exploratory phase II FIGHT-207 basket study, the investigators observed antitumour activity in cancers beyond cholangiocarcinoma and bladder cancer, as pemigatinib demonstrated also activity in patients with central nervous system tumours, pancreatic cancer (all KRAS wild-type) and cervical cancer. The findings suggest that FGFR inhibitors may be effective in cholangiocarcinoma with FGFR2 alterations other […]<\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_monsterinsights_skip_tracking":false,"footnotes":""},"categories":[5137],"tags":[],"class_list":["post-46633","post","type-post","status-publish","format-standard","hentry","category-world-news"],"_links":{"self":[{"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/posts\/46633","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/comments?post=46633"}],"version-history":[{"count":1,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/posts\/46633\/revisions"}],"predecessor-version":[{"id":47030,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/posts\/46633\/revisions\/47030"}],"wp:attachment":[{"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/media?parent=46633"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/categories?post=46633"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/ogkologos.com\/en\/wp-json\/wp\/v2\/tags?post=46633"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}