A phase Ib study of GSK3052230, an FGF ligand trap in combination with pemetrexed and cisplatin in patients with malignant pleural mesothelioma

Our plain-English summary of A phase Ib study of GSK3052230, an FGF ligand trap in combination with pemetrexed and cisplatin in patients with malignant pleural mesothelioma, by E.M.J. van Brummelen, E. Levchenko, M. Dómine, et al (Investigational New Drugs, 2020).

The study

• Authors: E.M.J. van Brummelen, E. Levchenko, M. Dómine, D.A. Fennell, H.L. Kindler, S. Viteri, S. Gadgeel, P.G. López, V. Kostorov, D. Morgensztern, S. Orlov, M.G. Zauderer, J.F. Vansteenkiste, K. Baker-Neblett, J. Vasquez, X. Wang, D.I. Bellovin, J.H.M. Schellens, L. Yan, I. Mitrica, M.P. DeYoung, J. Trigo
• Journal: Investigational New Drugs
• Published: 2020;38(2):457-467
• Cited by: 24 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background Fibroblast growth factors (FGFs) have a fundamental role in cancer. Sequestering FGFs with GSK3052230 (FP-1039) blocks their ability to activate FGFRs while avoiding toxicities associated with small molecule inhibitors of FGFR, including hyperphosphatemia and retinal, nail, and skin toxicities. Methods A multicenter, open-label, phase Ib study evaluated weekly GSK3052230 added to pemetrexed/cisplatin in patients with treatment-naive, unresectable malignant pleural mesothelioma. Doses were escalated according to a 3 + 3 design, followed by cohort expansion at the maximum tolerated dose (MTD). Endpoints included safety, overall response rate, progression-free survival, and pharmacokinetics. Results 36 patients were dosed at 10, 15, and 20 mg/kg doses of GSK3052230. Three dose-limiting toxicities were observed at 20 mg/kg and one at 15 mg/kg. The MTD was defined as 15 mg/kg and used for cohort expansion. The most common treatment-related adverse events (AEs) were nausea (56%), decreased appetite (36%), infusion reactions (36%), decreased neutrophil counts (36%), and fatigue (33%). The confirmed ORR was 39% (95% CI: 23.1-56.5) (14/36 PRs) and 47% had stable disease (17/36), giving a disease control rate of 86%. At 15 mg/kg GSK3052230 (n = 25), the ORR was 44% (95% CI: 24.4-65.1), and the median PFS was 7.4 months (95% CI: 6.7-13.4). Four patients had disease control for over 1 year, and three were still ongoing. Conclusion At 15 mg/kg weekly, GSK3052230 was well tolerated in combination with pemetrexed/cisplatin and durable responses were observed. Importantly, AEs associated with small molecule inhibitors of FGFR were not observed, as predicted by the unique mechanism of action of this drug.

In plain English

This nonrandomized, open-label, multicenter phase Ib trial added weekly GSK3052230 (10, 15 or 20 mg/kg), an experimental drug that traps fibroblast growth factors, to pemetrexed and cisplatin chemotherapy. It treated 36 patients with unresectable malignant pleural mesothelioma. None had prior systemic therapy except one, who had completed oxaliplatin and pemetrexed seven years before enrollment. Dose-limiting toxicities occurred in three of eight patients at 20 mg/kg (one a grade 5 intestinal ischemia/perforation) and in one of 25 at 15 mg/kg. Treatment-related adverse events affected 97% of patients, most often nausea (56%). No hyperphosphatemia or other toxicities linked to pan-FGFR kinase inhibitors were reported. Of the 36 patients, 14 had a partial response (39%, 95% CI 23.1 to 56.5) and 17 (47%) had stable disease. None had a complete response. Among the 25 patients at 15 mg/kg, the response rate was 44% (95% CI 24.4 to 65.1) and median progression-free survival was 7.4 months (95% CI 6.7 to 13.4). The authors concluded that 15 mg/kg weekly was well tolerated, with durable responses. They noted that the results were comparable to earlier pemetrexed/cisplatin studies, so the drug's contribution was difficult to ascertain, and that a randomized trial would be necessary.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Nonrandomized, open-label, multicenter phase Ib trial (dose escalation by a 3 + 3 design, then expansion at the maximum tolerated dose); results of Arm C (mesothelioma) are reported
• Who was studied: 36 adult patients with unresectable, measurable malignant pleural mesothelioma, treated at multiple centers. None had prior systemic therapy except one patient in the 15 mg/kg cohort, who had completed oxaliplatin and pemetrexed 7 years before enrollment. 25 (69%) were male and 19 (53%) were aged 65 or older. Data cut-off was 17 March 2017.
• Exposure: Treatment exposure, not asbestos exposure: GSK3052230 given intravenously once weekly at 10, 15 or 20 mg/kg, plus pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 on day 1 of each 21-day cycle
• Main results:
  • Dose-limiting toxicities occurred in 3 of 8 patients at 20 mg/kg and in 1 of 25 patients at 15 mg/kg; 15 mg/kg was defined as the maximum tolerated dose
  • At 20 mg/kg, one grade 5 intestinal ischemia/intestinal perforation occurred, considered possibly related to study treatment
  • Treatment-related adverse events were reported in 97% of all 36 patients; the most common were nausea (56%), decreased appetite (36%), infusion-related reactions (36%), decreased neutrophil counts (36%) and fatigue (33%)
  • No hyperphosphatemia or other toxicities associated with pan-FGFR kinase inhibitors were reported
  • Of all 36 patients treated, 14 had a partial response, a confirmed overall response rate of 39% (95% CI: 23.1 to 56.5). 17 (47%) had stable disease, for a disease control rate of 86%. There were no complete responses.
  • In the 15 mg/kg group (n = 25), the overall response rate was 44% (95% CI: 24.4 to 65.1) and median progression-free survival was 7.4 months (95% CI: 6.7 to 13.4)
  • Four patients received GSK3052230 for over 1 year, and three patients were still on treatment at data cut-off
  • FGF2 protein expression in tumor samples did not correlate with response rate. In the 15 mg/kg group, a statistically significant correlation between progression-free survival and cytoplasmic FGF2 H-score was observed (p = 0.0157), despite the small sample size (n = 15).
• The authors' conclusion: The authors concluded that GSK3052230 was well tolerated at 15 mg/kg weekly and that durable responses were achieved when it was combined with pemetrexed/cisplatin
• Limitations the authors state:
  • Response and progression-free survival results were comparable to earlier pemetrexed/cisplatin studies, so the authors found it difficult to ascertain the drug's contribution; a randomized trial would be needed
  • Neutropenia, anemia and increased blood creatinine were higher than expected, which the authors thought likely involved pemetrexed and cisplatin
  • The FGF2 and progression-free survival analysis had a small sample size

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pemetrexed (Alimta), Cisplatin, Pleural Mesothelioma, Fibroblast, Unresectable, Progression-Free Survival.

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