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Clinical Trial
. 2025 Feb 1;5(2):358-368.
doi: 10.1158/2767-9764.CRC-24-0601.

Phase Ib Study of Immunocytokine Simlukafusp Alfa (FAP-IL2v) Combined with Pembrolizumab for Treatment of Advanced and/or Metastatic Melanoma

Eva Munoz-Couselo  1 , Ainara Soria Rivas  2 , Shahneen Sandhu  3 , Georgina V Long  4   5   6 , Miguel F Sanmamed  7   8 , Anna Spreafico  9 , Elizabeth Buchbinder  10 , Mario Sznol  11 , Hans Prenen  12 , Alexander Fedenko  13 , Mohammed Milhem  14 , Ana Maria Arance Fernandez  15 , Jean-Jacques Grob  16 , Lev Demidov  17 , Caroline Robert  18 , Christin Habigt  19 , Stefan Evers  20 , Nassim Sleiman  20 , David Dejardin  20 , Caroline Ardeshir  21 , Nicole Martin  22 , Christophe Boetsch  20 , Jehad Charo  22 , Volker Teichgräber  20 , Anton Kraxner  20 , Nino Keshelava  22 , Oliver Bechter  23   24
Affiliations
Clinical Trial

Phase Ib Study of Immunocytokine Simlukafusp Alfa (FAP-IL2v) Combined with Pembrolizumab for Treatment of Advanced and/or Metastatic Melanoma

Eva Munoz-Couselo et al. Cancer Res Commun. .

Abstract

Purpose: This study explored the combination of fibroblast activation protein (FAP) IL2 variant (FAP-IL2v), a novel immune-cytokine, with pembrolizumab in patients with advanced and/or metastatic melanoma.

Patients and methods: This open-label, multicenter, phase Ib clinical study (NCT03875079) evaluated the safety, tolerability, pharmacodynamics, pharmacokinetics, and antitumor activity of FAP-IL2v (simlukafusp alfa, RO6874281) in combination with pembrolizumab. Patients with advanced and/or metastatic melanoma were either checkpoint inhibitor (CPI)-naïve or CPI-experienced. Patients received 10 mg FAP-IL2v either continuously once every 3 weeks (Q3W) or in an induction/maintenance setting consisting of a 3-week induction phase with weekly (QW) dosing followed by continuous Q3W dosing. Pembrolizumab was dosed Q3W at 200 mg.

Results: Eighty-three patients were treated: 16 patients in two safety run-in cohorts and 67 patients in two extension cohorts; 75 (90.4%) patients were CPI-experienced. The pharmacokinetics of FAP-IL2v in combination with pembrolizumab was similar to that after administration as monotherapy. Consistent with the proposed mode of action, FAP-IL2v preferentially expanded NK and CD8 T cells. The most common FAP-IL2v-related grade 3/4 adverse events were lymphopenia (23%), elevated γ-glutamyltransferase (8%), elevated alanine aminotransferase (6%), and infusion-related reaction (6%). A response was observed in 5 of 75 (6.7%) CPI-experienced patients (all partial responses) and 2 of 8 CPI-naïve patients (one complete response and one partial response). The median progression-free survival was 3.1 months.

Conclusions: The safety profile of FAP-IL2v in combination with pembrolizumab was manageable and consistent with the known safety profile. However, further exploration of FAP-IL2v and pembrolizumab was precluded in patients with melanoma with prior CPI due to the lack of clinical activity.

Significance: In this phase Ib study, the combination of FAP-IL2v, an immune-cytokine developed to overcome the limitations of wild-type IL2, with the CPI pembrolizumab did not show meaningful antitumor activity in patients who had progressed on prior CPI therapy, suggesting that FAP-IL2v alone cannot overcome CPI resistance or unresponsiveness.

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Conflict of interest statement

Dr. E. Muñoz-Couselo reports personal fees from Bristol Myers Squibb, Regeneron, Pierre Fabre, Immunocore, and Menarini and personal fees and nonfinancial support from MSD and Novartis outside the submitted work. S. Sandhu reports grants, personal fees, and nonfinancial support from MSD, AstraZeneca, and Bristol Myers Squibb; grants and nonfinancial support from Novartis, Amgen, Senhwa Biosciences Inc., and Pfizer; grants from Genentech and Merck Healthcare; and personal fees from Janssen outside the submitted work and participation on advisory boards or consulting roles for MSD, AstraZeneca, Novartis, SkylineDx, and AbbVie and participation as chair of data safety monitoring board for two Novartis-sponsored trials. G.V. Long reports personal fees from Agenus Inc, Amgen Inc, Array BioPharma, AstraZeneca, Bayer Healthcare, BioNTech, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion Biotech, GI Innovation, Hexal AG, Highlight Therapeutics, Immunocore, Innovent, IO Biotech, Iovance, MSD, Novartis, PHMR Limited, Pierre Fabre, Regeneron, Scancell, and SkylineDX outside the submitted work. M.F. Sanmamed reports grants from Roche during the conduct of the study and personal fees from MSD and Catalym and grants from Bristol Myers Squibb outside the submitted work. A. Spreafico reports grants from Roche during the conduct of the study and grants from Novartis, Symphogen, AstraZeneca, Bayer, Surface Oncology, Roche, Regeneron, Alkermes, Pfizer, NuBiyota, Oncorus, Treadwell, Amgen, ALX Oncology, Genentech, Seagen, Servier, Incyte, Alentis, Teva Therapeutics, and Merus; grants and personal fees from Bristol Myers Squibb, Merck, and GSK; and personal fees from Beigene outside the submitted work. E. Buchbinder reports personal fees from Obsidian, Anaveon, Merck, Werewolf, Iovance, and Sanofi outside the submitted work. M. Sznol reports personal fees from IO Biotech, BioNTech (DSMC), Immatics, GII Innovation, Regeneron, Simcha (SAB), Cullinan (SAB), AsherBio (SAB), Bioinvent, Normunity (SAB), Lyvgen, Ideaya (DSMC), Nextcure (SAB), Bristol Myers Squibb, Sanofi (DSMC), Turnstone, Pfizer, EvolveImmune (SAB), Innate Pharma (SAB), Incyte, Anaptys, Pliant, Iovance, Molecular Partners, Biond (DSMC), Sumitomo, Numab, Alligator, Partner Therapeutics, Oncohost, Teva, Verastem, Rootpath, Evaxion, Dragonfly, Jazz Pharmaceuticals, Ichnos, Adaptimmune, Nimbus, Xilio, Targovax, Alkermes, PIO Therapeutics, Merck, Pierre-Fabre, Ocellaris-Lilly, Immunocore, and Glaxo Smith Kline and other from Actym (stock options only), Adaptive Biotechnologies (stock options only), Asher Bio, EvolveImmune, Glaxo-Smith Kline (stock), Intensity (stock options only), Johnson and Johnson (stock), NextCure, Normunity, Oncohost, Rootpath, and Thetis outside the submitted work. H. Prenen reports personal fees from Amgen, Astra Zeneca, Merck, Pfizer, and Roche outside the submitted work. A.M. Arance Fernandez reports other from Almirall, Biontech, Bristol Myers Squibb, Novartis, Pierre Fabre, MSD, BionTech, and Replimune outside the submitted work. J.-J. Grob reports personal fees from Bristol Myers Squibb, MSD, Novartis, Philogen, and Sanofi outside the submitted work. C. Robert reports personal fees from Bristol Myers Squibb, IO BioTech, MaaT Pharma, Philogen, Egle, Regeneron, Ultimovacs, Sun Pharma, Merck, MSD, Pfizer, Sanofi, Novartis, Pierre Fabre, and Roche outside the submitted work. C. Habigt reports other from Roche Diagnostics GmbH outside the submitted work and medical writing assistance was provided by Christian Seitz, PhD, and was funded by F. Hoffmann-La Roche Ltd. S. Evers reports other from F. Hoffmann-La Roche AG during the conduct of the study and other from F. Hoffmann-La Roche AG outside the submitted work. N. Sleiman reports personal fees from Roche during the conduct of the study. D. Dejardin reports personal fees from Roche during the conduct of the study and personal fees from Roche outside the submitted work. C. Ardeshir reports other from Roche Products Ltd during the conduct of the study. C. Boetsch reports other from F. Hoffmann La Roche and F. Hoffmann La Roche during the conduct of the study. J. Charo reports personal fees from Roche during the conduct of the study and personal fees from Roche outside the submitted work, has a patent to EPO 22207100.3 pending, and is a stockholder at Roche. Dr. V. Teichgräber reports other from Roche during the conduct of the study and other from Roche outside the submitted work and that he is an employee and stockholder of Roche. A. Kraxner reports other from Hoffmann‐La Roche during the conduct of the study; Dr. Kraxner is an employee and stockholder of Hoffmann La‐Roche. N. Keshelava reports other from Hoffmann-La Roche and Jazz Pharmaceuticals outside the submitted work. O. Bechter reports other from Pierre Fabre and MSD outside the submitted work. No disclosures were reported by the other authors.

Figures

Figure 1
Figure 1
Antitumor activity following treatment with FAP-IL2v of CPI-experienced patients in the extension part with at least one postbaseline tumor assessment (n = 62). Best percentage change in the sum of diameters of target lesion from baseline (column color indicates confirmed best overall response) in CPI-experienced patients in the Q3W extension part (n = 41; A) and in the QW/Q3W extension part (n = 21; B). C, Kaplan–Meier estimate of progression-free survival in patients in the Q3W (blue) and QW/Q3W (red) extension part. Tick marks on the Kaplan–Meier plot show censoring of the data at the last time the patient was known to be alive. NE, not evaluable; PD, progressive disease; SD, stable disease; SLD, sum of longest diameters.
Figure 2
Figure 2
Pharmacodynamic results in peripheral blood. Peripheral blood collected at baseline and various on-treatment time points (e.g., C2D1, C3D1, and C4D1) was assessed for changes in key immune cell subsets such as NK cells, CD8 T cells, CD4 T cells, and Tregs (A) and markers for immune cell activation (sCD25) and proliferation (Ki-67+; B). BL, baseline; C, cycle; D, day.
Figure 3
Figure 3
Pharmacodynamic results in tumor tissue. Tumor tissue from biopsies taken at baseline and on treatment (C2D8) was assessed for changes in TIL density with respect to CD3 T cells, CD8 T cells, proliferating CD8 T cells, NK cells, and cytotoxic T lymphocytes (A) and Tregs as well as PD-L1 expression on immune and tumor cells (Ventana SP263 assay; B). For these exploratory PD assessments, the investigator assessment of tumor response was used. BL, baseline; C, cycle; D, day; IC, immune cell; PD, progressive disease; SD, stable disease; TC, tumor cell.
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