729MO - Final results of the first-in-human clinical trial of the GDF-15 neutralizing antibody CTL-002 in combination with nivolumab in subjects with solid tumors relapsed/refractory to prior anti-PD1/PD-L1 treatment

Background

Growth and differentiation factor 15 (GDF-15) is a major tumor-derived immunosuppressant. Tumoral expression correlates with poor clinical outcome [Front Imm 2020 May 19;11:951]. Here we present the results of the first-in-human, phase 1 trial of the GDF-15 neutralizing antibody CTL-002.

Methods

This was the first-in-human, phase 1 dose escalation clinical trial of CTL-002 given IV as monotherapy and in combination with nivolumab in subjects with advanced-stage solid tumors relapsed/refractory to at least one prior anti-PD-1/PD-L1 therapy and having exhausted all available therapeutic options. 25 subjects received escalating doses of CTL-002 IV (0.3 – 20 mg/kg) in an integrated monotherapy-followed-by-combination-design with one cycle CTL-002 followed by combo with nivolumab.

Results

The combination of CTL-002 and nivolumab showed excellent tolerability, no DLT and Grade ≥ 4 AE occurred. A substantial tumor-selective influx of CD8+ and CD4+ T cells was detected in most patients under treatment, and significant increases in proliferating and cytotoxic (CD3+GrzB+) T cells in tumor tissue. Five patients relapsed/refractory to prior anti-PD1/PD-L1 treatment and with all other available treatment options exhausted experienced tumor regression, three of them as confirmed, lasting partial responses (> 8 months and ongoing; HCC, CUP tumor and Mesothelioma), others experienced prolonged stable disease.The tumor regression rate observed at dose level 4+5 was 25%. Biomarker-analyses identified a marker that was present in ∼25% of patients and if employed for patient selection would have resulted in a 50% partial response rate and a clinical benefit rate of > 65% in this heavily pre-treated, last-line mixed solid tumor population.

Conclusions

CTL-002 neutralization of GDF-15 in combination with PD-1 blockade was safe, increased CD8+ and CD4+ T cell tumor infiltration and antitumoral activity and induced confirmed objective clinical responses and lasting tumor regression in heavily pre-treated and previously anti-PD-1/-PD-L1 relapsed/refractory patients at a rate of 25% for dose level 4 and 5. Phase 2 development is ongoing.

Clinical trial identification

NCT04725474.

Editorial acknowledgement

Legal entity responsible for the study

Catalym GmbH.

Funding

Catalym GmbH.

Disclosure

I. Melero: Financial Interests, Personal, Advisory Board: Gossamer Bio, Highlight Therapeutics, MSD, Alligator Bioscience, Genmab, Numab, Noxxon Pharma AG, BMS, CRISPR Therapeutics, Genentech, AstraZeneca, Boehringer Ingelheim, EMD Serono, Roche; Financial Interests, Personal, Consultant: Pharma Mar; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Roche, BMS, Genmab, Alligator; Financial Interests, Personal, Advisory Role: Catalym. M.J. De Miguel: Financial Interests, Personal, Advisory Role: Syneos, Janssen, MSD; Financial Interests, Institutional, Principal Investigator: AbbVie, Array, Achilles, Basilea, Bayer, Biontech, Faron, MSD, Novartis, Cytomex, Genentech, Genmab, Janssen, Menarini, Nektar, Catalym, Regeneron, Zenith. M. Goebeler: Financial Interests, Personal, Gemoab, BMS, Janssen, Roche, Pfizer, Novartis, Catalym. E. Calvo: Financial Interests, Personal, Full or part-time Employment, Medical Oncologist, Clinical Investigator; Director, Clinical Research: START, HM Hospitales Group; Financial Interests, Personal, Advisory Role: Nanobiotix, Janssen, Roche / Genentech, Amcure, TargImmune, Servier, BMS, PharmaMar, Alkermes, Amunix, Adcendo, Anaveon, AstraZeneca, MonTa, MSD, Nouscom, Novartis, OncoDNA, Sanofi, Syneos Health, T-Knife, Boehringer Ingelheim; Financial Interests, Institutional, Research Grant: BeiGene, Achilles; Non-Financial Interests, Personal, President and founder: Foundation INTHEOS (Investigational Therapeutics in Oncological Sciences); Financial Interests, Personal, Ownership Interest: START corporation, Oncoart Associated, International Cancer Consultants; Financial Interests, Personal, Scientific Board: Adcendo, Chugai Pharmaceuticals, PsiOxus Therapeutics; Financial Interests, Personal, IDMC Steering Committee: BeiGene; Non-Financial Interests, Personal, IDMC Chair: EORTC ; Financial Interests, Personal, Steering Committee: MedSIR, Novartis. E. Garralda: Financial Interests, Personal, Advisory Board: Genentech, F.Hoffmann/La Roche, Neomed Therapeutics1 Inc, Boehringer Ingelheim, Janssen Global Services, Alkermes, Thermo Fisher, MabDiscovery, Anaveon, Lilly, Hengrui; Financial Interests, Personal, Invited Speaker: Ellipses Pharma, Seattle Genetics, Bristol Myers Squibb, MSD, F-Star Therapeutics; Financial Interests, Institutional, Funding: Novartis, Roche, Thermo Fisher, AstraZeneca, Taiho. R. Dummer: Financial Interests, Personal, Consulting and/or advisory role: Novartis, Merck Sharp & Dohme (MSD), Bristol Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, MaviVAX SA, touchIME, T3 Pharma, Pfizer. C.M. Sayehli: Non-Financial Interests, Personal and Institutional, Principal Investigator: Amgen, Bayer, BMS, Boehringer Ingelheim, Chugai, Glenmark; Personal, Travel Support, Congress Fees, Hotel Costs: Novartis, Lilly, BMS, Celgene. M.F. Sanmamed: Financial Interests, Personal, Consultancy: Numab; Financial Interests, Personal, Advisory Role: Pieris; Financial Interests, Personal, Invited Speaker: MSD, BMS; Financial Interests, Personal, Project Research: Roche; Financial Interests, Institutional, Clinical Trial: Roche, BMS, Amgen, Genmab, Genentech, Replimune; Non-Financial Interests, Personal, Advisory Role: ASEICA (Spain). M.H.H. Schuler: Financial Interests, Personal, Invited Speaker: Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, Novartis, Roche; Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Merck Serono, Novartis, Roche, Sanofi, Takeda; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, AstraZeneca; Non-Financial Interests, Principal Investigator, Member, Study Steering Board: Janssen. P. Fettes: Financial Interests, Personal, Full or part-time Employment, Head of Clinical Operations: CatalYm; Financial Interests, Personal, Stocks/Shares: CureVac. K. Klar: Financial Interests, Personal, Full or part-time Employment: CatalYm. C. Schuberth-Wagner: Financial Interests, Personal, Scientific Advisor: Lodo Therapeutics LTD; Financial Interests, Personal, Full or part-time Employment: Rigontec GmbH, CatalYm GmbH; Financial Interests, Personal, Stocks/Shares: Rigontec GmbH, CatalYm GmbH; Financial Interests, Personal, Inventor: Rigontec GmbH, CatalYm GmbH. J. Wischhusen: Financial Interests, Personal: CatalYm GmbH, Aeterna Zentaris Inc.; Financial Interests, Personal, Stocks/Shares, founder shares: CatalYm GmbH; Financial Interests, Personal and Institutional, All payments go to the University which then distribute a proportion to the inventors.: CatalYm GmbH, Aeterna Zentaris Inc., Argenx; Financial Interests, Personal, Funding: CatalYm GmbH, Aeterna Zentaris Inc., Argenx. E. Leo: Financial Interests, Personal, Affiliate: Catalym GmbH; Financial Interests, Personal, Stocks/Shares: Catalym GmbH. All other authors have declared no conflicts of interest.