130P - Ipilimumab plus nivolumab (Ipi+Nivo) in patients with tumors harboring high tumor mutational burden or load (TMB/TML-H): Results from the Drug Rediscovery Protocol (DRUP)

Background

Tumor-agnostic application of ipi+nivo has shown effectiveness in various tumor types. TMB, the number of mutations per megabase of tumor genome, and TML, the non-synonymous mutations across the whole tumor genome, are frequently used as biomarkers for patient selection. However, few studies have used TMB/TML in a prospective, tumor-agnostic setting. Here, we present results of ipi+nivo in adult patients (pts) with advanced or metastatic TMB/TML-H cancers.

Methods

Treatment-refractory pts, progressive on last treatment lines, were treated in DRUP (NCT02925234) with off-label drugs, based on their tumors’ molecular profile. Eligible pts had microsatellite stable tumors and a TML of 200-1000 or TMB between 11-24 (Oncomine panel) or 15-39 (TSO500-panel). Pts received 4 cycles of 1mg/kg ipi with 3mg/kg nivo every 3 weeks, followed by 480mg nivo monotherapy every 4 weeks until progressive disease (PD) or unacceptable toxicity. Clinical benefit (CB: confirmed objective response (OR) or stable disease (SD) ≥16 weeks) and safety were primary endpoints. A pre-treatment biopsy was taken for post-hoc whole genome sequencing to identify biomarkers associated with CB or PD.

Results

A total of 30 pts started treatment, of whom 24 were evaluable, with 13 different tumor types, mostly colorectal cancer (33%). Median TML was 305 [IQR 238 – 521] and TMB 17 [IQR 13 – 24]. Two pts (8%) had complete response, 6 pts (25%) partial response, and 4 pts (17%) SD, resulting in a CB-rate of 50% (95% CI 29 – 71) and OR-rate of 33% (95% CI 16 – 55). Pts with CB had a significantly higher median TML (526 [IQR 351 – 560] vs. 240 [IQR 225 – 299], p=0.004) and TMB (23 [IQR 17 – 30] vs. 14 [IQR 13 – 17], p=0.005). Median duration of response (mDOR), progression-free and overall survival were 26.7 months (95% CI NA – NA), 5.6 months (95% CI 2.1 – NA) and 31.7 months (95% CI 12.7 – NA), respectively. In 11/30 pts (37%), 16 treatment-related adverse events grade ≥3 were observed, resulting in treatment discontinuation in 4 (13%).

Conclusions

Ipi+nivo showed notable efficacy and impressive mDOR in pts with TMB/TML-H tumors across tumor types. Higher TMB/TML correlated with CB, offering further opportunities to refine patient selection.

Clinical trial identification

NCT02925234.

Editorial acknowledgement

Legal entity responsible for the study

Netherlands Cancer Institute, Amsterdam, The Netherlands.

Funding

Stelvio for Life Foundation: funding; Dutch Cancer Society (KWF): funding; Hartwig Medical Foundation (HMF): genome sequencing; Pharmaceutical partners (Amgen, AstraZeneca, Bristol Myers Squibb, Eisai, GSK, Janssen, Lilly, Novartis, Pfizer, Roche): funding and study drugs.

Disclosure

P. Roepman: Financial Interests, Institutional, Full or part-time Employment: Hartwig Medical Foundation. D. Robbrecht: Financial Interests, Institutional, Advisory Board: Merck AG, Pfizer; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Astellas; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Institutional, Coordinating PI: Treatmeds, DUOS; Financial Interests, Institutional, Coordinating PI, For study purposes: Merck AG; Non-Financial Interests, Advisory Role: Bayer; Non-Financial Interests, Principal Investigator: Sanofi, Incyte, Roche, InteRNA, Numab Therapeutics, Menarini. E.E. Voest: Financial Interests, Personal, Advisory Board, Hourly rate: Biogeneration Ventures; Financial Interests, Personal, Member of Board of Directors, independent, non-executive director and share holder: Sanofi; Financial Interests, Personal, Other, Founder, strategic adviser and share holder: Mosaic Therapeutics; Financial Interests, Personal, Ownership Interest, Mandatory shares as part of board membership: Sanofi; Financial Interests, Personal, Ownership Interest, Start up company with shares: Mosaic Therapeutics; Financial Interests, Institutional, Coordinating PI, DRUP trial: Amgen, AstraZeneca, BMS, Eisai, Ipsen, MSD, Novartis, Pfizer, GSK, Seattle Genetics; Financial Interests, Institutional, Coordinating PI, DRUP trialDRUG Access Protocol: Bayer, Roche; Financial Interests, Institutional, Coordinating PI, DRUG Access Protocol: Sanofi; Non-Financial Interests, Other, Supervisory Board: HMF – Hartwig Medical Foundation; Non-Financial Interests, Principal Investigator, Senior group leader: Oncode Institute; Non-Financial Interests, Advisory Role, Editorial Board: JAMA Oncology. H. Gelderblom: Financial Interests, Institutional, Local PI: Deciphera, Cytovation; Financial Interests, Institutional, Coordinating PI: Boehringer Ingelheim, AmMax Bio, Debiopharm, Abbisko. All other authors have declared no conflicts of interest.