Abstract 664P
Background
Cabozantinib (Cabo) exhibits innate and adaptive immunomodulation providing a rationale for a phase I trial of CaboNivo or CaboNivoIpi in mGU tumors. We present the final results of the phase I with correlative peripheral blood immune subsets.
Methods
This phase I dose escalation and expansion study in pts with advanced mGU tumors refractory to front-line therapy. The objectives were to determine the clinical activity, safety/tolerability of both combinations CaboNivo (n=60) and CaboNivoIpi (n=56) and correlate activity with immunosuppressive peripheral blood immune subsets.
Results
120 pts (median age 59 yrs; range 20-82 yrs) were enrolled including urothelial carcinoma; renal cell carcinoma; bladder adenocarcinoma; penile carcinoma, and other mGU tumors: 64 pts received CaboNivo and 56 CaboNivoIpi. Median follow-up was 40.4 months (range 2.2-62.2). The ORR for 108 evaluable pts was 38% (95% CI: 28.8-47.8%) with 12 complete responses (11.1%) and 29 partial responses (26.9%). The progression free survival (PFS) was 5.5 months (95% CI: 4.5-10.1), with overall survival (OS) of 15.9 months (95% CI: 11.6 -23.9). CaboNivo and CaboNivoIpi decreased immunosuppressive monocytic MDSCs (M-MDSCs) and classical monocytes (p = 0.027, p<0.0001), and increased the CD8+/CD4+ T cell ratio (p = 0.0001). Dendritic cell (DC) subsets (CD1c+ mDC, CD141+ mDC, CD303+ pDC) decreased with treatment (p < 0.001, p = 0.0026, p<0.0001). CTLA-4 and Tim-3 on T cells increased (p<0.0001, p<0.0001) and higher CTLA-4 on CD4+ T cells was associated with higher PFS/OS (CaboNivoIpi OS: p = 0.046; CaboNivo PFS: p = 0.0347; CaboNivo OS p = 0.0335). CaboNivo treatment increased proliferative activated T cells (Ki67+HLA-DR+, Ki67+ICOS+, Ki67+GITR+) at C2 but not C3, and this increase correlated with better PFS (p=0.0097) and OS (p=0.004). CaboNivoIpi strongly increased these subsets at both C2D1 (p <0.0001) and C3D1 (p = 0.0004) without association with OS/ORR.
Conclusions
CaboNivo and CaboNivoIpi showed promising clinical activity and manageable safety in mGU tumors. These therapies modulated innate and adaptive peripheral blood immune subsets with response distinctive patterns.
Clinical trial identification
NCT02496208.
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
B. Saraiya: Other, Institutional, Other, Honoraria: Sanofi; Other, Institutional, Other, Honoraria: Eisai. S.K. Pal: Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Aveo; Financial Interests, Personal, Advisory Role: Myriad Pharmaceuticals; Financial Interests, Personal, Advisory Role: Genentech; Financial Interests, Personal, Advisory Role: Exelixis; Financial Interests, Personal, Advisory Role: Bristol Myers Squibb; Financial Interests, Personal, Advisory Role: Astellas Pharma; Financial Interests, Personal, Advisory Role: Ipsen; Financial Interests, Personal, Advisory Role: Eisai. P.N. Lara: Financial Interests, Personal, Advisory Role: Janssen; Financial Interests, Institutional, Funding: Aragon Pharmaceuticals; Financial Interests, Institutional, Funding: Janssen Biotech; Financial Interests, Institutional, Funding: TRACON Pharmaceuticals; Financial Interests, Institutional, Funding: Pharmacyclics; Financial Interests, Institutional, Funding: Incyte; Financial Interests, Institutional, Funding: Taiho. A. Mortazavi: Financial Interests, Personal, Other, Honoraria: Motive Medical Intelligence; Financial Interests, Personal, Advisory Role: Merck Sharp & Dohme; Financial Interests, Personal, Advisory Role: Exelixis; Financial Interests, Institutional, Funding: Oncoceutics; Financial Interests, Institutional, Funding: Merck Sharpe & Dohme; Financial Interests, Institutional, Funding: Janssen Oncology; Financial Interests, Institutional, Funding: Medivation/Astellas; Financial Interests, Institutional, Funding: Advaxis; Financial Interests, Institutional, Funding: Suzhou Kintor Pharmaceuticals; Financial Interests, Institutional, Funding: Harpoon; Financial Interests, Institutional, Funding: Bristol Myers Squibb; Financial Interests, Institutional, Funding: Genocea Biosciences; Financial Interests, Institutional, Funding: Eli Lilly; Financial Interests, Institutional, Funding: Nektar; Financial Interests, Institutional, Funding: Seattle Genetics; Financial Interests, Institutional, Funding: Xencor; Financial Interests, Institutional, Funding: Tmunity; Financial Interests, Institutional, Funding: Exelixis. S. Niglio: Financial Interests, Personal, Stocks/Shares: Regeneron; Financial Interests, Personal, Stocks/Shares: Gilead Sciences; Financial Interests, Personal, Other, (Family Member): STEMCELL Technologies. D. Bottaro: Financial Interests, Personal and Institutional, Royalties, US Patent No. 6,326,466; US Patent No. 6,566,098; US Patent No. 7,132,392; US Patent No. 7,605,127; US Patent No. 7,871,981; US Patent No. 7,964,365; US Patent No. 8,304,199; US Patent No. 8,569,360; US Patent No. 8,617,831; US Patent No. 8,754,081; US Patent No. 9,550,818; US Patent No. 10,035,833: US Patents. J. Trepel: Financial Interests, Institutional, Funding: Syndax; Financial Interests, Institutional, Funding: EpicentRX; Financial Interests, Institutional, Funding: AstraZeneca. All other authors have declared no conflicts of interest.