170MO - Tremelimumab +/- durvalumab plus paclitaxel as immune induction in metastatic urothelial cancer: translational results of the ICRA trial

Background

An unmet need remains for new therapies for patients with metastatic urothelial carcinoma (mUC) progressing after (at least) anti-PD-(L)1 immunotherapy. Here, we present the translational results of the phase I-II ICRA trial, in which we evaluated whether paclitaxel plus tremelimumab (anti-CTLA-4; T) +/- durvalumab (anti-PD-L1; D) could induce response in therapy-refractory mUC.

Methods

Patients with mUC, progressing on previous platinum-based chemotherapy and anti-PD-(L)1 were included. In the safety phase, we tested weekly paclitaxel (70mg/m²; 6 cycles) plus escalating doses of T +/- D every 4 weeks. In the two-staged main phase, patients received (arm A; n=20 after expansion) paclitaxel plus T750mg (cycles 2-8); (arm B; n=12) paclitaxel plus T300mg (cycle 2) plus D1500mg (cycles 2-13); (arm C; n=12) T750mg (cycles 1-7). PD-L1 assessment was performed on baseline tissues. Whole genome sequencing, including tumor mutational burden (TMB), was available in 18 patients. Transcriptomic analyses were performed on tissues acquired after pre-trial systemic treatment (n=28) and on-treatment biopsies (n=13).

Results

The objective response rate in arm A was 26% and 8% in arms B, and C. PD-L1 status and TMB were not correlated with overall survival (OS). Baseline tissue from patients with durable response exhibited higher levels of inflammation. High baseline expression of interferon-γ (IFN-γ) was associated with longer OS (p=0.021) and high CD8⁺ T effector expression showed a trend towards longer OS (p=0.064). Analyses of pre- versus on-treatment tissue showed increased expression of CD8⁺ T effector and IFN-γ signatures in paired (p=0.02 and p=0.01, respectively) and unpaired (p=0.01 and p=0.001, respectively) analyses, suggesting anti-CTLA4 may still induce anti-tumor immunity post-anti-PD(L)1.

Conclusions

Our transcriptomic results suggest that induction of anti-cancer immunity is possible in anti-PD-(L)1-refractory mUC, but in this setting a degree of preexisting immune activity might be necessary but not sufficient to mount a durable immune response upon anti-CTLA-4 treatment.

Clinical trial identification

NCT03871036.

Legal entity responsible for the study

Netherlands Cancer Institute.

Funding

KWF, AstraZeneca.

Disclosure

M.S. van der Heijden: Financial Interests, Institutional, Advisory Board: AstraZeneca, BMS, Janssen, MSD, Seagen, Pfizer, Astellas; Financial Interests, Institutional, Funding, Investigator-initiated trial: Roche, MSD, BMS, AstraZeneca, 4SC; Financial Interests, Institutional, Steering Committee Member, Local PI + SSC member: Seagen, MSD, BMS, AstraZeneca; Financial Interests, Institutional, Steering Committee Member, Local PI + study co-PI: Janssen. J. de Feijter: Financial Interests, Institutional, Advisory Board: Janssen, Merck. S. Oosting: Financial Interests, Institutional, Advisory Board: Bristol Myers Squibb, Genmab; Financial Interests, Institutional, Invited Speaker: Merck, Travel Congress Management B.V.; Financial Interests, Institutional, Research Grant, Investigator initiated research: Celldex; Financial Interests, Institutional, Research Grant, Investigator initiated study: Pfizer, Novartis; Financial Interests, Institutional, Research Grant, I am the principle investigator of EORTC 2120 for which EORTC has received funding from Merck; Merck; Non-Financial Interests, Institutional, Product Samples: Celldex, Pfizer, Novartis; Other, Personal, Other, Member of steering and safety monitoring committee, unpaid; ALX Oncology. B.B. Suelmann: Financial Interests, Institutional, Advisory Board: BMS , Pfizer, Ipsen, Astellas, Eisai, Merck, MSD; Financial Interests, Institutional, Funding: Pfizer, Ipsen, Astellas, AstraZeneca, Merck. All other authors have declared no conflicts of interest.