Main Session

Sep 29

PQA 06 - Genitourinary Cancer, Gynecological Cancer, and Health Care Access and Engagement

3314 - Neutron Radiotherapy with Concurrent Checkpoint Inhibitor in Patients with Advanced Urothelial Carcinoma (aUC): Results from a Phase II Clinical Trial

02:15pm - 03:30pm ET

Poster Hall - Exhibit Hall A

Screen: 1

POSTER

Presenter(s)

Ting Martin Ma, MD, PhD - University of Washington, Seattle, WA

M. Wolff¹, E. Bouvet¹, J. J. Liao², R. Rengan³, M. Schweizer⁴, P. Grivas⁴, E. Y. Yu⁵, H. H. Cheng⁴, B. Montgomery⁶, A. Hsieh¹, J. Lee⁷, T. Yezefski⁴, J. Zeng³, O. Y. Mian³, and T. M. M. Ma⁸; ¹Fred Hutch Cancer Center, Seattle, WA, ²University of Washington Fred Hutchinson Cancer Center, Seattle, WA, ³Department of Radiation Oncology, University of Washington/Fred Hutchinson Cancer Center, Seattle, WA, ⁴University of Washington, Seattle, WA, ⁵Seattle Cancer Care Alliance, Seattle, WA, ⁶University of Washington, Seattle, WA, United States, ⁷UCLA, Los Angeles, CA, ⁸University of Washington, Department of Radiation Oncology, Seattle, WA

Purpose/Objective(s):

We investigated whether high–relative biologic effectiveness (RBE) neutron radiotherapy (nRT), given concurrently with pembrolizumab, could improve systemic response rates with acceptable toxicity, and explored peripheral T-cell repertoire dynamics as a biomarker of immune activation in patients with aUC.

Materials/Methods:

This was a phase II, single-arm, single-center trial (NCT03486197). Eligible patients had pathologically confirmed aUC and at least two measurable lesions, with at least one lesion left unirradiated as the index lesion for iRECIST assessment. Pembrolizumab was administered every 3 weeks; focal nRT to 1–2 sites (primary and/or metastatic) was delivered between cycles 2 and 3. The primary endpoint was overall response rate (ORR) at non-irradiated index lesions per iRECIST. Secondary endpoints included toxicity (CTCAE v4.0), progression-free survival (PFS), and overall survival (OS). Peripheral blood was collected at baseline, pre-nRT, and 4 and 16 weeks post-nRT for T-cell receptor (TCR) sequencing, with antigen-specific responses quantified by convergent clonotype counts (CCC).

Results:

Twelve patients with aUC were enrolled (median age 67 years); 6 had bladder and 6 had upper tract urothelial primary tumor. Nine patients had at least three sites of disease, 3 had visceral metastasis (including 1 in liver). All but 1 had ECOG 0-1. Median follow-up was 28 months. The median nRT dose was 6 Gy in 3 fractions (biologically equivalent to 23.4 Gy in 3 fractions of photons; range 5.25–7.5 Gy in 2–3 fractions). ORR at non-irradiated index lesions was 56% (2 complete and 3 partial responses), with median PFS of 9.4 months (95% CI, 1.9–33.8) and median OS of 29.7 months (95% CI, 4–not reached). Immune-related toxicities attributable to pembrolizumab included grade 3 myositis and pancreatitis in 2/12 (17%) patients, and grade 2 pancreatitis, hypothyroidism, gastritis, and nephritis in 3/12 (25%) patients; no grade =2 adverse events were attributed to nRT. In the cohort with available biospecimens (n=10), TCR sequencing demonstrated dynamic clonal expansion comparable to a published cohort treated with conventional chemoradiation plus atezolizumab (CCC: 14.2 vs 11.2, p=0.12), with greater post-radiation clonal expansion and higher total convergent TCRs in clinical responders (CR/PR) than non-responders (CCC: 14.6 vs 8.3, p=0.0403).

Conclusion:

Concurrent pembrolizumab and focal nRT yielded a favorable systemic response rate and encouraging survival signal in patients with aUC, comparable to outcomes reported with photon-based RT, with an acceptable toxicity profile and no unexpected nRT-specific toxicity. Early TCR repertoire analyses showed expansion of convergent, tumor-reactive T-cell clones, but did not demonstrate a clearly discernible enhancement in tumor neoantigen-specific responses with high-RBE radiation. Limitations include small sample size, lack of randomization, potential selection and confounding biases.