PQA 04 - Breast Cancer, Patient Reported Outcomes/QoL/Survivorship, Functional Radiation Medicine, Hematologic Malignancies, Palliative Care, and International/Global Oncology
Presenter(s)
A. Fernandez1, E. M. Maverakis2, Y. S. Keum3, V. Grover4, X. Zhao5, S. S. D. Rao6, B. A. Dyer7, C. X. Wang8, A. Merleev2, A. Marusina2, S. Dhar4, G. Fananapazir1, M. Larson1, L. V. Vick4, R. Canter1, W. J. Murphy9, Y. H. Sun8, K. Kelly10, M. E. Daly11, and A. M. Monjazeb8; 1UC Davis Health, Sacramento, CA, 2University of California Davis, School of Medicine, Department of Dermatology, Sacramento, CA, 3University of Nevada Reno School of Medicine, Reno, NV, United States, 4UC Davis, Sacramento, CA, 5Department of Radiation Oncology, University of California Davis Comprehensive Cancer Center, Sacramento, CA, 6University of California Davis Comprehensive Cancer Center, Sacramento, CA, 7Seattle Cancer Care Alliance, Seattle, WA, 8University of California Davis, Department of Radiation Oncology, Sacramento, CA, 9University of California Davis, Sacramento, CA, 10Scientific Affairs, International Association for the Study of Lung Cancer, Sacramento, CA, 11Department of Radiation Oncology, University of California - Irvine, Orange, CA
Purpose/Objective(s): Targeting the PD-1/PD-L1 axis with immune checkpoint inhibitors (ICI) is among the most efficacious cancer therapies. Yet, a minority of patients respond to ICI and few maintain durable long-term responses. Lack of response has been linked to absence of a T cell inflamed tumor microenvironment (TME). Interleukin-2 (IL-2) can potently activate T cells, increase infiltration into the TME, and promote their anti-tumor activity. Studies suggest that IL-2 can enhance the immune modulatory effects of radiotherapy (RT) but toxicity with high dose systemic IL-2 has limited widespread use. We hypothesized that intra-lesional administration of IL-2 in combination with RT could induce a T cell inflamed TME and overcome ICI resistance with minimal toxicity. Materials/Methods: We initiated a single institution phase I/II study of pembrolizumab with RT (24 Gy / 3 fx) and intralesional IL-2 in ICI refractory patients. Pembrolizumab was administered until progression or intolerance. RT and four IL-2 injections were administered during cycle 2 of pembrolizumab. Phase I was a 3+3 dose finding design with de-escalation starting at the highest dose level of 15x106 IU of intralesional IL-2. Phase II was an expansion at the MTD with a binomial one stage design. We aimed to accrue 21 patients at the MTD and 3/21 abscopal responses were required for a positive trial (p0=0.05 and p1=0.20). The primary objective was to determine abscopal ORR by immune related response criteria (irRC) as well as ORR, DCR, and PFS by RECIST 1.1. The secondary objective was to determine the safety profile and MTD. Pre- and post-treatment tumor biopsy and blood sampling was collected for correlative analysis. Results: 18 adult patients with advanced solid tumors refractory to prior ICI (primarily lung and renal cancers) were enrolled. Seven patients enrolled in the phase I dose finding arm and 6 were evaluable for DLT. One patient developed a DLT and dose de-escalation was not required. An additional 11 patients enrolled in the phase II expansion cohort for a total of 18 patients of which 14 were evaluable for response and 15 for PFS. The abscopal response rate and ORR were the same, with 2 of 14 patients responding (14%, 95% CI: 3-41%). The DCR was 36% (95% CI: 16% to 61%). The median PFS for the cohort was 2 months with many patients progressing rapidly. However, patients who benefited had prolonged benefit with a 311 day median duration of disease control and the median duration of response not reached, with the two responders experiencing durable ongoing responses without additional off-trial therapy. Spatial transcriptomics and analysis of circulating PBMCs revealed significant treatment-induced changes. Protocol therapy increased the proliferation and activity of T cells systemically and in the TME and induced a T cell inflamed TME. Conclusion: Protocol therapy was safe and well tolerated. This approach is able to induce a T cell inflamed TME and rescue ICI refractory patients. Further study is warranted.
