Pavlos Msaouel, Assistant Professor of Genitourinary Medical Oncology at MD Anderson Cancer Center, shared a post on X about a recent article he and his colleagues co-authored, published in Clinical Cancer Research:
“New in Clinical Cancer Research: Results of the 1st prospective trial of a targeted agent in SMARCB1-deficient Renal Medullary Carcinoma (RMC).
We tested ixazomib plus gemcitabine plus doxorubicin in 30 patients.
Our hypothesis was that SMARCB1 loss in RMC creates parallel vulnerabilities: replication stress (targeted by gemcitabine plus doxorubicin) and proteotoxic stress (targeted by ixazomib).
Hit both at once may produce deeper and more durableresponses.
Results: ORR 36% (vs ~19% historic for the doublet), 91.4% posterior probability of beating doublet.
But 28-wk disease control rate was only 17% — crossing the futility boundary. Median PFS 3.5 mo, median OS 7.4 mo. Toxicity manageable, no treatment-related deaths.
Single-cell plus bulk multi-omics in 11 patients revealed who benefits and why resistance emerges.
Benefit immune-inflamed TMEs rich in T cells, pDCs and cDCs. Resistance stromal–myeloid niches, proliferative/plastic epithelial states, and upregulated UPR, proteostasis, NF-κB.
Bottom line: ixazomib triplet modestly boosts response but not durable control in unselected RMC. The real win is a roadmap: biomarker-guided selection&therapies targeting the stress-adaptation and stromal circuits identified here.
The next generation of RMC trials starts here.
Title: Phase II Trial of Ixazomib Combined with Gemcitabine and Doxorubicin in Patients with SMARCB1-Deficient Renal Medullary Carcinoma
Authors: Kai Yu, Rebecca Tidwell, Tharakeswara Bathala, Rahul Sheth, Menuka Karki, Jianfeng Chen, Jing Qian, Fei Duan, Luigi Perelli, Melinda Soeung, Priya Rao, Arlene Siefker-Radtke, Najat Daw, Davis Ingram, Diana Shamsutdinova, Khalida Wani, Wei-Lien Wang, Alexander Lazar, Zilong Zhao, Sabitha Prabhakaran, Neus Bota-Rabassedas, Andrew Futreal, Liuqing Yang, Chunru Lin, Giannicola Genovese, Jianjun Gao, Linghua Wang, Nizar Tannir, Pavlos Msaouel
Read the Full Article on Clinical Cancer Research
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