MD Anderson Research Highlights for August 24, 2022

Featuring rising response rates in Phase I trials, targeted therapy and cell therapy advances for B-cell lymphomas, and promising combination therapies in several cancers

The University of Texas MD Anderson Cancer Center’s Research Highlights provides a glimpse into recent basic, translational and clinical cancer research from MD Anderson experts. Current advances include confirmation of improving response rates in Phase I trials over the last 20 years, a novel targeted therapy combination and biomarkers of response for chimeric antigen receptor (CAR) T cell therapy in B-cell lymphomas, a combination therapy for patients with melanoma brain metastases, and new treatment options for metastatic sarcomas, HPV-driven cancers and uterine cancer.

Study finds response rates have doubled in Phase I trials for solid tumors over past two decades
Phase I clinical trials evaluate the safety of new investigational drugs and assess whether the treatment should proceed to Phase II trials to evaluate efficacy. Historically, Phase I trials have had relatively low response rates and raise questions about the clinical benefit for patients with advanced cancers. In this study, led by Dai Chihara, M.D., Ph.D., researchers analyzed patient-level data from 465 National Cancer Institute-sponsored investigator-initiated Phase I trials for solid tumors that enrolled patients from January 2000 to May 2019. They found that response rates nearly doubled during the study period without an increase in the treatment-related death rate. This study provides encouraging new evidence on the outcomes of modern Phase I trials with investigational therapies for patients with solid tumors. This research will help clinicians and patients have informed discussions about participation in early clinical trials. Learn more in The Lancet.

Targeted therapy before chemotherapy shows promise in newly diagnosed large B-cell lymphoma
For decades, patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) have been treated exclusively with chemoimmunotherapy, but many patients either do not respond or experience a relapse after treatment. The Smart Start trial, led by Jason Westin, M.D., evaluated the use of a targeted treatment regimen of rituximab, lenalidomide and ibrutinib (RLI) before chemotherapy. This is the first trial to treat patients with newly diagnosed aggressive lymphoma using a targeted therapy combination without chemotherapy. Sixty patients with newly diagnosed non-germinal center B-cell-like DLBCL were enrolled in the Phase II trial. After two treatment cycles, the overall response rate was 86.2% prior to any chemotherapy, and the complete response rate was 94.5% when chemotherapy was subsequently combined with RLI. Progression-free survival and overall survival were at 91.3% and 96.6% at two years, respectively. These results establish the potential for targeted therapy combinations without chemotherapy in this setting, which currently is being evaluated in the Smart Stop trial. Learn more in the Journal of Clinical Oncology.

Immunotherapy combination demonstrates activity in patients with metastatic sarcomas
Patients with advanced or metastatic soft tissue and bone sarcomas have few standard treatment options available. A new study led by Neeta Somaiah, M.D., investigated the safety and efficacy of combination treatment with durvalumab, an anti-PD-L1 drug, and tremelimumab, an anti-CTLA-4 drug, for recurring or metastatic sarcomas across multiple subtypes. The primary endpoint was progression-free survival (PFS) at 12 weeks after starting treatment. Sixty-two patients with recurrent or metastatic sarcomas were enrolled in the Phase II clinical trial and 57 (92%) received the combined treatment. The profile of side effects was consistent with those previously shown for anti-CLTA-4 and anti-PD-L1 therapies. The overall PFS at 12 weeks was 49%, with higher rates in specific patient cohorts. These findings suggest this combination is safe and merits further study in selected sarcoma subtypes. Learn more in The Lancet Oncology.

Phase II study shows first evidence of intracranial activity for combined immunotherapy and targeted therapy in patients with symptomatic melanoma brain metastasis
About 75% of patients with stage IV melanoma will develop brain metastases at some point. This advanced disease remains difficult to treat and, historically, these patients have been excluded from clinical trials. The international Phase II TRICOTEL study enrolled 65 patients with previously untreated BRAFV600 mutation-positive melanoma with central nervous system metastases to receive atezolizumab plus cobimetinib and vemurafenib. Importantly, the study allowed patients with symptomatic disease and/or corticosteroid use to enroll, reflecting clinical scenarios commonly seen but understudied in clinical trials. As Hussein Tawbi, M.D., Ph.D., co-director of MD Anderson’s Brain Metastasis Clinic, and colleagues report, the intracranial objective response rate of 42% overall and 46% in patients with symptomatic disease is the first such response described in this population. Learn more in The Lancet Oncology.

Genetic marker helps identify patients with large B-cell lymphomas unlikely to benefit from CAR T cell therapy
Chimeric antigen receptor (CAR) T cell therapy targeting CD19 is a breakthrough advance, but over half of patients with relapsed or refractory large B-cell lymphomas do not benefit from treatment. Prognostic biomarkers could help identify high-risk patients that may benefit from alternative therapies. Low-pass whole genome sequencing (lpWGS) is a quick and effective DNA-sequencing technology used to detect genetic variations by sequencing small amounts from multiple samples. To study copy number alterations (CNA) and develop prognostic markers of poor outcomes, researchers led by Hua-Jay J. Cherng, M.D., Michael Green, Ph.D., and Jason Westin, M.D., performed lpWGS on cell-free DNA in blood samples from 122 patients prior to CAR T cell therapy. They discovered that a high focal CNA score — a measure of genomic instability — was the most significant variable associated with poor outcomes. Combining a focal CNA score with traditional markers of increased tumor bulk provides a valuable risk model to help prioritize patients that may benefit from alternate treatment strategies. Learn more in Blood.

Combined TRIP13 and Aurora kinase inhibition induces apoptosis in HPV-driven cancers
Human papillomavirus (HPV) causes more than 5% of all cancers, but no current therapies uniquely target HPV-driven cancers. In a new study led by Soma Ghosh, Ph.D., and Faye Johnson, M.D., Ph.D., researchers identified Aurora kinase inhibitors as the only drug class consistently more effective against HPV-positive cancers than HPV-negative cancers. This finding led to the hypothesis that retinoblastoma (RB)-deficient, HPV-positive cells that overexpress the mitotic checkpoint gene MAD2L1 rely on both TRIP13 and Aurora kinase activity to maintain mitotic fidelity. Further investigation demonstrated that inhibiting both TRIP13 and Aurora kinase activity led to significantly more apoptosis than single pathway inhibition. The findings suggest this novel combination may have a wide therapeutic window for RB-deficient cancers. Read more in Clinical Cancer Research.

Repositioned drug could benefit chemotherapy-resistant uterine cancer patients
Uterine serous cancer (USC), the most aggressive type of uterine cancer, develops a progressive resistance to chemotherapy. Repositioning Food and Drug Administration (FDA)-approved drugs from other diseases offers the potential to rapidly advance a therapy already proven safe in patients. In a feasibility study led by Li Zhang, Chi Lam Au Yeung, Ph.D.Chunxian Huang and Samuel Mok, Ph.D., researchers identified RYR1 expression as a marker of USC disease stage and demonstrated that repositioning an approved RYR1 inhibitor may be a viable treatment option.  Upregulation of RYR1 – a protein channel involved in releasing calcium ions – and its downstream signaling pathways contributed to USC tumor progression. In laboratory models, treatment with the RYR1 suppressor dantrolene significantly reduced tumor mass and prolonged survival time. The findings suggest dantrolene merits further study as an additional therapeutic strategy for patients with USC. Learn more in the Journal of Experimental & Clinical Cancer Research.

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