MD Anderson Research Highlights: ESMO 2022 Special Edition

ABSTRACTS 735MO, 316O, 1MO, 1493MO, 457MO, 283MO, LBA68, 785O 

PARIS ― 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. This special edition features upcoming oral presentations by MD Anderson researchers at the European Society for Medical Oncology (ESMO) Congress 2022 focused on clinical advances across a variety of cancer types. Highlights include promising early data from a novel T cell therapy for solid tumors, targeted therapy progress in rare and advanced cancers, biomarkers of immunotherapy response, and features associated with clinical outcomes in leptomeningeal disease. More information on ESMO content from MD Anderson can be found at MDAnderson.org/ESMO. 

In addition to the studies summarized below, forthcoming press releases will feature the following late-breaking and oral presentations: 

• Results from the Phase II SWOG S1801 trial evaluating neoadjuvant immunotherapy in patients with high-risk resectable melanoma (Abstract LBA6)  
• Safety and efficacy data from the Phase III FRESCO-2 trial investigating the targeted therapy fruquintinib in patients with metastatic colorectal cancer (Abstract LBA25) 
• Results from the international Phase II trial of neoadjuvant immunotherapy in advanced cutaneous squamous cell carcinoma (Abstract 789O) 
• Patient-reported outcomes from the Phase III DESTINY-Breast04 study of trastuzumab deruxtecan for patients with HER2-low metastatic breast cancer (Abstract 217O) 

SURPASS cell therapy trial updates continue to signal promising early results (Abstract 735MO) 
The Phase I SURPASS trial is evaluating ADP-A2M4CD8, a next-generation T cell therapy that targets the MAGE-A4 cancer antigen, for solid tumors. ADP-A2M4CD8 is engineered to express not only the targeting T cell receptor but also the CD8α co-receptor, which could improve results on solid tumors. The trial, led by David S. Hong, M.D., has shown positive early results in patients with unresectable or metastatic tumors positive for MAGE-A4. The emerging data signals encouraging clinical outcomes, especially for gastroesophageal and ovarian cancers. Data available on 29 patients at the time of submission indicated an overall response rate of 31% and a disease control rate of 75.9%. The reported adverse events were consistent with those typically associated with nonmyeloablative lymphodepletion, cellular therapy and disease. An additional treatment cohort has been included to evaluate potential benefits of ADP-A2M4CD8 combined with nivolumab, and Phase II trials are being initiated for gastroesophageal and ovarian cancers. Hong will present updated clinical outcomes from the trial on Sept. 10. 

Colorectal cancer study uncovers mutations associated with targeted therapy resistance (Abstract 316O) Patients with colorectal cancer (CRC) carrying the BRAFV600E mutation have a poor prognosis, with many developing resistance to BRAF inhibitors because the signaling pathway is reactivated. The Phase III BEACON study, led by Scott Kopetz, M.D., Ph.D., showed that combination regimens of either encorafenib, binimetinib and cetuximab (triplet) or encorafenib and cetuximab (doublet) improved overall survival in previously treated BRAFV600E-mutated CRC patients compared with chemotherapy. To identify genetic alterations associated with acquired resistance by the end of either doublet or triplet combination treatment, Kopetz and colleagues performed a retrospective genome profiling analysis of circulating tumor DNA in these patients before and after treatment. In both the triplet and doublet arms, they identified mechanisms and potential biomarkers of acquired resistance, such as KRAS/NRAS mutations and MET amplification. The findings could help in developing strategies to overcome treatment resistance. Kopetz will present the findings on Sept. 12. 

Targeted therapy cabozantinib shows activity in Phase II study for patients with rare adrenal cancer (Abstract 1MO) Limited treatment options exist for adrenocorticol carcinoma (ACC), a rare form of cancer where tumors form on the outer layer of the adrenal glands. In a Phase II study led by Matthew Campbell, M.D., and Mouhammed Habra, M.D., researchers evaluated the safety and efficacy of cabozantinib, a tyrosine kinase inhibitor, in 18 patients with advanced ACC. The study met its primary endpoint, with a 72% progression-free survival (PFS) rate at four months. The treatment also achieved a median PFS of 7.2 months and median overall survival of 23.9 months. Cabozantinib provided sustained disease control and a manageable safety profile for patients with advanced ACC, and an ongoing study in Germany is enrolling more patients to further study its efficacy. Campbell will present the study results on Sept. 12. 

Sarcoma study identified potential markers for response to neoadjuvant immunotherapy (Abstract 1493MO) 
Recurrence after surgery is common for patients with dedifferentiated liposarcomas (DDLPS) and undifferentiated pleomorphic sarcomas (UPS), and previous clinical data suggest neoadjuvant immunotherapy may improve survival in UPS. To assess biomarkers of immune response, researchers led by Elise Nassif, M.D., studied samples from patients treated with neoadjuvant nivolumab plus ipilimumab. The team performed RNA sequencing and gene expression analysis on peripheral blood mononuclear cells (PBMCs) and tumor specimens to quantify 30 immune cell types/signatures, as well as T cell receptor (TCR) sequencing of PBMCs collected at baseline, on treatment and at surgery. Seventeen patients with DDLPS and 10 with UPS participated in the trial, and the median progression-free survival was 20 months. Investigators identified specific features at baseline and during treatment which may help identify patients with better prognosis, such as a high B cell signature in the blood before treatment or TCR density on treatment. The findings suggest further investigation is needed to clarify the prognostic value of these markers. Nassif will present the results on Sept. 12.  

Phase I trial establishes safety and tolerability parameters for ATR inhibitor M1774 (Abstract 457MO) 
Targeting components of the DNA damage response (DDR), such as ATR or PARP, can be effective in cancers with specific DDR defects. M1774 is an ATR inhibitor that has demonstrated antitumor activity in preclinical models. In an open-label multicenter Phase I study led by Timothy Yap, M.B.B.S., Ph.D., researchers are evaluating M1774, alone or in combination with the PARP inhibitor niraparib, in patients with advanced solid tumors. Early data to be presented will reveal the maximum tolerated dose and the recommended dose for expansion based on the safety, tolerability, pharmacokinetics, pharmacodynamics, as well as the preliminary antitumor activity that has been observed to date. The study is ongoing to further evaluate this novel ATR inhibitor. Yap will present the findings on Sept. 9. 

Researchers identify features associated with overall survival of leptomeningeal disease in metastatic melanoma patients (Abstract 283MO)  
The survival rate of most melanoma patients diagnosed with leptomeningeal disease (LMD) remains dismal. Led by Isabella Glitza Oliva, M.D., Ph.D., researchers analyzed data from 172 metastatic melanoma patients diagnosed with LMD. Most were male, and their average age was 53 years. Most patients had a history of primary cutaneous non-acral melanoma and the majority (66%) had a BRAF mutation. Overall survival (OS) for patients diagnosed with LMD varied based on the type of treatment received. Improved survival was observed in patients with negative cerebrospinal fluid cytopathology at diagnosis, normal LDH levels and no treatment with whole brain radiotherapy. Despite overall poor prognosis, even with available contemporary treatment, a subset of patients with LMD achieved better survival. The findings warrant further investigation of this patient population to guide management of the disease and to inform the design of future clinical trials that target LMD. Glitza Oliva will present her findings on Sept. 10. 

Immunotherapy combination does not improve outcomes in melanoma and kidney cancers (Abstracts LBA68, 785O) 
Bempegaldesleukin (BEMPEG) is an investigational cancer therapy designed to activate the interleukin-2 (IL-2) immune signaling pathway. Based on data from Phase II studies, the therapy has been evaluated in combination with the immune checkpoint inhibitor nivolumab in multiple Phase III clinical trials.  

The PIVOT IO-001 trial, led by Adi Diab, M.D., evaluated the combination of BEMPEG and nivolumab compared with nivolumab alone as a first-line treatment for patients with advanced melanoma. The trial did not meet its primary endpoints of objective response rate (ORR) and progression-free survival (PFS). A total of 783 patients were randomized on the trial, and median follow-up was 19.3 months and 11.6 months for ORR and PFS, respectively. The combination therapy achieved an ORR of 27.7%, compared with 36.6% with nivolumab alone. The median PFS was 4.17 months with the combination and 4.99 months with nivolumab alone. Median overall survival (OS) was similar across both arms, reaching 29.67 months on the combination arm and 28.88 months on monotherapy. Diab will present updated results on Sept. 10. 

The PIVOT-09 trial, led by Nizar Tannir, M.D., evaluated the efficacy of BEMPEG and nivolumab compared with the physician’s choice of the targeted therapies sunitinib or cabozantinib in patients with previously untreated renal cell carcinoma. The trial, which included 626 participants, did not meet its primary endpoints of ORR and OS. The ORR was 23% for the BEMPEG combination and 30.6% with sunitinib or cabozantinib. The median OS was 29 months on the BEMPEG arm and was not reached on the targeted therapy arm. Tannir will present updated results on Sept. 12.