Memorial Sloan Kettering Cancer Center (MSK) experts presented findings from their latest clinical, translational, and foundational cancer research at the American Association for Cancer Research (AACR) Annual Meeting 2023, held April 14 to 19 in Orlando, Florida.
Highlights included clinical research advances with implications for patients with gastric and gastroesophageal junction cancers; KRAS G12C-mutated cancers; and a new prognostic risk calculator for patients with myelodysplastic syndromes (MDS).
Additionally, MSK researchers presented their latest work in some of the hottest areas of translational and foundational cancer research, including the translation of predictable patterns in copy number alterations in p53-deficient cancers to the clinic; insights into the evolution of pancreatic cancer using single-nucleus DNA sequencing; and overcoming kidney cancer using engineered human leukocyte antigen-independent T cell receptor (HIT) T cells.
Advanced Gastric Cancer: Biomarker Analysis Suggests First-Line Benefit for Nivolumab Plus Ipilimumab Versus Chemotherapy
Physician-scientist Yelena Janjigian, MD, Chief of the Gastrointestinal Oncology Service at MSK, presented findings from an exploratory biomarker analysis from the global phase 3 CheckMate 649 trial (NCT02872116). The trial evaluated the efficacy of nivolumab plus chemotherapy or nivolumab plus ipilimumab versus chemotherapy alone for the first-line treatment of patients with advanced gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma.
Based on results for the nivolumab plus chemotherapy arm, the U.S. Food and Drug Administration approved the combination in April 2021. The approval was the first in more than a decade to confer a survival benefit for patients with gastric and esophageal cancers. The recent treatment breakthrough resulted from years of dedicated work at MSK.
In the trial, nivolumab plus ipilimumab versus chemotherapy did not meet the prespecified significance target for overall survival (OS). However, the combination resulted in a more durable median response of 13.2 months versus 6.9 months for chemotherapy, and a higher 24-month OS rate of 25% versus 17%, respectively.
Dr. Janjigian and colleagues found that multiple biomarker subgroups derived an OS benefit from nivolumab plus ipilimumab versus chemotherapy, including patients with tumors that were microsatellite instability-high and tumor mutational burden-high; tumors that were inflammation-high, fibroblast-low, proliferation-high, and had endothelial-low gene expression signatures; and tumors with Treg-high gene expression signatures, regardless of PD-L1 status.
Dr. Janjigian noted that while these results suggest methods for stratifying patients most likely to benefit from nivolumab plus ipilimumab as a first-line therapy for advanced gastric and esophageal cancers, the results need to be validated in future prospective studies.
Challenging Solid Tumors: Homing in on KRAS G12C Mutations
KRAS is the most common oncogene in the MSK-IMPACT® (which stands for Integrated Mutation Profiling of Actionable Cancer Targets) database. However, until recently, there were no targeted treatment options for patients with cancers driven by KRAS alterations. MSK medical oncologist Yonina Murciano-Goroff, MD, MSc, DPhil, gave two presentations on the latest research aimed at optimizing care for patients with KRAS G12C-mutated cancers.
The first-in-class KRAS G12C inhibitor sotorasib recently received accelerated approval in the United States and internationally for patients with pretreated KRAS G12C-mutated advanced NSCLC together with companion diagnostics. The approvals were based on results from a single arm within the international phase 1/2 CodeBreak 100 trial (NCT03600883).
Dr. Murciano-Goroff presented the results from an analysis of genomic alterations in circulating tumor DNA (ctDNA) in 624 plasma samples from 179 patients. The investigators analyzed ctDNA using the Resolution Bioscience ctDX Lung™ assay, a 23-gene panel.
Dr. Murciano-Goroff and colleagues observed dynamic changes in ctDNA throughout treatment with sotorasib. Interestingly, lower baseline ctDNA mutational burden was associated with a better response in these exploratory analyses. At cycle 2, day 1, patients with undetectable versus detectable KRAS G12C mutations had an improved progression-free survival of 8.25 months versus 4.4 months and a better OS of 17.8 months versus 8.6 months, respectively.
The results suggested the use of sotorasib may be most beneficial when KRAS G12C mutation is low. Further analyses from the subsequent phase 3 CodeBreak 200 study (NCT04303780) testing sotorasib versus docetaxel in patients with KRAS G12C-mutated NSCLC may provide additional insights, Dr. Murciano-Goroff said.
Read AACR Abstract 6519. The presentation was part of a Clinical Trials Mini Symposium chaired by MSK medical oncologist Rachel Grisham, MD. The study was funded by Amgen Inc. Access disclosures for Dr. Murciano-Goroff.
In a separate oral presentation, Dr. Murciano-Goroff shared interim findings from the ongoing phase 1 trial of LY3537982, an investigational inhibitor for patients with advanced cancers with KRAS G12C mutations. The international study (NCT04956640) began in 2021 and is actively recruiting, seeking to enroll 400 participants at more than 35 sites. The study design includes multiple arms of LY3537982 as a monotherapy or in combination with other drugs. Dr. Murciano-Goroff is the principal investigator of the clinical trial at MSK.
As a monotherapy, LY3537982 demonstrated preliminary efficacy across all dose levels and was well tolerated in all tumor types. No dose-limiting toxicities occurred at any dose level and no maximum tolerable dose was identified. Treatment-related adverse events were primarily grades 1 and 2. Notably, safety was favorable in patients with previous intolerance to other KRAS G12C inhibitors.
LY3537982 in combination with pembrolizumab demonstrated a low rate of immune-related adverse events and a favorable liver profile in patients with NSCLC, as observed to date for 50 mg BID and 100 mg BID dosages. Dr. Murciano-Goroff said the trial is now enrolling patients with NSCLC to randomized dose cohorts in combination with pembrolizumab, as well as in combination with the KEYNOTE-189 (NCT02578680) regimen of pemetrexed and a platinum-based drug plus either pembrolizumab or placebo.
MDS: A New Web Tool for Precision Diagnostic and Treatment Decisions
MSK computational oncologist Elli Papaemmanouil, PhD, has been leading a global effort to improve diagnosis and treatment decisions for patients with MDS in collaboration with the International Working Group for the Prognosis of MDS. The group developed a new risk stratification system, called the International Prognostic Scoring System-M (IPSS-M), based on a global data set of clinical, cytogenetic, and genetic data from almost 3,000 MDS patients. This work was led by Elsa Bernard, PhD, a postdoctoral fellow in the Elli Papaemmanouil Lab and lead author of the study.
The IPSS-M enables physicians to tailor diagnostic and treatment decisions by considering each patient’s clinical and genetic findings. To enable its adoption, the team developed a web-based version and a mobile app version of the IPSS-M Risk Calculator, which have been essential to its global dissemination and shared details in a poster presentation at AACR.
Nonexperts worldwide are leveraging the power of molecular biomarkers to predict distinct, long-term clinical outcomes for patients with MDS, such as the risk of developing acute myeloid leukemia and mortality. In 10 months since publication, the tool has been used by 24,000 users in more than 75 countries to calculate risk profiles for almost 90,000 patients. The development of the calculator was co-led by bioinformatics engineer Juan Arango-Ossa, MEng, and Dr. Bernard.
Tumors With p53 Loss: Translating Predictable Patterns in Copy Number Alteration Acquisition to the Clinic
Loss of p53 tumor suppressor function occurs in about 50% of tumors and is associated with aggressive disease, therapeutic resistance, and poor outcomes. However, precisely when this inactivation occurs and how it contributes to the initiation and progression of malignancy has not been well understood. As a result, previous efforts to target p53 loss have mainly faltered.
Cancer biologist Scott Lowe, PhD, Chair of the Cancer Biology and Genetics Program at MSK’s Sloan Kettering Institute, and members of his lab are world-renowned for deciphering the biological processes associated with p53 loss. Their groundbreaking findings, one of which was recently published in Nature in August 2022, detail how p53 inactivation in pancreatic cancer leads to a remarkably predictable pattern of copy number alteration acquisition during cancer genome evolution and disease progression.
At AACR 2023, cancer biologist Timour Baslan, PhD, the O’Neil Charitable Trust Fellow, member of the Scott Lowe Lab, and first author of the Nature paper, gave an oral presentation detailing how MSK is leading the way in translating their findings into early disease detection and therapeutic targeting approaches for p53-deficient pancreatic tumors as well as other tumor types. They aim to identify tissue-specific targets and develop prognostic and prospective monitoring tools across a range of lethal cancers.
Drs. Lowe and Baslan are collaborating with physician-scientist Ross Levine, MD, the Laurence Joseph Dineen Chair in Leukemia Research and Deputy Physician-in-Chief of Translational Research, and surgical oncologist Samuel Singer, MD, FACS, Chief of the Gastric and Mixed Tumor Service and Vincent Astor Chair of Clinical Research at MSK to explore in more detail similar evolutionary changes that occur in p53-deficient myeloid leukemias and sarcoma, respectively.
Read AACR Abstract 8382. Dr. Baslan reports no disclosures.
Pancreatic Cancer: Tracing Cancer Cell Evolution With Single-Nucleus DNA Sequencing
Single-nucleus DNA sequencing (snDNA-seq) allows scientists to perform cancer genomic studies at a much higher resolution than traditional bulk DNA sequencing. But so far, it has primarily been used to study liquid tumors or a small batch of solid tumors.
Now, physician-scientist Christine Iacobuzio-Donahue, MD, PhD, Director of the David M. Rubenstein Center for Pancreatic Research and a member of the Human Oncology and Pathogenesis Program at MSK, and colleagues are the first to use snDNA-seq to trace the subclonal evolution of pancreatic ductal adenocarcinoma (PDAC) using frozen tumor samples.
Dr. Iacobuzio-Donahue and members of her lab have been investigating the genomic evolution of cancer through tumorigenesis, metastasis, and treatment resistance, with a focus on pancreatic cancer. Using next-generation sequencing on multiregional samples, their study of clonal evolution has revealed the origin of recurrent and metastatic disease and their timing of formation.
At AACR 2023, Haochen Zhang, a PhD candidate in MSK’s Gerstner Sloan Kettering Graduate School of Biomedical Sciences and member of the Christine Iacobuzio-Donahue Lab, presented the team’s latest work as described in their paper published recently in Nature Communications. Using snDNA-seq, they analyzed 200,000 single nuclei from 80 samples of 25 patients with PDAC, including samples from patients with early- and late-stage and primary and metastatic disease. The snDNA-seq was conducted in collaboration with scientists at MSK’s Single Cell Analytics Innovation Laboratory.
They discovered the family tree, or phylogeny, of PDAC metastasis with a higher degree of resolution. In particular, they discovered novel subclonal copy number alterations that could be an important biomarker to predict tumors more likely to metastasize and may inform the development of precision medicine for PDAC and other solid tumors, Zhang said.
Read AACR 2023 Abstract 5741. All authors reported no disclosures. The research was supported by funding from the National Cancer Institute and Cycle for Survival® for the David M. Rubenstein Center for Pancreatic Cancer Research at MSK. Dr. Iacobuzio-Donahue was recently appointed Editor-in-Chief of Cancer Research, a peer-reviewed journal of the AACR.
Kidney Cancer: HIT T Cells Overcome Very Low Tumor Antigen Expression
Chimeric antigen receptor (CAR) T cell therapy has achieved impressive responses in hematologic malignancies such as leukemia. However, it has not had the same success in solid tumors, in part due to the heterogeneous expression of target tumor antigens.
Senior research scientist Sophie Hanina, MD, PhD, a member of the Michel Sadelain Lab at MSK, presented the team’s latest work analyzing tumor antigen profiles in relapsing kidney tumors using patient-derived xenograft models. After a combination of CD70 and carbonic anhydrase IX CAR T cells did not eradicate the kidney tumors, they performed a deeper analysis using transcriptomics and proteomics and identified cells with an ultra-low CD70 expression — so low that the CAR T cells had not eliminated them.
Dr. Hanina wondered if human leukocyte antigen-independent T cell receptor (HIT) T cells engineered at MSK by Dr. Sadelain and colleagues might be more effective for targeting the ultra-low CD70 population since they are at least 10 times more sensitive than conventional CAR T cells. Her hypothesis was correct: The CD70 HIT T cells resulted in complete and durable cures in xenograft models of kidney cancer.
The discovery represents a significant advance for developing an effective cellular therapy for kidney cancer and potentially other aggressive CD70-positive tumors, such as ovarian and pancreatic cancers. Dr. Hanina noted the finding also underscores the importance of assessing antigen expression with high sensitivity to determine if antigens are truly absent or present at low levels.
Read AACR 2023 Abstract 3382. All authors reported no disclosures.