by Lynne Lederman, PhD
Several late-breaking abstracts were presented today at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting. These studies include LBA1509, identifying new tumor types with high microsatellite instability are associated Lynch syndrome; LBA2553, a retrospective study showing the effect of a precision medicine approach on survival across tumor types; LBA4001, describing a chemotherapy regimen that prolongs survival in pancreatic cancer, and LBA4002, demonstrating that preoperative chemotherapy with radiation also increases survival in pancreatic cancer.
Pan-Cancer Microsatellite Instability Predicts for the Presence of Lynch Syndrome (LBA1509)
Results of a prospective genomic study of 15,045 tumor samples from over 50 types of cancer reported by Zsofia K. Stadler, MD, Memorial Sloan Kettering Cancer Center, (MSKCC) showed that patients whose tumors have high microsatellite instability (MSI-H), a marker of a large number of genetic mutations resulting from an inability of cells to repair damaged DNA are also more likely to have Lynch syndrome, an inherited that increases the risk of multiple types of cancer.
Tumors from patients treated at MSKCC were analyzed with a genomic test, MSK-IMPACT, which uses next-generation sequencing (NGS) to detect mutations in cancer-related genes as well as MSI. Blood samples were also tested for germline mutations (deficiency) in DNA mismatch repair genes (MMR-D).
Genomic analysis were used to classify tumors into 3 groups: MSI-stable (MSS, no MSI; 93.2% of tumors), MSI-intermediate (MSI-I, moderate levels of MSI; 4.6%)), and MSI-H (2.2%). Inherited mutations in Lynch-syndrome associated genes occurred in 16% of those with MSI-H versus 1.9% of those with MSI-I and 0.3% of those with MSS tumors. Nearly half of patients had cancer types not or rarely associated with Lynch syndrome, including mesothelioma, sarcoma, and adrenocortical cancer, and 45% did not meet Lynch syndrome genetic testing criteria. MMR-D was found in 98.3% of the 57 MSI-I/MSI-H tumor samples tested.
Dr. Stadler said that findings suggest that all patients with MSI -H or MMR-D tumors should be tested for Lynch syndrome whatever the cancer type or personal or family history of cancer.
Precision Medicine: Clinical Outcomes Including Long-Term Survival According to the Pathway Targeted and Treatment Period: The IMPACT Study (LBA2553)
Apostolia M. Tsimberidou, MD, PhD, MD Anderson Cancer Center, Houston, presented the results of a study to assess the impact of precision medicine approaches on the survival of patients with multiple types of cancers. She said that the findings from the Initiative for Molecular Profiling in Advanced Cancer Therapy (IMPACT) study (NCT00851032) demonstrate that NGS of tumors can be used to optimize therapy and should be used to help select treatment in difficult-to-treat cancers.
The IMPACT study enrolled patients who had received all possible standard treatment options or who had incurable, rare cancers. Tumors were tested using CLIA-certified molecular testing. Treatment was matched targeted therapy if available, otherwise therapy was non-matched. Cancers included GI, gynecologic, breast, melanoma, and lung. Of 3,743 patient tumors tested, 1,307 (34.9%) had one or more targetable molecular alteration; 711 of these patients (54.4%) were assigned to matched targeted therapy and 596 (45.6%) were assigned to non-matched therapy.
For evaluable patients, the 3-year overall survival (OS) rate was 15% in patients receiving matched targeted therapy (n =697) versus 7% in the non-matched group (n=571) (HR, 0.67; P<.001). The 10-year OS rates were 6% versus 1%, respectively, with a plateau of OS in the matched group beginning at 3.2 years.
Matched therapy was an independent factor predicting longer survival in a multivariate analysis. PI3K/AKT/mTOR pathway abnormalities were associated with poorer outcomes compared with other genetic alterations. Ongoing clinical trials to further precision medicine approaches to treatment include the IMPACT2 and ASCO’s TAPUR trials.
Unicancer GI PRODIGE 24/CCG PA.6 trial: a multicenter international randomized phase III trial of adjuvant mFOLFIRINOX versus gemcitabine (gem) in patients with resected pancreatic ductal adenocarcinomas (LBA4001)
Thierry Conroy, MD, Institut de Cancerologie de Lorraine, Nancy, said the PRODIGE 24/CCG PA.6 trial showed that adjuvant mFOLFIRINOX therapy is superior to gemcitabine, the standard of care for the past 10 years.
Patients with non-metastatic pancreatic ductal adenocarcinoma who had all visible tumor surgically removed were randomly assigned to gemcitabine (n=246) or mFOLFIRINOX (n=247) for 6 months. At a median follow-up of 33.6 months the disease-free survival (DFS), the primary endpoint, was 21.6 months in the mFOLFIRINOX groups versus 12.8 months in the gemcitabine group (HR 0.58; 95% CI 0.46, 0.73; P<.0001). The median OS was 54.4 months for mFOLFIRINOX versus 35.0 months for gemcitabine (HR 0.64; 95% CI 0.48, 0.86; P=.003).
Although there were more severe adverse events (AEs), primarily hematologic, with mFORFIRINOX (76% versus 53%), they were manageable. It is recommended that patients be screened for underlying heart disease before treatment as a history of ischemic heart disease is a risk with either treatment, especially mFOLFIRINOX.
Dr. Conroy suggested mFOLFIRINOX should be considered a new standard of care for pancreatic cancer after surgical resection. Ongoing trials are examining optimal timing of chemotherapy in this setting, including pre-surgery as neoadjuvant therapy and dosing of half the cycles before and half after surgery as perioperative chemotherapy.
Preoperative chemoradiotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer (PREOPANC-1): a randomized, controlled, multicenter phase III trial (LBA4002).
In other encouraging news for patients with pancreatic cancer, the result s of the PREOPANC-1 trial showed that patients (n=119) randomly assigned to chemoradiotherapy for 10 weeks prior to surgery for pancreatic cancer as well as post-surgical chemotherapy had a better DFS than patients (n=127) who were randomly assigned to the same amount of chemotherapy after immediate surgery (9.9 months versus 7.9 months; P=.023). The 2-year survival for the preoperative chemotherapy group was 42% versus 30% in the post-surgery chemotherapy group. There was no significant difference between groups in median OS; however, in the subgroups of patients with complete resections, median OS was 42.1 months for preoperative chemotherapy versus 16.8 months for immediate surgery. Distant metastases-free interval was longer for the presurgical treatment group (HR 0.71; P=.013), as was locoregional recurrence-free interval (HR 0.55; P=.002).
Although these results are preliminary, Geertjan Van Tienhoven, MD, PhD, said the study investigators believe that this trial may be practice-changing. After the final analysis, efforts will be made to test for more effective preoperative treatments, eg, FOLFIRINOX alone or combined with stereotactic radiation therapy.