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In pancreatic cancer, [approximately] 80% to 90% of patients will have a mutation somewhere in 

 [These mutations are common enough] that it makes a lot of sense to chase down [these targeted therapies]. It's something where probably most patients, if not all patients, are going to have something that we can offer them if we can understand the status of their mutation."

Brandon G. Smaglo, MD, FACP, associate professor, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, discusses how advances in understanding the biology of 

mutations have helped catalyze the further development of novel RAS-targeted therapies for pancreatic cancer. Smaglo expanded upon these developments during Pancreatic Cancer Awareness Month, which occurs in November each year.

 can be found in the vast majority of patients with pancreatic cancer, making this a logical target in this malignancy. The role of RAS mutations in pancreatic cancer and other solid tumors has long been understood, but 

 mutations were historically considered "undruggable" targets, Smaglo explains. However, the prevalence and oncogenic role of 

 alterations in driving tumor progression and resistance have ensured that research efforts to develop RAS inhibitors have remained a priority, Smaglo explains.

Recent advances in molecular biology and drug development have enabled the identification of compounds capable of selectively targeting 

 mutations, which could eventually lead to additional treatment options, he says. Although work attempting to develop safe and efficacious RAS inhibitors has persisted, developments with novel agents in recent years have started to shift the needle, Smaglo says.

Data emerging from early-stage clinical trials evaluating these inhibitors has been encouraging, and the development of these agents could open the door for targeted therapies to play a larger role in the pancreatic cancer treatment paradigm, which has largely been a chemotherapy-only space, Smaglo concludes.

Videos

Brandon G. Smaglo, MD, FACP, discusses the ongoing research with RAS-targeted therapies for pancreatic cancer.

Dr Smaglo on the Evolution of RAS-Targeted Therapies for Pancreatic Cancer

Brandon G. Smaglo, MD, FACP, associate professor in the Department of Gastrointestinal Medical Oncology of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discusses the future of immunotherapy in gastric cancer.

Future directions in gastric cancer all come back to immunotherapy, says Smaglo. For example, full data from the phase 3 KEYNOTE-026 trial, which examined pembrolizumab as first-line treatment for patients with advanced gastric or gastroesophageal junction adenocarcinoma, are highly anticipated, says Smaglo.

Additionally, now that the field understands the scoring system better there are different ways in which that information can be applied to better utilize immunotherapy, which will be exciting, adds Smaglo. For example, unfortunately, the JAVELIN Gastric 100 data with avelumab (Bavencio) was a negative study. In that trial, investigators evaluated a maintenance approach with immunotherapy. Patients were started on chemotherapy to achieve initial cancer control and then they were switched to receive immunotherapy; that approach did not prove beneficial.

However, notably, that study did not examine the different biomarker data. It will be interesting to see in similar studies if there is a subset of patients with gastric cancer who would benefit from maintenance immunotherapy if a tumor biomarker like PD-L1 is present and potentially indicative of benefit, concludes Smaglo.

Brandon G. Smaglo, MD, FACP, discusses the future of immunotherapy in gastric cancer.

Dr. Smaglo on the Future of Immunotherapy in Gastric Cancer

Brandon G. Smaglo, MD, FACP, associate professor in the Department of Gastrointestinal Medical Oncology of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discusses the role of immunotherapy in advanced gastric cancer.

Immunotherapy has demonstrated utility in patients with gastric cancer whose tumors are microsatellite instable or PD-L1—positive, says Smaglo.

Although patients with any level of PD-L1 positivity are more likely to benefit from immunotherapy, early KEYNOTE studies revealed that a combined positive score (CPS) of 10 or greater could indicate improved response, explains Smaglo. Moreover, patients with higher CPS may benefit from checkpoint inhibitors such as pembrolizumab (Keytruda) in earlier lines of therapy.

The randomized, phase 3 KEYNOTE-062 trial showed that frontline pembrolizumab monotherapy elicited noninferior overall survival versus chemotherapy in patients with PD-L1—positive, HER2-negative, advanced gastric/gastroesophageal junction cancer.

These data highlight the need to test a patient’s PD-L1 status prior to starting treatment in order to optimize their response to treatment, concludes Smaglo.

Brandon G. Smaglo, MD, FACP, discusses the role of immunotherapy in advanced gastric cancer.

Dr. Smaglo on the Role of Immunotherapy in Advanced Gastric Cancer

Brandon G. Smaglo, MD, FACP, associate professor in the Department of Gastrointestinal Medical Oncology of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discusses novel therapies in advanced gastric cancer.

For a long time, treatment for patients with gastric cancer had been chemotherapy followed by more chemotherapy, says Smaglo. While chemotherapy continues to serve as the backbone, what physicians investigators have found that they are able to add appropriate additional targeted agents to that paradigm. For example, for a long time, the first-line treatment would be a 2-drug combination of chemotherapy and then trastuzumab (Herceptin) would be added to that regimen if the tumor was HER2 expressive, explains Smaglo.

The antiangiogenic ramucirumab (Cyramza) has since emerged as an option in the second-line setting. As such, many will build their first-line regimen in order to tailor the second-line regimen to use ramucirumab in combination with the chemotherapy agent paclitaxel, concludes Smaglo.

Brandon G. Smaglo, MD, FACP, discusses novel therapies in advanced gastric cancer.

Dr. Smaglo on Novel Therapies in Advanced Gastric Cancer

Brandon G. Smaglo, MD, FACP, assistant professor and medical director of hematology/oncology at the Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, discusses the FDA approval of TAS-102 (trifluridine/tipiracil; Lonsurf) in gastric/gastroesophageal junction (GEJ) adenocarcinoma.

On February 25, 2019, the FDA approved TAS-102 for use in adult patients with metastatic gastric or GEJ adenocarcinoma who had been previously treated with at least 2 prior lines of chemotherapy that included a fluoropyrimidine, a platinum, either a taxane or irinotecan, and if appropriate, HER2/neu-targeted therapy. The approval was based on positive data from the phase III TAGS trial, in which TAS-102 reduced the risk of death by about one-third compared with placebo in patients with heavily pretreated gastric or GEJ cancer. Findings also demonstrated improvements in progression-free survival and disease control, in addition to a predictable and manageable safety profile.

According to Smaglo, TAS-102 is going to fill an important niche for patients who still have a good performance status and want to continue with treatment after exhausting other options.

Brandon G. Smaglo, MD, FACP, assistant professor of internal medicine, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, discusses the FDA approval of TAS-102 (trifluridine/tipiracil; Lonsurf) in gastric/gastroesophageal junction (GEJ) adenocarcinoma.

Brandon G. Smaglo, MD, FACP

Articles

Dr Smaglo on the Evolution of RAS-Targeted Therapies for Pancreatic Cancer

Dr. Smaglo on the Future of Immunotherapy in Gastric Cancer

Dr. Smaglo on the Role of Immunotherapy in Advanced Gastric Cancer

Dr. Smaglo on Novel Therapies in Advanced Gastric Cancer

Dr. Smaglo on Novel Therapies in Advanced Gastric Cancer

Dr. Smaglo Discusses the FDA Approval of TAS-102 for Gastric/GEJ Cancer