Mike J. Pishvaian, MD, PhD, is director of Gastrointestinal, Developmental Therapeutics and Clinical Research Programs and an associate professor of oncology at Johns Hopkins Medicine in Baltimore, Maryland.

Martin Dietrich, MD, PhD, is a medical oncologist with The US Oncology Network Cancer Care Centers of Brevard and an assistant professor of internal medicine at the University of Central Florida College of Medicine in Orlando, Florida.

Mike J. Pishvaian, MD, PhD, and Martin Dietrich, MD, PhD, discuss how KRAS(ON) inhibitors differ in mechanism from KRAS(OFF) inhibitors.

Mechanisms of KRAS(ON) Inhibitors

Videos

How the Mechanisms of KRAS(ON) Inhibitors Differ From KRAS(OFF) Inhibitors

Mike J. Pishvaian, MD, PhD, and Martin Dietrich, MD, PhD, discuss the evolving role of KRAS G12C and pan-KRAS inhibitors in pancreatic cancer.

The Current and Evolving Role of KRAS G12C and Pan-KRAS Inhibitors in Metastatic PDAC

Mike J. Pishvaian, MD, PhD, and Martin Dietrich, MD, PhD, discuss the prevalence of RAS mutations in pancreatic ductal adenocarcinoma.

RAS Mutations in PDAC

The Prevalence of RAS Mutations in Metastatic PDAC

Mike J. Pishvaian, MD, PhD, and Martin Dietrich, MD, PhD, detail the continued interest in RAS inhibition for pancreatic ductal adenocarcinoma.

RAS Inhibition in PDAC

Explaining the Continued Interest in RAS Inhibition for PDAC

Michael Jon Pishvaian, MD, PhD, director, Gastrointestinal, Developmental Therapeutics and Clinical Research Programs, associate professor of Oncology, Johns Hopkins Medicine, discusses the clinical implications of the phase 3 RATIONALE 306 trial (NCT03783442) and the adverse effects (AEs) associated with immunotherapy in patients with advanced esophageal squamous cell carcinoma (ESCC).

The study evaluated chemotherapy plus the anti–PD-1 agent tislelizumab (BGB-A317) vs chemotherapy alone in patients with metastatic or unresectable ESCC. Updated findings from RATIONALE 306 presented at the 2022 ESMO World Congress on Gastrointestinal Cancer showed that the combination elicited a median overall survival of 17.2 months (95% CI, 15.8-20.1) compared with 10.6 months (95% CI, 9.3-12.1) for chemotherapy alone, reducing the risk of death by 34% (HR, 0.66; 95% CI, 0.54-0.80; 

 < .0001). These were practice-changing results showing the benefit of adding tislelizumab to chemotherapy for the treatment of patients with metastatic ESCC, Pishvaian says.

When telling patients about the toxicities associated with treatment, it is important to note the varying AEs that can occur when receiving immunotherapy, Pishvaian notes. Although patients may be familiar with the AEs associated with chemotherapy, including nausea, vomiting, diarrhea, myelosuppression, and potentially hair loss, immunotherapy can produce a different set of immune-related AEs. Treatment with immunotherapy can lead to fever, chills, myalgia, and arthralgia. Although the rates of these AEs are not high, they can occur, and patients should be informed, Pishvaian says. Moreover, treatment with immunotherapy can also cause patients to develop endocrinopathies, such as hypothyroidism, adrenal insufficiency, type 1 diabetes, and, in rare cases, panhypopituitarism.

Serious AEs that can arise from treatment with immunotherapy include pneumonitis, hepatitis, and autoimmune conditions, Pishvaian explains. When immunotherapy treatments were first introduced, clinicians were still learning to recognize these serious AEs; however, with time and experience using immunotherapy, careful monitoring and quick intervention for any serious AEs that do occur have allowed for these toxicities to become more manageable, Pishvaian concludes.

Michael Jon Pishvaian, MD, PhD, discusses the clinical implications of the phase 3 RATIONALE 306 trial and the adverse effects associated with immunotherapy in patients with advanced esophageal squamous cell carcinoma.

Dr. Pishvaian on the Implications of the RATIONALE-306 Trial in ESCC

Michael J. Pishvaian, MD, PhD, a gastrointestinal oncologist and head of the Phase I Program at the Georgetown Lombardi Comprehensive Cancer Center, discusses the FDA approval of the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) for the treatment of patients with hepatocellular carcinoma (HCC).

The combination of the PD-L1 inhibitor and anti-VEGF agent was approved by the FDA on May 29, 2020 for the treatment of patients with unresectable or metastatic HCC who have not received prior systemic therapy. The approval is based on findings from the phase 3 IMbrave150 study, which demonstrated that atezolizumab plus bevacizumab led to a 42% reduction in the risk of death compared with sorafenib (Nexavar; HR, 0.58; 95% CI, 0.42-0.79; 

 = .0006). The combination was also associated with a 41% reduction in the risk of disease progression or death versus sorafenib (HR, 0.59; 95% CI, 0.47-0.76; 

This combination has been shown to improve outcomes for patients with advanced HCC, demonstrating very durable responses, Pishvaian says. Some patients are achieving complete responses, allowing them to return to a normal quality of life.

Multikinase inhibitors were the traditional therapies used in this space, but although these drugs were effective, they came with notable toxicities. While immunotherapy agents bring along their own unique set of adverse events, this combination has been generally well tolerated in the vast majority of patients.

Michael J. Pishvaian, MD, PhD, discusses the FDA approval of the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) for the treatment of patients with hepatocellular carcinoma (HCC).

Mike J. Pishvaian, MD, PhD

Articles

How the Mechanisms of KRAS(ON) Inhibitors Differ From KRAS(OFF) Inhibitors

The Current and Evolving Role of KRAS G12C and Pan-KRAS Inhibitors in Metastatic PDAC

The Prevalence of RAS Mutations in Metastatic PDAC

Explaining the Continued Interest in RAS Inhibition for PDAC

Dr. Pishvaian on the Implications of the RATIONALE-306 Trial in ESCC

Dr. Pishvaian on FDA Approval of Atezolizumab Plus Bevacizumab in HCC