Paul E. Oberstein, MD

Patients facing second-line therapy for metastatic pancreatic cancer most often want to know how long they will live.

The phase 3 RASolute 302 trial randomly assigned 500 patients with metastatic pancreatic cancer and progression on 1 prior regimen to oral daraxonrasib 300 mg once daily or investigator's choice of 4 standard chemotherapy regimens.

Before daraxonrasib, second-line therapy for metastatic pancreatic cancer meant more chemotherapy with overlapping toxicities. Jonathan Lee, MD, describes telling patients that response was unlikely and focusing instead on limiting tumor growth and controlling symptoms. Shiraj Sen, MD, PhD, estimates that about half of patients reach second-line therapy and emphasizes offering clinical trials at every step. Tanios S. Bekaii-Saab, MD, notes that the approved indication covers patients with at least 1 prior systemic therapy and patients who are not candidates for multiagent therapy, although every trial participant had progressed on 1 prior line. Anne Noonan, MB BCh, PhD, sees a role for frail patients; however, she urges caution in defining frailty given the side effect profile. Paul E. Oberstein, MD, hopes the drug expands the pool of treated patients and advises giving chemotherapy first when patients can receive it, because the trial sequenced chemotherapy before RAS inhibition. Dr. Lee wants real-world evidence and stresses frank conversations, since first-line data remain limited.

For decades, small molecules could not directly target RAS, the primary oncogenic driver of pancreatic cancer. Tanios S. Bekaii-Saab, MD, opens this discussion on metastatic pancreatic ductal adenocarcinoma by asking what changed. Anne Noonan, MB BCh, PhD, credits the 2013 discovery of a drug-binding pocket on the surface of mutant RAS, known as the switch II pocket, which enabled the first preclinical RAS inhibitors. She explains that RAS proteins cycle between an inactive guanosine diphosphate-bound off state and an active guanosine triphosphate-bound on state, and that oncogenic mutations shift this equilibrium toward the on state. Paul E. Oberstein, MD, describes the tri-complex approach: the oral drug enters the cell, binds the chaperone protein cyclophilin A, and that complex then binds active RAS to block downstream signaling, using the cell's own machinery. Shiraj Sen, MD, PhD, shares how he explains this mechanism to patients, comparing the medicine to a Trojan horse that uses a chaperone protein to reach and block RAS.

Paul E. Oberstein, MD, discusses the rationale for the anti-PD-1/IL-15 fusion protein SAR445877 in microsatellite-stable colorectal cancer.

Paul E. Oberstein, MD, discusses a personalized mRNA vaccine being evaluated in pancreatic ductal adenocarcinoma and why it matters.

Paul Oberstein, MD, discusses results of the phase 3 RASolute 302 for daraxonrasib in pretreated metastatic pancreatic cancer.

Drs Seery, Oberstein, and Pathak discuss data from the NAPOLI 3 trial of NALIRIFOX vs nab-paclitaxel and gemcitabine in treatment-naive pancreatic cancer.

Panelists discuss how promising developments at ASCO 2025 include novel immunotherapy combinations, KRAS G12D-targeted therapies in phase 3 trials, tumor treating fields for locally advanced disease, and the importance of addressing nutrition and quality of life alongside pharmacologic advances.

Panelists discuss how the NAPOLI-1 trial established 5-FU/leucovorin plus liposomal irinotecan as the standard second-line therapy for patients who received gemcitabine-based first-line treatment, though patient selection remains challenging.

Panelists discuss how second-line therapy sequencing involves using the backbone not received in first-line (5-FU or gemcitabine-based), with increased emphasis on quality of life discussions and the importance of early tumor sequencing for potential targeted therapies.

Panelists discuss how real-world data suggest similar efficacy between NALIRIFOX and FOLFIRINOX, and how sequential therapy approaches using doublets don’t appear superior to up-front triplet regimens for appropriate patients.

Panelists discuss how NALIRIFOX differs from modified FOLFIRINOX primarily in lower neuropathy rates due to reduced oxaliplatin dosing, higher diarrhea rates, and lower neutropenia, while UGT1A1 testing is generally not required up front.

Panelists discuss how recent ASCO data showed long-term responders on NALIRIFOX were younger, fitter patients with lower disease burden who could tolerate treatment longer, reinforcing the strategy of dose modifications to maintain patients on therapy.

Panelists discuss how the PRODIGE-4 and NAPOLI-3 trials differed in patient populations, age limits, and comparator arms, leading to similar regimens with dosage modifications that have become standard practice.

Panelists discuss how patient choice and long-term toxicity considerations, particularly neuropathy differences between NALIRIFOX and FOLFIRINOX, influence treatment decisions while managing patient expectations about stable disease being a positive outcome.

Panelists discuss how the evolution of pancreatic cancer treatment has progressed since 2011 with key trials like PRODIGE-4 (FOLFIRINOX) and NAPOLI-3 (NALIRIFOX), and how clinicians choose between regimens based on patient characteristics and adverse effect profiles.

Panelists discuss how treatment decisions for locally advanced pancreatic cancer should consider systemic therapy followed by radiation, with triplet regimens preferred for younger patients with good performance status, while acknowledging the limited evidence base requiring extrapolation from metastatic data.

Panelists discuss how to approach a 55-year-old woman with locally advanced pancreatic cancer involving portal vein invasion, emphasizing the importance of staging, performance status assessment, and systemic chemotherapy as first-line treatment.

Paul E. Oberstein, MD, discusses the clinical applications of the Oncodetect test for molecular residual disease detection in patients with solid tumors.

Paul E. Oberstein, MD, discusses the efficacy and safety of pamrevlumab plus chemotherapy in first- and second-line PDAC.

Paul E. Oberstein, MD, discusses remaining challenges in metastatic colorectal cancer.

Paul E. Oberstein, MD, discusses the phase 2/3 CheckMate 9X8 trial in metastatic colorectal cancer.

Paul E. Oberstein, MD, discusses the utilization of ctDNA in metastatic colorectal cancer.

Paul E. Oberstein, MD, discusses the current treatment landscape of colorectal cancer.

Paul E. Oberstein, MD, assistant professor of medicine, assistant director, Pancreatic Cancer Center, director, Gastrointestinal Medical Oncology Program, NYU Langone’s Perlmutter Cancer Center, discusses the use of PEGPH20 in advanced pancreatic cancer.