Welcome to The Five Under 5, your go-to roundup of the top 5 videos of the week.
These short videos are designed for busy oncologists to view on the go, and feature expert insights on breaking news, regulatory updates, practice-changing data shared at medical meetings, and other key topics in the realm of oncology.
Here's what you may have missed:
FDA Approval of Daraxonrasib for Metastatic PDAC: Kim A. Reiss Binder, MD
Kim A. Reiss Binder, MD, of the Hospital of the University of Pennsylvania, examined the FDA approval of daraxonrasib (Rasonque) for metastatic pancreatic ductal adenocarcinoma (PDAC) and what the ability to broadly target RAS could mean for other RAS-driven cancers. On August 26, 2026, the FDA approved daraxonrasib, an oral RAS(ON) multiselective inhibitor, for adult patients with metastatic PDAC who received at least 1 prior systemic therapy or are not candidates for multi-agent systemic therapy, based on findings from the phase 3 RASolute 302 trial (NCT06625320). In the RAS G12–mutated population, the median overall survival (OS) was 13.2 months (95% CI, 10.0-not estimable) with daraxonrasib vs 6.6 months (95% CI, 5.4-8.2) with chemotherapy (HR, 0.40; 95% CI, 0.30-0.54; P = 5.9×10⁻¹⁰), with 12-month OS rates of 53.3% vs 18.7%, respectively. The median progression-free survival (PFS) by blinded independent central review was 7.3 months (95% CI, 6.3-8.1) vs 3.5 months (95% CI, 2.9-3.8), respectively (HR, 0.45; 95% CI, 0.34-0.59; P = 3.2×10⁻⁹), and the confirmed objective response rate (ORR) was 33.2% vs 11.8%, respectively (P < .0001). Reiss Binder noted that this approval marked one of the biggest breakthroughs in the pancreatic cancer field to date, adding that it opens the door for treatment advances in other RAS-driven cancers, such as non–small cell lung cancer and colorectal cancer.
FDA Approval of Zanidatamab for HER2+ Gastric Cancer: Zev A. Wainberg, MD
Zev A. Wainberg, MD, of UCLA, reviewed the mechanism of the HER2-directed bispecific antibody zanidatamab-hrii (Ziihera) and its FDA approval as a new frontline option for HER2-positive gastric cancer. Wainberg explained that zanidatamab binds 2 separate epitopes of the HER2 domain: the site typically bound by trastuzumab (Herceptin) and a second extracellular domain typically bound by pertuzumab (Perjeta), which is designed to more effectively inhibit HER2 signaling. On August 25, 2026, the FDA approved zanidatamab plus fluoropyrimidine- and platinum-containing chemotherapy, with or without tislelizumab-jsgr (Tevimbra), for patients with frontline HER2-positive unresectable locally advanced or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma, based on findings from the phase 3 HERIZON-GEA-01 trial (NCT05152147). The triplet regimen (n = 302) improved the median PFS to 12.4 months (95% CI, 9.8-18.5) vs 8.1 months (95% CI, 7.0-8.9) with trastuzumab plus chemotherapy (n = 308; HR, 0.63; 95% CI, 0.51-0.78; P < .0001) and improved the median OS to 26.4 months (95% CI, 21.5-30.3) vs 19.2 months (95% CI, 16.8-21.8), respectively (HR, 0.72; 95% CI, 0.57-0.90; P = .0043). Wainberg noted that the approval provided additional treatment options that will likely need to be tailored to individual patients, and he pointed to ongoing phase 3 trials that could further reshape the treatment landscape in the coming years.
Efficacy Data for Bezuclastinib Plus Sunitinib in Advanced GIST: Neeta Somaiah, MD
Neeta Somaiah, MD, of The University of Texas MD Anderson Cancer Center, detailed efficacy data for bezuclastinib (CGT0486) plus sunitinib (Sutent) from the phase 3 Peak study (NCT05208047) in patients with advanced gastrointestinal stromal tumor (GIST). Findings showed that patients who received the combination (n = 204) achieved a median PFS of 16.5 months (95% CI, 13.8-19.2) vs 9.2 months (95% CI, 7.2-11.0) with sunitinib alone (n = 209; HR, 0.50; 95% CI, 0.39-0.65; P < .0001). The combination also produced an ORR of 45.6% (95% CI, 38.6%-52.7%) compared with 25.8% (95% CI, 20.0%-32.3%) with sunitinib monotherapy (P < .0001). Somaiah noted that the PFS data outperformed those seen with other post-imatinib (Gleevec) treatments for GIST, translating to a 50% reduction in the risk of disease progression or death with the combination vs sunitinib alone. She added that the sunitinib monotherapy data in Peak were also better than previously reported findings for the TKI due to improved management of associated adverse effects. She concluded that the combination helps suppress disease in patients with focal progression by addressing resistant clones. She also emphasized the need for additional OS data with this regimen.
FIT-001 Study in Renal Cell Carcinoma: Adanma Ayanambakkam, MD, MS
Adanma Ayanambakkam, MD, MS, of the Stephenson Cancer Center at the University of Oklahoma Health Sciences Center, highlighted the background of the phase 1a FIT-001 trial (NCT06026410) evaluating darlifarnib plus cabozantinib (Cabometyx) in patients with renal cell carcinoma (RCC). Ayanambakkam explained that the rationale for the combination was based on the established role of TKI therapy in RCC and the involvement of the mTOR pathway in tumor growth, angiogenesis, disease progression, and treatment resistance. Darlifarnib, a next-generation farnesyltransferase inhibitor, was designed to block farnesylation and thereby selectively inhibit mTORC1 but avoid inhibition of mTORC2, he said. He noted that toxicities associated with earlier mTOR inhibitors were predominantly attributed to mTORC2 inhibition, so selectively targeting mTORC1 could preserve antitumor activity and reduce some of those toxicities. Ayanambakkam concluded that the goal of investigating the combination was to determine whether selectively inhibiting mTORC1 alongside TKI therapy could produce meaningful activity but maintain a favorable safety profile.
Differences Between BTK Degraders and BTK Inhibitors in CLL: Zulfa Omer, MD
Zulfa Omer, MD, of the University of Cincinnati College of Medicine, outlined how BTK degraders operate, the key differences that separate this class of agents from BTK inhibitors, and topics that future research needs to address for chronic lymphocytic leukemia (CLL) management. Omer explained that BTK inhibitors simply inhibit the BTK protein, whereas BTK degraders initiate the degradation of the entire protein, including its scaffolding function. She noted that this distinction underlies the appeal of BTK degraders, since BTK mutations that often develop during treatment with BTK inhibitors are less likely to compromise efficacy when the entire protein is degraded. Omer emphasized that sequencing remains the biggest open question for BTK degraders in CLL, particularly whether they should be used in the frontline setting or reserved for later lines of therapy after relapse on a BTK inhibitor. She concluded that understanding mechanisms of resistance to BTK degraders will be key to clarifying optimal sequencing as the CLL field moves forward.
