Elaine Shum, MD, of NYU Langone’s Perlmutter Cancer Center discusses the evolving treatment landscape in EGFR-mutated non–small cell lung cancer, highlighting a shift toward frontline combination regimens. She explained that although osimertinib (Tagrisso) monotherapy has been the standard due to its efficacy and intracranial activity, new strategies aim to delay resistance and improve long-term outcomes. The phase 3 FLAURA2 trial (NCT04035486) demonstrated improved progression-free survival (PFS) with the addition of platinum-based chemotherapy to osimertinib, and the MARIPOSA trial (NCT04487080) supported the use of amivantamab-vmjw (Rybrevant) plus lazertinib (Lazcluze), leading to FDA approval in August 2024. Shum emphasized that although single-agent EGFR TKIs remain important, combination treatments are increasingly favored for select patients, especially those at higher risk of early progression.
James J. Harding, MD, of Memorial Sloan Kettering Cancer Center, discusses the phase 3 CheckMate 9DW trial (NCT04039607), which supported the FDA’s April 2025 approval of nivolumab (Opdivo) plus ipilimumab (Yervoy) for the first-line treatment of unresectable or metastatic hepatocellular carcinoma (HCC). He reported that the dual checkpoint inhibitor regimen demonstrated a statistically significant overall survival benefit over sorafenib (Nexavar) or lenvatinib (Lenvima), with Kaplan-Meier curves separating at 12 months and 49% and 38% of patients remaining alive at 24 and 36 months, respectively. Although no significant difference in PFS was observed, the combination showed a higher objective response rate (ORR)—36.1% vs 13.2% in the control arm—with more complete and partial responses. Harding emphasized that these results affirm the durable benefit of CTLA-4–based combinations and support their use as a frontline standard for advanced HCC.
Van K. Morris, MD, of The University of Texas MD Anderson Cancer Center, discusses the phase 3 CheckMate 8HW trial (NCT04008030), which supported the April 2025 FDA approval of nivolumab plus ipilimumab for patients with untreated microsatellite instability–high or mismatch repair–deficient unresectable or metastatic colorectal cancer (CRC). He noted that the combination showed a significant PFS benefit over nivolumab monotherapy (HR, 0.62; P = .0003), with 2-year PFS rates of 71% vs 56% and ORRs of 71% vs 58%, respectively. Although the trial wasn’t powered for subgroup comparisons, consistent benefit was observed across multiple stratification factors, including tumor sidedness and metastatic sites, as well as in patients with BRAF V600E mutations. Morris emphasized that these findings provide strong support for dual immune checkpoint blockade as a frontline treatment option in this setting.
Bradley Monk, MD, FACOG, FACS, of Florida Cancer Specialists & Research Institute, discusses the clinical relevance of the FDA’s May 2025 accelerated approval of avutometinib in combination with defactinib (Avmapki Fakzynja Co-pack) for patients with KRAS-mutant recurrent low-grade serous ovarian cancer. He highlighted data from the phase 2 RAMP-201 trial (NCT04625270), which showed a 44% confirmed ORR and durable responses ranging from 3.3 to 31.1 months in previously treated patients. Monk explained that the combination targets both the MAPK and FAK pathways to enhance efficacy beyond what is typically achieved with MEK inhibition alone. While expressing enthusiasm about the therapeutic potential, he emphasized the need for clinicians to be familiar with the regimen’s safety profile and proactively educate patients about common adverse effects to support adherence.