2025 West Oncology Conference: Established and New Targeted Therapies in NSCLC
Presented by:
Fred R. Hirsch, MD, PhD; Tisch Cancer Institute, Mount Sinai, NY
Conference:
2025 West Oncology Conference
Introduction: The Rapid Expansion of Targeted Therapies in NSCLC
At the 10th Annual West Oncology Conference held in 2025, Dr Fred R. Hirsch from the Tisch Cancer Institute at Mount Sinai in New York opened his presentation by acknowledging the rapidly evolving landscape of targeted therapies for non-small cell lung cancer (NSCLC). He noted that new approvals and clinical trial findings emerge almost monthly, making it essential for oncologists to stay informed about emerging biomarkers, resistance mechanisms, as well as next-generation treatment strategies.
“Twenty years ago, we discovered EGFR mutations, and that changed everything… now, we are in the fourth generation of EGFR inhibitors, and similar advances are happening across other oncogenic drivers.”
Targeting EGFR Mutations: Where Are We Now?
Dr Hirsch emphasized that epidermal growth factor receptor (EGFR) mutations remain one of the most well-characterized targets in NSCLC, with multiple treatment options available across first-line, second line, and treatment resistant settings. He further highlighted some of the key milestones and ongoing challenges. In the first line setting, he noted that osimertinib remains the preferred standard, based on results from the FLAURA trial which demonstrated a median PFS of 18.9 months versus 10.2 months with first-generation EGFR tyrosine kinase inhibitors (TKIs). He also described some combination approaches currently under investigation, including the use of EGFR TKIs in combination with vascular endothelial growth factor (VEGF) inhibitors or chemotherapy. Dr Hirsch noted that resistance to first-generation EGFR TKIs was generally mediated by the T790M mutation, a finding that ultimately led to the development of osimertinib. With the growing use of osimertinib, Dr Hirsch cited other mutations such as C797S which is now emerging as key driver of osimertinib resistance and necessitating the development of fourth-generation EGFR inhibitors.
Reviewing the current treatment landscape for EGFR-driven NSCLC, Dr Hirsch cited trials like FLAURA2, which is investigating the addition of platinum-pemetrexed to osimertinib, a combination that improves progression-free survival (PFS) to 25.5 versus 16.7 months, at the cost of increased toxicity with the combination. He also noted trials like MARIPOSA and MARIPOSA-2, which are seeking to address other mechanisms like MET-amplification and bypass pathways, with the combination of osimertinib plus amivantamab, an EGFR-MET bispecific antibody. Lastly, he noted that fourth-generation EGFR inhibitors targeting key mutations like C797S are currently in early-phase clinical trials, with promising results.
EGFR-Driven NSCLC: Clinical Implications
Osimertinib remains the first-line standard, but combinations with VEGF inhibitors, chemotherapy, or MET inhibitors may improve durability.
Patients progressing on osimertinib should undergo molecular testing to guide second-line therapy.
Fourth-generation EGFR TKIs will soon reshape the treatment paradigm for resistant disease.
ALK-Positive NSCLC: Moving into the Fourth Generation
Anaplastic lymphoma kinase (ALK) is another key oncogenic driver for patients with NSCLC, and Dr Hirsch noted that ALK rearrangements specifically, can occur in about 3 to 5% of NSCLC cases. In this regard, he cited the availability of first-, second-, and third-generation ALK inhibitors (i.e., crizotinib → alectinib → lorlatinib) which have helped to dramatically improve survival in these cases. Results from the CROWN trial were especially notable, demonstrating an unprecedented 5-year PFS of over 60% with lorlatinib, highlighting its potential for long-term disease control. Beyond these results, Dr Hirsch also noted the development of now fourth-generation ALK inhibitors (e.g., NVL-655 and others) currently in clinical trials, which show promising efficacy even after lorlatinib failure.
ALK-Driven NSCLC: Clinical Implications
ALK testing remains critical in NSCLC diagnosis.
Lorlatinib is the current standard of care, but sequencing strategies based on resistance mutations will soon emerge.
Patients progressing on lorlatinib should be considered for fourth-generation ALK inhibitors, currently in clinical trials.
KRAS-Mutant NSCLC: A Long-Awaited Breakthrough
Dr Hirsch reviewed the treatment options for NSCLC patients having KRAS mutations which were long considered “undruggable” mutations but have now become a highly actionable target. Some of the key developments in this area include the advent of KRAS G12C inhibitors including adagrasib and sotorasib, which have to date shown response rates of about 40% when used as a second-line therapy. In addition, he noted the combination strategies which are currently under investigation, including KRAS inhibitors combined with SHP2 inhibitors as a means to address emerging resistance mechanisms. Like other drugs which have been used, initially in later line settings, Dr Hirsch further noted several first-line trials which are underway, and the potential that KRAS targeted therapies may soon challenge immunotherapy as an initial therapy for KRAS-mutant NSCLC.
KRAS-Mutant NSCLC: Clinical Implications
All NSCLC patients should undergo KRAS testing, as targeted therapy is now an option.
KRAS inhibitors are already a standard treatment in second line, and their first line use in NSCLC may be imminent.
Combination approaches will likely improve outcomes, particularly for KRAS-inhibitor resistant disease.
Emerging Frontiers: Antibody-Drug Conjugates (ADCs) and Bispecific Antibodies
Referring to the emergence of the antibody-drug conjugates (ADCs) and their potentially expanding role in NSCLC, Dr Hirsch expressed overall cautious enthusiasm, while at the same time raising concerns about appropriate patient and biomarker selection with these agents. He noted the meaningful treatment responses that have been observed with ADCs such as trastuzumab deruxtecan and TROP2-targeting agents like Sacituzumab govitecan, even among biomarker-unselected populations of NSCLC patients. Another class of drugs Dr Hirsch considered in the emerging frontier space is that of the bispecific antibodies. These include agents like ivonescimab, which has the dual target of the immunotherapy marker programmed death ligand 1 (PD-L1) and VEGF. Overall, Dr Hirsch thought that while agents like these are generating interest, they will require more a rigorous validation that includes biomarkers.
ADCs and Bispecific Antibodies in NSCLC: Clinical Implications
ADCs offer a new treatment avenue for NSCLC, including TROP2 and HER3-expressing tumors.
Bispecific antibodies are an emerging class, but patient selection remains a challenge.
More mechanistic studies are needed before ADCs and bispecifics become mainstream.
“I still don’t fully understand the target for many of these ADCs… We have been trained to associate mutations with targeted therapy (TKIs), but ADCs don’t necessarily follow that logic…. We need smarter, biomarker-driven clinical trials before rushing into large-scale Phase III studies.”
Final Thoughts: Where Are We Headed?
In the final portion of his presentation Dr Hirsch expressed a forward-looking perspective, with three key insights on how the field of targeted therapy in NSCLC must continue to evolve. First, Dr Hirsch emphasized the need for increased use of comprehensive biomarker testing, with liquid and tissue biopsies needing to become a standard of care at every stage of treatment. “We cannot afford to start patients on the wrong therapy because we missed a targetable mutation,” he stressed. Secondly, he cited a need for smarter clinical trials, with many trials enrolling with still too broad criteria that is not biomarker-driven; in this regard, he thought that smaller, more targeted trials should precede large-scale studies to ensure meaningful outcomes with appropriate scientific rigor. Thirdly, he thought that combination therapies will be the defining regimens in the next decade, with appropriately designed, dual blockade approaches (e.g., EGFR + MET, ALK + SHP2) shaping the future of targeted treatment. If these principles can be applied, Dr Hirsch thought, it could allow for much more personalized sequencing strategies to replace the current, rigid, “one-size-fits-all” treatment algorithms for NSCLC. As a final thought, he expressed the classic perspective of “The tissue is the issue” and urged oncologists to prioritize molecular testing and evidence-based treatment selection, ensuring that every patient receives the right therapy at the right time.
Targeted Therapies in NSCLC: Key Takeaways
EGFR, ALK, and KRAS-targeted therapies have transformed NSCLC treatment, and next-generation inhibitors will further refine outcomes.
Fourth-generation EGFR and ALK inhibitors are on the horizon and will soon redefine standard-of-care sequencing.
KRAS inhibitors are now second-line standards, with first-line use expected in the near future.
ADCs and bispecific antibodies are promising but require further biomarker validation.
Molecular testing and biomarker-driven treatment selection are more critical than ever.
Speaker Disclosure Information: Dr Hirsch reported the following disclosures for this presentation: Advisory Boards:BMS, Genentech/Roche, AstraZeneca/Daiichi, Merck, Novartis, Regeneron/Genzyme/Sanofi, OncoCyte, Oncohost, Amgen, Nectin Therapeutics, NextCure, G1 Therapeutics, Merus, Agilent/DAKO, Novocure. Patents: EGFR Protein and/or EGFR Copy Number as Biomarkers for EGFR-directed therapy (University of Colorado).
You can see the full presentation by Dr Fred Hirsch at the 2025 West Oncology Conference on our YouTube channel here.