Is Oncology Precision Medicine Coming of Age?
By Thomas Pataillot-Meakin, Ph.D., Laura Knighton, Ph.D., and Kasia Koczula, Ph.D., Lifescience Dynamics
Developers of targeted therapies are now releasing trial data that suggest these agents may finally address some of oncology’s toughest challenges, including brain metastases in lung cancer.
Baby Steps: Early Breakthroughs In Targeted Therapy
The September 1998 FDA approval of Herceptin (trastuzumab; HER2 mAb) for HER2-positive breast cancer ushered in a new era of cancer treatment, with additional targeted therapies revolutionizing indications such as Zelboraf (vemurafenib; BRAF kinase inhibitor) for BRAFV600E-mutant melanoma and Xalkori (crizotinib; ALK TKI) for patients with ALK-positive non-small cell lung cancer (NSCLC), both in August 2011. Mechanisms such as tyrosine kinase inhibitors (TKIs) have come to define the targeted medicine space. However, despite gains from first-generation agents, there is still substantial room for improvement in efficacy, safety, and overcoming resistance.
For instance, patients with rare mutations such as exon20 insertions (ex20ins) in EGFR-mutant NSCLC or brain metastases respond poorly to standard-of-care targeted therapies; similarly, following progression on targeted therapy, options are often limited and lack non-chemotherapeutic options.
Growing Pains: Navigating Complex Challenges
One area where these challenges are particularly evident is in the design and performance of EGFR TKIs. These therapies are designed to bind structurally altered proteins due to specific cancer-related mutations, such as exon 19 deletions (ex19del) or exon 21 L858R substitutions in EGFR-mutant NSCLC; thus, where rarer mutations, such as ex20ins for EGFR-mutant NSCLC, result in a differently folded protein, binding efficiency is lower and therefore also therapeutic efficacy.
Brain metastases are traditionally harder to treat due to the limited permeability of the blood-brain barrier, requiring drugs specifically designed to achieve intracranial concentrations. However, achieving effective brain exposure often necessitates higher systemic doses, which can lead to intolerable toxicities.
Brain metastases also tend to exhibit unique mutational landscapes and alternative resistance pathways compared to primary tumors or extracranial lesions. Because they are rarely biopsied, the mutational profile used to guide therapy is often inferred from extracranial disease, which can limit the effectiveness of targeted approaches.
Early Maturity: Expanding Reach And Impact
The tide appears to be turning in recent years with several targeted therapies showing promise in both rare mutations and for patients with brain metastases in NSCLC with iterative improvements in duration of response and progression-free survival.
Zipalertinib (EGFR TKI) previously received FDA Breakthrough Therapy designation for patients with ex20ins EGFR-mutant NSCLC who had progressed on platinum-based chemotherapy. Data presented at the International Association for the Study of Lung Cancer (IASLC) 2025 for the Phase 1/2 REZILIENT1 trial in ex20ins EGFR-mutant NSCLC patients with brain metastases, previously treated with Rybrevant (amivantamab; EGFRxcMET bsAb), showed similar confirmed objective response rates compared with the combined population of brain metastasis-positive and -negative patients (29% vs. 31.5%) and a median duration of response of 8.3 months. Although these response rates are lower than those reported for Zegfrovy (sunvozertinib; EGFR TKI), the absence of duration-of-response data for Zegfrovy currently gives zipalertinib an advantage in terms of demonstrated long-term efficacy. Interim data from the Phase 2 REZILIENT2 trial at European Society for Medical Oncology (ESMO) 2025 showed meaningful intracranial antitumor effects, with a 31.3% (n=5/16) response rate and 68.8% disease control rate in NSCLC patients with EGFR ex20ins or other rare mutations. These results strengthen zipalertinib’s profile as a novel EGFR inhibitor with broad potential in treating ex20ins NSCLC, including the ~25%-40% of patients with challenging brain metastases, and support Taiho Oncology’s and Cullinan Therapeutics’ initiation of a rolling submission to the FDA with anticipated completion in Q1 2026 and request for priority review.
Hernexeos (zongertinib; HER2 TKI) also showed encouraging efficacy in data presented at the World Conference on Lung Cancer (WCLC) 2025 from the Phase 1b Beamion LUNG-1 trial in HER2 tyrosine kinase domain (TKD)-mutated non-squamous NSCLC with brain metastases (41% objective response rate, 8.2 months median progression-free survival) compared to 7.1 months median progression-free survival for Enhertu (trastuzumab deruxtecan; HER2 ADC) and in rarer HER2 V777L mutations as seen at ESMO 2025. The FDA granted accelerated approval to Hernexeos in August 2025 for HER2 TKD-mutated non-squamous NSCLC based on data from Beamion LUNG-1, broadening therapeutic options for a rarer subpopulation (2%-4% of NSCLC), and it was recently granted an FDA Commissioner’s National Priority Voucher for “HER2 lung cancer” as the first asset in NSCLC to receive one, underscoring confidence in the asset to meet an unmet need in this indication.
Progress is not unique to NSCLC. For rarer or more specific mutations, Vyloy (zolbetuximab; CLDN18.2 mAb) was approved in October 2024 for previously untreated CLDN18.2-positive, HER2-negative gastric and gastroesophageal junction cancers. And beyond antibodies and TKIs, several antibody-drug conjugates (ADCs), including sacituzumab govitecan (HER2 ADC; ASCENT-07) and disitamab vedotin (HER2 ADC; NCT06157892), are in development for HER2-low breast cancer – a subgroup that historically responds poorly to traditional HER2-targeted therapies. Enhertu (HER2 ADC) was also approved in January 2025 for metastatic HER2-low breast cancer.
Flying The Nest: Precision Medicine Meets Real-World Challenges
Precision medicine has been transforming oncology over the past several decades by enabling treatments tailored to the unique genetic and molecular profiles of individual patients, offering the potential for more effective and less toxic therapies. While novel therapeutic targets continue to emerge and advancements are made, physicians face the growing challenge of navigating an increasingly complex treatment landscape to determine the most appropriate therapy, or combination of therapies, for each individual patient, assessing evolving clinical evidence. This was reflected at ESMO 2025 for NSCLC, where presentations and discussants across NSCLC subtypes focused on subgroup data and the need to better stratify and monitor the evolving genetic landscape of patients.
Current clinical guidelines, such as those from the National Comprehensive Cancer Network (NCCN) and ESMO, still lack comprehensive recommendations for several patient populations. There remains an unmet need for tailored guidance in complex cases, such as those involving brain metastases, frailty, actionable mutations, or other biomarkers. As clinical evidence evolves, updated recommendations are anticipated to better reflect the growing role of targeted and personalized therapies.
The debate around treatment sequencing is likely to continue as more therapies and data emerge. For instance, treatment sequencing within the ex19del EGFRm NSCLC space remains a hot topic among KOLs and physicians. Although osimertinib monotherapy has long been the standard of care and many clinicians have been reluctant to escalate treatment too early, the impressive overall survival (OS) data from FLAURA2 (WCLC 2025), supported by subgroup analyses at ESMO 2025 and the recent Category 1 recommendation in the NCCN guidelines (V1.2026), may encourage earlier use of osimertinib + chemo despite the potential for increased toxicity.
Additionally, for EGFR-mutant NSCLC patients with brain metastases, COMPEL data presented at WCLC 2025 is particularly impactful. Although full statistical analysis is still pending, the findings support the use of CNS-active regimens like osimertinib ± chemotherapy after amivantamab + chemo, potentially guiding more tailored treatment decisions for this challenging population.
Looking ahead, other tumor types are undergoing a similar shift toward more targeted therapies and biomarker-based treatment paradigms, with TKIs and ADCs continuing to drive progress. This trend highlights a broader transformation in oncology, where precision medicine is not only improving outcomes but also reshaping clinical decision-making across diverse cancer types. Future strategies will likely build on lessons from further developed indications like NSCLC, where subgroup analyses and CNS-active regimens such as osimertinib ± chemotherapy are guiding sequencing decisions. As more agents such as zipalertinib and Hernexeos show efficacy in rare mutations and brain metastases, the field is likely to place even greater emphasis on tailoring treatment for complex patient populations. Taken together, these developments highlight the growing need for adaptive guidelines and greater integration of real-world evidence.
About The Authors:
Thomas Pataillot-Meakin, Ph.D., is a business analyst at Lifescience Dynamics with a doctorate in oncology. He has supported clients over a wide range of oncology, immunology, and early GI therapeutic areas with expertise in competitive intelligence, market research, and market forecasting. His work spans pipeline strategy, conference intelligence, and cross-functional insight generation to inform commercialization and medical strategy.
Laura Knighton, Ph.D., is a consultant at Lifescience Dynamics, bringing five years of Competitive Intelligence experience, spanning diverse clinical landscapes including oncology, rare diseases, immunology, and neurology. Laura has managed projects across a broad range of practice areas such as competitive intelligence, market research, and market access. Her academic work included four years of research focused on protein interactions, using technologies such as CRISPR-Cas9.
Kasia Koczula, Ph.D., is an engagement manager at Lifescience Dynamics, bringing over eight years of consulting experience in the life sciences sector. She holds a Ph.D. in hematological oncology and has worked across a broad range of therapy areas, including oncology, cardiovascular diseases, and rare diseases. Kasia specializes in competitive intelligence, market research, and strategic advisory services, supporting clients with evidence-based insights to drive informed decision-making.