From Mutation to Medicine: Targeted Therapies in Lung Cancer

Decades of clinical research has led to the discovery of key biomarkers, development of novel agents, and the subsequent improvement in patient survival outcomes.

At the European Society for Medical Oncology 2025 Congress, Jürgen Wolf, MD, medical director at the Center for Integrated Oncology, and chair of the Lung Cancer Program at Center for Integrated Oncology at the University Hospital of Cologne, shared key updates in non-small cell lung cancer (NSCLC) treatment. He discussed novel drugs and emphasized the crucial role of molecular diagnostics in guiding treatment decisions to ensure every patient receives the right therapy at the right time.

Lung cancer represents the second most common cancer in the United States, with over 260,000 new cases in 2025. NSCLC is the most prevalent type of lung cancer, representing roughly 80% to 85% of cases. Pivotal advancements in drug development have significantly improved survival rates for patients over the past 40 years—12.4% in the mid-1970s to 26.7% by 2020. Various investigational and FDA approved agents are responsible—from tyrosine kinase inhibitors (TKIs) to other targeted therapies.^1-3

However, mutations present continued obstacles to optimal outcomes. In NSCLC, there are various mutations not limited to EGFR, ALK fusion, ROS1, BRAF V600E, HER2, and KRAS. Wolf discussed the benefit of molecular diagnostic testing even prior to initiation of therapy for NSCLC. Liquid biopsy has a high specificity but limited sensitivity. He establishes tissue biopsy as the continuing gold standard for molecular diagnostics.⁴

“Molecular diagnostics remains the foundation of personalized care in [NSCLC],” Wolf said. “Comprehensive testing before first line therapy should include all guideline recommended markers. RNA next-generation sequencing is essential for sensitive fusion detection."⁴

EGFR

EGFR mutations are the most common in NSCLC—representing 10% to 15% of lung adenocarcinomas. It is more prevalent and in nonsmokers, women, and Asian populations, with exon 19 deletion and exon 21 L858R being the most frequent mutations. In the adjuvant setting following surgery, osimertinib (Tagrisso; AstraZeneca), a TKI, is the standard of care with proven overall survival (OS) benefit in resected early-stage NSCLC.^4,5

Osimertinib’s successfully secured multiple FDA approvals, supported by data showing its efficacy in adjuvant and neoadjuvant settings. The first approval was supported by data from the randomized, double-blind, placebo-controlled ADAURA trial (NCT02511106). Four years later, the FDA granted osimertinib another approval in the adjuvant setting supported by data from the double blind, randomized, placebo-controlled LAURA trial (NCT03521154).^6-9

Wolf highlights the FLAURA-2 and MARIPOSA trials (NCT04035486; NCT04487080), which is exploring osimertinib as a monotherapy. Both trials had a primary end point of progression-free survival (PFS) and OS and showed osimertinib’s superiority over other available TKIs. OS was favorable and similar between both trials at 60% vs 51% (for combination vs monotherapy) in MARIPOSA and 63% vs 51% (for combination vs monotherapy) in FLAURA-2. The researchers report an approximate 10 to 12 months improvement with a hazard ratio of 0.75 for both trials.^4,10,11

Compared with combination therapies, osimertinib as a monotherapy was associated with less toxicity. Combination therapies yielded more severe adverse events (AEs) and higher rates of treatment interruption. Patients in FLAURA-2 experienced chemotherapy-associated side effects, while MARIPOSA patients had painful infusion reactions such as rash and pulmonary embolism.⁴

“However, this improved efficacy comes at the cost… combination therapies are significantly more toxic than monotherapy,” explained Wolf. “But I think it's fair enough to say that toxicity management has improved substantially with prophylactic skincare, subcutaneous formulation and anti-coagulation. Nevertheless, they remain challenging in clinical routine."⁴

However, osimertinib shows additional efficacy across as a neoadjuvant treatment. Wolf highlights the NEOADURA trial (NCT04351555), a randomized phase 2 trial comparing osimertinib to placebo. The primary end point was major pathological response, which showed a clear advantage for osimertinib.^4,12

"I think this is really an attractive option for these patients, and should be considered and discussed in the tumor growth.”⁴

ALK Fusion

ALK fusions are detected in approximately 1% to 4% of lung cancers, most often in adenocarcinomas. These alterations tend to occur in younger patients and those with minimal smoking history. Alectinib (Alecensa; Genentech) is the current standard-of-care therapy for ALK-positive NSCLC and received FDA approval in 2024 for adjuvant use following tumor resection.^2,4

Wolf highlights other approved agents in this setting including lorlatinib (Lorbrena; Pfizer Inc) and crizotinib (Xalkori; Pfizer), which were compared head-to-head in the CROWN trial (NCT03052608).^4,13

“Lorlatinib has been tested in a phase 3 study against crizotinib, which has already shown progression-free survival benefits in use,” said Wolf, “and it’s a better drug—65% versus around 40% with the second-generation inhibitors.”⁴

CROWN results showed a 5-year PFS of 60% in lorlatinib with favorable brain activity. In patients without initial brain metastases, the data showed a hazard ratio of 0.05 for central nervous system progression.Permanent discontinuation rates were 11% vs 7%.⁴

“However, there are still a lot of reservations against this drug, and this is based on new side effects, such as hydrochlorist weight gain and, in particular, neurologic AEs,” Wolf explained. “There were also some reservations from patients about stem cell use, but when we look at the permanent discontinuation rates from the trial—11% versus 7%—it’s not necessarily more toxic. There’s a learning curve involved.”⁴

ROS1

ROS1 rearrangements account for 1% to 2% of NSCLC cases with an estimated 10,000 to 15,000 new cases every year around the world. Although relatively uncommon in comparison to other mutations. Patients with ROS1 mutations are younger with a history of light smoking; however, some diagnosed patients have no history of smoking.¹⁴

ROS1 mutated lung cancers exhibit clinical similarities to ALK-rearranged NSCLC, though ROS1, EGFR, and ALK rearrangements are generally mutually exclusive. After exposure to TKIs, a subset of ROS1-positive tumors acquires secondary driver mutations, predominantly in KRAS or EGFR.⁴

“For ROS1 fusions, we have active TKIs approved in the first line—entrectinib (Rozlytrek; Genentech), crizotinib, and epotrectinib (Augtyro; Bristol Myers Squibb)—entering for resistant fusions,” said Wolf. “In this field, we already have a next-generation agent approved now after TKI failure.”⁴

HER2

HER2 mutations are seen across cancer types. In lung cancer, they are rarer than ROS1 and ALK fusions, occurring in approximately 0.2% of patients. Wolf highlights datopotamab deruxtecan-dlnk (Datroway;_Daiichi Sankyo, Inc) and zongertinib (Hernexeos; Boehringer Ingelheim Pharmaceuticals, Inc), which are both FDA approved for treatment of patients with NSCLC as of 2025. D-DXd is approved for adults with locally advanced or metastatic EGFR-mutated NSCLC who received prior EGFR-directed therapy and platinum-based chemotherapy.^4,15

Zongertinib is the most recent approval for adults with unresectable or metastatic nonsquamous NSCLC whose tumors have HER2 mutations based on positive data from the Beamion LUNG-1 trial (NCT04886804).^16,17

Beamion LUNG-1 is an open-label, phase 1 dose escalation trial evaluating zongertinib as a monotherapy in patients with unresectable or metastatic, nonsquamous NSCLC with HER2 TKD mutations. The overall response rate was about 75% (95% CI, 63–83), with 58% experiencing a duration of response of 6 months or longer.¹⁸

KRAS

KRAS G12C mutations represent one of the most significant oncogenic drivers in lung cancer, though therapeutic progress in this space has historically been limited. Currently, only two targeted therapies—sotorasib (Lumakras; Amgen) and adagrasib (Krazati; Mirati Therapeutics)—have received FDA approval, both indicated for second-line treatment following chemotherapy.⁴

Despite these advances, clinical benefit remains modest, with disease-free survival rates around 30% and a median duration of response of approximately 5 to 6 months. Although both agents have demonstrated improvements compared with docetaxel, outcomes underscore the ongoing need for more durable and effective options.⁴

The field of KRAS inhibition is rapidly evolving, with multiple next-generation agents currently in clinical development. Ongoing studies are exploring monotherapy and combination approaches, as well as agents that target the GDP-bound (inactive) form of KRAS and emerging pan-KRAS inhibitors designed to address resistance and broader mutation coverage.⁴

Conclusion

The evolution of molecularly targeted therapies has transformed the treatment landscape of NSCLC, turning what was once a fatal disease into one defined by precision and personalization. As highlighted by Wolf, the continued integration of comprehensive molecular diagnostics remains essential to ensuring that each patient receives the most effective therapy for their unique tumor profile. According to Wolf:

“Continuous innovation demands not only better products, but also better data, smarter networks and genuine partnership with our patients to guide everyday decisions”

REFERENCES

1. Key Statistics for lung cancer. American Cancer Society. Updated January 16, 2025. Accessed October 18, 2025. https://www.cancer.org/cancer/types/lung-cancer/about/key-statistics.html

2. Gerlach A. Zongertinib receives breakthrough therapy designation for patients with HER2 non-small cell lung cancer. Pharmacy Times. September 4, 2025. Accessed October 18, 2025. https://www.pharmacytimes.com/view/zongertinib-receives-breakthrough-therapy-designation-for-patients-with-her2-non-small-cell-lung-cancer

3. Eldridge L. Lung cancer survival rates by type, age, and stage. Very Well Health. Updated April 14, 2025. Accessed October 18, 2025. https://www.verywellhealth.com/lung-cancer-survival-rates-by-type-and-stage-2249401#:~:text=The%20survival%20rate%20for%20lung,also%20contribute%20to%20your%20survival.

4. Wolf J, Jänne P, Leighl N. Targeting oncogenes in NSCLC. Presented at: European Society for Medical Oncology 2025 Congress. October 17, 2025, to October 21, 2025. Berlin, Germany.

5. Gerlach A. Navigating EGFR mutations and ALK fusions in early-stage non-small cell lung cancer. Pharmacy Times. July 19, 2025. Accessed October 18, 2025. https://www.pharmacytimes.com/view/navigating-egfr-mutations-and-alk-fusions-in-early-stage-non-small-cell-lung-cancer

6. FDA approves osimertinib as adjuvant therapy for non-small cell lung cancer with EGFR mutations. FDA. December 18, 2024. Accessed October 18, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-osimertinib-adjuvant-therapy-non-small-cell-lung-cancer-egfr-mutations

7. AZD9291 versus placebo in patients with stage IB-IIIA non-small cell lung carcinoma, following complete tumour resection with or without adjuvant chemotherapy. (ADAURA). Clinicaltrials.gov. August 28, 2025. Accessed October 18, 2025. https://clinicaltrials.gov/study/NCT02511106

8. FDA approves osimertinib for locally advanced, unresectable (stage III) non-small cell lung cancer following chemoradiation therapy. FDA. September 25, 2024. Accessed October 18, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-osimertinib-locally-advanced-unresectable-stage-iii-non-small-cell-lung-cancer

9. A Global Study to Assess the Effects of Osimertinib Following Chemoradiation in Patients With Stage III Unresectable Non-small Cell Lung Cancer (LAURA) (LAURA). Clinicaltrials.gov. October 16, 2025. Accessed October 18, 2025. https://clinicaltrials.gov/study/NCT03521154

10. A study of osimertinib with or without chemotherapy as 1st line treatment in patients with mutated epidermal growth factor receptor non-small cell lung cancer (FLAURA2) (FLAURA2). Clinicaltrials.gov. October 10, 2025. Accessed October 18, 2025. https://clinicaltrials.gov/study/NCT04035486

11. A study of amivantamab and lazertinib combination therapy versus osimertinib in locally advanced or metastatic non-small cell lung cancer (MARIPOSA). Clinicaltrials.gov. September 15, 2025. Accessed October 18, 2025. https://clinicaltrials.gov/study/NCT04487080

12. A study of osimertinib with or without chemotherapy versus chemotherapy alone as neoadjuvant therapy for patients with eGFRm positive resectable non-small cell lung cancer (NeoADAURA). Clinicaltrials.gov. May 23, 2025. Accessed October 18, 2025. https://www.clinicaltrials.gov/study/NCT04351555

13. A study of lorlatinib versus crizotinib in first line treatment of patients with ALK-positive NSCLC. Clinicaltrials.gov. December 24, 2024. Accessed October 18, 2025. https://clinicaltrials.gov/study/NCT03052608

14. D'Angelo A, Sobhani N, Chapman R, et a;. Focus on ROS1-Positive Non-Small Cell Lung Cancer (NSCLC): Crizotinib, Resistance Mechanisms and the Newer Generation of Targeted Therapies. Cancers (Basel). November 6, 2020. doi: 10.3390/cancers12113293. PMID: 33172113

15. FDA grants accelerated approval to datopotamab deruxtecan-dlnk for EGFR-mutated non-small cell lung cancer. FDA. June 23, 2025. Accessed October 18, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-datopotamab-deruxtecan-dlnk-egfr-mutated-non-small-cell-lung-cancer

16. FDA grants accelerated approval to zongertinib for non-squamous NSCLC with HER2 TKD activating mutations. FDA. August 8, 2025. Accessed October 18, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zongertinib-non-squamous-nsclc-her2-tkd-activating-mutations

17. Beamion LUNG-1: a study to test different doses of zongertinib in people with different types of advanced cancer (solid tumours with changes in the HER2 Gene). Updated July 28, 2025. Accessed October 18, 2025. https://clinicaltrials.gov/study/NCT04886804#study-overview

18. Gerlach A. Zongertinib receives breakthrough therapy designation for patients with HER2 non-small cell lung cancer. Pharmacy Times. September 4, 2025. Accessed October 18, 2025. https://www.pharmacytimes.com/view/zongertinib-receives-breakthrough-therapy-designation-for-patients-with-her2-non-small-cell-lung-cancer