The year 2025 was framed as a breakout year in thoracic oncology, with multiple FDA decisions further segmenting treatment for non–small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) and accelerating the shift toward precision medicine. The updates emphasized new antibody-drug conjugates and next-generation tyrosine kinase inhibitors (TKIs) tailored to specific biomarkers, expanding options for patients with defined molecular alterations and highlighting the growing need for broader testing at diagnosis and progression.

On the NSCLC side, the piece highlights accelerated approvals for datopotamab deruxtecan in previously treated EGFR-mutated disease and telisotuzumab vedotin for c-Met high overexpression. It also notes approvals of more selective TKIs—zongertinib for HER2 (ERBB2) TKD mutations and taletrectinib for ROS1-positive NSCLC, with central nervous system activity positioned as a key advantage. In SCLC, advances focused on extending benefit with immunotherapy, including lurbinectedin plus atezolizumab as a maintenance approach in extensive-stage disease and the move of tarlatamab to full approval in previously treated extensive-stage SCLC—underscoring new sequencing and toxicity-management considerations as these agents enter practice.

Reference: Serani S. 2025 FDA Lung Cancer Approvals: Precision Medicine and Immunotherapy Advances. Targeted Oncology. Published December 28, 2025. Accessed January 16, 2026. https://www.targetedonc.com/view/2025-fda-lung-cancer-approvals-precision-medicine-and-immunotherapy-advances

Investigators of a large real-world retrospective study (463 patients across 9 centers, 2020–2023) in stage III non–small cell lung cancer (NSCLC) compared sequencing chemoimmunotherapy before definitive chemoradiotherapy (CRT; neoadjuvant/induction) vs immunotherapy after CRT (adjuvant; PACIFIC-like). The neoadjuvant approach was associated with significantly better outcomes: median progression-free survival was 25.0 vs 16.3 months (HR 0.57; P<.001) and overall survival was not reached vs 41.1 months (HR 0.54; P=.001). These benefits persisted after propensity-score matching and sensitivity analyses. Patterns of recurrence differed somewhat between cohorts, but both locoregional and distant failures were observed in each group.

Safety findings suggested no definitive increase in severe pneumonitis with the neoadjuvant strategy. Any-grade radiation pneumonitis occurred in 49.4% (neoadjuvant) vs 57.9% (adjuvant) (not significant), grade ≥2 rates were similar (~31% in both), and grade ≥3 pneumonitis was 14.0% vs 7.5% (P=.071). Any-grade checkpoint inhibitor pneumonitis was 9.3% vs 5.3% (not significant). The authors concluded that an induction immunotherapy approach followed by concurrent CRT and then consolidation may improve survival vs a PACIFIC-like regimen while maintaining an acceptable pneumonitis profile. They also called for further research to refine patient selection and optimize induction cycles and agents.

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Reference: Conroy R. Chemoimmunotherapy Before Radiation Improves Survival in Stage III NSCLC. Cancer Network. Published January 8, 2026. Accessed January 15, 2026. https://www.cancernetwork.com/view/chemoimmunotherapy-before-radiation-improves-survival-in-stage-iii-nsclc

Amivantamab is an EGFR-MET bispecific antibody used intravenously—often with lazertinib—for EGFR-mutated advanced non–small-cell lung cancer (NSCLC). The phase 2 SKIPPirr trial tested four prophylactic strategies on top of standard premedication (antihistamines, antipyretics, intravenous dexamethasone 10 mg) in patients with advanced EGFR exon 19 deletion or L858R–mutated NSCLC previously treated with osimertinib and platinum chemotherapy. Cohorts received either low-dose oral dexamethasone 4 mg twice daily (BID), higher-dose dexamethasone 8 mg BID, montelukast, or a single dose of subcutaneous methotrexate, in a Simon two-stage design. Among 68 participants (median age 63.5 years; 65% female; 62% Asian), the dexamethasone 8 mg BID cohort was the only regimen to meet predefined criteria and advance to expansion.

In the dexamethasone 8 mg cohort, infusion-related reaction (IRRs) on the first infusion (C1D1) occurred in 22.5% of patients—all grade 1 to 2—representing roughly a threefold reduction versus historical data with standard IRR management alone. By the end of cycle 3, 24.4% had experienced an IRR, with only one grade 3 event. Overall adverse events (rash, paronychia, hypoalbuminemia) were consistent with known EGFR/MET inhibition, and steroid-related toxicities were minimal. The investigator-assessed objective response rate with amivantamab–lazertinib plus dexamethasone 8 mg BID was 33% (28% confirmed), aligning with prior trials and suggesting no loss of efficacy. Infusion times were modestly shorter than historical controls. The authors conclude that adding short-course dexamethasone 8 mg BID to standard premedication meaningfully reduces IRRs, maintains antitumor activity, and may improve the practicality and tolerability of intravenous amivantamab in routine care.

Reference: Spira AI, Paz-Ares L, Han JY, et al. Preventing Infusion-Related Reactions With Intravenous Amivantamab-Results From SKIPPirr, a Phase 2 Study: A Brief Report. J Thorac Oncol. 2025;20(6):809-816. doi: 10.1016/j.jtho.2025.01.018.

Authors of a recent review outline how non–small-cell lung cancer (NSCLC) management has rapidly evolved through advances in screening, diagnostics, and systemic therapies across early-stage and advanced disease. Low-dose CT screening has reduced lung cancer mortality. Updated United States Preventive Services Task Force and American Cancer Society criteria now capture younger, higher-risk, and historically underserved populations, though further outreach to low-socioeconomic status groups is still needed. Staging continues to be refined by International Association for the Study of Lung Cancer to better reflect prognosis and treatment planning. Molecular profiling via next-generation sequencing has become central to care—identifying key driver alterations and immunotherapy biomarkers and increasingly incorporating tools like circulating tumor DNA.

On the treatment side, immunotherapy has moved from metastatic salvage to frontline and perioperative standard of care in actionable genomic alteration-negative NSCLC. It improves event-free and disease-free survival in resectable disease and overall survival in unresectable stage III and metastatic settings. For tumors with actionable genomic alterations, targeted agents are now used in both early-stage adjuvant and advanced disease, with an expanding armamentarium that includes newer tyrosine kinase inhibitors, bispecific antibodies, and antibody–drug conjugates. Collectively, improved screening, more precise staging, and increasingly personalized systemic therapy have transformed NSCLC into a disease where outcomes are steadily improving.

Reference: Jeon H, Wang S, Song J, Gill H, Cheng H. Update 2025: Management of Non‑Small-Cell Lung Cancer. Lung. 2025;203(1):53. doi: 10.1007/s00408-025-00801-x.

Zongertinib is an oral, irreversible, HER2-selective TKI evaluated in a multicohort phase 1a/1b trial for previously treated HER2-mutant non-small cell lung cancer (NSCLC). The analysis included three groups: cohort 1 (tyrosine kinase domain [TKD] mutations), cohort 5 (TKD mutations after HER2-directed antibody drug conjugate therapy), and cohort 3 (non-TKD mutations). Cohort 1 began with a 120 mg vs 240 mg once-daily randomization; cohorts 5 and 3 started at 240 mg. Following an interim review, all subsequent patients received 120 mg daily. The primary endpoint was objective response rate (ORR; blinded independent central review for cohorts 1 and 5, investigator for cohort 3), with duration of response (DOR) and progression-free survival (PFS) as key secondary endpoints.

At the November 29, 2024 cutoff, zongertinib 120 mg achieved a 71% confirmed ORR (95% CI, 60–80; P<0.001 vs ≤30% benchmark) in cohort 1 (n=75), with median DOR 14.1 months and median PFS 12.4 months. Grade ≥3 drug-related adverse events occurred in 17%. In cohort 5 (n=31), ORR was 48% with 3% grade ≥3 events, and in cohort 3 (n=20), ORR was 30% with 25% grade ≥3 events. Importantly, no drug-related interstitial lung disease was observed across cohorts. Overall, zongertinib demonstrated meaningful antitumor activity with mainly low-grade toxicity in previously treated HER2-mutant NSCLC—most pronounced in TKD-mutant disease. These results support continued development at the 120 mg dose, highlighting its potential to deliver durable disease control and improved outcomes for this patient population.

Reference: Heymach JV, Ruiter G, Ahn MJ, et al. Zongertinib in Previously Treated HER2-Mutant Non-Small-Cell Lung Cancer. N Engl J Med. 2025;392(23):2321-2333. doi: 10.1056/NEJMoa2503704.

Final overall survival results from the phase 3 FLAURA2 trial show that osimertinib plus platinum–pemetrexed chemotherapy extends survival vs osimertinib alone as first-line therapy for untreated EGFR-mutated advanced NSCLC. In this international, open-label study (n=557), patients were randomized 1:1 to the combination or monotherapy; overall survival (OS) was a key secondary endpoint. Median OS was 47.5 vs 37.6 months (hazard ratio [HR] 0.77, 95% CI 0.61–0.96; P=0.02), a 23% reduction in risk of death, building on the previously reported progression-free survival benefit (HR 0.62, P<.001). Investigators described this as the longest OS reported to date in this population, presented at the European Society for Medical Oncology Congress 2025 (LBA77) and published in The New England Journal of Medicine, supporting the combination as a first-line standard of care.

The OS advantage was consistent across prognostic subgroups. With baseline central nervous system (CNS) metastases, median OS was 40.9 vs 29.7 months (HR 0.72); without CNS disease, not reached vs 43.9 months (HR, 0.77). In those with L858R, median OS was 38.1 in the combination group vs 32.4 months (HR 0.76). In those with exon 19 deletions, median OS was not reached vs 43.0 months (HR ,0.76). In patients with TP53 alterations, median OS was 51.1 vs 43.1 months (HR, 0.71); for TP53 wild-type mutations, median OS was not reached in either arm (HR, 0.70). Taken together, these findings validate starting with combination therapy from the outset and provide a foundation for exploring additional first-line combinations to further enhance efficacy.

Reference: The ASCO Post Staff. Final FLAURA2 Analysis Confirms First-Line Benefit of Osimertinib/Chemotherapy in EGFR-Positive NSCLC. The ASCO Post. Published October 21, 2025. Updated November 11, 2025. Accessed November 12, 2025. https://ascopost.com/news/october-2025/final-flaura2-analysis-confirms-first-line-benefit-of-osimertinib-chemotherapy-in-egfr-positive-nsclc/

Definitive concurrent chemoradiation (CRT) followed by consolidation durvalumab in patients without progression remains the standard of care for unresectable stage III non-small cell lung cancer (NSCLC). In the phase 3 PACIFIC-2 trial, adding durvalumab concurrently with CRT (then continuing as consolidation) did not significantly improve progression-free survival (PFS; hazard ratio [HR], 0.85; 95% CI, 0.65–1.12; P=0.247) or overall survival (OS; HR, 1.03; 95% CI, 0.78–1.39; P=0.823), vs CRT plus placebo. Median PFS was 13.8 vs 9.4 months. Median OS was 36.4 vs 29.5 months. Kaplan–Meier curves overlapped early, with later separation favoring durvalumab (after ~9 months for PFS; after ~27 months for OS), but without statistical significance. Objective response rates were virtually identical (60.7% vs 60.6%), though median duration of response was longer with durvalumab (30.7 vs 18.6 months).

Safety was broadly comparable between arms, with high rates of treatment-emergent adverse events (TEAEs: 98.6% vs 100%). Grade ≥3 TEAEs occurred in 53.4% vs 59.3% of patients, with grade 5 events occurring in 13.7% vs 10.2% of patients. Common any-grade events included anemia (42.0% vs 38.0%), pneumonitis/radiation pneumonitis (28.8% vs 28.7%), neutropenia (27.4% vs 25.9%), and nausea (25.6% vs 24.1%). Grade ≥3 neutropenia was more frequent with durvalumab (13.7% vs 7.4%). Taken together, PACIFIC-2 shows no added benefit to giving durvalumab concurrently with CRT, while the established strategy—consolidation durvalumab post-CRT in non-progressors—continues to deliver the most robust, long-term efficacy and manageable safety.

Reference: Fabbricatore R. Durvalumab Plus Concurrent CRT Does Not Add Benefit in Stage III NSCLC. CancerNetwork. Published October 31, 2025. Accessed November 12, 2025. https://www.cancernetwork.com/view/durvalumab-plus-concurrent-crt-does-not-add-benefit-in-stage-iii-nsclc

Perioperative checkpoint inhibition is reshaping treatment for resectable early-stage non-small cell lung cancer (NSCLC). Building on prior successes in unresectable stage III (PACIFIC) and in neoadjuvant or adjuvant settings alone (CheckMate 816, IMpower010, KEYNOTE-091), the phase 3 KEYNOTE-671 trial tested a combined approach: neoadjuvant pembrolizumab plus cisplatin-based chemotherapy (4 cycles), surgery, and adjuvant pembrolizumab (up to 13 cycles) vs matched placebo with chemotherapy, surgery, and placebo. Eligible patients had stage II to IIIB (N2) NSCLC, Eastern Cooperative Oncology Group performance status score of 0 to 1, and resectable disease.

Among 797 randomized participants (median follow-up 25.2 months), perioperative pembrolizumab significantly improved event-free survival (24-mo event-free survival 62.4% vs 40.6%; HR 0.58; P<0.001) and deepened pathologic responses (major pathologic response 30.2% vs 11.0%; pathologic complete response 18.1% vs 4.0%; both P<0.0001). Overall survival at this interim analysis favored pembrolizumab (80.9% vs 77.6% at 24 months) but did not cross the prespecified boundary. Surgical feasibility and complication profiles were similar. Grade ≥3 treatment-related adverse events occurred in 44.9% vs 37.3% (grade 5: 1.0% vs 0.8%), consistent with known chemo-immunotherapy risks. Together with other perioperative trials, these data support perioperative immunochemotherapy as a new standard option for resectable stage II to III NSCLC, pending longer-term survival follow-up and refined patient selection.

Reference: Wakelee H, Liberman M, Kato T, et al. Perioperative Pembrolizumab for Early-Stage Non–Small-Cell Lung Cancer. N Engl J Med. 2023;389(6):491-503. doi:10.1056/NEJMoa2302983.

Frontline aumolertinib plus carboplatin/pemetrexed significantly prolonged progression-free survival (PFS) vs aumolertinib alone for EGFR-mutated advanced non-small cell lung cancer (NSCLC) with concomitant tumor suppressor gene (TSG) alterations in the phase 3 ACROSS-2 trial. At 25.3 months median follow-up, investigator-assessed median PFS was 19.8 months with the combination vs 16.5 months with monotherapy (hazard ratio [HR] 0.55; 95% confidence interval [CI], 0.34–0.91; P=.021). Benefit was consistent in key subgroups with TP53 co-mutations (18.7 vs 16.3 months; HR 0.55; P=.024) and numerically favored the combination in EGFR 19del (not reached vs 16.3 months; HR 0.46; P=.055) and L858R (18.7 vs 16.5 months; HR 0.63; P=.154). Overall response rates were similar (70.4% vs 67.2%), and disease control was high in both arms (92.6% vs 98.4%).

Safety reflected added chemotherapy: In the combination arm, common any-grade treatment-emergent adverse events (TEAEs) included anemia (61%), decreased white blood cell count (54%), AST/ALT elevations (52%/48%), and decreased neutrophils (44%). Monotherapy had lower overall TEAE rates, with the most often reported being creatine kinase elevation (42%), transaminase elevations (27%/19%), and rash (20%). These data support aumolertinib-chemotherapy as a feasible option to improve PFS in EGFR-mutated NSCLC with co-occurring TSG alterations, while balancing higher myelosuppression and hepatic laboratory abnormalities associated with chemotherapy.

Reference: DiEugenio J. Aumolertinib Plus Chemotherapy Improves PFS in EGFR-Mutated NSCLC. OncLive. Published September 7, 2025. Accessed September 22, 2025. https://www.onclive.com/view/aumolertinib-plus-chemotherapy-improves-pfs-in-egfr-mutated-nsclc

Researchers of the phase 3 FLAURA2 trial showed that adding platinum–pemetrexed chemotherapy to first-line osimertinib significantly improved overall survival (OS) for patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC) vs osimertinib alone. At ~51 months’ follow-up, median OS was 47.5 vs 37.6 months (hazard ratio [HR] 0.77; P=.02), with higher 24-/36-/48-month OS rates in the combination arm (80%/63%/49% vs 72%/51%/41%). Prior primary analysis also demonstrated a progression-free survival advantage (25.5 vs 16.7 months; HR 0.62; P<.001), supporting the 2024 FDA approval of osimertinib plus platinum–pemetrexed. OS benefit was consistent across predefined subgroups, including patients with baseline central nervous system metastases.

Safety with longer follow-up remained consistent and manageable: Any-grade adverse events occurred in nearly all patients, with grade ≥3 events more frequent with the combination (70% vs 34%) but few discontinuations of osimertinib itself (12% vs 7%) and no new treatment-related deaths (one with monotherapy). Patients receiving the combination had prolonged osimertinib exposure (median 30.5 months) and a long chemotherapy-free period after the initial four platinum cycles plus maintenance pemetrexed. Despite most monotherapy patients receiving subsequent standard chemotherapy at progression, the OS advantage for the upfront combination persisted, confirming osimertinib plus chemotherapy as a first-line standard of care in EGFR-mutated advanced NSCLC.

Reference: Rosa K. Frontline Osimertinib Plus Chemo Significantly Improves OS in EGFR-Mutated Advanced NSCLC. OncLive. Published September 7, 2025. Accessed September 22, 2025. https://www.onclive.com/view/frontline-osimertinib-plus-chemo-significantly-improves-os-in-egfr-mutated-advanced-nsclc

Researchers of two single-arm, phase 2 trials (TRUST-I and TRUST-II) evaluated once-daily taletrectinib 600 mg in ROS1-positive non-small cell lung cancer (NSCLC). The integrated efficacy set included 273 patients. Independent review committee–assessed confirmed objective response rate (cORR) was 88.8% in patients who were tyrosine kinase inhibitor (TKI)-naïve (n=160) with an intracranial ORR 76.5%. In patients who were TKI-pretreated (n=113), confirmed ORR was 55.8% with an intracranial ORR of 65.6%. Median duration of response and progression-free survival were 44.2 and 45.6 months in patients who were TKI-naïve, and 16.6 and 9.7 months in patients who were TKI-pretreated, respectively. In the G2032R-mutant subset, cORR was 61.5% (8/13). Both trials were registrational, open-label, and nonrandomized, with cORR by independent review as the primary end point.

Across 352 treated patients, the most frequent treatment-emergent adverse events (TEAEs) were gastrointestinal events (88%) and laboratory elevations in AST (72%) and ALT (68%), predominantly grade 1. Neurologic adverse events were comparatively infrequent (dizziness 21%, dysgeusia 15%; mostly grade 1), and discontinuations due to TEAEs were 6.5%. Overall, taletrectinib demonstrated high systemic and intracranial activity with durable responses and a generally manageable safety profile in both TKI-naïve and pretreated cohorts. These data support taletrectinib as a central nervous system-active ROS1 inhibitor with durable efficacy across lines of therapy.

Reference: Pérol M, Li W, Pennell NA, et al. Taletrectinib in ROS1–Positive Non-Small Cell Lung Cancer: TRUST. J Clin Oncol. 2025;43(16). doi: 10.1200/JCO-25-00275.

Researchers of a single-center, retrospective pre/post project at the University of Pennsylvania tested whether early oncology nurse navigator (ONN) involvement plus concurrent liquid biopsy at tissue biopsy shortens time to treatment for stage III/IV lung cancer. The pathway embedded same-day ONN referral, social determinants of health (SDOH) assessment, biomarker education, and liquid-biopsy ordering/logistics. Among 49 patients (29 pre; 20 post), liquid-biopsy use rose, with a median turnaround of 7 days vs 28 days for tissue next-generation sequencing. Liquid biopsy was associated with faster treatment selection and initiation. ONN involvement similarly reduced time to selection and increased first-visit selection. The share of liquid biopsies performed prior to/same day as tissue increased from 33% to 75%, enabling results to inform earlier oncology visits.

Limitations include a single-site, small nonrandomized sample, exclusion of uninsured patients, and confounding from scheduling. Still, ONNs effectively coordinate diagnostics and address SDOH barriers, while liquid biopsy provides a rapid, complementary route to actionable results (with tissue remaining the gold standard). The researchers suggest early ONN navigation and to perform liquid biopsy concurrently with tissue biopsy to streamline workflows and reduce delays to treatment. This standardized pathway appears feasible to replicate with interprofessional coordination and may improve patient experience.

Reference: Polo J, Coughlin R, Lynch MP. Time to Treatment in Advanced Lung Cancer: A Quality Improvement Project Using Nurse Navigation and Liquid Biopsy. Clin J Oncol Nurs. 2025;29(1):E28-E36. doi: 10.1188/25.CJON.E28-E36.

Researchers of a registrational phase 2 cohort of the KRYSTAL-1 study evaluated adagrasib 600 mg twice daily in previously treated KRAS^G12C-mutated non-small cell lung cancer (NSCLC) after platinum chemotherapy and anti–PD-1/PD-L1 therapy. Among 116 treated patients (median follow-up 12.9 months; 98.3% pretreated with both chemotherapy and immunotherapy), 112 had measurable disease and 48 achieved a confirmed objective response (overall response rate, 42.9%). Median duration of response was 8.5 months (95% confidence interval [CI], 6.2–13.8), median progression-free survival was 6.5 months (95% CI, 4.7–8.4), and at a later cutoff (median follow-up 15.6 months), median overall survival was 12.6 months (95% CI, 9.2–19.2). Objective responses were assessed by blinded independent central review as the primary endpoint.

Safety was consistent with prior experience: Treatment-related adverse events occurred in 97.4% of patients (grade 1–2 in 52.6%, grade ≥3 in 44.8%, including two grade 5 events), and led to discontinuation in 6.9%. Overall, adagrasib demonstrated clinical activity and manageable toxicity in this heavily pretreated KRAS^G12C-mutated NSCLC population, without new safety signals. Findings support adagrasib as a post-chemotherapy targeted option.

Reference: Jänne PA, Riely GJ, Gadgeel SM, et al. Adagrasib in Non-Small-Cell Lung Cancer Harboring a KRASG12C Mutation. N Engl J Med. 2022;387(2):120-131. doi: 10.1056/NEJMoa2204619.