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/

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.

The 5-year exploratory analysis of KEYNOTE-189 (N=616) shows that adding pembrolizumab to platinum-pemetrexed in previously untreated metastatic nonsquamous non–small cell lung cancer (NSCLC) without EGFR/ALK alterations sustained significant survival advantages over placebo plus chemotherapy. At a median 64.6-month follow-up, the combination achieved an overall survival (OS) hazard ratio (HR) of 0.60 (95% confidence interval [CI], 0.50–0.72) and progression-free survival (PFS) HR of 0.50 (0.42–0.60), with 5-year OS being  19.4% vs 11.3% and 5-year PFS being 7.5% vs 0.6%. Benefit was observed regardless of PD-L1 status, and toxicity remained manageable. Objective response rate was 48.3% vs 19.9%, and median duration of response was 12.7 vs 7.1 months. Patients were randomized 2:1 to pembrolizumab 200 mg every 3 weeks or placebo plus platinum-pemetrexed, with pemetrexed maintenance for up to 35 cycles.

Despite an effective 57% crossover from the control arm to anti–PD-L1 therapy, the pembrolizumab arm maintained superiority, and PFS2 favored the combination (HR 0.54; median 17.0 vs 9.1 months), suggesting durable downstream benefit. Among the 57 patients completing 35 cycles of pembrolizumab, the overall response rate was 86%, median duration of response was 57.7 months, and estimated OS was 71.9% three years after completion (~5 years from randomization). Safety findings were consistent with prior reports, with immune-mediated adverse events and infusion reactions occurring in a minority and generally manageable. Collectively, these long-term data reinforce first-line pembrolizumab plus platinum-pemetrexed as standard of care in this population.

Reference: Garassino MC, Gadgeel S, Speranza G, et al. Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non-Small-Cell Lung Cancer: 5-Year Outcomes From the Phase 3 KEYNOTE-189 Study. J Clin Oncol. 2023;41(11):1992-1998. doi: 10.1200/JCO.22.01989.

Biomarker testing is emphasized in the 2021 National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology for Non–Small Cell Lung Cancer (NSCLC), which is recommended for all appropriate stage IV cases—including consideration in squamous—and pushed earlier into resectable stage IB to IIIA. The guidelines state that first-line targeted therapy improves outcomes when a driver is found. Broad panel testing is advised. PD-L1 immunohistochemistry is essential to guide first-line choices when no actionable mutations are present. The ADAURA trial supports adjuvant osimertinib for resected EGFR-mutated stage IB to IIIA, and is now listed for eligible patients after—or instead of—platinum chemotherapy per criteria. When clinically safe, defer systemic therapy until molecular results return to optimize first-line selection.

The guidelines suggest using next-generation sequencing (NGS) and to consider RNA-based NGS to detect fusions and MET exon 14 events missed by DNA-only tests, and liquid biopsy when tissue is limited. Therapeutically, drivers steer care. Without drivers, PD-L1 guides single-agent immunotherapy (≥50%) or immunotherapy/chemotherapy across PD-L1 strata. Overall, the guidelines recommend to test early, wait for molecular results when feasible, and match therapy to biology. Multidisciplinary coordination (pathology, interventional pulmonology, oncology) helps secure adequate samples and faster turnaround.

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Reference: Aisner DL, Riely GJ. Non–Small Cell Lung Cancer: Recommendations for Biomarker Testing and Treatment. J Natl Compr Canc Netw. 2021;19(5.5). doi: 10.6004/jnccn.2021.5020.

Investigators of a phase 3 randomized trial presented at the 2025 ASCO Annual Meeting examined whether time of day influences immunotherapy outcomes in stage IV non–small cell lung cancer. Authors enrolled 210 driver gene–negative patients (age ≥18) with no prior systemic therapy for metastatic disease and randomized them 1:1 to receive immunotherapy before 3 PM (early group) or after 3 PM (late group). Outcomes favored earlier dosing: median progression-free survival was 11.3 vs 5.7 months (HR 0.42; P<0.0001) and median overall survival was 16.4 vs 10.9 months (HR 0.45; P<0.0001), suggesting earlier infusions may be associated with better treatment effectiveness.

To explore a potential mechanism, investigators pointed to circadian rhythm effects on immune function. The late group had a decline in circulating CD8+ T cells, whereas the early group showed increases in activated CD8+ subsets (eg, HLA-DR+ and TIM-3+PD-1+ populations), which could reflect a more favorable immune state earlier in the day. Importantly, the safety profile appeared similar between groups, including grade 3 to 4 leukopenia and neutropenia rates and pneumonitis at 2.9% in both arms. With a median follow-up of 22.3 months, the findings raise a practical clinical question: whether simply scheduling immunotherapy earlier in the day could improve outcomes without changing the regimen—an approach that would benefit from confirmation in additional studies.

Reference: Timing of Immunotherapy NSCLC: Survival Gains at ASCO 2025. OncologyTube.com. Published June 3, 2025. Updated June 4, 2025. Accessed January 15, 2026. https://oncologytube.com/timing-of-immunotherapy-nsclc-asco-2025/

Researchers of a phase 1/2 trial evaluated neoadjuvant nivolumab (two doses, 3 mg/kg over 4 weeks pre-surgery) in 21 patients with resectable stage I–IIIA non–small cell lung cancer (NSCLC). At a median 63-month follow-up, 5-year recurrence-free survival (RFS) and overall survival were 60% and 80%, respectively, comparing favorably with historical outcomes. Major pathologic response (MPR) and pre-treatment PD-L1 positivity (TPS ≥1%) each showed trends toward improved RFS (hazard ratio [HR] 0.61; 95% confidence interval [CI], 0.15–2.44 and HR 0.36; 95% CI, 0.07–1.85), though the study was not powered for definitive subgroup conclusions. The regimen had previously been shown to be safe and feasible with encouraging MPR.

Durability signals were notable: 8 of 9 patients (89%) with MPR were alive and disease-free at 5 years, and no cancer-related deaths occurred among MPR achievers. By contrast, 6 of 11 patients without MPR relapsed and 3 died. These data—among the longest follow-up reported for neoadjuvant anti–PD-1 in any cancer—support the feasibility and potential long-term benefit of perioperative checkpoint blockade in resectable NSCLC, while underscoring the need for larger studies to validate biomarkers and optimize perioperative strategies. The findings also argue for integrating pathologic response and PD-L1 status into future perioperative trial designs.

Reference: Rosner S, Reuss JE, Zahurak M, et al. Five-Year Clinical Outcomes after Neoadjuvant Nivolumab in Resectable Non-Small Cell Lung Cancer. Clin Cancer Res. 2023;29(4):705-710. doi: 10.1158/1078-0432.CCR-22-2994.

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.

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.

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.

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

Nicolas Girard, MD, PhD, presented interim data from the phase 3 COCOON trial (NCT06120140) at the 2025 European Lung Cancer Congress. He evaluated whether a simple, prophylactic dermatologic regimen could reduce skin toxicity in treatment-naive patients with EGFR-mutant advanced non–small-cell lung cancer (NSCLC) receiving amivantamab plus lazertinib (the MARIPOSA regimen). Because this combination causes more dermatologic adverse events (AEs) than osimertinib, patients were randomized to either standard reactive skin care or a proactive “COCOON regimen” consisting of doxycycline, clindamycin lotion to the scalp, chlorhexidine to the nails, and a ceramide-based moisturizer to the face and body. At the first interim analysis, COCOON met its primary endpoint, cutting the rate of dermatologic AEs grade of at least 2 roughly in half—from 77% with standard care to 39% with prophylaxis—substantially improving daily tolerability for patients on amivantamab plus lazertinib.

Girard noted that the COCOON regimen was also associated with fewer dose interruptions, dose reductions, and treatment discontinuations, which he links to better overall treatment continuity and, ultimately, improved overall survival for patients on this combination. He emphasized that these preventive strategies are simple and widely accessible and should be implemented routinely alongside other supportive measures: dexamethasone given for 3 days before the first amivantamab infusion to reduce infusion-related reactions, and prophylactic anticoagulation to lower venous thromboembolism risk. With these proactive toxicity-management steps in place, Girard argues that clinicians can both optimize the benefit–risk profile of amivantamab-based regimens and meaningfully improve the patient experience in everyday practice.

Reference: Girard N. Girard Shares Early COCOON Data of Amivantamab/Lazertinib in EGFR+ NSCLC. Targeted Oncology. Published March 27, 2025. Accessed December 5, 2025. https://www.targetedonc.com/view/girard-shares-early-cocoon-data-of-amivantamab-lazertinib-in-egfr-nsclc