Tag: Lung Cancer: Non-Small Cell

SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2025, about 226,650 new cases of lung cancer will be diagnosed and 124,730 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers and Adenocarcinoma is now the most frequent histologic subtype of lung cancer.

BRAF V600E mutations occur in approximately 1% to 2% of patients with NSCLC and define a biologically distinct subset for which targeted therapy has become a cornerstone of treatment. Dual inhibition of the MAPK pathway with BRAF and MEK inhibitors is currently recommended by clinical guidelines as the preferred first-line approach for patients with BRAF V600E–mutant metastatic NSCLC (mNSCLC), with immunotherapy and chemotherapy-based regimens serving as alternative options.

The Phase II PHAROS study (NCT03915951) is an ongoing, open-label, single-arm, multicenter trial designed to evaluate the efficacy and safety of Encorafenib (BRAFTOVI®) in combination with Binimetinib (MEKTOVI®) in patients with BRAF V600E–mutant mNSCLC. Eligible patients included both treatment-naïve individuals and those with prior systemic therapy for metastatic disease. All patients received oral Encorafenib 450 mg once daily plus oral Binimetinib 45 mg twice daily, administered in continuous 28-day cycles until disease progression, unacceptable toxicity, or treatment discontinuation.

The Primary endpoint of PHAROS was Objective Response Rate (ORR) as assessed by Independent Radiology Review (IRR), with separate analyses prespecified for treatment-naïve and previously treated cohorts. Key Secondary endpoints included Duration of Response (DOR), Progression-Free Survival (PFS), Overall Survival (OS), Disease Control Rate, Safety, and Tolerability. Exploratory analyses evaluated efficacy across clinically relevant subgroups, including smoking history.

A total of 98 patients were enrolled and treated, including 59 treatment-naïve and 39 previously treated patients. At the March 14, 2025 data cutoff, a small proportion of patients in both cohorts remained on active treatment, reflecting durable disease control in a subset of patients. Median treatment duration was substantially longer in the frontline cohort compared with previously treated patients, with more than 40% of treatment-naïve patients receiving therapy for longer than two years.

PHAROS met its Primary endpoint in both cohorts.

In treatment-naïve patients, the confirmed ORR by IRR was 75%, with responses demonstrating marked durability. Median Duration of Response was 40.0 months, and median PFS reached 30.4 months. After a median follow-up of more than four years for overall survival, median OS was 47.6 months, with an estimated 4-year OS rate of 49%, underscoring the potential for prolonged survival with frontline targeted therapy.

In the previously treated cohort, Encorafenib plus Binimetinib also demonstrated clinically meaningful activity. The ORR was 49%, with a median Duration of Response of 16.7 months. Median PFS was 9.3 months, and median OS was 22.7 months after nearly four years of follow-up. The estimated 4-year OS rate in this cohort was 31%.

Post hoc subgroup analyses suggested that clinical benefit was generally consistent across baseline characteristics. Notably, both PFS and OS were numerically longer in patients without a smoking history compared with those with a history of smoking, a finding that may be related to pharmacokinetic effects on Binimetinib exposure and warrants further investigation.

The safety profile observed with extended follow-up was consistent with prior analyses and with known toxicities associated with BRAF and MEK inhibition. Most treatment-related adverse events were low grade and manageable, with gastrointestinal symptoms, fatigue, and nausea among the most frequently reported. Rates of dose modification and discontinuation were similar across treatment lines, and no new safety signals emerged with longer-term exposure.

Although cross-trial comparisons should be interpreted cautiously, the Overall Survival outcomes observed in PHAROS compare favorably with historical data for targeted therapy in this population. Given that a significant proportion of patients with metastatic NSCLC may not receive subsequent lines of therapy, these findings emphasize the importance of selecting the most effective treatment upfront.

In conclusion, updated results from the PHAROS study demonstrate durable responses and sustained long-term survival with Encorafenib plus Binimetinib in patients with BRAF V600E–mutant mNSCLC. The depth and durability of benefit, particularly in treatment-naïve patients, further support this combination as a preferred first-line targeted therapy option and reinforce its role in the evolving treatment landscape for this molecularly defined NSCLC subgroup.

Updated Overall Survival Analysis From the Phase II PHAROS Study of Encorafenib Plus Binimetinib in Patients With BRAF V600E-Mutant Metastatic Non–Small Cell Lung Cancer. Johnson ML, Smit EF, Felip E, et al. J Clin Oncol. 2025;43:3706-3713

SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2025, about 226,650 new cases of lung cancer will be diagnosed and 124,730 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers and Adenocarcinoma is now the most frequent histologic subtype of lung cancer. Approximately 10-15% of Caucasian patients and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR mutations, and 90% of these mutations are either exon 19 deletions or L858R substitution mutation in exon 21.

Epidermal Growth Factor Receptor (EGFR) plays an important role in regulating cell proliferation, survival and differentiation, and is overexpressed in a variety of epithelial malignancies. EGFR targeted Tyrosine Kinase Inhibitors (TKIs) such as Gefitinib, Erlotinib, Afatinib, Dacomitinib and Osimertinib (TAGRISSO®) target the EGFR signaling cascade. However, patients eventually develop drug resistance due to new EGFR mutations. Another important cause of drug resistance to TKIs is due to the activation of parallel RTK (Receptor Tyrosine Kinase) pathways such as Hepatocyte Growth Factor/Mesenchymal-Epithelial Transition factor (HGF/MET) pathway, thereby bypassing EGFR TKI inhibitors. These patients are often treated with platinum-based chemotherapy as the next line of therapy, resulting in a median Progression Free Survival of about 5 months.

Amivantamab (RYBREVANT®) is a fully human bispecific antibody directed against EGFR and MET receptors. Amivantamab binds extracellularly and simultaneously blocks ligand-induced phosphorylation of EGFR and c-MET, inhibiting tumor growth and promoting tumor cell death. Further, Amivantamab down regulates receptor expression on tumor cells thus preventing drug resistance mediated by new emerging mutations of EGFR or c-MET. By binding to the extracellular domain of the receptor protein, Amivantamab can bypass primary and secondary TKI resistance at the active site. Amivantamab also engages effector cells such as Natural Killer cells, monocytes, and macrophages via its optimized Fc domain. Amivantamab demonstrated activity against a wide range of activating and resistance mutations in EGFR-mutated NSCLC, and in patients with MET exon 14 skip mutations, as well as patients with EGFR exon 20 insertion mutations, whose disease progressed on or after platinum-based chemotherapy.

Lazertinib (LAZCLUZE®) is a highly selective, third-generation TKI that penetrates the CNS, with demonstrated efficacy in activating EGFR mutations and acquired T790M “gatekeeper” point mutation. Combining Amivantamab with Lazertinib has been shown to provide a synergistic benefit by targeting the extracellular and catalytic EGFR domains. The combination of Amivantamab plus Lazertinib has shown clinically meaningful and durable antitumor activity in patients with previously untreated or Osimertinib-pretreated EGFR-mutated advanced NSCLC, with clinical activity against a broad spectrum of secondary EGFR and MET molecular alterations and even in tumors of patients without an identified resistance mechanism.

The MARIPOSA trial is an international, randomized Phase 3 study, conducted to assess the efficacy and safety of a combination of Amivantamab and Lazertinib as compared with Osimertinib alone, as first-line treatment in patients with EGFR-mutated advanced NSCLC. In this study, a third arm evaluated Lazertinib monotherapy, to dissect the individual contributions of each component in the combination. This study included 1074 patients (N=1074) with untreated EGFR-mutated advanced NSCLC who were randomly assigned in a 2:2:1 ratio to receive Amivantamab plus Lazertinib (N=429), Osimertinib monotherapy (N=429), or Lazertinib monotherapy (N=216). Amivantamab was administered weekly at a dose of 1050 mg IV (or 1400 mg IV in patients with a body weight of 80 kg or more) for the first 4 weeks (cycle 1), with the first infusion split over a period of 2 days (with 350 mg given on cycle 1, day 1, and the remainder given on cycle 1, day 2). Starting at cycle 2, the same Amivantamab dose was administered every 2 weeks. Osimertinib 80 mg and Lazertinib 240 mg were taken orally daily respectively. The median age was 63 years, majority of patients were Asian women or White and had never smoked. Approximately 60% had EGFR exon 19 deletions and 40% had exon 21 L858R mutations. Randomization was stratified according to EGFR mutation type (ex19del or L858R), Asian race (yes or no), and history of brain metastases (yes or no). Crossover was not included in this trial design. The Primary end point was Progression-Free Survival (PFS) in the Amivantamab plus Lazertinib group as compared with the Osimertinib group, as assessed by Blinded Independent Central Review. Secondary end points included Overall Survival (OS), Objective Response (defined as a Complete or Partial Response), Duration of Response, and Safety.

The authors previously reported that the median PFS (Primary endpoint), was significantly longer in the Amivantamab plus Lazertinib group at 23.7 months compared to 16.6 months in the Osimertinib group ((HR for progression or death = 0.70; P<0.001).

The researchers in this publication reported the results of the protocol-specified final Overall Survival analysis.

The combination of Amivantamab plus Lazertinib demonstrated a significant Overall Survival (OS) advantage over Osimertinib in patients with previously untreated, EGFR-mutated advanced NSCLC. After a median follow-up of 37.8 months, treatment with Amivantamab–Lazertinib reduced the risk of death by 25% compared with Osimertinib (HR=0.75; 95% CI, 0.61–0.92; P=0.005). Estimated 3-year OS rates were 60% with the combination versus 51% with Osimertinib, while 24-month OS was 75% and 70%, respectively. These findings were supported by multiple parametric modeling approaches, indicating a projected survival benefit exceeding one year.

A greater proportion of patients in the Amivantamab–Lazertinib arm remained on treatment at data cutoff (38% vs 28%). The combination also prolonged time to symptomatic progression, time to treatment discontinuation, and time to next therapy relative to Osimertinib. Notably, most patients in both groups who discontinued study therapy received subsequent anticancer treatment, primarily chemotherapy-based regimens.

The superior outcomes observed with Amivantamab–Lazertinib are thought to stem from its dual targeting of EGFR and MET pathways, enabling proactive suppression of key resistance mechanisms. This regimen was also associated with a lower frequency of complex acquired resistance (28% vs 43%) and potentially beneficial immune-mediated activity.

Among participants with baseline brain metastases (approximately 40% in each group), intracranial outcomes favored Amivantamab–Lazertinib and were consistent with those from the MARIPOSA-2 trial, supporting its efficacy in CNS disease.

As expected, Grade ≥3 adverse events were more frequent with Amivantamab–Lazertinib (80% vs 52%), most commonly dermatologic reactions, venous thromboembolism, and infusion-related events. However, no new safety signals emerged. Emerging evidence from other studies, such as COCOON, suggests that prophylactic strategies (enhanced dermatologic care, anticoagulation, and optimized infusion protocols) can substantially reduce these toxicities. Furthermore, a newly approved subcutaneous formulation of Amivantamab markedly lowers infusion-related reactions (13% vs 66%) and reduces administration time from hours to minutes while maintaining efficacy.

Overall, the MARIPOSA trial establishes Amivantamab–Lazertinib as a superior first-line, chemotherapy-free option for patients with EGFR-mutated advanced NSCLC, offering meaningful improvements in both Progression-Free and Overall Survival compared with Osimertinib.

Overall Survival with Amivantamab–Lazertinib in EGFR-Mutated Advanced NSCLC. Yang JC, Lu S, Hayashi H, et al. for the MARIPOSA Investigators. N Engl J Med 2025;393:1681-1693.

 

SUMMARY: The FDA on May 14, 2025, granted accelerated approval to Telisotuzumab vedotin-tllv (EMRELIS®), a c-Met-directed antibody and microtubule inhibitor conjugate, for adults with locally advanced or metastatic, non-squamous Non-Small Cell Lung Cancer (NSCLC) with high c-Met protein overexpression [50% or more of tumor cells with strong (3+) staining], as determined by an FDA-approved test, who have received a prior systemic therapy. FDA also approved the VENTANA MET (SP44) RxDx Assay (Roche Diagnostics) as a companion diagnostic test to aid in detecting c-Met protein overexpression in patients with non-squamous NSCLC who may be eligible for treatment with Telisotuzumab vedotin .

The American Cancer Society estimates that for 2025, about 226,650 new cases of lung cancer will be diagnosed and 124,730 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers and Adenocarcinoma is now the most frequent histologic subtype of lung cancer.

Background

The MET proto-oncogene encodes the receptor tyrosine kinase c-Met, a key regulator of tumor cell proliferation, survival, invasion, and angiogenesis. Dysregulation of MET signaling can occur in NSCLC via gene amplification (about 5% of cases), exon 14 skipping mutations (about 2%-4%), or through c-Met protein overexpression, which is observed in approximately one-quarter to one-third of patients. Notably, c-Met protein overexpression represents a negative prognostic marker in both early and advanced NSCLC, particularly in nonsquamous, EGFR-wildtype disease, yet no therapies have been approved to directly address this biomarker.

Telisotuzumab vedotin (Teliso-V; EMRELIS®) is a first-in-class, c-Met–directed antibody-drug conjugate (ADC). It couples a c-Met–binding monoclonal antibody with the microtubule-disrupting agent MonoMethyl Auristatin E (MMAE) through a cleavable linker. Preclinical work showed that tumoricidal activity requires high levels of c-Met expression (>100,000 receptors per cell), which supports patient selection strategies for clinical use.

The LUMINOSITY Trial Design

LUMINOSITY study (NCT03539536) is an ongoing, nonrandomized, two-stage, Phase II, multicenter trial designed to identify and validate the NSCLC populations most likely to benefit from Teliso-V monotherapy in the second-line or third-line setting, and then to expand the groups to further evaluate efficacy in the selected populations.

• Stage I: Patients were enrolled into three cohorts based on histology and EGFR mutation status: (1) nonsquamous EGFR-wildtype NSCLC, (2) nonsquamous EGFR-mutant NSCLC, and (3) squamous NSCLC.
• Stage II: Only the nonsquamous EGFR-wildtype NSCLC cohort fulfilled expansion criteria and was carried forward for further evaluation.

Biomarker Definition:

• Nonsquamous NSCLC: c-Met protein overexpression defined as 25% or more of tumor cells showing 3+ membrane staining intensity (with high expression 50% or more and intermediate expression 25-less than 50%).
• Squamous NSCLC: a broader cutoff was applied (75% or more of tumor cells at any intensity) given generally lower c-Met expression levels.

Treatment regimen: Teliso-V was administered intravenously at 1.9 mg/kg every 2 weeks.

Endpoints: The Primary endpoint was Overall Response Rate (ORR) by Independent Central Review (ICR). Secondary endpoints included Duration of Response (DOR), Disease Control Rate (DCR), Progression-Free Survival (PFS), Overall Survival (OS), and Safety.

Key Efficacy Results in the Nonsquamous EGFR-wildtype NSCLC Cohort

As of February 21, 2024, 172 patients had received at least one dose of Teliso-V, with 168 patients (N=168) included in efficacy analyses (c-Met high, N=84, c-Met intermediate, N=84). The majority (97.6%) had previously received platinum-based chemotherapy, and nearly 80% had also received immune checkpoint inhibitors (ICIs).

• Overall Response Rate (ORR):
  • Total c-Met overexpressing population: 29.2%
  • High expression: 34.5%
  • Intermediate expression: 23.8%
• Median Duration of Response (DOR):
  • Overall: 7.2 months
  • High expression: 9.0 months
  • Intermediate expression: 7.2 months

Responses were consistent across patients pretreated with platinum alone or with both platinum and ICI, suggesting durability irrespective of prior therapy type.

Safety Profile

The safety of Teliso-V was generally manageable and consistent with its mechanism of action.

• Most common treatment-related adverse events (any grade): peripheral sensory neuropathy (31%), peripheral edema (16%), and fatigue (14%).
• Most common grade 3 or more TRAE: peripheral sensory neuropathy (7%).

These findings align with the known toxicity profile of MMAE-based ADCs, highlighting neuropathy as the principal dose-limiting concern.

Limitations and Next Steps

While encouraging, the Phase II design lacked a comparator arm, limiting definitive conclusions about comparative efficacy. A randomized, Phase III trial, TeliMET NSCLC-01 (NCT04928846), is underway, directly comparing Teliso-V against Docetaxel in previously treated, c-Met–overexpressing, nonsquamous EGFR-wildtype NSCLC. Additionally, exploratory biomarker analyses may help refine patient selection, particularly given potential overlap between c-Met protein expression and other MET pathway genomic alterations.

Clinical Implications

LUMINOSITY demonstrates that Teliso-V can achieve durable clinical responses in a biomarker-selected subset of NSCLC patients who currently lack targeted treatment options. Response enrichment among patients with high c-Met protein expression reinforces the relevance of robust biomarker screening in clinical practice. Teliso-V represents the first therapy specifically directed against c-Met protein overexpression in NSCLC, addressing an important unmet need.

LUMINOSITY, a phase 2 study of telisotuzumab vedotin in patients with c-Met protein–overexpressing non-squamous EGFR-wildtype advanced NSCLC: Efficacy outcomes by prior therapy. Goldman JW, Lu S, Bar J, et al. Journal of Clinical Oncology. Volume 43, Number 16_suppl. https://doi.org/10.1200/JCO.2025.43.16_suppl.8618

SUMMARY: The FDA on August 8, 2025, granted accelerated approval to Zongertinib (HERNEXEOS®), a kinase inhibitor, for adults with unresectable or metastatic non-squamous Non-Small Cell Lung Cancer (NSCLC) whose tumors have HER2 (ERBB2) Tyrosine Kinase Domain (TKD) activating mutations, as detected by an FDA-approved test, and who have received prior systemic therapy. FDA also approved the Oncomine Dx Target Test (Life Technologies Corporation) as a companion diagnostic device to aid in detecting HER2 (ERBB2) TKD activating mutations in patients with non-squamous NSCLC who may be eligible for treatment with Zongertinib.

The American Cancer Society estimates that for 2025, about 226,650 new cases of lung cancer will be diagnosed and 124,730 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers and Adenocarcinoma is now the most frequent histologic subtype of lung cancer.

The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. HER2 is a Tyrosine Kinase Receptor expressed on the surface of several tumor types including Breast, Gastric, Lung and Colorectal cancers. It is a growth-promoting protein, and HER2 overexpression/HER2 gene amplification is often associated with aggressive disease and poor prognosis in certain tumor types.

HER2 mutations unlike HER2 overexpression and gene amplification are oncogenic drivers and are detected in 2 to 4% of NSCLCs. They are more often detected in younger, female and never-smokers, and almost exclusively in Adenocarcinomas. Next-generation sequencing is used to identify HER2 mutations. Majority of HER2 mutations (80-90%) occur in exon 20, as either a duplication or an insertion of 12 nucleotides, resulting in the addition of four amino acids (YVMA) at codon 775 in the kinase domain. This distinct molecular entity is characterized by specific pathological and clinical behavior. These acquired HER2 gene mutations have been independently associated with cancer cell growth, aggressive form of disease and poor prognosis, and with an increased incidence of brain metastases.

The FDA in 2022 granted accelerated approval to ENHERTU® (Trastuzumab deruxtecan), for adult patients with unresectable or metastatic NSCLC whose tumors have HER2 (ERBB2) mutations. This is the first drug approved for HER2-mutant NSCLC. Trastuzumab deruxtecan, however, can be associated with toxicities including Interstitial Lung Disease (ILD). Similarly, Pan-HER TKIs such as Poziotinib and Pyrotinib have shown limited efficacy and are frequently associated with EGFR-related adverse events, underscoring the urgent need for more targeted, better-tolerated therapies.

Zongertinib is a novel, oral, irreversible Tyrosine Kinase Inhibitor designed to selectively target HER2 while sparing EGFR, thus minimizing common toxicities such as rash and diarrhea.

Beamion LUNG-1 is an ongoing Phase 1a/1b trial evaluating Zongertinib in previously treated patients with HER2-altered advanced or metastatic solid tumors (Phase 1a) and those with HER2-mutant advanced or metastatic NSCLC across multiple clinically relevant patient cohorts (Phase 1b). In the Phase 1a dose-escalation trial, Zongertinib showed encouraging preliminary activity at the recommended expansion doses of 120 mg and 240 mg once daily, with a low incidence of Grade 3 or higher adverse events.

The Phase 1b portion of the study evaluated Zongertinib in three key populations:

• Cohort 1: Pretreated NSCLC patients with tumors harboring HER2 mutations in the TKD (Tyrosine Kinase Domain), the most common category of HER2 mutations encountered in the clinic.
• Cohort 5: NSCLC patients whose tumors had HER2 mutations within the TKD and had previously received HER2-directed ADCs, including Trastuzumab deruxtecan.
• Cohort 3: NSCLC patients whose tumor had HER2 mutations outside the TKD.

Patients were initially treated at 120 mg or 240 mg daily and following interim analysis, 120 mg was selected as the optimal dose based on a favorable efficacy and safety balance. The median age in Cohort 1 was 62 yrs. The Primary end point was an Objective Response Rate (ORR) assessed by Blinded Independent Central Review (Cohorts 1 and 5) or by Investigator Review (Cohort 3). Secondary end points included the Duration of Response and Progression-Free Survival (PFS).

Efficacy Outcomes
The median follow-up was 11.3 months at the data-cutoff date. Zongertinib demonstrated robust and durable activity, particularly in Cohort 1:

• Cohort 1 (N=75 at 120 mg daily dose):
  • Objective response rate (ORR): 71% (P<0.001)
  • Median Duration of Response (DoR): 14.1 months
  • Median progression-free survival (PFS): 12.4 months

Importantly, responses were consistent across subgroups, including patients with brain metastases (ORR: 64%) and common TKD insertion subtypes such as A775_G776insYVMA (ORR: 81%).

• Cohort 5 (N=31):
  • ORR: 48%, including patients previously treated with Trastuzumab deruxtecan (ORR: 42%)
  • Median Duration of Response: 27% had a DOR ≥ 6 months
• Cohort 3 (N=20):
  • ORR: 30%
  • Activity observed across several non-TKD mutations (e.g., S310X, V659E)

These findings suggest that Zongertinib may offer a viable treatment option even in patients who have progressed on ADCs or harbor atypical HER2 alterations.

Safety and Tolerability
Zongertinib was well tolerated across all cohorts:

• Grade ≥3 drug-related adverse events occurred in:
  • 17% of patients in Cohort 1
  • 3% in Cohort 5
  • 25% in Cohort 3
• No cases of drug-related interstitial lung disease were observed
• Most common adverse event was diarrhea (any grade: 56%; grade ≥3: 1%), followed by rash (all grade ≤2)

The safety profile compares favorably with existing HER2-targeted agents, including Trastuzumab deruxtecan, which has reported interstitial lung disease rates of up to 26% in earlier trials.

Clinical Context and Future Directions
Compared with other HER2-targeted agents including Trastuzumab deruxtecan and investigational pan-HER TKIs, Zongertinib stands out for its high response rates, durability, and manageable toxicity. While cross-study comparisons have inherent limitations, these results support Zongertinib as a promising, HER2-selective oral agent for patients with HER2-mutant NSCLC. The ongoing Phase 3 Beamion LUNG-2 trial (NCT06151574) will further assess Zongertinib in the first-line setting, providing critical data on its role relative to current standard-of-care therapies.

Conclusion
Zongertinib has emerged as a strong candidate in the evolving landscape of HER2-mutant NSCLC. With high response rates, durable outcomes, and a favorable safety profile, it may soon offer oncologists a powerful new tool for treating this difficult-to-manage patient population.

Zongertinib in Previously Treated HER2-Mutant Non–Small-Cell Lung Cancer. Heymach JV, Ruiter G, Ahn M-J, et al. for the Beamion LUNG-1 Investigators. N Engl J Med 2025;392:2321-2333.

SUMMARY: The American Cancer Society estimates that for 2025, about 226,650 new cases of lung cancer will be diagnosed and 124,730 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers and Adenocarcinoma is now the most frequent histologic subtype of lung cancer.

Stage III NSCLC represents a diverse and complex clinical scenario, historically guided by resectability and nodal involvement. Approximately one third of all patients with NSCLC have Stage III, locally advanced disease at the time of initial presentation and 60 to 90% of these patients have unresectable disease. However, recent ASCO guideline updates emphasize the integration of biomarker testing and precision medicine to improve outcomes across both resectable and unresectable disease.

Unresectable Stage III NSCLC with EGFR Mutation: Osimertinib Now Preferred

The Phase III LAURA trial established a new benchmark for patients with unresectable Stage III NSCLC harboring common EGFR mutations (exon 19 deletion or exon 21 L858R mutation). Osimertinib (TAGRISSO®), administered after completion of definitive chemoradiotherapy, led to a nearly 7-fold improvement in median Progression-Free Survival (39.1 vs 5.6 months; HR 0.16, P<0.001) compared with placebo. The incidence of brain metastases was also significantly reduced (8% vs 29%).

Given this magnitude of benefit and the modest toxicity profile (Grade ≥3 adverse events in 35%, including low rates of severe pneumonitis), Osimertinib is now considered the preferred consolidation therapy in this setting. Immune checkpoint inhibitors (ICIs), commonly used in other NSCLC populations, should be avoided in EGFR-mutated cases due to lack of efficacy and potential toxicity with sequential therapy.

Resected Stage III NSCLC: Targeted Adjuvant Therapies Lead the Way

EGFR-Mutated Disease – Adjuvant Osimertinib

Updated results from the Phase III ADAURA trial confirmed that adjuvant Osimertinib for 3 years significantly improves both Disease-Free Survival (DFS) and Overall Survival (OS) in patients with completely resected Stage IB–IIIA EGFR-mutated (exon 19 deletion or exon 21 L858R mutation) NSCLC. For patients with Stage IIIA, the DFS was extended to 55.1 months vs 14.4 months (HR=0.22), and 5-year OS rates reached 85% with Osimertinib compared to 67% with placebo (HR=0.37). There was greater DFS and OS benefit with adjuvant Osimertinib among patients with Stage III disease than that observed for Stage II or IB.

Platinum-based chemotherapy remains recommended before initiating Osimertinib, despite its non-mandatory use in ADAURA trial. Clinicians should counsel patients on the 3-year treatment duration plan with Osimertinib, cost considerations, and manageable toxicity profile.

ALK-Positive Disease – Adjuvant Alectinib

The Phase III ALINA trial established that 2 years of adjuvant Alectinib (ALECENSA®) as a superior alternative to chemotherapy in completely resected stage II–IIIA ALK-rearranged NSCLC. Two-year DFS was 93.8% with alectinib versus 63.0% with chemotherapy (HR=0.24; P<0.001). Alectinib also significantly reduced CNS relapse risk. While the trial did not include chemotherapy in the Alectinib arm, many experts still recommend preceding adjuvant Alectinib with four cycles of platinum–Pemetrexed doublet chemotherapy, based on known chemosensitivity in ALK-positive tumors.

Targeted Therapy for Rare Driver Mutations: Proceed with Caution

Although actionable mutations like ROS1 and RET are increasingly identified, there is limited evidence to guide adjuvant or consolidation therapy in Stage III NSCLC for these alterations. Clinicians should be cautious when extrapolating data from EGFR or ALK trials, given the lack of prospective data in this setting.

Immunotherapy in the Perioperative Setting: Expanding Options for Resectable Stage III NSCLC

Emerging data support the use of neoadjuvant and perioperative chemoimmunotherapy in resectable Stage III NSCLC without EGFR or ALK alterations. Trials such as CheckMate-816 (Nivolumab), KEYNOTE-671 (Pembrolizumab), AEGEAN (Durvalumab), and CheckMate-77T showed improvements in pathological Complete Response and Event-Free Survival when Immune Checkpoint Inhibitors (ICIs) were added to neoadjuvant chemotherapy.

These studies typically continued ICI therapy for up to one year post-surgery. Although overall survival data remain immature, perioperative immunotherapy has become a viable treatment paradigm in patients with PD-L1-positive, driver mutation-negative disease. Conversely, patients with EGFR or ALK alterations should not be offered ICIs in the adjuvant or consolidation setting.

Take-Home Message

ASCO’s guideline update underscores a paradigm shift in Stage III NSCLC, integrating molecular profiling and personalized treatment strategies. Key recommendations include:

• Osimertinib for unresectable EGFR-mutant NSCLC post-chemoradiotherapy
• Adjuvant Osimertinib or Alectinib in resected Stage III disease with EGFR or ALK alterations, respectively
• Chemoimmunotherapy in resectable, driver mutation-negative Stage III NSCLC

As the treatment landscape rapidly evolves, multidisciplinary collaboration and upfront biomarker testing are essential to optimize outcomes.

Management of Stage III Non–Small Cell Lung Cancer: ASCO Guideline Rapid Recommendation Update Clinical Insights. Singh N, Früh M, Gubens MA, et al. JCO Oncol Pract. 2024;21:463-466

SUMMARY: The FDA on May 14, 2025, granted accelerated approval to Telisotuzumab vedotin-tllv (EMRELIS®), a c-Met-directed antibody and microtubule inhibitor conjugate, for adults with locally advanced or metastatic, non-squamous Non-Small Cell Lung Cancer (NSCLC) with high c-Met protein overexpression [≥50% of tumor cells with strong (3+) staining], as determined by an FDA-approved test, who have received a prior systemic therapy. FDA also approved the VENTANA MET (SP44) RxDx Assay as a companion diagnostic test to aid in detecting c-Met protein overexpression in patients with non-squamous NSCLC who may be eligible for treatment with Telisotuzumab vedotin.

The American Cancer Society estimates that for 2025, about 226,650 new cases of lung cancer will be diagnosed and 124,730 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers and Adenocarcinoma is now the most frequent histologic subtype of lung cancer.

The MET proto-oncogene encodes c-Met, a receptor tyrosine kinase also known as the Hepatocyte Growth Factor (HGF) receptor, that plays a central role in regulating cellular processes such as proliferation, survival, and angiogenesis. Aberrations in the MET pathway, including gene amplification or exon 14 skipping mutations, are implicated in a subset of non–small cell lung cancer (NSCLC) cases. Approximately 5% of patients harbor MET amplification and 2-4% carry MET mutations, making this an increasingly relevant therapeutic target. While MET tyrosine kinase inhibitors (TKIs) are approved for MET exon 14 skipping mutations and are under investigation for amplification, no targeted therapies are currently available for MET protein overexpression, a phenomenon observed in roughly 25-39% of NSCLCs and associated with poor prognosis.

Telisotuzumab vedotin is a first-in-class Antibody-Drug Conjugate directed against c-Met. It combines a monoclonal antibody targeting c-Met with the cytotoxic agent MonoMethyl Auristatin E (MMAE). Telisotuzumab uses c-Met protein overexpression as a biomarker to deliver its cytotoxic payload selectively to tumor cells, distinguishing it from therapies that rely on genomic alterations alone. In early-phase studies, it demonstrated encouraging antitumor activity and manageable toxicity in c-Met–overexpressing NSCLC.

LUMINOSITY Trial Design
The Phase II LUMINOSITY trial evaluated Telisotuzumab in patients with locally advanced or metastatic c-Met–overexpressing NSCLC who had received ≤2 prior lines of systemic therapy. Stage I of this study enrolled three cohorts based on tumor histology and EGFR status:

1. Nonsquamous EGFR-wildtype
2. Nonsquamous EGFR-mutant
3. Squamous NSCLC

Stage II of this trial focused on the nonsquamous EGFR-wildtype cohort, which showed the most promise in Stage I part of the study. c-Met overexpression was determined by immunohistochemistry (IHC), with high expression defined as ≥50% of tumor cells showing 3+ membrane staining, and intermediate expression as ≥25% to <50%. Telisotuzumab was administered at a dose of 1.9 mg/kg IV every two weeks. The Primary endpoint was Overall Response Rate (ORR) as assessed by Independent Central Review using RECIST v1.1 criteria. Secondary endpoints included Duration of Response (DOR), Disease Control Rate (DCR), Progression-Free Survival (PFS), and Overall Survival (OS).

Efficacy Outcomes
Among 172 patients with nonsquamous EGFR wild-type NSCLC treated at the 1.9 mg/kg dose, 161 were evaluable for efficacy. This group included 84 patients with high c-Met expression and 84 with intermediate expression. The ORR in the total c-Met overexpression group was 28.6% (95% CI, 21.7–36.2). When stratified, ORRs were higher in the c-Met high group at 34.6% (95% CI, 24.2–46.2) compared to 22.9% (95% CI, 14.4–33.4) in the intermediate group.

The median time to response was 1.41 months. Duration of response was also encouraging, with medians of 9.0 months in the high-expression group and 7.2 months in the intermediate group. Median PFS across all c-Met–overexpressing patients was 5.7 months, with similar figures for the high and intermediate groups. Median OS was 14.5 months overall and nearly identical across subgroups.

Safety Profile
Telisotuzumab was generally well tolerated. The most common treatment-related Adverse Events (AEs) were peripheral sensory neuropathy (30%), peripheral edema (16%), and fatigue (14%). Grade ≥3 AEs were infrequent, with peripheral sensory neuropathy being the most common (7%).

Conclusion
Telisotuzumab demonstrated durable antitumor activity and manageable toxicity in patients with c-Met protein–overexpressing, nonsquamous EGFR-wildtype NSCLC, especially those with high c-Met expression. Although the LUMINOSITY trial lacked a comparator arm, the results support further evaluation of Telisotuzumab in this population. A randomized phase III trial is ongoing and will compare Telisotuzumab monotherapy with Docetaxel in previously treated patients. Given the unmet need and lack of approved therapies targeting c-Met protein overexpression, Telisotuzumab represents a promising therapeutic advance in NSCLC.

 Telisotuzumab Vedotin Monotherapy in Patients With Previously Treated c-Met Protein–Overexpressing Advanced Nonsquamous EGFR-Wildtype Non–Small Cell Lung Cancer in the Phase II LUMINOSITY Trial. Camidge DR, Bar J, Horinouchi H, et al.  J Clin Oncol 42:3000-3011, 2024