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Summary

Introduction: lung cancer treatment has evolved significantly with specific therapies for the different types of non-small cell lung cancer (NSCLC) guided by biomarkers and with emerging new drugs

Treatment of EGFR-mutant NSCLC: from 2018, the preferred treatment was single-agent osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI); the FLAURA study (Soria et al [2018]) — first-line osimertinib for EGFR-mutant advanced NSCLC improved overall survival (OS) and progression-free survival (PFS) when compared with gefitinib and erlotinib; osimertinib had better central nervous system (CNS) penetration and less toxicity; newly approved combination regimens — chemotherapy plus osimertinib (the FLAURA2 study; Planchard et al [2023]) and amivantamab (an EGFR-MET bispecific antibody) plus lazertinib (a third-generation EGFR-inhibitor) from the MARIPOSA study (Cho et al [2024])

The FLAURA-2 study: when compared with osimertinib monotherapy, treatment with osimertinib plus platinum-doublet chemotherapy (ie, pemetrexed plus cisplatin or carboplatin) led to significantly longer PFS (29 mo vs 19.9 mo) and better response rates (92% vs 83%) in patients with newly diagnosed EGFR-mutated (exon 19 or 21 mutations) advanced NSCLC (Planchard et al [2023]); the combination therapy led to a 15% higher PFS at 2 yr and a trend toward improved OS (hazard ratio [HR] of 0.75); the combination therapy improved PFS in patients without CNS metastasis and with CNS metastasis (higher improvement in PFS [25 mo vs 13 mo]) when compared with osimertinib monotherapy; osimertinib monotherapy did not have a durable duration of response (Janne et al [2024])

Benefit in the high-risk population: the PFS benefit with osimertinib plus chemotherapy may be higher for high-risk patients, eg, patients with brain metastasis and symptomatic patients with a performance-status (PS) score of 1; patients with a PS score of zero without brain metastasis may not need the combination therapy; disadvantages — osimertinib plus chemotherapy increases grade 3 or higher adverse events (64% vs 27%), requires every 3 wk intravenous (IV) treatment and imaging every 12 wk (vs daily once-a-day oral therapy), and may not be necessary for all

The MARIPOSA study: in patients with previously untreated EGFR-mutated NSCLC, the median PFS was significantly longer in the amivantamab plus lazertinib group than in the osimertinib group (24 mo vs 16.6 mo); there was a trend toward OS improvement with amivantamab plus lazertinib (Cho et al [2024]); when compared with osimertinib, the combination of amivantamab plus lazertinib appeared to be more effective in prolonging PFS across multiple high-risk groups, ie, patients with liver metastasis, TP53 mutations, detectable baseline EGFR mutation circulating tumor DNA (ctDNA), and without cleared ctDNA at 9 wk (Felip et al [2024])

Optimal therapy: combination therapy may not be required for all patients, as single-agent osimertinib has good and durable patient outcomes with a good quality of life; however, subsequent therapy in patients treated with first-line osimertinib remains unclear

The MARIPOSA-2 study (Passaro et al [2024]): amivantamab plus chemotherapy significantly improved PFS, intracranial control, response rate, and duration of response (vs chemotherapy) in patients with EGFR-mutated NSCLC who had disease progression on osimertinib; a trend towards OS improvement was also observed

Adverse effects (AEs): in addition to the chemotherapy AEs, amivantamab causes EGFR and MET-specific AEs, ie, rashes (≈43%; grade 3 in 6%), paronychia (≈37%), swelling and hypoalbuminemia (20%-30%)

Choosing the best regimen: personalized treatment according to patient-specific needs, disease characteristics, and quality of life concerns, and shared decision-making are recommended; high-risk features, eg, brain metastasis, high disease burden (eg, liver metastasis), p53 mutation, ctDNA-positive do predict shorter PFS with osimertinib alone; however, none of the regimens clearly improve OS compared with TKI monotherapy; for many patients, osimertinib alone may be the best option with chemotherapy plus amivantamab used as second-line treatment

Amivantamab-specific issues: complex schedule — day 1 and 2 (the first dose is split in half and administered), day 8, day 15, and then every 21 days in combination with lazertinib or chemotherapy; infusion-related reactions (IRRs) — most patients develop IRRs on the first dose, ie, dyspnea, flushing, fever, chills, nausea, or hypotension (mild; responsive to fluids and hypersensitivity medications); IRRs do not occur with subcutaneous amivantamab; in the PALOMA-3 study (Leighl et al [2024]), subcutaneous amivantamab plus lazertinib demonstrated noninferiority to IV amivantamab plus lazertinib with reduced IRRs (13% vs 66%); prophylaxis with 8-mg oral dexamethasone (twice a day; administered for 2 days before the infusion and on the morning of the infusion) reduced the rate of IRRs to 24% (the SKIPPirr study; Spira et al [2025]); venous thromboembolism (VTE) — a higher rate of VTE is observed with amivantamab; the US Food and Drug Administration recommends prophylactic or full-dose anticoagulation for patients starting amivantamab (4 mo)

First-line treatment options for ALK-positive NSCLC: include alectinib (a second-generation anaplastic lymphoma kinase (ALK) inhibitor; most common), ceritinib, brigatinib, and lorlatinib (a third-generation ALK-TKI); though approved for first-line treatment, lorlatinib has been used in patients who develop resistance to second-generation inhibitors; the global ALEX study (Mok et al [2020]) — demonstrated significantly improved PFS (34.8 mo) and OS (60% 5 yr OS) with alectinib vs crizotinib in treatment-naive ALK-positive NSCLC

The CROWN study (Solomon et al [2024]): lorlatinib significantly improved PFS (60% at 5 yr) vs crizotinib in patients with previously newly diagnosed ALK-positive NSCLC (including those with brain metastasis); the patients may be able to use the drug long term (indefinitely) for sustained disease control (similar to chronic disease)

AEs of lorlatinib: AEs include hypertriglyceridemia (25%), hypercholesterolemia (20%-25%), weight gain, and CNS AEs (42%; most were grade 1-2); neurocognitive AEs of lorlatinib — include cognitive AEs, mood AEs (eg, a rapid change from emotional crying to anger), speech AEs (slurring of speech), and psychotic AEs, ie, delusions and hallucinations; clinical trials reported a significantly higher frequency (4 times) of mood effects than was indicated by real-world data (Priantti et al [2024]); thus, it is important to ask the patients about these mild AEs as they respond to dose hold or reduction

Previously treated small cell lung cancer (SCLC): single agent chemotherapy agents, eg, topotecan, have been used for decades; lurbinectedin has a reasonable response rate and was recently approved for SCLC; tarlatamab, a δ-like ligand 3 (DLL3)-targeted bispecific T-cell engager has been recently approved for previously treated SCLC

The DeLLphi-301 study (Ahn et al [2023]): among patients with previously treated SCLC, the overall response rate with 10-mg dose of tarlatamab was 40%; the duration of response was significantly longer with the 10-mg dose (vs 100 mg dose); tarlatamab (10-mg dose) improved survival, with a median PFS of 5 mo and a median OS of 14 mo

AEs of tarlatamab: include cytokine release syndrome (CRS; mostly grade 1-2), gastrointestinal AEs, fatigue, hematologic toxicities, and immune effector cell associated neurotoxicity syndrome (ICANS); CRS (ie, fever, hypotension, tachycardia, or hypoxia) is common with the first dose; the patients should be admitted to the hospital for 24-hr observation on days 1, 8, and 15; recurrent CRS occurred in ≈24% of patients (12-13 hr after the first dose); patients with ICANS develop tremor, confusion, aphasia, seizures, and depressed level of consciousness; ICANS occurred in ≈9% of patients (≈30 days after treatment); recurrence of ICANS is rare (1.6%)

Outpatient management of the CRS and ICANS: patients with mild symptoms are observed; CRS is managed with acetaminophen (Tylenol), high-dose dexamethasone, and tocilizumab (for recurrence of symptoms and cardiovascular instability); 10 mg of oral dexamethasone can be used to manage ICANS (followed by observation); IV steroids can be administered if they do not respond to oral steroids