Novel Agents in Metastatic Non–Small Cell Lung Cancer

Lung cancer affects more than 200,000 people in the United States annually; non–small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases.^1-3 Lung cancer is the leading cause of cancer-related mortality in the United States, responsible for more than 120,000 deaths each year. In many cases, NSCLC is not diagnosed until distant metastasis has occurred; this contributes substantially to its high mortality rate.¹ The overall 5-year survival rate for lung cancer is approximately 29%, but 5-year survival rates are less than 10% for patients with distant metastases at diagnosis.

Tumorigenesis in NSCLC is driven by heterogeneous genetic and epigenetic alterations, commonly referred to as driver mutations.² In recent years, the identification of various driver mutations in NSCLC has led to the explosive development of molecularly targeted therapies, with the goal of improving survival among patients with metastatic disease.^2,3 This article reviews some of these newer therapies and discusses their role in the increasingly complex treatment paradigm for metastatic NSCLC. A summary of the indications, dosing/administration, premedications/prophylactic measures, and monitoring parameters for these medications is presented in the Table.

Table. Recently Approved Drugs for Advanced NSCLC
Product name	Indication in NSCLC	Dosing and administration	Premedication and prophylactic measures	Pregnancy testing and contraceptive recommendations	Monitoring parameters
Kinase inhibitors
Ensartinib (Ensacove, Xcovery Holdings)	ALK-positive locally advanced or metastatic NSCLC in adults who had not previously received an ALK inhibitor	225 mg orally once daily Take with or without food	Limit direct sun exposure during treatment and =1 wk after discontinuation	Females of reproductive potential and males with such female partners: use effective contraception during treatment and for 1 wk after the last dose	LFTs: at baseline and every 2 wk during first cycle of treatment, then monthly thereafter Blood glucose: at baseline and periodically during treatment ILD/pneumonitis: monitor for symptoms Dermatologic reactions: monitor for symptoms Heart rate: monitor regularly during treatment CPK: monitor during treatment Serum uric acid: monitor at baseline and periodically during treatment
Lazertinib (Lazcluze, Janssen Biotech)	First-line treatment of locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations in adults; used in combination with amivantamab-vmjw	240 mg orally once daily Take with or without food Administer any time prior to amivantamab-vmjw when given on the same day	Anticoagulant prophylaxis required for the first 4 mo of treatment (consider discontinuation if no VTE signs/symptoms occur) Use alcohol-free emollient cream, limit sun exposure, and wear protective clothing/broad-spectrum sunscreen during treatment and for 2 mo after discontinuation; consider prophylactic measures (eg, oral antibiotics) to reduce risk for dermatologic adverse reactions	Females of reproductive potential and males with such female partners: use effective contraception during treatment and for 3 wk after the last dose	VTE: monitor for signs and symptoms ILD/pneumonitis: monitor for symptoms
Sunvozertinib (Zegfrovy, Dizal)	Locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations in adults whose disease has progressed on or after platinum-based chemotherapy	200 mg orally once daily Take with food	Use alcohol-free emollient cream during treatment and avoid use of irritating skin products	Females of reproductive potential and males with such female partners: use effective nonhormonal contraception during treatment and for 2 wk after the last dose	GI toxicity: monitor for nausea/vomiting/diarrhea; provide supportive care and/or modify dosage as appropriate ILD/pneumonitis: monitor for symptoms
Taletrectinib (Ibtrozi, Nuvation Bio)	Locally advanced or metastatic ROS1-positive NSCLC in adults	600 mg orally once daily Take on an empty stomach (no food 2 h before or after the medication)	Minimize sun exposure and use sun protection (including broad-spectrum sunscreen) during treatment and for =5 d after discontinuation	Females of reproductive potential and males with such female partners: use effective contraception during treatment and for 3 wk after the last dose	LFTs: at baseline, every 2 wk for the first 2 mo, then monthly thereafter Electrolytes and ECG: at baseline and periodically thereafter (frequency depends on risk for QT prolongation) Serum uric acid: at baseline and periodically thereafter Serum CPK: every 2 wk during the first month then as clinically indicated for unexplained muscle pain, tenderness, or weakness ILD/pneumonitis: monitor for symptoms
Zongertinib (Hernexeos, Boehringer Ingelheim)	Unresectable or metastatic nonsquamous NSCLC with HER2 tyrosine kinase domain–activating mutations in adults who have received prior systemic therapy	Weight <90 kg: 120 mg orally once daily Weight =90 kg: 180 mg orally once daily Take with or without food	None	Females of reproductive potential: use effective contraception during treatment and for 2 wk after the last dose	LFTs: at baseline, every 2 wk for the first 12 wk, then monthly thereafter LVEF: at baseline and regular intervals during treatment ILD/pneumonitis: monitor for symptoms
Bispecific antibodies
Zenocutuzumab-zbco (Bizengri, Partner Therapeutics)	Advanced unresectable or metastatic NSCLC with an NRG1 gene fusion in adults whose disease has progressed on or after prior systemic therapy	750 mg IV every 2 wk Infuse over 4 h	Prior to each infusion, administer an oral or IV H1 antihistamine, acetaminophen, and dexamethasone (dexamethasone optional after the first infusion)	Females of reproductive potential: use effective contraception during treatment and for 2 mo after the last dose	LVEF: at baseline and regular intervals during treatment IRRs: monitor closely during each infusion and for =1 h following the first infusion ILD/pneumonitis: monitor for symptoms
Antibody–drug conjugates
Datopotamab deruxtecan-dlnk (Datroway, Daiichi Sankyo)	Locally advanced or metastatic EGFR-mutated NSCLC in adults who have received prior EGFR-directed therapy and platinum-based chemotherapy	6 mg/kg (maximum of 540 mg) IV every 3 wk Administer first infusion over 90 min; if well tolerated, administer subsequent infusions over 30 min	Administer preservative-free lubricant eye drops and a steroid-containing mouthwash 4 times daily and as needed; avoid use of contact lenses during treatment Administer oral or IV diphenhydramine and acetaminophen 30-60 min prior to each infusion Administer oral or IV antiemetics prior to each infusion and as needed thereafter Consider systemic corticosteroid Hold ice chips or ice water in the mouth throughout the infusion	Females of reproductive potential and males with such female partners: use effective contraception during treatment and for 7 mo (females) or 4 mo (males) after the last dose	Ocular adverse events: perform ophthalmic testing at baseline, annually during treatment, at end of treatment, and as clinically indicated IRRs: monitor during infusion and for =1 h after the first 2 infusions; if no reactions observed, monitor for =30 min following all subsequent infusions ILD/pneumonitis: monitor for symptoms Stomatitis: monitor for symptoms
Telisotuzumab vedotin-tllv (Emrelis, AbbVie)	Locally advanced or metastatic nonsquamous NSCLC with high c-Met protein overexpression in adults who have received prior systemic therapy	1.9 mg/kg (maximum of 190 mg) IV every 2 wk Administer over 30 min	Premedication with an H1 antihistamine, H2 antihistamine, acetaminophen, and IV glucocorticoid recommended if IRR occurs (administer 30-60 min prior to subsequent infusions)	Females of reproductive potential and males with such female partners: use effective contraception during treatment and for 2 mo (females) or 4 mo (males) after the last dose	Peripheral neuropathy: monitor for symptoms ILD/pneumonitis: monitor for symptoms Ocular surface disorders: monitor during treatment IRRs: monitor during infusion
ALK, anaplastic lymphoma kinase; CPK, creatine phosphokinase; EGFR, epidermal growth factor receptor; GI, gastrointestinal; ILD, interstitial lung disease; IRR, infusion-related reaction; LFT, liver function test; LV, left ventricular; LVEF, left ventricular ejection fraction; NSCLC, non–small cell lung cancer; VTE, venous thromboembolism. Based on references 7 and 8.

Molecular Drug Targets in NSCLC

Targetable molecular alterations are identified in an estimated 60% of patients with lung adenocarcinoma in Western countries; at present, these can include alterations in EGFR, ALK, BRAF, ROS1, RET, NTRK1/NTRK2/NTRK3, MET, KRAS, HER2, and NRG1.^3-5 The American Society of Clinical Oncology (ASCO) recommends that all patients with NSCLC undergo biomarker testing to identify potentially targetable mutations.⁵ Choice of therapy in NSCLC depends heavily on whether a targetable driver alteration is present, and recent data suggest that patients who have actionable molecular alterations have better clinical outcomes than those who do not.^5,6

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Novel Kinase Inhibitors

Lazertinib and Sunvozertinib

Epidermal growth factor receptor (EGFR) mutations are identified in approximately 15% of lung adenocarcinomas occurring in Western populations.⁴ Approximately 90% of EGFR alterations in NSCLC are exon 19 deletions or exon 21 L858R point mutations. Exon 20 insertions occur in approximately 2.5% of lung adenocarcinomas and represent approximately 6% of EGFR-mutant NSCLC cases.

The FDA recently approved 2 kinase inhibitors targeting different EGFR alterations: lazertinib (Lazcluze, Janssen Biotech) on August 19, 2024, and sunvozertinib (Zegfrovy, Dizal) on July 2, 2025.^7,8 Lazertinib was approved for combination therapy with amivantamab-vmjw (Rybrevant, Janssen Biotech) for the first-line treatment of locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test. The lazertinib approval was based on data from the randomized, active-controlled MARIPOSA study, which compared combination therapy with amivantamab-vmjw and lazertinib (n=429) with osimertinib (Tagrisso, AstraZeneca) monotherapy (n=429).^7,9,10 (The FDA approved osimertinib in April 2018 for the first-line treatment of metastatic NSCLC in patients whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, as confirmed with an FDA-approved test.^7,8) In the primary progression-free survival (PFS) analysis, amivantamab-vmjw and lazertinib combination therapy significantly prolonged median PFS compared with osimertinib monotherapy (23.7 vs 16.6 months; P<0.001).⁹ The final overall survival (OS) analysis from MARIPOSA indicated that combination therapy with amivantamab-vmjw and lazertinib also prolonged OS compared with monotherapy with osimertinib (median OS not estimable with combination therapy vs 36.7 months with osimertinib; P=0.005).¹⁰ However, grade 3 or higher adverse events were more common among patients who received combination therapy, particularly dermatologic adverse events, venous thromboembolism, and infusion-related reactions (IRRs). Of note, most patients who experienced venous thromboembolism were not receiving anticoagulant prophylaxis.⁹ Other common adverse events with lazertinib (in combination with amivantamab-vmjw) included nail toxicity (eg, infected skin around the nail), musculoskeletal pain, edema, stomatitis, paresthesia, fatigue, diarrhea, constipation, hemorrhage, decreased appetite, pruritus, nausea, and ocular toxicity.⁷ For patients with stage IV NSCLC and EGFR exon 19 deletions or exon 21 L858R substitutions, ASCO recommends osimertinib as first-line therapy; however, certain high-risk patients may benefit from first-line combination therapy with either osimertinib plus platinum doublet chemotherapy or amivantamab-vmjw plus lazertinib.⁵

The FDA granted accelerated approval to sunvozertinib for adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.⁸ The approval was based on preliminary results from the open-label WU-KONG1B study.^8,11 Among the 85 patients who received the recommended dosage of sunvozertinib in WU-KONG1B, an overall response rate (ORR) of 45.9% was observed, with a median duration of response (DOR) of 11.1 months.¹¹ The most common adverse events were diarrhea, rash, decreased appetite, stomatitis, fatigue, nausea, paronychia, vomiting, constipation, musculoskeletal pain, pruritus, dry skin, urinary tract infection, abdominal pain, and weight loss.⁸ The drug carries warnings for gastrointestinal, dermatologic, and ocular toxicities.

The ASCO guidelines have not yet been updated to address the role of sunvozertinib, and as of press time, launch plans for this drug are still pending; current recommendations state that clinicians may offer chemotherapy plus amivantamab-vmjw first line, or standard treatment for tumors without driver alterations if amivantamab-vmjw is not available.⁵ In patients with exon 20 insertions who have been previously treated with platinum-based chemotherapy, clinicians may offer second-line treatment with amivantamab-vmjw. In an ongoing phase 3 trial (WU-KONG28), sunvozertinib will be directly compared with platinum doublet chemotherapy; this will further inform its place in therapy.¹¹

Ensartinib

ALK rearrangements are found in approximately 4% of NSCLC cases.⁴ Ensartinib (Ensacove, Xcovery Holdings) is a kinase inhibitor targeting anaplastic lymphoma kinase (ALK); in vitro, it has been shown to inhibit phosphorylation of ALK and its downstream signaling proteins, thereby blocking ALK-mediated signaling pathways and inhibiting proliferation of cell lines with ALK mutations.⁷

On December 18, 2024, the FDA approved ensartinib for adult patients with ALK-positive locally advanced or metastatic NSCLC who had not previously received an ALK inhibitor.^7,8 The approval was based on data from the open-label, randomized, active-controlled eXalt3 study; in this study, 290 ALK inhibitor–naive patients were randomized to receive ensartinib (n=143) or crizotinib (Xalkori, Pfizer) (n=147), approved in August 2011 for metastatic NSCLC in adults whose tumors are ALK-positive, until disease progression or unacceptable toxicity.^7,8,12 After a median follow-up of 23.8 months in the ensartinib group and 20.2 months in the crizotinib group, median PFS was significantly greater with ensartinib (25.8 vs 12.7 months with crizotinib; P<0.001).^7,12 The ORR was 74% with ensartinib and 67% with crizotinib, while median DOR was not reached for ensartinib and 27.3 months for crizotinib. Common adverse reactions with ensartinib included rash, musculoskeletal pain, constipation, pruritus, cough, nausea, edema, vomiting, fatigue, and pyrexia.⁷ Other adverse effects of concern included hepatotoxicity, dermatologic adverse reactions, bradycardia, hyperglycemia, visual disturbances, and increased serum uric acid or creatine phosphokinase (CPK). The ASCO guidelines have not yet been updated to reflect the availability of ensartinib.⁵ Currently, guidelines recommend alectinib (Alecensa, Genentech), brigatinib (Alunbrig, Takeda), or lorlatinib (Lorbrena, Pfizer) for first-line treatment of stage IV, ALK-positive NSCLC; if these treatments are unavailable, ceritinib (Zykadia, Novartis) or crizotinib should be offered.

Taletrectinib

ROS1 rearrangements occur in 1% to 2% of patients with NSCLC.⁴ Taletrectinib (Ibtrozi, Nuvation Bio) is an inhibitor of ROS1 tyrosine kinase that prevents the growth of cancer cells expressing ROS1 mutations.⁷ The FDA approved taletrectinib on June 11, 2025, for adults with locally advanced or metastatic ROS1-positive NSCLC.^7,8 The approval was based on the results of 2 single-arm, open-label trials (TRUST-I and TRUST-II).^7,13,14 The TRUST-I trial was conducted in China, while TRUST-II was conducted globally; both trials enrolled patients with locally advanced or metastatic ROS1-positive NSCLC.¹³ In TRUST-I, ORRs with taletrectinib were 90% among tyrosine kinase inhibitor (TKI)-naive patients (n=103) and 52% among TKI-pretreated patients (n=66); the median DOR was not reached in TKI-naive patients and was 13.2 months in TKI-pretreated patients.⁷ In TRUST-II, ORRs with taletrectinib were 85% among TKI-naive patients (n=54) and 62% among TKI-pretreated patients (n=47). The most common adverse events with taletrectinib were diarrhea, nausea, vomiting, dizziness, rash, constipation, and fatigue. Other important risks with taletrectinib include hepatotoxicity, QT interval prolongation, skeletal fractures, and elevations in serum uric acid or CPK.

The ASCO guidelines have not yet been updated to include recommendations for taletrectinib.⁵ Recommended first-line therapies for ROS1-positive stage IV NSCLC include crizotinib, entrectinib, and repotrectinib. If these are not available or tolerated, ceritinib or lorlatinib may be offered. Second-line options for ROS1-positive disease include repotrectinib (Augtyro, Bristol Myers Squibb), approved in November 2023 for adults with locally advanced or metastatic ROS1-positive NSCLC.^5,8 Another second-line option is platinum-based chemotherapy, if the patient has been previously treated with multiple ROS1 inhibitors.⁵ An ongoing phase 3 trial (TRUST-III) will compare taletrectinib with crizotinib, thereby clarifying taletrectinib’s place in therapy.¹³

Zongertinib

Variants in HER2 occur in 1% to 4% of patients with nonsquamous NSCLC.³ Zongertinib (Hernexeos, Boehringer Ingelheim) is a kinase inhibitor that selectively inhibits phosphorylation of HER2, leading to decreased downstream signaling and reduced proliferation of cancer cells harboring HER2 tyrosine kinase domain–activating mutations.^7,15

The FDA granted an accelerated approval to zongertinib on August 8, 2025, for adults with unresectable or metastatic NSCLC whose tumors have HER2 (ERBB2) tyrosine kinase domain–activating mutations, as detected by an FDA-approved test, and who have received prior systemic therapy.^7,8 The approval was based on preliminary results from the single-arm, open-label, multicohort Beamion LUNG-1 trial.^7,15 In a cohort of 71 previously treated patients who had unresectable or metastatic nonsquamous NSCLC with HER2 tyrosine kinase domain mutations, an ORR of 75% was observed with zongertinib treatment; the median DOR was 14.1 months.^7,8 In another cohort of 34 patients who had been previously treated with platinum-based chemotherapy and a HER2-targeted antibody–drug conjugate, the observed ORR with zongertinib treatment was 44%.⁷ The median DOR was 5.4 months. Common adverse effects with zongertinib include diarrhea, hepatotoxicity, rash, fatigue, and nausea. Left ventricular dysfunction may also occur. The ASCO guidelines state that treatments targeting HER2 overexpression (specifically fam-trastuzumab deruxtecan-nxki; Enhertu, Daiichi Sankyo) should be considered in the second-line setting for patients with HER2 mutations.⁵ The guidelines have not been updated to include a recommendation on zongertinib. A phase 3 trial (Beamion LUNG-2) comparing zongertinib with standard of care in the first-line setting is in progress (ClinicalTrials.gov Identifier: NCT06151574).¹⁵

Novel Bispecific Antibodies

Zenocutuzumab-zbco

Neuregulin 1 (NRG1) fusions are rare mutations found in approximately 0.3% of NSCLC tumors.⁴ These mutations lead to the production of chimeric NRG1 fusion proteins, which bind to HER3 and cause HER2/HER3 heterodimerization.¹⁶ Zenocutuzumab-zbco (Bizengri, Partner Therapeutics) is a bispecific immunoglobulin G (IgG) 1 antibody targeting HER2 and HER3.^7,16 By binding HER2 and HER3 on tumor cell surfaces, it prevents HER2/HER3 dimerization and NRG1 fusion interactions with HER3.

On December 4, 2024, the FDA granted zenocutuzumab-zbco accelerated approval for adults with advanced, unresectable, or metastatic NSCLC harboring an NRG1 gene fusion with disease progression on or after prior systemic therapy.^7,8 The approval was based on preliminary data from the open-label, multicohort eNRGy study.^7,16 In a subgroup analysis of 64 patients with unresectable or metastatic NRG1 fusion–positive NSCLC previously treated with systemic therapy, treatment with zenocutuzumab-zbco resulted in a 33% ORR, with a median DOR of 7.4 months.⁷ Common adverse effects included diarrhea, musculoskeletal pain, fatigue, nausea, IRRs, dyspnea, rash, constipation, vomiting, abdominal pain, and edema. Cardiac failure can also occur. The ASCO guidelines state that clinicians may offer zenocutuzumab-zbco as second-line therapy in patients with NRG1 fusions; no specific first-line therapy is recommended for this mutation.⁵

Novel Antibody–Drug Conjugates

Telisotuzumab vedotin-tllv

Telisotuzumab vedotin-tllv (Emrelis, AbbVie) is a c-Met-directed antibody–drug conjugate consisting of a humanized IgG1 monoclonal antibody linked to monomethyl auristatin E (a microtubule-disrupting agent).⁷ The c-Met protein (encoded by MET) is overexpressed by an estimated 25% to 39% of NSCLC tumors; this overexpression can occur alongside MET genomic alterations but may also occur in patients without such alterations.^4,17 Overexpression of c-Met is detected by immunohistochemistry; telisotuzumab vedotin-tllv is specifically indicated in patients with high c-Met protein overexpression, defined as at least 50% of tumor cells with 3+ membrane staining intensity.^7,17

The FDA granted accelerated approval to telisotuzumab vedotin-tllv on May 14, 2025, for adults with locally advanced or metastatic NSCLC with high c-Met protein overexpression (=50% of tumor cells with strong [3+] staining), as determined by an FDA-approved test, who received a prior systemic therapy.^7,8 The approval was based on preliminary data from the phase 2, open-label, single-arm LUMINOSITY trial.^7,17 In this trial, 84 previously treated patients with locally advanced/metastatic, nonsquamous, EGFR-wildtype NSCLC and high c-Met protein overexpression were treated with telisotuzumab vedotin-tllv and followed for a median of 20.2 months.¹⁷ The ORR in this population was 34.6%, with a median DOR of 9 months, median PFS of 5.5 months, and median OS of 14.6 months. Common adverse reactions included peripheral neuropathy, fatigue, decreased appetite, and peripheral edema.⁷ The drug can also cause ocular surface disorders and IRRs. Current guidelines from ASCO do not provide specific treatment recommendations for patients with c-Met overexpression, as there are no other therapies that target this specific population.⁵ An ongoing phase 3 trial (TeliMET NSCLC-01) will compare telisotuzumab vedotin-tllv with docetaxel, which is frequently used in the second-line setting and beyond for stage IV NSCLC without driver mutations.¹⁷

Datopotamab deruxtecan-dlnk

Datopotamab deruxtecan-dlnk (Datroway, Daiichi Sankyo) is a trophoblast cell-surface antigen-2 (Trop-2)-directed antibody–drug conjugate consisting of a humanized IgG1 monoclonal antibody linked to deruxtecan (a topoisomerase I inhibitor).⁷ Expression of Trop-2 has been linked to resistance against anti-EGFR treatment; therefore, datopotamab deruxtecan-dlnk may have a specific role in the treatment of patients with EGFR-mutated NSCLC previously treated with EGFR-directed therapy.^7,18

The FDA granted accelerated approval to datopotamab deruxtecan-dlnk on June 23, 2025, for adult patients with locally advanced or metastatic EGFR-mutated NSCLC who have received prior EGFR-directed therapy and platinum-based chemotherapy.^7,8 The approval was based on pooled data from a subgroup of patients enrolled in 2 studies (TROPION-Lung05 and TROPION-Lung01).^7,19-21 A total of 117 patients with heavily pretreated, EGFR-mutated advanced or metastatic NSCLC received datopotamab deruxtecan-dlnk over a median of 16.9 months; among these patients, the ORR was 43%.²¹ Median DOR was 7 months, while median PFS was 5.8 months and median OS was 15.6 months. Common adverse effects included stomatitis, nausea, alopecia, fatigue, constipation, musculoskeletal pain, decreased appetite, rash, and various laboratory abnormalities.⁷ Other significant adverse effects include ocular adverse events and IRRs. The ASCO guidelines have not been updated to incorporate datopotamab deruxtecan-dlnk.⁵ Phase 3 trials (TROPION-Lung15; NCT06417814 and TROPION-Lung14; NCT06350097) are underway to compare datopotamab deruxtecan-dlnk with other therapies in the setting of EGFR-mutated advanced NSCLC and further refine its place in therapy.²¹

Conclusion

Several drugs for advanced NSCLC have emerged from the pipeline, expanding both the number of treatable molecular alterations and the available options for established driver mutations. Many of these drugs were granted accelerated approval, and additional efficacy assessments are ongoing. However, these treatments offer significant promise for patients with advanced NSCLC.

Dr. Koppen reported no relevant financial disclosures.

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A Breath of Fresh Air: Novel Agents in Metastatic Non?Small Cell Lung Cancer

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