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HER2 Altered NSCLC

CE / CME

HER2-Directed ADCs in HER2-Mutant and HER2-Overexpressing NSCLC

Physician Assistants/Physician Associates: 1.00 AAPA Category 1 CME credit

Pharmacists: 1.00 contact hour (0.1 CEUs)

Physicians: maximum of 1.00 AMA PRA Category 1 Credit™

Nurse Practitioners/Nurses: 1.00 Nursing contact hour

Released: March 18, 2026

Expiration: September 17, 2026

Matthew Gubens
Matthew Gubens, MD, MS, FASCO
Estelamari Rodriguez
Estelamari Rodriguez, MD, MPH
CME/CE Information

Activity

Progress
1 2 3
Course Completed

Beamion LUNG-1: Antitumor Activity of Zongertinib (HER2 TKI) in HER2-Mutated NSCLC Cohort

Matthew Gubens, MD, MS, FASCO:
Targeting HER2 in HER2-positive NSCLC is a rapidly evolving space because not only are we able to administer HER2-directed ADCs, we also have HER2-directed TKIs available for use.

The single-arm, multicohort phase Ia/Ib Beamion LUNG-1 trial investigated single-agent zongertinib, an orally available agent, for patients with HER2-altered advanced solid tumors (NCT04886804). In a cohort of 75 patients with previously treated unresectable or metastatic nonsquamous NSCLC whose tumors harbored HER2 TKD–activating mutations at baseline, the ORR with zongertinib was 71%, the DCR was 96%, and the median PFS was 12.4 months.48 Based on these results, on August 8, 2025, the FDA approved zongertinib for patients with unresectable or metastatic nonsquamous NSCLC whose tumors have HER2 TKD–activating mutations, as detected by an FDA-approved test, and who have received prior systemic therapy.21 

On February 26, 2026, the FDA granted accelerated approval to zongertinib for an expanded indication for adults with unresectable or metastatic nonsquamous NSCLC whose tumors have HER2 TKD–activating mutations, as detected by an FDA-authorized test based on the results of the Beamion LUNG-1 trial.

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Beamion LUNG-1: Safety in Patients With Pretreated NSCLC With HER2 TKD Mutations (Phase Ib)

Matthew Gubens, MD, MS, FASCO:
As a TKI, zongertinib has a different safety profile from T-DXd. As expected, the AEs of zongertinib include diarrhea, rash, elevated transaminases, dry skin, pruritus, and some cytopenias. Most of these were grade 1 or 2, and only 3% of the patients had to discontinue treatment. The randomized Beamion LUNG-2 study is investigating zongertinib vs standard of care (SoC) as first-line therapy for patients with advanced nonsquamous NSCLC with HER2 TKD mutations (NCT06151574).

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SOHO-01: Antitumor Activity of Sevabertinib in HER2-Mutated NSCLC (Cohort D)

Matthew Gubens, MD, MS, FASCO:
Sevabertinib, another orally available HER2-directed TKI, was investigated in the multicohort, first-in-human phase I SOHO-01 trial for patients with unresectable locally advanced, recurrent or metastatic NSCLC with mutations in EGFR and/or HER2 with disease progression after receiving ≥1 prior systemic therapy in the advanced disease setting (NCT05099172). In a cohort of 81 patients with NSCLC and HER2-activating mutations or HER2 exon 20 insertion mutations without prior exposure to targeted therapy, the ORR was 64%, the DCR was 81%, and the median PFS was 8.3 months.49 The safety profile of sevabertinib is similar to that for zongertinib and included diarrhea, rash, and pruritus, and only 5% of the patients experienced AEs that led to treatment discontinuation.

On November 19, 2025, the FDA granted accelerated approval to sevabertinib for adults with locally advanced or metastatic, nonsquamous NSCLC whose tumors have HER2 TKD–activating mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy based on SOHO-01 trial results.23 The ongoing randomized phase III SOHO-02 trial is investigating the efficacy and safety of sevabertinib vs SoC as first-line therapy for patients with advanced NSCLC with HER2-activating mutations (NCT06452277).

Now that there are 2 HER2-directed TKIs with recent approval in similar settings for patients with advanced NSCLC harboring HER2 mutations, it has become very important to work out how to appropriately sequence these agents for our patients. 

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Future Directions in NSCLC: Phase III Trials Targeting HER2 With ADCs as Monotherapy and in Combination

Matthew Gubens, MD, MS, FASCO:
These are exciting times for our patients with HER2-positive NSCLC with several evolving new agents and new approaches targeting HER2 and with several ongoing trials. There are multiple studies investigating the use of HER2-directed agents in earlier lines of therapy for patients with HER2-positive advanced NSCLC.

Of note, the focus of this module is on HER2-directed ADCs, and there are several ongoing efforts to investigate the utility of HER2-directed ADCs in the frontline setting. With that in mind, it is important to note that the randomized phase III DESTINY-Lung04 trial is investigating the efficacy and safety of T-DXd vs SoC (platinum plus pemetrexed plus pembrolizumab) as first-line therapy for patients with unresectable, locally advanced, or metastatic NSCLC harboring HER2 exon 19 or 20 mutations (NCT05048797). Also, the randomized phase III DESTINY-Lung06 trial is investigating the combination of T-DXd with pembrolizumab vs platinum-based chemotherapy plus pembrolizumab as first-line therapy for patients with locally advanced unresectable or metastatic HER2 overexpressing and PD-L1 tumor proportion score <50% nonsquamous NSCLC (NCT06899126).

BL-M07D1 is another HER2-directed ADC being investigated in a phase III trial vs platinum plus pemetrexed and pembrolizumab as first-line therapy for patients with HER2-mutant advanced or metastatic nonsquamous NSCLC (NCT07178795).

HER3 plays an important role in resistance to EGFR-directed and HER2-directed agents.50 So, there is an ongoing randomized phase III trial investigating SHR-A1811, a HER3-directed ADC, vs SoC as first-line therapy for patients with locally advanced or metastatic NSCLC harboring HER2 mutations (NCT06430437). 

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Future Directions in NSCLC: Select Early Phase Trials Targeting HER2 With ADCs

Matthew Gubens, MD, MS, FASCO:
Aside from the phase III trials previously mentioned, there are other earlier-phase trials of T-DXd and other ADCs under investigation in NSCLC. The phase II ELPIS trial is investigating T-DXd monotherapy for the treatment of patients with locally advanced unresectable, recurrent or de novo metastatic NSCLC and asymptomatic or stable brain metastasis harboring HER2 mutations with or without HER2 expression (NCT06250777).

A phase I/II trial is investigating SHR-A1811 in patients with advanced NSCLC with HER2 expression, amplification, or mutation (NCT04818333). Disitamab vedotin is another HER2-directed ADC that is being investigated in combination with tislelizumab and carboplatin or with the third-generation EGFR TKI furmonertinib for patients with advanced NSCLC and HER2 mutation, amplification, or HER2 overexpression (NCT05847764).

The phase Ib DESTINY-Lung03 trial is investigating the tolerability and safety of T-DXd in combination with an immune checkpoint inhibitor with or without chemotherapy in the first-line treatment of patients with HER2-expressing (IHC 3+ or IHC 2+) advanced or metastatic nonsquamous NSCLC (NCT04686305).51

Of note, the phase II HUDSON trial is a multicohort, biomarker-directed umbrella study for patients with NSCLC and disease progression on an immune checkpoint inhibitor–containing therapy (NCT03334617). On this trial, the combination of T-DXd with durvalumab will be investigated in a cohort of patients with HER2 alterations.

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