Tolerability and ILD Prevention Drive Second-Line Treatment Sequencing in HER2+ NSCLC

With three FDA-approved options now available for previously treated HER2-mutated non–small cell lung cancer (NSCLC), the question has shifted from whether to treat to which agent to reach for first. During a recent OncLive® Scientific Interchange and Workshop, faculty discussed how they weigh efficacy, tolerability, and patient priorities when making that call.

“[Familiarity] with fam-trastuzumab deruxtecan-nxki [T-DXd; Enhertu] is the community experience. [In] breast cancer, it's ubiquitously used across the board from HER2-amplified to triple-negative [disease] with HER2 expression, as well as in hormone receptor–positive [disease]. Lung cancer is very different,” Martin F. Dietrich, MD, PhD, the workshop moderator, said.

Dietrich is a medical oncologist at Cancer Care Centers of Brevard and an assistant professor of internal medicine at the University of Central Florida in Orlando.

What are the presently available targeted therapies in second-line HER2+ NSCLC?

Currently, there are 2 HER2-directed TKIs that have earned FDA approval in pretreated HER2-mutated NSCLC: zongertinib (Hernexeos) and sevabertinib (Hyrnuo).^2,3 Zongertinib earned accelerated approval from the FDA in August 2025 in adult patients with unresectable or metastatic nonsquamous NSCLC harboring HER2 (ERBB2) tyrosine kinase domain (TKD) activating mutations, as detected by an FDA-authorized test, and who have received prior systemic therapy.² Sevabertinib was granted accelerated approval by the agency for the same indication in November 2025.³

Beyond zongertinib and sevabertinib, the HER2-targeted antibody-drug conjugate (ADC)T-DXd was approved by the FDA in August 2022 for the treatment of adult patients with unresectable or metastatic NSCLC whose tumors have activating HER2 mutations, as detected by an FDA-approved test, and who have received previous systemic therapy.⁴

Findings from the 1a/1b Beamion LUNG-1 trial (NCT04886804), which supported the FDA approval of zongertinib, showed that pretreated patients with HER2 TKD mutations who received zongertinib (n = 75) had an objective response rate (ORR) per RECIST 1.1 criteria of 71% (95% CI, 60%-80%), with a complete response (CR) rate of 7%.⁵ The disease control rate (DCR) and median progression-free survival (PFS) were 96% (95% CI, 89%-99%) and 12.4 months (95% CI, 8.2-not evaluable [NE]), respectively.

Patients with previously treated disease harboring non–TKD mutations (n = 20) achieved an ORR of 30% (95% CI, 15%-52%) and a DCR of 65% (95% CI, 43%-82%). Those who received a prior HER2-directed ADC with TKD-mutated disease (n = 31) had an ORR of 48% (95% CI, 32%-65%), with a CR rate of 3%, and a DCR of 97% (95% CI, 84%-99%).

Data from the phase 1/2 SOHO-01 trial (NCT05099172) informed the FDA approval of sevabertinib; patients with pretreated HER2-mutated NSCLC but were naive to therapy targeting HER2 mutations who received the agent achieved an ORR of 66.7% (95% CI, 55.3%-76.8%) and a DCR of 81.5% (95% CI, 71%-89%).⁶ At a median follow-up of 19.5 months, the median duration of response (DOR) was 9.5 months (95% CI, 6.3-13.5) and the median PFS was 8.3 months (95% CI, 6.9-12.3).

Data from the final analysis of the phase 2 DESTINY-Lung02 study (NCT04644237), which supported the HER2-mutated NSCLC lung indication of T-DXd, showed that patients who received the agent at the FDA-recommended dose of 5.4 mg/kg (n = 102) had a confirmed ORR of 50.0% (95% CI, 39.9%-60.1%), with a CR rate of 2.9%.⁷ At a median follow-up of 15.8 months (range, 1.1-28.6). the median PFS, DOR, and overall survival values were 10.0 months (95% CI, 7.7 -15.2), 12.6 months (95% CI, 6.4-NE), and 19.0 months (95% CI, 14.7-NE), respectively. The DCR was 93.1% (95% CI, 86.4%-97.2%).

How should treatment be sequenced in the second line and beyond?

In terms of selecting between the available agents, Tarek Mekhail, MD, MSC, FRCSI, FRCSEd, the medical director of the Thoracic Oncology Program at AdventHealth Cancer Institute and an associate professor at the University of Central Florida, both in Orlando, contended that the data between the available agents don’t differ greatly for patients with non–TKD mutations.

“Conceptually, HER2 should be the mechanism that would work. But the data aren’t much different [between zongertinib and sevabertinib]. You have a 30% vs 40% response rate. I'm going to try the easier drug, if I can get it, and it's approved and on the NCCN guidelines. So, I will start zongertinib and I will see what happens 6 weeks down the line. I'm not going to lose the battle over 6 weeks. It's a very easy drug to tolerate,” he explained

Dietrich agreed that he would use zongertinib first due to its tolerability. “I would take the milder drug first. I think interstitial lung disease [ILD] is typically treatment-ending in my experience. Many patients when they have grade 2 or even grade 3 [ILD], they never come back for treatment in lung [cancer]. It may be different in other diseases where you have a little bit more time, but lung cancer is so unforgiving that I think it's a problem,” he underscored.

In patients with brain metastases, Lyudmila A. Bazhenova, MD, a medical oncologist and professor of medicine at UC San Diego Health in California, explained that she favors a HER2-directed TKI over and ADC. “[Approximately] 50% of patients with T-DXd get alopecia. Yes, it's not ILD, but it's a vanity issue for a lot of our patients that they have to contend with. Many patients don't want to have alopecia.”

Dietrich noted that although community oncologists may be more comfortable using T-DXd due to familiarity with the agent via its widespread use in other disease areas such as breast cancer, this should not contribute to treatment sequencing decisions in lung cancer.

“It's all about personal experiences. But at the same time, we cannot get ourselves in a comfort zone because if we stay in a comfort zone, we're still going to be using paclitaxel and cisplatin. You've got to explore and try things. I will give [colleagues practicing in the community] my cell phone [and tell them] to try zongertinib [and] call me if they have an issue,” Bazhenova said.

References

1. Optimizing treatment selection and sequencing strategies for HER2-mutated advanced NSCLC. An OncLive Scientific Interchange and Workshop. OncLive. January 23, 2026. Accessed June 17, 2026.
2. FDA grants accelerated approval to zongertinib for non-squamous NSCLC with HER2 TKD activating mutations. FDA. August 8, 2025. Accessed June 17, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zongertinib-non-squamous-nsclc-her2-tkd-activating-mutations
3. FDA grants accelerated approval to sevabertinib for non-squamous non-small cell lung cancer. FDA. November 19, 2025. Accessed June 17, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-sevabertinib-non-squamous-non-small-cell-lung-cancer
4. Enhertu approved in the US as the first HER2-directed therapy for patients with previously treated HER2-mutant metastatic non-small cell lung cancer. News release. AstraZeneca. August 12, 2022. Accessed https://www.astrazeneca.com/media-centre/press-releases/2022/enhertu-approved-in-us-for-her2-mutant-nsclc.html#
5. Heymach JV, Ruiter G, Ahn MJ, et al. Zongertinib in previously treated HER2-mutant non-small-cell lung cancer. N Engl J Med. 2025;392(23):2321-2333. doi:10.1056/NEJMoa2503704
6. Loong HH, Le X, Prelaj A, et al. SOHO-01: updated safety and efficacy of sevabertinib in patients with advanced HER2-mutant non-small cell lung cancer (NSCLC). J Clin Oncol. 2026;44(suppl 16):8622. doi:10.1200/JCO.2026.44.16_suppl.8622
7. Jänne PA, Goto Y, Kubo T, et al. Final analysis results and patient-reported outcomes from DESTINY-Lung02-a dose-blinded, randomized, phase 2 study of trastuzumab deruxtecan in patients with HER2-mutant metastatic NSCLC. J Thorac Oncol. 2025;20(12):1814-1828. doi:10.1016/j.jtho.2025.07.129