Treating HER2-Mutated Advanced Non-Small Cell Lung Cancer
Kelsey Pan, MD, Emory University, Atlanta, Georgia, presents a case of metastatic non-small cell lung cancer (NSCLC) with a HER2 exon 20 mutation and extensive brain metastases, highlighting second-line treatment options following progression on chemoimmunotherapy.
Dr Pan reviews emerging HER2-targeted therapies, including trastuzumab deruxtecan and newer oral tyrosine kinase inhibitors, with a focus on efficacy, intracranial activity, and tolerability. This case illustrates how precision oncology is reshaping treatment selection in HER2-mutant lung cancer.
Transcript:
Hi, everyone, my name is Kelsey Pan. I'm a thoracic medical oncologist at Emory University, and today I'll be discussing a case of metastatic lung adenocarcinoma with a HER2 exon 20 mutation and extensive brain metastases, and explain second-line therapeutic options based on the latest evidence.
For second-line therapy in HER2-mutant non-small cell lung cancer, which is distinct from HER2 overexpression, we have several recently approved targeted therapy options following progression on frontline chemoimmunotherapy including trastuzumab deruxtecan, zongertinib, and sevabertinib– all of which are listed as preferred agents in this setting according to the NCCN guidelines.
While trastuzumab deruxtecan was the first FDA-approved HER2-targeted therapy for this indication, the recent approval of not 1 but 2 oral TKIs has transformed the treatment landscape. Zongertinib was evaluated in the Beamion LUNG-1 trial in previously treated patients with HER2 tyrosine kinase domain mutations receiving the 120 mg dose. The confirmed objective response rate was 71%, the median duration of response was 14.1 months, and median PFS was 12.4 months– both exceeding 1 year. This led to its approval in pretreated, HER2-mutant non-small cell lung cancer, and very recently, it was also approved as frontline therapy in the treatment-naive population.
Importantly, for our patient with extensive CNS disease, zongertinib demonstrated activity in patients with brain metastases. Among 28 patients with baseline brain metastases, the systemic response rate was 64% and intracranial ORR was 41% per RANO-BM, confirming effective CNS penetration. In terms of safety, zongertinib as a HER2-selective inhibitor, spares wild-type EGFR, hence avoids the classic EGFR-related toxicities as seen with pan-HER inhibitors like poziotinib. Seventeen percent of patients experienced grade ≥3 drug-related adverse events and only 3% discontinued treatment due to adverse events. Importantly, no cases of drug-related ILD occurred. Diarrhea, the most common side effect, was grade 1/2 in about half the patients and grade 3 in only 1%. This favorable tolerability profile was another reason why we decided on this therapy after extensive discussion with the patient.
Trastuzumab deruxtecan is another option that is approved in the subsequent-line setting for those with HER2 mutation, as well as 3+ overexpression by IHC. While trastuzumab deruxtecan achieved a 55% response rate with median PFS of 8.2 months in DESTINY-Lung01, it requires IV administration every 3 weeks and carries potential risk of interstitial lung disease. Sevabertinib, another oral HER2 TKI, showed a 64% response rate with median PFS of 8.3 months, effective results, but with a higher frequency of diarrhea, with grade ≥3 occurring in 5% to 23% of patients. It's important to mention that both sevabertinib and trastuzumab deruxtecan have demonstrated intracranial efficacy that could be beneficial in this patient with brain metastases.
Poziotinib was not approved by the FDA for the treatment of HER2-mutant non-small cell lung cancer. While it did show some activity, it has high rates of EGFR-related toxicity as a pan-HER inhibitor. Docetaxel, on the other hand, would be offered if no targeted approach to her HER2 mutation were available, but in the setting of three potential HER2-targeted options we haven't used, we would reserve docetaxel for later lines.
In conclusion, for this patient with HER2-mutant non-small cell lung cancer and extensive brain metastases with progression on chemoimmunotherapy, the patient's choice was zongertinib as the next preferred line. It offers a high response rate and PFS of 12.4 months, with intracranial activity and a highly favorable safety profile with minimal EGFR-related toxicity and no risk of ILD.
At that time, this was the only oral HER2 TKI approved and the convenience of taking an oral drug was another reason why she opted for this choice. Now we also have sevabertinib as another HER2 oral targeted therapy available today and trastuzumab deruxtecan remains an equally reasonable option in this setting, with IV administration being its main distinction. This case illustrates how precision oncology with targeted therapies is transforming outcomes for patients with HER2-mutant lung cancer, even in challenging scenarios with extensive CNS involvement.
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