Results from phase II trials of two HER2-targeting agents, the antibody–drug conjugate trastuzumab deruxtecan and the HER2-targeting tyrosine kinase inhibitor poziotinib, indicate promising efficacy that could lead to new standards of care for HER2-mutant non–small cell lung cancer.

Although HER2 is best known for its role in promoting breast and gastric cancers when ERBB2 is amplified, activating ERBB2 mutations are also established drivers of non–small cell lung cancer (NSCLC). They occur in about 3% of cases and are associated with poor prognosis. However, screening for ERBB2 mutations is not routine in NSCLC because there are no approved HER2-targeted therapies for the disease, leaving patients with low-efficacy options such as chemotherapy and immunotherapy.

According to results presented at the 2021 European Society for Medical Oncology (ESMO) Congress, held September 16–21, the lack of established options for this patient population may change if regulatory agencies give the green light. Notably, results from the phase II DESTINY-Lung01 trial showed that in 91 patients with HER2-mutant relapsed or refractory NSCLC, the HER2-targeting antibody–drug conjugate trastuzumab deruxtecan, or T-DXd (Enhertu; Daiichi Sankyo), produced an overall response rate (ORR) of 52.9%, with a median progression-free survival (PFS) of 8.2 months. The data were presented by Bob Li, MD, PhD, MPH, of Memorial Sloan Kettering Cancer Center in New York, NY, and concurrently published (N Engl J Med 2021 Sep 18 [Epub ahead of print]).

Investigators observed responses across different mutation subtypes, in patients with no detectable HER2 protein expression or ERBB2 gene amplification, and in those who previously received HER2-targeting tyrosine kinase inhibitors (TKI). Safety and tolerability were generally as expected for T-DXd, which is approved for certain breast and gastric cancers. The most common side effects were nausea, vomiting, fatigue, and hair loss; the most common grade 3 and 4 adverse events were hematologic—neutropenia and anemia. Treatment-related interstitial lung disease led to the death of two patients, indicating a need for careful monitoring and management.

Another therapy highlighted during ESMO showed efficacy in HER2-mutant NSCLC. Among 48 previously untreated patients given poziotinib (Spectrum Pharmaceuticals), an investigational HER2 TKI, the ORR was 43.8% and the median PFS was 5.6 months. Presented by Robin Cornelissen, MD, PhD, of Erasmus University Rotterdam in the Netherlands, the phase II ZENITH20-4 study also found that gastrointestinal side effects were common, along with rash. However, pneumonitis rarely occurred and was not associated with fatal interstitial lung disease.

Although not presented at ESMO, a separate investigator-initiated phase II trial of poziotinib, this time in previously treated NSCLC, also reported promising findings (J Clin Oncol 2021 Sep 22 [Epub ahead of print]). Poziotinib produced an ORR of 27% and a median PFS of 5.5 months. These results, along with those of DESTINY-Lung01 and ZENITH20-4, compare favorably with real-world data from patients with HER2-mutant disease who received immunotherapy or chemotherapy.

“Now we have two different studies [on poziotinib in NSCLC]: One demonstrates clear activity in patients who are refractory or progressed after standard therapy, and then the results at ESMO show that it has even higher activity in patients who have not received prior therapy,” said John Heymach, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, who led the investigator-initiated trial of poziotinib.

Both studies presented at ESMO “really represent one of the larger cohorts [of patients with HER2-mutant NSCLC] thus far and do show robust efficacy in terms of objective response rates and PFS,” said discussant Daniel Tan, PhD, of the National Cancer Centre Singapore. However, Tan cautioned, real-world efficacy data for first-line immunotherapy indicate that further research is warranted before recommending HER2-targeted therapies over other options for untreated patients. –Nicole Haloupek