In a French phase II trial (IFCT-1703-R2D2) reported in the Journal of Clinical Oncology, Julien Mazieres, MD, PhD, and colleagues found that the combination of trastuzumab, pertuzumab, and docetaxel produced durable responses in previously treated patients with advanced HER2-mutant non–small cell lung cancer (NSCLC).

Julien Mazieres, MD, PhD

As stated by the investigators, “HER2 exon 20 insertions and point mutations are oncogenic drivers found in 1% to 2% of patients with NSCLC. No targeted therapy is approved for this subset of patients.”

Study Details

In the multicenter study, 45 patients with HER2 exon 20 mutations progressing after one or more platinum-based treatment were enrolled between May 2019 and October 2020. Treatment consisted of 3-week cycles of pertuzumab at a loading dose of 840 mg on day 1 of cycle 1 and 420 mg thereafter; trastuzumab at a loading dose of 8 mg/kg on day 2 of cycle 1 and 6 mg/kg on day 1 thereafter; and docetaxel at 75 mg/m² on day 1 of each cycle. Treatment was continued until disease progression or unacceptable toxicity. The primary outcome measure was objective response rate.

Responses

Median follow-up was 12 months (95% confidence interval [CI] = 6.7–14.4 months). Objective response was observed in 13 patients (29%, 95% CI = 17.8%–40.0%). An additional 26 patients (58%, 95% CI = 45.7%–69.9%) had stable disease. Median duration of response was 11 months (95% CI = 2.9–14.9 months); at data cutoff, 15 patients (33%) remained on treatment. Objective response was observed in 2 (14.3%) of 14 patients with and 11 (35.5%) of 31 without brain metastasis at baseline.

Median progression-free survival was 6.8 months (95% CI = 4.0–8.5 months), with a 1-year rate of 29% (95% CI = 15.2%–44.4%). The progression-free survival hazard ratio for patients without vs with baseline brain metastasis was 0.51 (95% CI = 0.24–1.07). Median overall survival was 17.6 months (95% CI = 11.6–18.9 months).

Adverse Events

The most common treatment-related adverse events of any grade were diarrhea (69%), fatigue (60%), anemia (51%), and alopecia (49%). Grade 3 or 4 treatment-related adverse events occurred in 64% of patients, most commonly neutropenia (33%), diarrhea (13%), and anemia (9%). Treatment-related serious adverse events occurred in 16%. No treatment-related adverse events led to discontinuation of treatment. Sudden death occurred in one patient, and potential relationship to treatment could not be excluded.

The investigators concluded, “Triple therapy with trastuzumab, pertuzumab, and docetaxel is feasible and effective for HER2-mutated pretreated advanced NSCLC. These results highlight the effectiveness of the HER2 antibody–based strategy, which should be considered for these patients.”

Dr. Mazieres, of Toulouse University Hospital, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the Intergroupe Francophone de Cancérologie Thoracique (IFCT) and Roche. For full disclosures of the study authors, visit ascopubs.org.