Dual HER2 Therapy Active in Previously Treated Lung Cancer

Nearly nine in 10 patients with advanced HER2-positive non-small cell lung cancer (NSCLC) achieved disease control with an anti-HER2 doublet plus chemotherapy, a small prospective study showed.

Objective responses occurred in 13 of 45 patients, and an additional 26 patients had stable disease in response to the combination of trastuzumab (Herceptin), pertuzumab (Perjeta), and docetaxel. Median duration of response was 11 months, and median progression-free survival (PFS) was 6.8 months.

Two-thirds of patients had treatment-related adverse events, but no patient discontinued treatment because of toxicity, reported Julien Mazieres, MD, PhD, of Toulouse University Hospital in France, and co-authors in the Journal of Clinical Oncology.

“We confirm that HER2 mutations are treatable targets in patients with NSCLC and should be systematically screened,” the authors concluded. “Antibodies targeting HER2 appear to be the best strategy for these patients. The extrapolation of the use of a combination of trastuzumab, pertuzumab, and docetaxel from the treatment of breast cancer to the treatment of lung cancer appears feasible and promising.”

Research into the molecular basis of lung cancer has identified multiple pathways that are deregulated in tumorigenesis. HER2 is a major driver of proliferation, and HER2 mutations occur in 1% to 2% of NSCLCs, most often as exon 20 insertions, the authors noted.

Strategies targeting HER2 in lung cancer have included nonspecific tyrosine kinase inhibitors (TKIs), which have yielded disappointing results, the authors continued. Exon 20-specific TKIs have demonstrated activity but have not-insignificant toxicities. Retrospective studies have suggested that anti-HER2 antibodies might be more effective in HER2-mutated NSCLC. Currently, no drug has FDA approval for HER2-mutated NSCLC.

Following a trend in HER2-targeted therapy, Mazieres and colleagues evaluated a strategy previously validated in breast cancer: dual HER2 inhibition in addition to chemotherapy. They conducted a phase II single-arm trial of trastuzumab, pertuzumab, and docetaxel for stage III NSCLC (inoperable or unsuitable for radiation therapy) or stage IV nonsquamous NSCLC associated with HER2 mutations. The primary endpoint was objective response rate, and a response rate <20% was considered unacceptable.

The 45 patients included in the study had a median age of 64.5; 72% were women, and 35% were current smokers. The patients had no other oncogenic drivers besides HER2, and 36% of the patients had PD-L1 expression ≥1%. Three-fourths had received one prior line of therapy, and the rest had received two or more.

With a 29% objective response rate, the trial met the primary objective. Combined with the 26 patients who had stable disease, the disease control rate was 87%. Subgroup analysis did not identify any patients who had a median PFS that exceeded the 6.8-month median. The 1-year PFS rate was 29%.

The most frequently reported grade ≥3 adverse events were neutropenia (33%), diarrhea (13%), and anemia (9%).

The strategy described by Mazieres and colleagues is one of three dominant approaches that have emerged for HER2-mutant NSCLC: TKIs, monoclonal antibodies, and antibody-drug conjugates (ADCs). Studies of ADCs targeting HER2 have been particularly promising, showing response rates as high as 55%, noted the authors of an accompanying editorial.

The relative rarity of HER2-mutated NSCLC will make future evaluation of novel therapies challenging. Moreover, single-arm trials conducted thus far have had varied eligibility criteria and definitions of HER2-positive NSCLC, adding to the usual caveats of cross-trial comparison.

“Multiple HER2-targeting agents have shown promising activity in HER2-mutant NSCLC, an important step forward in the field,” wrote Alissa Cooper, MD, and Justin Gainor, MD, of Massachusetts General Hospital in Boston. “Nonetheless, challenges remain. Future efforts will need to focus on defining optimal sequential treatment strategies, elucidating mechanisms of resistance, and better characterizing CNS [central nervous system] activity. More broadly, HER2 mutations now define a distinct molecular subtype of NSCLC and screening for these alterations should be incorporated into clinical practice.”