Colorectal Cancer Yields to Dual HER2 Blockade

Dual HER2 blockade with the antibody trastuzumab (Herceptin; Roche) and lapatinib (Tykerb; GlaxoSmithKline), a tyrosine kinase inhibitor, is an established therapy for HER2-positive breast cancer. According to data from the phase II HERACLES study, this combination is also active in patients with KRAS–wild-type, HER2-positive metastatic colorectal cancer who are refractory to standard regimens that include chemotherapy and the EGFR inhibitors cetuximab (Erbitux; Bristol-Myers Squibb) or panitumumab (Vectibix; Amgen).

The study investigators—led by Silvia Marsoni, MD, of Istituto di Candiolo, and Salvatore Siena, MD, of Niguarda Cancer Center, both in Italy—had previously shown that mice bearing KRAS–wild-type, HER2-positive, and cetuximab-resistant human colorectal tumors responded to trastuzumab plus lapatinib, but not to either as monotherapy. The researchers decided to investigate the clinical efficacy of dual HER2 blockade in this genotype-specific patient population, and launched HERACLES as a proof-of-concept trial at four Italian cancer centers.

The HERACLES team screened 914 KRAS–wild-type patients and found 5% with HER2-positive tumors: Of these 48 patients, 27 met the study's full criteria and were enrolled. All had extensive metastatic disease and had previously received at least four drug regimens; notably, none responded to cetuximab or panitumumab. The objective response rate was 30%, including one complete response. Twelve patients had stable disease. The responses were durable, with a median of 9.5 months. The median progression-free survival was 5.2 months, and the median overall survival was 11.5 months.

The trastuzumab–lapatinib combination was well tolerated, the team reported. Diarrhea, rash, and fatigue were common side effects, but there were no toxicity-related treatment interruptions or withdrawals.

Although applicable to only a subgroup of patients, these findings “show the relevance of HER2 as a therapeutic target for a common, lethal malignancy,” Marsoni says. Given the “predictably poor efficacy of panitumumab or cetuximab” in this population, the researchers wrote, after disease progression occurs on first-line chemotherapy, perhaps dual HER2 blockade should be recommended in lieu of EGFR inhibition.

Neal Meropol, MD, chief of hematology and oncology at Case Western University School of Medicine in Cleveland, OH, considers HERACLES “a well-designed study of a noncytotoxic regimen that shows clear clinical activity” in the right patient subset. “Further research is warranted to confirm the contribution of dual versus single-agent HER2 blockade,” he says. “It's also notable that only 5% of KRAS–wild-type tumors were HER2-positive, meaning few patients overall would be eligible for this regimen. Given the high cost of these agents, a greater understanding of the magnitude of benefit is needed to ultimately permit an accurate assessment of value.”

The team will soon launch HERACLES B to evaluate a different anti-HER2 combination—pertuzumab (Perjeta; Roche) plus ado-trastuzumab emtansine (T-DM1, Kadcyla; Roche)—in metastatic colorectal cancer. They've developed a more efficient HER2-enrichment strategy for patient screening and selection, Marsoni says. Patients will also be enrolled earlier—“as soon as they become refractory to chemotherapy, sparing them from ineffective and unnecessary anti-EGFR treatment.” –Alissa Poh