Dual HER2 Targeting Effective in Refractory mCRC Subset

Silvia Marsoni, MD

A dual attack on HER2 expression resulted in a 30% objective response rate (ORR) in heavily pretreated patients with HER2-positive metastatic colorectal cancer (mCRC), suggesting a new targeted therapy strategy for later lines of treatment that supports testing for the aberration, researchers said at the 2017 AACR Annual Meeting.¹

The combination of trastuzumab (Herceptin) and lapatinib (Tykerb) generated responses in 10 of 33 patients, including 2 complete responses (CRs) and 8 partial responses (PRs), in the phase II HERACLES A trial. Additionally, 13 patients achieved stable disease (SD), bringing the clinical benefit rate (CR + PR + SD) to 70% at the time of data cutoff on February 28.

The findings signal a potential new chemotherapy-free treatment for a significant subset of patients with mCRC, according to Silvia Marsoni, MD, director of the precision medicine unit at the Istituto di Candiolo, Fondazione del Piemonte per l’Oncologia—IRCCS in Turin, Italy, a member of the research team who discussed the study during a presscast.

“One of these 2 complete responders is still alive without evidence of disease almost 36 months from the beginning of his treatment,” Marsoni said. “We had very good duration of response.”

Marsoni said the response rate compares favorably with standard third-line therapies, which range from averages of 5% for chemotherapy to 15% for EGFR-targeting treatment, and with the approximately 35% response rate to PD-1 inhibitors in microsatellite instability—high disease.

The findings indicate that “HER2-targeted therapy can be a potential stand-alone, low-toxicity treatment approach for this patient population,” lead investigator Salvatore Siena, MD, director of Niguarda Cancer Center at Grande Ospedale Metropolitano Niguarda in Milan, Italy, said in a statement.

Overall, abnormal HER2 gene function is found in 3% of mCRC cases; amplifications and mutations occur in approximately 6% to 8% of RAS/RAF wild-type CRC, a category that, in turn, accounts for about 60% of the tumor type. Considering the number of patients worldwide diagnosed annually with CRC and the fact that 50% of these patients will develop metastases, the number of individuals who may be considered for HER2-targeting therapy represents a sizable subset, Marsoni said.

The HERACLES A study enrolled patients with RAS wild-type, HER2-positive tumors that were refractory to standard-of-care treatments, including the EGFR inhibitors cetuximab (Erbitux) or panitumumab (Vectibix). Participants had received a median of 5 prior treatments.

The trial, conducted at 4 Italian cancer centers, is 1 of 7 studies that are part of the HERACLES Project in HER2-positive mCRC. The HERACLES B study is evaluating the combination of pertuzumab (Perjeta) and trastuzumab emtansine (T-DM1; Kadcyla), which both target HER2, as second- or third-line therapy in chemorefractory mCRC. As of March 2017, 12 patients have been treated in the HERACLES B study; 7 of 8 evaluable patients (87%) have shown clinical benefit with tumor shrinkage including 2 participants with durable responses.

In HERACLES A, participants received trastuzumab, a monoclonal antibody, intravenously with a 4 mg/kg loading dose followed by 2 mg/kg weekly. Lapatinib, a tyrosine kinase inhibitor, was administered orally at 1000 mg daily. Patients were treated until progression.

Investigators treated the avatars with cetuximab, which targets EGFR, and confirmed a lack of response in tumors with mutations in KRAS, NRAS, or BRAF, or abnormal copies of HER2. Researchers then treated the avatars of patients with HER2-positive expression and wild-type RAS with single-agent trastuzumab or lapatinib, or with the combined therapies. Complete regression could only be accomplished by HER2 blockade using both drugs, explained Marsoni.

In order to assess the HER2 status of patients for the HERACLES Project, investigators developed an algorithm that was different from the definitions used in breast cancer and lung cancer, Marsoni said. HER2 positivity was defined as tumors with a 3+ HER2 score in more than 50% of cells by immunohistochemistry testing or with a 2+ HER2 score and a HER2:CEP17 ratio higher than 2 in more than 50% of cells by fluorescence in-situ hybridization.²

The combination regimen was more effective in patients with greater numbers of HER2 copies. The median time to progression was more than 12 months in patients whose tumors had ≥10 HER2 copies versus approximately 8 months for those with tumors with <10 HER2 copies.

In terms of toxicity, the trastuzumab/lapatinib regimen was well tolerated, Marsoni said, although she noted that investigators gave a 20% lower lapatinib dose than is typically administered in breast cancer because of concerns about diarrhea and gastrointestinal toxicities.

Among the 33 patients, reports of severe toxicities consisted of 1 patient with diarrhea, 4 with fatigue, and 1 with skin reactions. For mild toxicities, diarrhea was reported in 25 patients, fatigue in 13, and skin reactions in 22.

Marsoni said no patients experienced life-threatening toxicities and none withdrew from the study because of adverse events. She also said that more than 50% of responders remained on treatment for 6 months or longer.

Siena said the HERACLES A study succeeded, because patients were appropriately selected for therapy. “It is clear from our results that HER2 amplification is both a positive predictor of response to anti-HER2 treatment and a negative predictor of response to anti-EGFR therapy,” he said in the statement. “… We suggest that oncologists determine HER2 status at diagnosis of metastatic disease in colorectal cancer patients, and collect information about anti-EGFR response in HER2-positive cases.”

References

1. Siena S, Sartore-Bianchi A, Trusolino L, et al. Final results of the HERACLES trial in HER2-amplified colorectal cancer. Presented at: 2017 AACR Annual Meeting; April 1-5, 2017; Washington, DC. Abstract CT1005.
2. Sartore-Bianchi A, Trusolino L, Martino C, et al. Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016:17(6):738-746. doi: 10.1016/ S1470-2045(16)00150-9.

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The rationale for dual HER2 targeting was established in preclinical studies in which investigators created avatars by transplanting liver metastases collected from hundreds of patients with mCRC into mice, Marsoni said.