ANTI-HER2 THERAPY OFR HER2+ COLORECTAL CANCER

A combination of two HER2-targeted therapies, trastuzumab (Herceptin) and lapatinib (Tykerb), showed clinical benefit in patients with heavily pretreated HER2-positive metastatic colorectal cancer, according to final results from the phase II HERACLES clinical trial, presented by Siena et al at the 2017 American Association for Cancer Research (AACR) Annual Meeting (Abstract CT005).

“Amplification and mutations in the gene HER2 are found in 6% to 8% of RAS/RAF wild-type colorectal cancers,” said Salvatore Siena, MD, Professor of Medical Oncology at Università degli Studi di Milano, and Director of Niguarda Cancer Center at Grande Ospedale Metropolitano Niguardain Milan, Italy. RAS/RAF wild-type colorectal cancers account for about 60% of colorectal cancers.

Extensive preclinical studies conducted by Livio Trusolino, MD, at Candiolo Cancer Institute and University of Turin, and by Dr. Siena and their teams in the past had demonstrated that shutting down the HER family of proteins through multiple mechanisms is necessary for effectiveness against HER2-positive colorectal cancer.

HERACLES Trial

On the basis of these preclinical studies, Siena and colleagues initiated the HERACLES clinical trial with two cohorts of patients with heavily pretreated metastatic colorectal cancer.

In cohort A (L+T), patients received a combination of trastuzumab, a monoclonal antibody that targets HER2, and lapatinib, a HER1/HER2 tyrosine kinase inhibitor. In cohort B (P+T-DM1), patients received a combination of pertuzumab (Perjeta), another monoclonal antibody that targets HER2, and ado-trastuzumab emtansine (also known as T-DM1; Kadcyla), an antibody-drug conjugate that pairs trastuzumab with the cytotoxic drug emtansine.

“Final results from cohort A showed that the L+T combination resulted in a 70% clinical benefit with an overall objective response rate (ORR) of 30%. These are very positive results, bearing in mind that these patients had received an average of five previous treatments,” Dr. Siena said. ORR was 50% in patients with tumors with highly amplified HER2, he noted.

Interim results from this portion of the clinical trial were published last year by Sartore-Bianchi et al in The Lancet Oncology.

All patients in this trial had RAS wild-type tumors that were HER2-positive and refractory to standard of care treatments, including the EGFR inhibitors cetuximab (Erbitux) or panitumumab (Vectibix). At data cutoff (February 28, 2017), 10 of the 33 patients in cohort A achieved an objective response, which included 2 complete responses and 8 partial responses; 13 had stable disease. Six patients experienced grade 3 adverse events.

The two patients who had a complete response continue to be disease-free for 1 and almost 4 years, respectively, since treatment initiation, according to Dr. Siena. “Both had tumors refractory to cetuximab and had become resistant to all standard chemotherapies. This means that HER2-targeted therapy can be a potential stand-alone, low-toxicity treatment approach for this patient population,” he added.

“It is also 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,” Dr. Siena said.

Historically, the response rate for metastatic colorectal cancer patients after second-line treatment is less than 5% with chemotherapy, and about 10% in unselected patients to 20% in RAS/RAF wild-type patients with anti-EGFR therapy, Dr. Siena noted.

The team has enrolled 10 patients in cohort B, so far. Of the eight patients who received P+T- DM1 and are evaluable for response, seven had a clinical benefit (with tumor shrinkage); of those, two have already met the RECIST objective response criteria, Dr. Siena said.

“We believe that HERACLES demonstrated the efficacy of HER2-targeting because the right patients were selected for the right treatment,” Dr. Siena said. “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.”

A limitation to the study is that the HER2-targeted therapy combinations were tested only against colorectal cancer tumors with HER2 amplifications but not against those with HER2 mutations, Dr. Siena noted.