AACR 2017: Cancer Type and Mutation Identity Influenced Response to Neratinib in a Basket Clinical Trial

Key Points

  • 141 patients with cancers harboring HER2 or HER3 mutations had received neratinib as part of the clinical trial. Among these patients were 21 unique types of cancer, 30 unique HER2 gene mutations, and 12 HER3 gene mutations.
  • The best response rate was seen for breast cancer; biliary and cervical cancers showed an intermediate response rate; there were no responses seen for colorectal cancer.
  • Researchers said pan-HER inhibition will likely need to be combined with other treatment modalities, such as chemotherapy or antihormone therapy, in order to obtain practice-changing response rates and durability of response.

In the phase II SUMMIT clinical trial, the likelihood that a patient’s cancer responded to the investigational pan-HER–targeted therapeutic neratinib was influenced by both the cancer type and the identity of the gene mutation present in the cancer, according to results presented by Hyman et al at the 2017 American Association for Cancer Research (AACR) Annual Meeting (Abstract CT001).

“Mutations in the HER2 and HER3 genes are found at relatively low frequency in a variety of types of cancer,” said David M. Hyman, MD, Director of Developmental Therapeutics at Memorial Sloan Kettering Cancer Center. “We designed a clinical trial to validate whether these mutations are rational therapeutic targets, and whether the investigational therapeutic neratinib, which targets members of the HER family, has anticancer activity.”

He continued, “By enrolling patients with a wide variety of cancer types harboring many different mutations, we have assembled a data set large enough to unravel the complex relationship between cancer type, mutation identity, and susceptibility to pan-HER inhibition. It appears that there is not a binary relationship and that both cancer type and mutation identity are important.”

Study Findings

At interim data cutoff—which was December 16, 2016—141 patients with cancers harboring HER2 or HER3 mutations had received neratinib as part of the clinical trial. Among these patients were 21 unique types of cancer, 30 unique HER2 gene mutations, and 12 HER3 gene mutations. The most common types of cancer were bladder, breast, colorectal, and non–small cell lung cancer; the most common HER2 gene mutations included S310, L755, A755_G776insYVMA, and V777.

When looking at the data by cancer type, the best response rate was seen for breast cancer; biliary and cervical cancers showed an intermediate response rate; there were no responses seen for colorectal cancer. “Analyzing the data in this way shows that cancer type is important, but it is not the whole answer; for example, there were no responses for any cancer type harboring a HER3 mutation, and when considering individual cancer types, different HER2 mutations had different sensitivity to neratinib,” said Dr. Hyman.

“The take-home message at this point is that there are areas of promise, but we will likely need to combine pan-HER inhibition with other treatment modalities, such as chemotherapy or antihormone therapy, in order to obtain practice-changing response rates and durability of response. This is not surprising given that the FDA-approved HER2-targeted therapeutics trastuzumab (Herceptin), pertuzumab (Perjeta), and lapatinib (Tykerb) are used in combination with chemotherapy for the treatment of breast cancer,” added Dr. Hyman.

According to Dr. Hyman, the main limitation of the study is that even though it has enrolled a comparatively large number of patients for a phase II clinical trial selecting a rare molecular subtype, they have still not saturated enrollment with patients harboring each combination of cancer type and specific mutation.

“Despite this, we have learned a huge amount from the trial,” he said. “There have been reports on the responsiveness of HER2-mutant cancers to off-label use of [U.S. Food and Drug Administration]-approved HER2- targeted therapeutics, but this study provides a rigorous analysis of the many variables that are involved and will provide the most definitive data to guide the clinical development of HER family–targeted therapeutics in HER2/3 mutant tumors.” 

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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