Trastuzumab Disappoints in HER2-low Patient Cohort

Lou Fehrenbacher, MD

A trial to determine the value of trastuzumab (Herceptin) plus standard adjuvant chemotherapy in patients with low levels of HER2 protein has shown no significant efficacy, confounding investigators who launched the trial based on opposing results from 2 earlier studies.

The findings were presented today at the San Antonio Breast Cancer Symposium (SABCS).

In a slide presented by Louis Fehrenbacher, MD, medical director of Kaiser Permanente Oncology Clinical Trials and an oncologist with the Kaiser Permanente Vallejo Medical Center, at the SABCS press conference, the invasive disease-free survival (IDFS) lines for both arms of the study—with and without trastuzumab—were plotted on top of each other and a difference was virtually indistinguishable. Fehrenbacher said that the primary objective of improving IDFS was not met, neither were any of the secondary endpoints, and “no trends of efficacy were seen.”

“We could magnify this slide, you still couldn’t see a difference between those 2 arms whatsoever,” he said. “There was no hint of efficacy in any of the stratification variables.”

The 5-year IDFS rate was 89.6% among the 1640 patients who received trastuzumab and 89.2% among the 1630 patients who did not (HR 95%; CI, 0.77-1.26; P = .9). Investigators said the findings were no different whether patients were subdivided by HER2 IHC level, extent of lymph node involvement, or hormone receptor status.

Fehrenbacher noted that the event rate was essentially equal between the two groups—134 for the chemotherapy arm and 130 for chemotherapy plus trastuzumab. There were no statistically significant differences in the 5-year estimates for recurrence-free interval, distant recurrent-free interval, and overall survival between those who received trastuzumab and those who did not.

Although the National Surgical Adjuvant Breast and Bowel Project (NSABP) study of trastuzumab and chemotherapy demonstrated improved outcomes for patients with early stage HER2-low breast cancer, the study (NSABP B-47) is valuable because it makes clear that patients with this form of the disease “can unequivocally know that trastuzumab is not a beneficial treatment for them,” Fehrenbacher said.

Trastuzumab can cause serious adverse effects such as cardiotoxicity, so these findings help ensure that patients are not treated unnecessarily, Investigators added.

A moderator for the press conference noted that although SABCS normally does not present negative findings from trials, an exception was made in this case because of the importance to the large number of patients whose test outcomes are HER2-low and for whom studies like this offer hope for potential treatment.

“It doesn’t answer the question completely, but certainly if there’s a high suspicion or increased suspicion, one can certainly test other areas of the tumor,” Fehrenbacher said.

About 15% of breast cancers are HER2 positive and another 45% have low levels of HER2, and those latter patients are not currently treated with adjuvant trastuzumab.

NSABP-B-47 was prompted based on results of 2 earlier studies that suggested patients with HER2-low scores appeared to have benefited from trastuzumab in addition to chemotherapy. The results of one of those studies, NSABP B-31, were “bewildering,” and the samples from the 174 FISH-negative/IHC <3 patients were submitted to repeat testing to confirm for HER2-low status, which in fact was confirmed.

Patients who are IHC 1+ and 2+ (nonamplified) are 3 times as common as those found to be HER2-amplified, so the benefit associated with trastuzumab could be enormous. To test the efficacy of trastuzumab in this population, the National Cancer Institute and the NSABP initiated B-47, a randomized study evaluating IHC 1+ and 2+ and FISH <2.0 patients assigned to doxorubicin and cyclophosphamide followed by paclitaxel (Taxol) or docetaxel and cyclophosphamide, with or without trastuzumab.

“Current guidelines classify a breast cancer as HER2-positive if immunohistochemistry testing shows it has high levels of HER2 protein, defined as IHC 3+, or in-situ hybridization shows it has increased numbers of copies of the HER2 gene, defined as ISH positive,” Fehrenbacher said.

The study enrolled 3270 patients with early stage breast cancer that was either IHC 1+, IHC 2+, and/or ISH negative. The patients were randomized 1:1 to standard adjuvant chemotherapy with or without a year of trastuzumab. The primary endpoint was IDFS.

After a median follow-up of 46.1 months, 264 patients had either recurrence of their original breast cancer, a diagnosis of a new breast cancer, a diagnosis of cancer outside the breast, or had died. These events triggered the trial endpoint. In B-31, 9.7% of patients did not meet the threshold of HER2 IHC 3+ or FISH+ >2.0, and yet “the result was essentially identical” to that of patients who met the HER2-positive standard, Fehrenbacher said.

“The hypothesis had been that it would be only the HER2-amplified patients who would benefit from this.” An additional study, N9831, added to the confusion by showing similar outcomes for 156 patients whose samples were found to be HER2-low.

Severe toxicities were infrequent and no new safety signals were observed. It was not possible to explain the outcome differences among patients in the earlier, adjuvant trials. Investigators concluded that “there is no benefit with trastuzumab therapy in patients with FISH ratios <2.0 and IHC staining intensity of 1+ or 2+.”

Asked if changes in testing procedures over time may have contributed to the findings, Fehrenbacher said that, if anything, testing has gotten better, and in the case of B-47, the testing was tightened up to ensure higher quality results.

He said the results came as a surprise, particularly because of the sharpness of the demarcation between those who benefit from trastuzumab and those who do not. “Biologically, it’s hard to imagine that a FISH ratio of 2.1 gets full benefit and a FISH ratio of 1.9 gets no benefit.”

Fehrenbacher L, Cecchini RS, Geyer CE, et al. NSABP B-47 (NRG Oncology) phase III RCT comparing adjuvant chemotherapy ACweekly paclitaxel (WP) or TC x 6 with or without trastuzumab for 1 year in high-risk, invasive breast cancer, negative for HER2 by ISH and with IHC 1+ or 2+ (HER2-Low IBC). Presented at: SABCS; December 5-9, 2018; San Antonio, Texas.