Pertuzumab-trastuzumab regimen remains clinically beneficial long-term

ByAlaina Tedesco

The HER2 protein is amplified and/or overexpressed in approximately 25% to 30% of patients with invasive breast cancer. The HER2-positive subtype is associated with more aggressive disease and poor prognosis when not treated with HER2-targeted therapy.

“Antibodies against HER2 not only affect the function of this growth factor receptor when it is overexpressed. They also appear to activate the immune system against HER2 and have been shown to lower the risk of progression and mortality in HER2-positive breast cancer,” Debu Tripathy, MD, professor and chair of the department of breast medical oncology at the University of Texas MD Anderson Cancer Center, told Healio.

Debu Tripathy

The development of HER2-targeted therapies has drastically transformed the treatment landscape of early-stage and advanced HER2-positive breast cancer in recent years.³ The first anti-HER2 treatment to be approved was trastuzumab (Herceptin, Genentech).² Since its approval, trastuzumab has demonstrated efficacy in reducing recurrence and mortality when combined with chemotherapy, such as docetaxel, paclitaxel, vinorelbine and capecitabine, compared with chemotherapy alone, according to Tripathy.

“More recently, there has been a search for newer and better therapies for patients with HER2-positive disease because we know that, in the advanced setting, most patients on these treatments eventually develop resistance and experience progression,” Tripathy said.

CLEOPATRA trial

More than 10 years ago, the monoclonal antibody pertuzumab (Perjeta, Genentech) demonstrated activity in HER2-positive breast cancer, particularly when combined with trastuzumab, Tripathy said, adding that the combination was evaluated in a randomized clinical trial called CLEOPATRA.

In the trial, 808 patients with HER2-positive metastatic breast cancer were randomly assigned to receive either pertuzumab plus trastuzumab plus docetaxel or placebo plus trastuzumab plus docetaxel.

“The results of the CLEOPATRA trial were rather dramatic,” Tripathy said.

The trial revealed that the combination of pertuzumab, trastuzumab and docetaxel, when used as a first-line treatment, significantly lengthened median PFS compared with the combination of placebo, trastuzumab and docetaxel (18.5 months vs. 12.4 months; HR = 0.62; 95% CI, 0.51-0.75).⁴ Median OS also significantly increased with the pertuzumab combination versus the placebo combination (56.5 months vs. 40.8 months; HR = 0.68; 95% CI, 0.56-0.84).

CLEOPATRA is considered a breakthrough trial that has revolutionized clinical practice in HER2-positive breast cancer because of its role in establishing the immense value of adding another monoclonal antibody as first-line treatment.

Update at ASCO

When the CLEOPATRA trial was first reported in 2012, combining pertuzumab, trastuzumab and docetaxel became the standard of care, Tripathy said. However, for many therapies, the rate of mortality or the benefit of therapy among treatment arms may not stay constant long-term.

“Many times, in practice, we have to make important decisions when patients are experiencing toxicities or in cases where the financial toxicity is a problem,” he said. “Patients may have to pay extra out-of-pocket costs to receive these therapies or experience debilitating side effects, making decisions quite difficult, so it is critical for us to know that, over time, these benefits are stable and unchanging. Long-term follow up information is also necessarily to optimally design future trials with new agents.”

At ASCO 2019, researchers presented an end-of-study analysis of the CLEOPATRA trial, assessing whether the impact on survival changed over a median follow-up of 99 months. The update showed a persistent improvement in median OS among patients treated with the first-line combination of pertuzumab, trastuzumab and docetaxel. Specifically, patients treated with the pertuzumab combination had a consistently longer median OS than those treated with the placebo combination (57.1 months vs. 40.8 months; HR = 0.69; 95% CI, 0.58-0.82).

In terms of safety, the main concern with adding pertuzumab was worsening diarrhea, according to Tripathy. However, the more serious adverse events observed with trastuzumab, such as cardiac dysfunction, were not different in the trastuzumab plus pertuzumab arm.

“The significance of the study is that it clearly establishes dual antibody therapy as the standard of care in the metastatic setting in first-line treatment,” Tripathy said.

Resistance

Resistance to pertuzumab plus trastuzumab will ultimately occur in almost all patients with HER2-positive metastatic breast cancer. Why patients with this subtype of breast cancer recur needs to be understood, according to Tripathy.

“We don’t know, precisely, what mechanisms drive resistance to therapy,” he said. “This is a common problem for all cancer drugs, but in the case of pertuzumab and trastuzumab, the only way we’re really going to learn about this is by following patients long-term and collecting biospecimens as was done in the CLEOPATRA trial.”

Information provided by tumor and blood samples will help establish what drugs and targets need to be addressed to develop better therapies that demonstrate continued improvements in outcomes, he added. The CLEOPATRA trial has already elucidated some resistance mechanisms, such as activating mutations in the PIK3CA gene.

“We all believe that we are going to make things even better for patients who develop metastatic HER2-positive breast cancer and that maybe, someday, they can live with what we consider more of a chronic disease that does not affect mortality,” Tripathy said. “However, that’s only going to come through following patients for longer periods of time and understanding the basic biology.” – by Alaina Tedesco