Sarah Karlovitch

The addition of trastuzumab to chemotherapy for the treatment of early-stage, HER2-positive breast cancer helps to reduce disease recurrence and can potentially reduce the mortality from breast cancer by a third worldwide, according to a study published in the 

Trastuzumab is designed to target the extracellular domain of the HER2 protein. It is already known that adding trastuzumab to chemotherapy for this patient population help to reduce death and recurrence. However, trastuzumab is also associated with cardiac toxicity, warranting further investigation on the actual benefit of the agent as well as its effect on cause-specific mortality

Investigators conducted a meta-analysis of individual patient data from randomized trials that assessed the efficacy of chemotherapy plus trastuzumab versus chemotherapy alone. Data was collected on baseline characteristics and first distant breast cancer recurrence and any previous local recurrence or second primary cancer, and the date and underlying cause of death.

In total, 13,864 participants with early-stage, HER2-positive breast cancer who were randomized to receive either chemotherapy plus trastuzumab or chemotherapy alone were identified across 7 relevant trials between February 2000 and December 2005. Of those women, 26

% had breast cancer recurrence, and 19.7% died. Of those deaths, 12.7% were from causes unrelated to breast cancer and without a record of disease recurrence. Across all trials, the mean of scheduled treatment duration was 14.4 months. No significant heterogeneity between the 7 trial results for recurrence or breast cancer mortality was found.

The analysis found that there was a highly statistically significant connection between the use of trastuzumab and chemotherapy on the reduced risk of recurrence and mortality compared to chemotherapy alone (RR, 0.66, 95% CI 0.62-0.71; 

 <.0001). The average 10-year reduction in risk of recurrence for the combination was 9% (95% CI, 0.4 -10.7; 

 <.0001) with a 6.4% (range, 4.9% to 7.8%) reduction in 10-year breast cancer mortality. The all-cause mortality risk was reduced by 6.5% (range, 5.0%-8.0%). There was no increase in death without recurrence.

The addition of trastuzumab to chemotherapy reduced the risk of both distant and local recurrence. Distant recurrence was reduced from 0.57 to 0.70 (RR, 0.63; 99% CI), and local recurrence was reduced from 0.72, 0.59 to 0.89. However, contralateral breast cancer incidence rates did not reduce (0.93, 0.68 to 1.26). Little to no reduction was seen in the incidence of brain metastases as the first site of distant recurrence (RR 0.91; 95% CI, 0.73-1.13; 

The largest proportional reduction in recurrence occurred in years 0-1 (RR 0.53; 99% CI 0.46-0.61). Smaller reductions were seen in years 2-4 (0.73, 0.62-0.85) and years 5–9 (0.80, 0.64-1.01). The studies provided little follow-up beyond year 10. The proportional reduction in the risk of recurrence for ER-negative and ER-positive cancers followed a similar trend (RR, 0.62; 95% CI 0.56−0.69) versus (RR, 0.67; 95% CI, 0.60-0.74). Higher recurrence rates in the first 2 years were more common in ER-negative cancers than ER-positive cancer. However, the trend flipped in years 5-9. This led to a similar recurrence rate between the 2 cancer types.

Proportional recurrence did not vary by age, duration of trastuzumab treatment, traditional histopathological features, and body mass index. The absolute 5-year risk of recurrence was the greatest in patients with more involved nodes due to their higher risk of recurrence. Additionally, the reduction in recurrence did not differ significantly from studies that administered trastuzumab and chemotherapy concurrently or after the completion of chemotherapy. The risk of death unrelated to breast cancer in the first year after randomization appeared to be no greater when trastuzumab was given concurrently or sequentially.

Of the 7 trials included in the analysis, only 1 had available data on cardiac toxicity. In total, few fatal toxic events were reported with no excess deaths in the trastuzumab group.

“We found no overall increase in mortality from causes unrelated to breast cancer. Nevertheless, there were more deaths without recurrence in the first year after randomization with trastuzumab than with control, which was not explained by administering trastuzumab concurrently with chemotherapy,” study authors wrote. “This finding could well be due to chance, as the difference is spread over several different causes. However, even if the apparent excess risk is real, the excess number of these deaths was 30 times smaller than the number of deaths from breast cancer prevented.”

Early Breast Cancer Trialists’ Collaborative group. Trastuzumab for early-stage, HER2-positive breast cancer: a meta-analysis of 13864 women in seven randomised trials. 

This article was originally published on Targeted Oncology®. 

Articles

The addition of trastuzumab to chemotherapy for the treatment of early-stage, HER2-positive breast cancer helps to reduce disease recurrence and can potentially reduce the mortality from breast cancer by a third worldwide.

 Addition of trastuzumab to chemotherapy for treatment of early-stage, HER2-positive breast cancer 

The FDA has accepted a new supplemental biologics license application (sBLA) for pembrolizumab (Keytruda), an anti-PD-1 therapy, as a single agent for the treatment of patients with advanced endometrial carcinoma that is microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), who have diseased progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation, according to a press release by Merck.

The sBLA is based on the results of cohorts D and K of the KEYNOTE-158 trial (NCT02628067), which evaluated pembrolizumab monotherapy in participants with advanced solid tumors. The phase 2 parallel assignment, non-randomized, interventional study had an estimated enrollment of 1595 participants with an estimated completion date of June 2026. The primary end point of the study is objective response rate (ORR). Secondary end points include duration of response (DoR), progression-free survival (PFS), and overall survival (OS).

During the ongoing study, patients receive either 200 mg or 400 mg of pembrolizumab. Solid tumors included in the study include advanced cancer, anal carcinoma, anal cancer, biliary cancer, cholangiocarcinoma, bile duct cancer, neuroendocrine tumor, carcinoid tumor, endometrial carcinoma, endometrial cancer, cervical carcinoma, cervical cancer, vulvar carcinoma, vulvar cancer small cell lung carcinoma, small cell lung cancer, mesothelioma, thyroid cancer, salivary gland carcinoma, salivary gland cancer, salivary cancer, parotid gland cancer, advanced solid tumors, and colorectal carcinoma.

In order to participate in the study, patients must have progressed or are intolerant to therapies with known clinical benefit, have radiologically measurable disease, have an ECOG status of 0 or 1, a life expectancy of at least 3 months, adequate organ function, and must be willing to provide adequate contraception. Patients with a diagnosed immunodeficiency, autoimmune disease, treatment with an anti-cancer monoclonal antibody within 4 weeks prior to study day 1, active infections, or known active central nervous system metastases are not eligible to participate.

“The FDA’s acceptance of our application adds to our momentum of advancing new treatment options to address the most challenging cancers facing women,” said Scot Ebbinghaus, MD, vice president of clinical research at Merck Research Laboratories, in a press release. “Keytruda monotherapy is already playing a role for the treatment of certain patients with advanced endometrial carcinoma through the tumor-agnostic MSI-H indication which received accelerated approval four years ago. We look forward to sharing the latest results from KEYNOTE-158, including updated data for Keytruda in certain types of MSI-H/dMMR advanced endometrial carcinoma, at the ESMO Congress in September.”

 in combination with lenvatinib (Lenvima). The combination led to a median OS of 17.4 months in patients with MMR proficient (pMMR) disease versus 12 months with chemotherapy. Among all patients, the median OS was 18.3 months for the combination compared to 11.4 months with chemotherapy.

The median PFS for the combination was 6.6 months in patients with pMMR and 7.2 months in the overall population. For patients who received the chemotherapy, the median PFS was 3.8 months for those with pMMR disease and 3.8 months in the general population. The ORR for the combination in patients with pMMR disease was 30.3% versus 15.1% for those who received the combination. The rate of complete responses was 5.2% in the combination cohort versus 2.6% in the chemotherapy cohort.

1.FDA accepts application for Merck’s KEYTRUDA® (pembrolizumab) as single agent for certain patients with MSI-H/dMMR advanced endometrial carcinoma. News release. Merck. August 10, 2021. Accessed August 10, 2021. 

2. Study of Pembrolizumab (MK-3475) in participants with advanced solid tumors (MK-3475-158/KEYNOTE-158). ClinicalTrials.gov. Accessed August 10, 2021.

This article was originally published in Targeted Oncology®. 

The FDA has accepted a new supplemental biologics license application for pembrolizumab, an anti-PD-1 therapy, as a single agent for the treatment of patients with advanced endometrial carcinoma that is microsatellite instability-high or mismatch repair deficient, who have diseased progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.

Sarah Karlovitch

Articles

Addition of trastuzumab to chemotherapy for treatment of early-stage, HER2-positive breast cancer

FDA accepts pembrolizumab as single agent for treatment of advanced endometrial cancer