Two Important Trials Show Improved Survival in Metastatic Breast Cancer

Two phase 3 trials found that women with metastatic breast cancer survived longer when given combination therapy including standard care and an additional drug, according to the results of late-breaking studies presented at the annual meeting of the European Society for Medical Oncology (ESMO). The MONALEESA-2 trial found that adding Kisqali (ribocliclib), a category of drug known as a CDK4/6 inhibitor, to hormonal treatment extended survival for women with hormone receptor-positive (HR-positive), HER2-negative advanced breast cancer. Similarly, results from the KEYNOTE-355 trial showed increased survival for women whose metastatic triple-negative breast cancer (TNBC) expressed a biomarker known as PD-L1.

MONALEESA-2: Kisqali Plus Standard Hormone Therapy Extends Survival by One Year in Metastatic HR-Positive/HER2-Negative Breast Cancer

What’s New Postmenopausal women with HR-positive, HER2-negative advanced breast cancer who received Kisqali in addition to the standard hormone therapy Femara (letrozole) survived one year longer than those who received Femara alone. CDK4/6 inhibitors target proteins known as cyclin-dependent kinases 4 and 6, interrupting how cancer cells divide and multiply.

Study Details In this phase 3 clinical trial, known as MONALEESA-2, researchers randomly assigned 668 women to receive Femara plus either Kisqali or a placebo. The trial was held in 29 countries in the Americas, Europe, and Asia. MONALEESA-2’s primary results appeared in The New England Journal of Medicine in November 2016, when researchers reported that, in women who received Kisqali, the cancer did not progress for a median of 25.3 months. Women in the Femara-only group, however, experienced disease progression at a median of 16 months. In the current study presented at ESMO, researchers evaluated overall survival at a predetermined point: the deaths of 400 study participants. Follow-up data showed that women who received Kisqali survived for a median 63.9 months, compared with 51.4 months for Femara alone. The MONALEESA-2 researchers are continuing to study whether some patients responded better to the combined treatment than others.

Why It Matters MONALEESA-2 is the first study to report a statistically significant and clinically meaningful overall survival benefit for these patients. “In my 45 years as an oncologist, a [progression-free survival] benefit has been shown many, many times, [but] we have rarely seen an improvement in overall survival,” said study author Gabriel N. Hortobagyi, MD, of the University of Texas MD Anderson Cancer Center in Houston. “It is difficult to show a statistically significant extension in survival for first-line therapy in this type of breast cancer [because] patients receive 4 to 15 different types of treatment over the course of their disease, and these dilute the effect of the first therapy.”

KEYNOTE-355: Keytruda Plus Chemotherapy Increased Survival in Women With PD-L1-Positive Metastatic TNBC

What’s New In the phase 3 trial known as KEYNOTE-355, researchers pitted Keytruda, a type of immunotherapy drug known as an immune checkpoint inhibitor, plus standard chemotherapy against chemotherapy alone in women with PD-L1-positive metastatic TNBC whose tumors were also positive for PD-L1, a biomarker that suggests that the tumor will be responsive to checkpoint inhibitors. Women survived for seven months longer when they also received Keytruda, according to study results presented at ESMO.

Study Details KEYNOTE-355 is a double-blind trial in which researchers randomly assigned 847 women with recurrent inoperable or metastatic TNBC to receive standard chemotherapy as chosen by their doctor plus either Keytruda or a placebo. In each treatment group, about 4 in 10 women had strong PD-L1 expression in their tumor. Women with high PD-L1 expression in their tumor had the biggest survival increase with Keytruda, according to KEYNOTE-355’s final overall survival results, with a median survival of 23 months, compared with a median 16.1 months for women who received chemo alone. At 18 months of follow-up, 58.3 percent of women in the Keytruda group with high PD-L1 expression were still alive, while only 44.7 percent of those who received chemo alone were. At two years of follow-up, 48.2 percent of women in the Keytruda group were still alive, while only 34 percent of women in the chemo-only group were. The overall median follow-up was 44 months in both groups. “Only women whose cancer expresses a higher level of PD-L1 benefit significantly from the addition of pembrolizumab to chemotherapy,” said study author Hope S. Rugo, MD, of the University of California in San Francisco.

Why It Matters Triple-negative breast cancer is aggressive and tends to be more common in people who are younger than 40 years of age, who are Black American, or who have a BRCA1 mutation. On November 13, 2020, the Food and Drug Administration granted accelerated approval to Keytruda in combination with chemotherapy for the treatment of patients with locally recurrent, unresectable or metastatic TNBC whose tumors express high levels of PD-L1. This accelerated approval was based on KEYNOTE-355’s progression-free survival data. Now that the trial’s final overall survival data is in, oncologists should be even more likely to use this treatment option for patients with PD-L1-positive TNBC, Dr. Rugo said.

Gonzalo Gomes-Abuin, MD, of the Hospital Alemán in Buenos Aires, Argentina, who is not involved with KEYNOTE-355, agreed. “This very important, very well-designed trial shows that pembrolizumab plus chemo is a transformative treatment for a subset of patients with PD-L1-positive metastatic TNBC and should be considered the new standard of care,” he said.

DESTINY-Lung01: Promising Results for Enhertu in HER2-Mutated Metastatic Lung Cancer

What’s New In an international phase 2 trial, researchers observed good results in patients with metastatic lung cancer that carries a HER2 mutation who received Enhertu (trastuzumab deruxtecan), a HER2 antibody-drug conjugate also used to treat metastatic HER2-positive breast and gastric cancers. (Antibody-drug conjugates are therapies that link a targeted antibody to a cancer-killing drug.)

Study Details Researchers treated 91 patients with HER2-mutated metastatic lung cancer with Enhertu, then observed how they responded to the drug at two doses. Two-thirds of the participants were women, and nearly 60 percent had never smoked.

Fifty participants, or 55 percent, had a measurable response to Enhertu. One patient had a complete response, meaning that the cancer disappeared, while 49 patients saw some improvement in their disease. The median duration of response was 9.3 months, and the median follow-up was 13.1 months.

Nearly half the participants developed a moderate to severe side effect related to the Enhertu. These side effects led about one-quarter of the participants to withdraw from the trial. Fifteen patients were still taking the drug as of mid-September.

“DESTINY-Lung01 provides compelling evidence of positive benefit-risk balance with Enhertu and supports its establishment as a potential new treatment standard,” said Bob T. Li, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.

As a phase 2 trial, DESTINY-Lung01 can’t make comparisons between competing treatments. Phase 2 trials are used to test drug safety and effectiveness. Researchers’ preferred dose of Enhertu is moving on to a larger global phase 2 trial, DESTINY-Lung02, which is now enrolling patients.

Why It Matters Approximately 3 percent of patients with non-small cell lung cancer (NSCLC) have a HER2 mutation. These patients, who tend to be women who never smoked, face a poor prognosis and a higher chance of developing brain metastases. There are currently no approved HER2-targeted therapies for patients with NSCLC, and oncologists don’t routinely test patients with lung cancer for a HER2 mutation. They typically receive standard chemotherapy, immunotherapy, or both. When the disease recurs, oncologists observe improvement in only one-quarter of patients at most, so there is a pressing need for new treatments for these patients.

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