Keytruda-Chemo Combo Improves Survival Outcomes in Advanced Lung Cancer

Keytruda-Chemo Combo Improves Survival Outcomes in Advanced Lung Cancer
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First-line treatment with a combination of Keytruda (pembrolizumab) plus chemotherapy significantly prolongs survival, and extends life without disease progression, in people with advanced non-squamous non-small cell lung cancer (NSCLC), regardless of PD-L1 status, results from a Phase 1/2 trial show.

Compared with platinum-based chemotherapy alone, the combo treatment also led to higher response rates in these patients, whose tumors contained no mutations in the EGFR or ALK genes.

These are the four-year follow-up results of one of the patient groups — Cohort G — participating in KEYNOTE-021 (NCT02039674), a trial that aimed to assess the safety and efficacy of multiple combinations of Keytruda in people with inoperable or metastatic NSCLC.

These findings, which represent the longest follow-up data available for NSCLC patients receiving a combination of an immune checkpoint inhibitor and chemotherapy in a first-line setting, were recently presented in a featured poster at the IASLC 2020 North America Conference on Lung Cancer, recently held online. The poster was titled “Keytruda in Combination With Chemotherapy: Long-Term Data in Advanced NSCLC From KEYNOTE-021 (Cohort G).”

According to Merck, Keytruda’s developer, these long-term findings continue to support the use of this therapy in certain patients with advanced forms of NSCLC.

“Over the last five years, Keytruda has become foundational in the treatment of metastatic lung cancer. The long-term data from KEYNOTE-021 (Cohort G) reinforce the use of Keytruda in combination with chemotherapy in certain advanced lung cancer patients,” Vicki Goodman, MD, vice president of oncology clinical research, at Merck Research Laboratories, said in a press release.

Keytruda is an immune checkpoint inhibitor developed and marketed by Merck (known as MSD outside North America) that has been approved in the U.S. and Europe for the treatment of different types of cancer.

The therapy works by preventing PD-1, a protein receptor found on the surface of immune cells, from interacting with its ligands, PD-L1 and PD-L2, which are produced by cancer cells. By interfering with this interaction, Keytruda effectively prevents the activation of a signaling cascade that cancer cells use to avoid being recognized and eliminated by immune cells.

KEYNOTE-021 is currently investigating the safety and efficacy of Keytruda in combination with several chemotherapy and immunotherapy regimens in people with advanced NSCLC. In Cohort G, patients with advanced non-squamous NSCLC were randomly assigned to receive a first-line combination therapy of Keytruda plus chemotherapy. A total of 60 participants were given Alimta (pemetrexed) and platinum-based chemo, while 63 patients received chemotherapy alone.

After approximately four years of follow-up (median of 49.4 months), the study findings revealed that individuals receiving the combination therapy lived longer than those on chemotherapy only (median of 34.5 vs. 21.1 months). They also had a 29% lower risk of death, though that reduction failed to reach statistical significance.

The Keytruda combo therapy also prolonged the time patients lived without disease worsening from a median of 9.9 months (less than one year) to 24.5 months (just over two years), significantly lowering the risk of disease progression or death by 46%.

After three years, the percentage of patients who were still alive (50% vs. 37%) and the proportion of those whose disease was estimated to not have progressed (37% vs. 16%) were both higher with Keytruda.

Moreover, Keytruda increased the percentage of patients who responded to treatment (58% vs. 33%) and increased the duration of such responses (36.3 months vs. 22.8 months).

The incidence of severe to fatal treatment-related adverse events was similar among the individuals receiving the Keytruda combo (39%) and those given chemotherapy alone (31%), Treatment discontinuation and deaths due to adverse events also were similar among the two groups.

No new safety concerns were identified for this Keytruda combination therapy during the study.

In addition to these long-term findings, Merck also presented updated follow-up data from a Phase 1/2 trial (NCT03179436) assessing a first-line combination therapy of Keytruda and quavonlimab (MK-1308) for the treatment of advanced NSCLC.

Quavonlimab is a new immune checkpoint inhibitor developed by Merck that, instead of targeting PD-1 like Keytruda, works by blocking the activity of CTLA-4, another protein receptor that is often exploited by cancer cells as a way of evading the body’s immune cells.

In a poster titled, “Quavonlimab (anti-CLTA-4) in Combination With KEYTRUDA: Phase 1/2 Results in Advanced NSCLC,” the company reported the latest data from the study’s dose confirmation phase, which aimed to gather additional safety and preliminary efficacy data to complement the findings of the trial’s initial dose-escalation phase.

During the confirmation phase of the trial, the participants received one of two doses of quavonlimab (25 or 75 mg), every three or six weeks, plus Keytruda at a dose of 200 mg every three weeks, for about two years.

Data gathered so far indicates that the combination therapy of quavonlimab and Keytruda had a favorable safety profile and promising anti-tumor activity. Although nearly all patients (98%) experienced side effects, only 36% had serious treatment-related adverse events, which included pneumonitis and high levels of liver enzymes. No unexpected toxicities were reported thus far.

From all four dosing regimens, the one in which quavonlimab is given at a dose of 25 mg every six weeks seems to be the most favorable so far.

After a median follow-up of 16.9 months, patients in this group were those who lived longer without showing signs of disease progression (median of 7.8 months). In addition, this dosing regimen was one of the best in terms of treatment response rates (37.5%) and median overall survival (median of 18.1 months).

Based on these findings, the company is planning to adopt this dosing regimen as the recommended dose to be used in future studies. A Phase 3 trial testing the combination therapy in patients with advanced NSCLC is being planned.

“Updated data from our anti-CTLA-4 antibody quavonlimab in combination with Keytruda support the continued development of this new combination and a Phase 3 study of quavonlimab coformulated with Keytruda in advanced non-small cell lung cancer is planned,” Goodman said.

The KEYNOTE-021 (Cohort G) trial was conducted in collaboration with Eli Lilly, the makers of Alimta.

Joana holds a BSc in Biology, a MSc in Evolutionary and Developmental Biology and a PhD in Biomedical Sciences from Universidade de Lisboa, Portugal. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that made up the lining of blood vessels — found in the umbilical cord of newborns.
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Inês holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she specialized in blood vessel biology, blood stem cells, and cancer. Before that, she studied Cell and Molecular Biology at Universidade Nova de Lisboa and worked as a research fellow at Faculdade de Ciências e Tecnologias and Instituto Gulbenkian de Ciência. Inês currently works as a Managing Science Editor, striving to deliver the latest scientific advances to patient communities in a clear and accurate manner.
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Joana holds a BSc in Biology, a MSc in Evolutionary and Developmental Biology and a PhD in Biomedical Sciences from Universidade de Lisboa, Portugal. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that made up the lining of blood vessels — found in the umbilical cord of newborns.
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