New Cancer Drug Combination Reduced Risk of Death by 31%

When compared to standard treatment, the combination of ramucirumab and pembrolizumab decreased the risk of mortality by 31% in patients with advanced non-small cell lung cancer that had progressed on previous immunotherapy.

According to a study done under the Lung Cancer Master Protocol (Lung-MAP), patients with advanced non-small cell lung cancer whose cancer had advanced on prior immunotherapy lived noticeably longer when treated with ramucirumab (Cyramza) and pembrolizumab (Keytruda) combined than when treated with one of the current standard therapies for this type of cancer.

The hazard ratio (with an 80 percent confidence interval) for overall survival (OS) time for patients on the investigational arm versus the standard of care arm was 0.69 (0.51-0.92). The two arms’ respective median OS times were 14.5 and 11.6 months.

The findings, which were published in the Journal of Clinical Oncology, were also presented at the American Society of Clinical Oncology (ASCO) 2022 annual conference in Chicago (abstract 9004).

The Lung-MAP trial, the first lung cancer precision medicine trial funded by the National Cancer Institute (NCI), a component of the National Institutes of Health (NIH), was conducted as part of the S1800A study, which was carried out within the NCI’s National Clinical Trials Network (NCTN) and the NCI Community Oncology Research Program (NCORP).

Karen Reckamp, MD, MS, assistant director of clinical research and head of the Division of Medical Oncology at Cedars-Sinai Medical Center in Los Angeles, is the lead investigator for the S1800A study. The trial’s findings were presented by her at the ASCO conference.

Combination Therapy with ICIs and VEGFR Inhibition

“This is the first trial to show a survival benefit with ICI and VEGFR inhibition for patients with advanced lung cancer who have experienced tumor progression on prior ICI,” Reckamp said.

Pembrolizumab is one of a class of immunotherapy drugs known as immune checkpoint inhibitors (ICIs), and ramucirumab is a vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitor, a class of drugs that block an enzyme needed to form blood vessels.

The randomized phase 2 S1800A study enrolled 136 eligible patients with stage IV or recurrent non-small cell lung cancer. These patients had been previously treated with ICIs. In all cases, patients’ tumors eventually became resistant to these drugs and grew or spread before the patient enrolled in the S1800A trial.

The trial accrued rapidly and with a diverse population, in large part because of the robust outreach of the Lung-MAP master screening protocol. Roy S. Herbst, MD, Ph.D., deputy director of Yale Cancer Center, Lung-MAP founding and principal investigator, and senior author of the paper commented, “The unique nature of the public-private partnership of Lung-MAP, supported by the expansive and diverse nature of the NCI’s NCTN and NCORP, allowed us to bring these new therapies to patients with advanced lung cancer nationwide at no cost to patients – an important improvement in patient access.”

Secondary Endpoints: PFS and ORR

Overall survival was the trial’s primary endpoint. Secondary endpoints included progression-free survival time (PFS) and objective response rate (ORR). The researchers found no significant difference between the arms in PFS (hazard ratio [80 percent confidence interval]: 0.86 [0.66-1.14]; medians: 4.5 months on the ramucirumab plus pembrolizumab arm vs. 5.2 months on the standard of care arm) or in ORR (22 percent vs. 28 percent).

Grade 3 or higher adverse events (side effects) related to the treatment were recorded in 42 percent of the patients on the ramucirumab plus pembrolizumab arm and in 60 percent of patients on the standard-of-care arm.

Treatment on the trial’s control arm was chosen by the physician and patient from among a set of four standard chemotherapy options: docetaxel plus ramucirumab, docetaxel alone, gemcitabine, or pemetrexed. Approximately two-thirds of patients on standard therapy received docetaxel and ramucirumab as the most active therapy approved in this setting.

The researchers note that S1800A’s relatively small sample size means the trial’s results cannot be seen as definitive, and the combination should be studied in a larger trial.

“These results represent a potential paradigm-changing regimen in a setting where limited options exist,” Reckamp said. “A phase 3 trial of the combination is warranted to better evaluate the impact.”

Reference: “Phase II Randomized Study of Ramucirumab and Pembrolizumab Versus Standard of Care in Advanced Non–Small-Cell Lung Cancer Previously Treated With Immunotherapy—Lung-MAP S1800A” by Karen L. Reckamp, MD; Mary W. Redman, Ph.D.; Konstantin H. Dragnev, MD; Katherine Minichiello, MS; Liza C. Villaruz, MD; Bryan Faller, MD; Tareq Al Baghdadi, MD; Susan Hines, MD; Leah Everhart, BS; Louise Highleyman, BA; Vassiliki Papadimitrakopoulou, MD; David R. Gandara, MD; Karen Kelly, MD and Roy S. Herbst, MD, Ph.D., 20 July 2022, Journal of Clinical Oncology.
DOI: 10.1200/JCO.22.00912

The study was funded by the NIH/National Cancer Institute, the Foundation for the National Institutes of Health, Eli Lilly and Company, and Merck Sharp and Dohme.

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