Keytruda-Cyramza Combo Bests Standard-of-Care Therapies in Previously Treated Non-Small Cell Lung Cancer

Treatment with Keytruda (pembrolizumab) plus Cyramza (ramucirumab) proved more beneficial to patients with non-small cell lung cancer previously treated with chemotherapy and immunotherapy than other standard-of-care treatments.

The findings of the Lung-MAP nonmatched phase 2 substudy S1800A, which were presented during the 2022 American Society of Clinical Oncology Annual Meeting, showed that Keytruda plus Cyramza induced an improvement in median overall survival (time a patient remains alive) at 14.5 months versus 11.6 months with standard-of-care therapies.

“Most patients with advanced non–small cell lung cancer will receive immunotherapy as part of their initial therapy. Despite improved survival and clinical benefit, resistance develops,” Dr. Karen L. Reckamp, medical oncology director of the Lung Institute at Cedars-Sinai Medical Center in Los Angeles, said during a presentation of the data. “Developing therapies to overcome resistance to immunotherapy is a major area of unmet need for our patients.”

In a previous early-phase study, the use of Keytruda with Cyramza induced an overall response rate (percentage of patients whose disease fully or partially responds to treatment) of 30% and a disease control rate of 85% in patients with previously treated non-small cell lung cancer.

Patients included in S1800A were those who were not eligible for a biomarker-matched substudy of the Lung-MAP protocol and had acquired resistance to immune checkpoint inhibitors, which was defined as prior immunotherapy for at least 84 days with progressive disease on or after therapy. Patients must also have received prior platinum-based doublet therapy, either sequentially or in combination with immunotherapy.

In total, 130 eligible patients were enrolled from May 17, 2019, to Nov. 16, 2020, and were randomized to receive either Keytruda combined with Cyramza (69 patients) or standard of care (67 patients), which could include either docetaxel plus Cyramza (45 patients), docetaxel (3 patients), gemcitabine (12 patients), pemetrexed (1 patient), or no treatment (6 patients).

“Importantly, over two-thirds of patients received docetaxel and (Cyramza) as a standard-of-care therapy, representing the most active treatment in this setting for the majority of patients in the (standard-of-care group),” Reckamp said.

Measuring the overall survival benefit between the two treatment groups was the main goal of the study. The investigators also wanted to analyze overall response rates, as well as duration of response (length of time a tumor responds to treatment without getting worse), investigators-assessed progression-free survival (time a patient is alive without disease progression) and safety.

The median progression-free survival between the two treatment groups was similar, at 4.5 months in the Keytruda plus Cyramza group versus 5.2 months with standard of care.

The overall response rates were also similar between the two groups: 22% in those who received the Keytruda and Cyramza combination versus 28% with standard of care.

Treatment with the combination, however, elicited a much better duration of response (12.9 months) than standard of care (5.6 months).

A subgroup analysis showed the most pronounced overall survival benefit with Keytruda plus Cyramza was in those with squamous cell or mixed histology disease. Additionally, although the total number of patients with STK11 mutations was small (n = 7), there appeared to be a benefit with the combination vs SOC (HR, 0.23; 95% CI, 0.10-0.54; P = .01) that will require further follow-up.

The investigators used data from a previous trial to explain the discrepancies between overall survival benefit and similar outcomes in terms of response and progression-free survival. For instance, results of the phase 3 OAK trial of Tecentriq (atezolizumab) versus the chemotherapy docetaxel showed that the study drug improved overall survival, but that progression-free survival and responses to treatment were similar between the two groups.

Findings from that trial were subsequently used by the Food and Drug Administration in 2016 to approve Tecentriq for patients with metastatic non-small cell lung cancer whose disease progressed after treatment with a prior platinum-containing regimen.

Serious or greater treatment-related side effects in the combination group occurred in 42% of patients versus 60% in the standard of care group.

Reckamp stated that the trial was the first in the immune checkpoint inhibitor–refractory setting to demonstrate a benefit of treatment without a chemotherapy backbone compared with standard-of-care treatment options. Further evaluation of the approach is warranted.

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