Important Advance in Lung Cancer: Ramucirumab plus Pembrolizumab in 2nd-Line Treatment

Starting treatment for advanced lung cancer with immunotherapies revolutionized lung cancer treatment for most patients without targetable mutations. Despite highly significant improvements in overall survival, most patients’ cancers eventually progress. There is therefore a substantial need for effective second-line treatment options in lung cancer.

To address this need, the ASCO 2022 meeting featured the notable study S1800A. The S1800A team set out to investigate the combination of pembrolizumab immunotherapy with the monoclonal antibody targeting the extracellular domain of VEGF receptor 2 (VEGFR2), ramucirumab. They hypothesized that combination treatment with the PD-1 inhibitor pembrolizumab and the VEGFR2 inhibitor ramucirumab could overcome treatment resistance by reducing tumor revascularization through inflammation-triggering cytokines.

This study established an important foundation for VEGF/R inhibition and immune checkpoint inhibitors in lung cancer. A similar combination (atezolizumab + bevasizumab + paklitaksel + karboplatin) was found effective in the IMpower150 study in 2018 and received FDA approval (see related approval). This combination has shown activity in other cancers, including kidney, uterine, and liver cancer. However, this four-drug combination also included chemotherapy in addition to immunotherapy and the VEGFR inhibitor.

Details of the S1800A Study

S1800A is a phase-II clinical study that randomized 130 patients with advanced non-small cell lung cancer (KHDAK) who had previously received PD-1 or PD-L1 inhibitor therapy and had progressed at least 84 days after starting treatment with an immune checkpoint inhibitor and a platinum-based doublet.

The study design is shown in Figure 1.

Results

• Median overall survival was 14.5 months for ramucirumab plus pembrolizumab (80% CI [13.9, 16.1]) and 11.6 months for the standard treatment arm (80% CI [9.9, 13.0]).
• Choosing ramucirumab plus pembrolizumab over standard treatments reduced the risk of death by 31% (HR 0.69, 80% CI [0.51, 0.92], P = 0.05).
• The same benefit was not observed in two of the secondary endpoints, progression-free survival or objective response rate.

Using overall survival as the primary endpoint for second-line treatment of advanced non-small cell lung cancer is a rather unusual and bold step. With immunotherapy, a discrepancy between overall response rate and progression-free survival on the one hand and overall survival on the other is sometimes observed.

From Cedars-Sinai Medical Center, Dr. Karen L. Reckamp presented the study and said: "When planning this study, we worked with our biostatisticians to choose overall survival as the primary endpoint, which becomes important because we saw a benefit of ramucirumab plus pembrolizumab only in overall survival, not progression-free survival."

Dr. Reckamp also emphasized the study design. "While most trials in this setting use only single-agent chemotherapy in the control arm, we used ramucirumab plus docetaxel, which is better than monotherapy. This is not just a positive trial; it is a positive trial against our best standards of care.”

The benefit of ramucirumab plus pembrolizumab did not vary according to PD-L1 positivity or performance status. Dr. Reckamp said, "Usually, when we use immunotherapy without a chemotherapy backbone, PD-L1 status drives responses. We saw greater benefit in patients with squamous histology, but it was similar across all PD-L1 expression levels."

Patients treated after sequential chemotherapy followed by immunotherapy benefited more than those receiving chemoimmunotherapy concurrently.

The S1800A team also presented treatment side-effect data at the 2021 ASCO Annual Meeting. Dr. Reckamp said, "Our findings at one year of follow-up show that serious (grade 3 to 5) side effects in patients receiving pembrolizumab/ramucirumab were less frequent and that pembrolizumab/ramucirumab was better tolerated than chemotherapy".

Given this strong performance, the S1800A researchers plan to continue investigating the combination in a phase-III trial.