Superior Survival Benefit With Ramucirumab Plus Pembrolizumab Observed in ICI-Resistant NSCLC


The addition of ramucirumab to pembrolizumab elicited significant response among patients with advanced non–small cell lung cancer who experienced disease progression following treatment with PD-1/PD-L1 inhibitors and platinum-based doublet chemotherapy.

Karen L. Reckamp, MD

Karen L. Reckamp, MD

The addition of ramucirumab (Cyramza) to pembrolizumab (Keytruda) elicited significant response among patients with advanced non–small cell lung cancer (NSCLC) who experienced disease progression following treatment with PD-1/PD-L1 inhibitors and platinum-based doublet chemotherapy according to results of the phase 2 S1800A substudy (NCT03971474), presented at the 2022 ASCO Annual Meeting.1

Among patients enrolled to S1800A, a part of the Lung-MAP nonmatched protocol, who received the PD-1/VEGFR2 inhibitor combination the median overall survival (OS) was 14.5 months (95% CI, 13.9-16.1) vs 11.6 months (95% CI, 9.9-13.0) with investigator’s choice of standard-of-care therapy (HR, 0.69; 95% CI, 0.51-0.92; standard log-rank P = .05).

This benefit was consistent across all subgroups examined, including those stratified by PD-L1 expression. Other outcomes, including progression-free survival (PFS) and objective response rates (ORRs), were comparable between the 2 groups.

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

Investigators on the trial hypothesized that dual blockade of VEGFR2 with ramucirumab and PD-1 with pembrolizumab could potentially overcome immunotherapy resistance by reducing neovascularization with upregulation of proinflammatory cytokines. This strategy has been successful in other solid tumor types, resulting in FDA approvals in renal cell carcinoma, endometrial cancer, and hepatocellular carcinoma. In a phase 1 study, the combination demonstrated an ORR of 30% (95% CI, 13.8%-50.2%) and a disease control rate of 85% (95% CI, 66.3%-95.8%) in patients with previously treated NSCLC.2

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 had prior platinum-based doublet therapy, either sequentially or in combination with immunotherapy, and an ECOG performance status of 0 or 1. Patients were stratified by PD-L1 expression, histology, and intent to receive ramucirumab in the SOC arm.

In total, 130 eligible patients were enrolled from May 17, 2019, to November 16, 2020, and were randomized in a 1:1 fashion to received either pembrolizumab plus ramucirumab (n = 69) or SOC (n = 67), which could include either docetaxel plus ramucirumab (n = 45), docetaxel (n = 3), gemcitabine (n = 12), pemetrexed (n = 1), or no treatment (n = 6). In the experimental arm, patients received 200 mg of pembrolizumab every 3 weeks for up to 35 cycles and 10 mg/kg of ramucirumab every 3 weeks.

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

The primary end point was OS between the 2 arms using a 1-sided 10% level log-rank test upon 90 deaths, with secondary end points of ORR, duration of response (DOR), investigator-assessed PFS, and safety.

Median PFS between the 2 arms was similar, at 4.5 months (95% CI, 4.2-6.1) in the experimental arm vs 5.2 months (95% CI, 4.2-5.7) with SOC (HR, 0.86; 95% CI, 0.66-1.14; standard log-rank P = .25). Kaplan-Meier curves for PFS separated later, suggesting a benefit for pembrolizumab plus ramucirumab. Outcomes favored the regimen in certain subgroups, such as in those with squamous cell or mixed histology (HR, 0.55; 95% CI, 0.38-0.80; P = 0.2).

Responses were similar between groups, with an ORR of 22% (90% CI, 14%-30%) observed in the pembrolizumab plus ramucirumab group vs 28% (90% CI, 19%-37%) with SOC. Median DOR was better with the combination at 12.9 months (90% CI, 2.8-not applicable) vs 5.6 months (90% CI, 4.6-7.8) with SOC.

Subgroup analysis for OS showed the most pronounced benefit with pembrolizumab plus ramucirumab in those with squamous cell or mixed histology (HR, 0.43; 95% CI, 0.28-0.65; P = .005). 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.

To explain the discordance between OS and secondary outcome measures, the investigators pointed to prior research from the phase 3 OAK trial (NCT02008227) of atezolizumab (Tecentriq) vs docetaxel for patients with previously treated NSCLC, in which the experimental regimen similarly resulted in OS improvement, although PFS and ORR were consistent between treatment arms.3 Results from that trial went on to support the FDA approval of the single agent as treatment for the indicated patient subgroup.4

Grade 3 or greater treatment-related adverse events (AEs) occurred in 42% of patients in the combination arm vs 60% in the SOC arm. In total, there were 9 (31%) grade 3 or greater immune-related AEs with ramucirumab/pembrolizumab. In addition, grade 3 or higher vascular events were more common with the combination.

Patient characteristics were well balanced in the pembrolizumab/ramucirumab and SOC arms, with most patients being men (59% vs 63%, respectively) and White (87% each). There were more patients in the SOC arm with a performance status of 1 at 87% vs 67% with the experimental regimen. More patients receiving ramucirumab and pembrolizumab had PD-L1 expression less than 1% (47%) vs the SOC arm (41%). The median tumor mutational burden was also slightly higher in the combination arm at 10.1 mutations/megabase vs 7.6 mutations/megabase with SOC.

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 SOC options. Further evaluation of the approach is warranted.


  1. Reckamp, KL Redman MW, Dragnev KH, et al. Overall survival from a phase II randomized study of ramucirumab plus pembrolizumab versus standard of care for advanced non–small cell lung cancer previously treated with immunotherapy: Lung-MAP nonmatched substudy S1800A. J Clin Oncol. 2022;40(suppl 16):9004. doi:10.1200/JCO.2022.40.16_suppl.9004
  2. Herbst RS, Arkenau HT, Santana-Davila R, et al. Ramucirumab plus pembrolizumab in patients with previously treated advanced non-small-cell lung cancer, gastro-oesophageal cancer, or urothelial carcinomas (JVDF): a multicohort, non-randomised, open-label, phase 1a/b trial. Lancet Oncol. 2019;20(8):1109-1123. doi:10.1016/S1470-2045(19)30458-9
  3. Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017;389(10066):255-265. doi:10.1016/S0140-6736(16)32517-X
  4. Atezolizumab (Tecentriq). FDA. News Release. Updated October 19, 2016. Accessed June 3, 2022.
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