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CHICAGO -- Randomized data suggest that an anti-angiogenic agent can kick-start immunotherapy's antitumor activity in non-small cell lung cancer (NSCLC) patients whose disease has already progressed after chemotherapy and a checkpoint inhibitor.

In the phase II study, median overall survival improved by nearly 3 months with ramucirumab (Cyramza) plus pembrolizumab (Keytruda) versus standard-of-care options (14.5 vs 11.6 months), a difference that met prespecified criteria for statistical significance (HR 0.69, 80% CI 0.51-0.92), reported Karen Reckamp, MD, of Cedars-Sinai Medical Center in Los Angeles.

"This is the first trial in the [immune checkpoint inhibitor]-refractory setting to improve overall survival compared to standard of care," said Reckamp in a presentation at the American Society of Clinical Oncology (ASCO) annual meeting. "Importantly, over two-thirds of patients received docetaxel and ramucirumab as the standard-of-care therapy, representing the most active treatment in this setting."

According to the findings, which were published simultaneously in the , the improved survival with the PD-1 checkpoint inhibitor pembrolizumab plus ramucirumab -- an anti-vascular endothelial growth factor (VEGF) receptor 2 inhibitor with indications in NSCLC and other cancers -- was most pronounced in those with squamous or mixed histology and was seen regardless of PD-L1 expression level.

"As we incorporate immune checkpoint inhibition across all stages of non-small cell lung cancer, developing therapies to overcome resistance to immunotherapy is a major area of unmet need," Reckamp explained. "Angiogenic factors can modulate the tumor immune microenvironment through several mechanisms."

VEGF or VEGF receptor inhibition combined with immunotherapy has already demonstrated benefit across a range of tumor types, with approvals in , hepatocellular carcinoma, and , she noted.

In the current study, progression-free survival, as assessed by investigators, was not significantly different between groups (HR 0.86, 80% CI 0.66-1.14), nor were rates of response (22% with ramucirumab-pembrolizumab vs 28% with standard options, one-sided P=0.19).

ASCO discussant Christine Bestvina, MD, of the University of Chicago Comprehensive Cancer Center, called the fact that most patients in the control arm received docetaxel-ramucirumab as their treatment "reassuring," as it suggests the observed benefit in the investigational arm was not just from second-line ramucirumab, but rather a "synergistic benefit" of immunotherapy plus ramucirumab.

"Is this practice changing tomorrow? In my opinion, yes," said Bestvina. "We see promising results with less toxicity."

But she cautioned that the combination is not necessarily better for all patients, and that a phase III is needed for confirmation.

Notably, she highlighted that the survival benefit with ramucirumab-pembrolizumab appeared mostly reserved for patients who had previously received chemotherapy and immunotherapy sequentially (HR 0.45, 80% 0.30-0.68) rather than in combination (HR 0.84, 80% 0.58-1.21).

"This is important for us all to acknowledge given that almost all of our patients are receiving combination [chemotherapy-immunotherapy] as frontline therapy," she said.

The data presented by Reckamp were derived from the Lung-MAP non-matched substudy S1800A and included 136 eligible NSCLC patients whose disease had progressed on platinum-based chemotherapy combined with an immune checkpoint inhibitor (n=74) or chemotherapy following by immunotherapy (n=59). Patients were enrolled from May 2019 to November 2020 and were included if they were not eligible for a Lung-MAP biomarker study enrolling at the time.

Prior immunotherapies included pembrolizumab in 60% of the patients, nivolumab (Opdivo) in 20%, durvalumab (Imfinzi) in 17%, and atezolizumab (Tecentriq) in 3%. Progression needed to have started at least 84 days following initiation of immunotherapy to be eligible for the trial. About 60% of the patients had stage IV disease when they first received a checkpoint inhibitor, and the median time on the previous immunotherapy was 8 months.

Patients were randomized 1:1 to either IV pembrolizumab (200 mg every 3 weeks) plus ramucirumab (10 mg/kg) or to the control arm, where 67% received ramucirumab-docetaxel, 18% received gemcitabine, 9% received no therapy, 4% received docetaxel, and 1% received pemetrexed (Alimta).

Median patient age was 66, 61% were men, 87% were white, and most were current or former smokers (91%). For tumor histology, 52-58% had adenocarcinoma, 40-41% had squamous cell carcinoma, and the rest were mixed or not specified. Where PD-L1 expression was known, 41-47% had a level below 1%, about one-third had a level of 1%-49%, and the rest had an expression level of 50% or greater.

Reckamp noted some imbalances between groups, with more patients in the control arm having an Eastern Cooperative Oncology Group performance status of 1 (87% vs 67%, though sensitivity analyses suggested this did not have an effect on the primary outcome). More patients in the control group had high PD-L1 expression (≥50%), while more participants in the ramucirumab-pembrolizumab group had low PD-L1 levels (<1%).

Grade ≥3 treatment-related adverse events were less frequent with ramucirumab-pembrolizumab than with standard of care (42% vs 60%). "For patients in later-line therapy, toxicity is a really important part of that shared decision-making process," Bestvina noted.

Grade 3 vascular events were more frequent in patients receiving ramucirumab in either the investigational or control arm. Grade ≥3 immune-related events were reported in 31% of patients who received ramucirumab-pembrolizumab. There were three treatment-related deaths in the investigational arm and four in the control arm.