In a phase 2 clinical trial, the combination of an immune checkpoint inhibitor (ICI) and a vascular endothelial growth factor (VEGF) inhibitor led to improved overall survival versus standard of care in patients with non–small cell lung cancer (NSCLC) who had failed previous ICI therapy.
NSCLC patients usually receive immune checkpoint inhibitor therapy at some point, whether in the adjuvant or neoadjuvant setting, or among stage 3 patients after radiation. “The majority of patients who get diagnosed with lung cancer will get some sort of immunotherapy, and we know that at least from the advanced setting, about 15% of those will have long-term responses, which means the majority of patients will develop tumor resistance to immune checkpoint inhibitor therapy,” said Karen L. Reckamp, MD, who is the lead author of the study published online in Journal of Clinical Oncology.
That clinical need has led to the combination of ICIs with VEGF inhibitors. This approach is approved for first-line therapy of renal cell cancer, endometrial, and hepatocellular cancer. Along with its effect on tumor vasculature, VEGF inhibition assists in the activation and maturation of dendritic cells, as well as to attract cytotoxic T cells to the tumor. “By both changing the vasculature and changing the tumor milieu, there’s a potential to overcome that immune suppression and potentially overcome that (ICI) resistance,” said Dr. Reckamp, who is associate director of clinical research at Cedars Sinai Medical Center, Los Angeles. “The results of the study were encouraging. . We would like to confirm this finding in a phase 3 trial and potentially provide to patients an option that does not include chemotherapy and can potentially overcome resistance to their prior immune checkpoint inhibitor therapy,” Dr. Reckamp said.
The study included 136 patients. The median patient age was 66 years and 61% were male. The ICI/VEGF arm had better overall survival (hazard ratio, 0.69; SLR one-sided P = .05). The median overall survival was 14.5 months in the ICI/VEGF arm, versus 11.6 months in the standard care arm. Both arms had similar response rates, and grade 3 or higher treatment-related adverse events were more common in the chemotherapy arm (60% versus 42%).
The next step is a phase 3 trial and Dr. Reckamp hopes to improve patient selection for VEGF inhibitor and VEGF receptor inhibitor therapy. “The precision medicine that’s associated with other tumor alterations has kind of been elusive for VEGF therapies, but I would hope with potentially a larger trial and understanding of some of the biomarkers that we might find a more select patient population who will benefit the most,” Dr. Reckamp said.
She also noted that the comparative arm in the phase 2 study was a combination of docetaxel and ramucirumab. “That combination has shown to be more effective than single agent docetaxel alone so [the new study] was really improved overall survival over the best standard of care therapy we have,” Dr. Reckamp said.
The study was funded, in part, by Eli Lilly and Company and Merck Sharp & Dohme Corp. Dr. Reckamp disclosed ties to Amgen, Tesaro, Takeda, AstraZeneca, Seattle Genetics, Genentech, Blueprint Medicines, Daiichi Sankyo/Lilly, EMD Serono, Janssen Oncology, Merck KGaA, GlaxoSmithKline, and Mirati Therapeutics.