In our Lung-MAP S1800A trial utilizing Ramucirumab and Pembrolizumab versus standard of care we found an improvement in overall survival with a median of 14.5 months for patients who receive Ramucirumab and Pembrolizumab versus 11.6 months in patients who received standard of care. In this trial, it's important to understand that resistance to immune checkpoint inhibitor therapy is common for patients with advanced non-small cell lung cancer. As most patients will receive immune checkpoint inhibitor therapy as part of their initial frontline therapy. We are also utilizing immune checkpoint inhibitor therapy now in the adjuvant setting and neoadjuvant setting. So as we move this therapy into earlier stages of disease, we need to look at and find ways to overcome resistance to these therapies. We did find that progression free survival was not different between the two arms, as far as the median. Though the tail of the curve did show a prolonged progression-free survival for Ramucirumab and Pembrolizumab. We have seen this in other trials utilizing immune checkpoint inhibitor therapy as second-line therapy and beyond. And this is known as a post-progression prolongation of survival, and there may be secondary immune modulating pieces that are overcoming resistance to cause this survival to be improved when we don't see the same in the progression free survival and overall response rates. Overall in this trial, we saw that all subgroups benefited from the therapy. Across PD-L1, the efficacy was similar and hazard ratio was similar across all subgroups. And we did see a slight benefit in patients with squamous cell carcinoma versus non-squamous. Though again, all subgroups did benefit. When we look at toxicity, we see significantly more grade three and four toxicities in patients who receive the standard of care. And importantly, the majority of patients, over two-thirds of patients receive Docetaxel Ramucirumab as the most potent standard of care. And in the Ramucirumab, Pembrolizumab arm, about 40% had grade three, four toxicities. There are different toxicities that we see with standard of care therapies that are cytopenias and neutropenic fever. Whereas the Pembrolizumab, Ramucirumab, we saw a significant number of immune related AE's and Ramucirumab specific AE's, such as hypertension and some vascular events. But these were similar across all patients who receive Ramucirumab. Those who receive the Ramucirumab and the standard of care also experience the Ramucirumab specific toxicities. So overall, much better tolerated than standard of care chemotherapy. And when we look at this combination therapy, this is exciting for patients who have developed resistance on prior immunotherapy and is a potential next therapy option. Seeing this overall survival benefit, we do hope to evaluate this in a phase three trial, to get more robust results. We also think that there may be some modulation of the tumor microenvironment. We know that the VEGF pathway has significant modulation of the tumor immune cells directly on the endothelium and on the vasculature. And through modulating these pieces with inhibition of VEGF receptors to with Ramucirumab, we may be altering the tumor microenvironment to resensitize tumors to immune checkpoint inhibition therapy. It is an exciting time for our patients and potentially having an option that removes chemotherapy from the treatment that they need will be beneficial for many patients. And we're excited to see where this goes next.
