Julie R. Brahmer, MD, FASCO, on Previously Untreated Advanced Squamous NSCLC: HARMONi-6 Trial

This trial was a first-line advanced non–small cell lung cancer trial that randomized patients with squamous non–small cell lung cancer to either ivonescimab plus paclitaxel plus carboplatin or tislelizumab, which is a PD-1 antibody, and chemotherapy. And then the primary overall survival, which was previously presented, was progression-free survival. And today, we heard the interim overall survival analysis that was made possible because the prior progression-free survival was positive. Now, this study is a study of ivonescimab, which is a VEGF/PD-1 bispecific antibody. So it has both a VEGF antibody toward VEGF combined with a PD-1 antibody. And this combination is felt to have an advantage because it pulls the antibody into the tumor microenvironment and it increases the affinity of that antibody to PD-1. And the hope is that it increases antitumor immunity but potentially cuts down on VEGF systemic toxicity. But that's unclear right now. But today, Dr. Liu and colleagues presented the overall survival advantage. Now, this study didn't make an interim cut, so this is an early look, but it was preplanned. And because it showed an improved survival in these patients, it's important for us to know these data. And so the hazard ratio was 0.66. So that is nearly a 40% reduction in death for those patients who received ivonescimab plus chemotherapy. And then also the median overall survival was approximately 28 months in the experimental arm, but in the control arm, it was about 24 months. Now, the median follow-up was about 21 months. And with that, it does give us a little bit of pause because there was a lot of censoring and the hazard ratio and the median survival numbers may change over time when we see the final analysis. But it's exciting to see. And the curves, the survival curves, continued to widen over time. So we hope that this is a true reflection of the power of a bispecific antibody that blocks both VEGF and PD-1. Now, it does come along with side effects. The VEGF antibodies are known to have side effects, and these are VEGF-related, typically proteinuria, that means protein spilling into your urine from the kidneys, as well as a risk of bleeding, a risk of hypertension, and then a very rare risk of clotting. And we did see overall increased treatment-related adverse events as well as serious adverse events that were treatment-related compared with the standard arm. But in general, the treatment-related deaths, though, were exactly the same. So, you know, ivonescimab did not increase the risk of death due to side effects. Now, when we look at the VEGF antibody and those side effects in general, the high-grade, or grade 3 and higher, side effects were relatively uncommon except for proteinuria that occurred in about 6% to 8% in grade 3 or higher. But you also have to pay attention to the grade 2 side effects, and the grade 2 side effects were present, and grade 2 side effects, even when they are anti-VEGF-related, then you do have to treat those. So it was important to understand that overall, in my take, you know, these are significant findings, but they are for a Chinese patient population. This study was only performed in China, and the Chinese patient population typically does better with all treatments that have been tested recently in general compared with a global patient population. So we have to take that in context. So my key takeaways were that this combination, ivonescimab plus chemotherapy, will be practice-changing for a squamous lung cancer patient population in China. Based on the interim survival results, we see adverse events that were mainly VEGF-related, and they were higher in the ivonescimab arm, and there is some uncertainty about how best to pick those patients for treatment and how those patients were enrolled. And then lastly, you know, how applicable will this be to our global lung cancer patient population? We need to await the global studies to resolve that.