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Akeso's Bispecific Antibody Ivonescimab Bests Keytruda in PD-L1-Expressing NSCLC

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NEW YORK – Akeso Biopharma's bispecific antibody ivonescimab (AK112), which targets both PD-1 and VEGF, bested Merck's anti-PD-1 drug Keytruda (pembrolizumab) as a frontline treatment for patients with advanced, PD-L1-positive non-small cell lung cancer in a Phase III trial. 

At the International Association for the Study of Lung Cancer's World Conference on Lung Cancer in San Diego on Sunday, Caicun Zhou, the director of the oncology department at Tongji University's Shanghai Pulmonary Hospital, presented the primary results of the HARMONi-2 clinical trial. In this late-stage trial, investigators randomized 398 treatment-naive patients with PD-L1-positive, locally advanced or metastatic NSCLC to either ivonescimab or Keytruda. Patients were PD-L1 positive if they had a PD-L1 tumor proportional score of at least 1 percent, and patients with EGFR- or ALK-altered tumors were not eligible for the trial. 

After nine months, Zhou reported, 56 percent of patients who received ivonescimab were alive without disease progression versus 40 percent of those who received Keytruda. The median progression-free survival for ivonescimab-treated patients was 11.14 months versus 5.82 months for those on Keytruda. 

The progression-free survival improvement with ivonescimab was consistent across almost all subgroups, including based on PD-L1 expression score and squamous versus non-squamous histology, Zhou reported. 

Among patients who received ivonescimab, the overall response rate was 50 percent and the disease control rate was 89.9 percent versus 38.5 percent and 70.5 percent, respectively, in Keytruda-treated patients. The overall survival data were not mature at the time of the data cutoff. 

In terms of safety, Zhou said that the incidence of grade 3 or higher treatment-related adverse events was slightly higher with ivonescimab than Keytruda. In the ivonescimab arm, 28.4 percent of patients experienced grade 3 or higher treatment-related adverse events, whereas the same was true of 15.6 percent of Keytruda-treated patients. However, one patient on ivonescimab died due to a treatment-related adverse event, whereas two patients on Keytruda died due to an adverse event. 

"This is the first randomized Phase III trial to demonstrate a clinically significant improvement in efficacy [over] the approved drug pembrolizumab in non-small cell lung cancer," Zhou said. "Ivonescimab is a novel first-line therapy for advanced non-small cell lung cancer with positive PD-L1 expression that is a TPS 1 percent or higher but without EGFR or ALK translocations." 

Lingering questions, limitations 

Despite the clear progression-free survival benefit observed with ivonescimab versus Keytruda in HARMONi-2, oncologists raised several concerns. For instance, the trial was conducted exclusively in China, noted John Heymach, the chief of thoracic and head and neck medical oncology at the MD Anderson Cancer Center, in a discussion following Zhou's presentation. 

Heymach also called into question whether there might be a better choice for a control arm for patients with a PD-L1 tumor proportional score between 1 and 49 percent. Single-agent Keytruda is currently sold in the US and in Europe as a first-line treatment for patients with advanced PD-L1-expressing NSCLC, though the US Food and Drug Administration has approved it for those with PD-L1 expression in at least 1 percent of tumor cells while European regulators have stipulated a higher PD-L1 expression cutoff in this setting of at least 50 percent or more. 

"The question is, is [Keytruda] monotherapy the appropriate comparator for this 1 to 49 [percent] group?" he asked. This concern, he explained, was rooted in the fact that in the past KEYNOTE-042 trial of Keytruda versus chemotherapy there was no significant difference in overall survival for patients whose NSCLC expressed PD-L1 with a tumor proportional score of 1 to 49 percent. That said, in another study, KEYNOTE-189, which was limited to non-squamous histology, there was a substantial benefit seen with Keytruda plus chemo versus chemo alone in patients with PD-L1 expression in this range. 

Keytruda monotherapy is indeed approved in the US in the PD-L1 1 percent to 49 percent tumor proportional score population, Heymach noted, "but it would not be the treatment of choice for a good performance status patient in the US and, I think, most of the rest of the world." 

Based on this, Heymach proposed that additional studies will be necessary to explore the outcomes with ivonescimab in NSCLC patients with PD-L1 tumor proportional scores between 1 percent and 49 percent. 

Heymach briefly touched on the higher incidence of grade 3 treatment-related events observed with ivonescimab but noted that virtually none of these patients discontinued treatment. "[This drug has] a manageable safety profile with adverse events consistent with its known mechanism of activity," he noted. 

Ultimately, though, Heymach found the HARMONi-2 data "really striking." 

"They exceeded my expectations going into this study," he said. 

Mechanistic explanations unclear 

Heymach, though, also questioned why the bispecific antibody seemed to perform so much better than Keytruda alone. "Even our best-established stars will sometimes have an off day. … Did [Keytruda] just randomly have a bad day here?" he wondered, though he pointed out that Keytruda performed similarly in the earlier KEYNOTE studies. 

Digging a bit deeper into why blocking VEGF would enhance the activity of a PD-L1 checkpoint inhibitor like ivonescimab, Heymach said VEGF can suppress the tumor microenvironment in a variety of ways, which is perhaps less appreciated than its known role in tumor angiogenesis. The immunosuppressive effects, he continued, seem to be linked to VEGF1, and some VEGF drugs out there only block VEGF2. "This is important, because drugs that block VEGF receptor 2 alone may not have the immunomodulatory effects," he said. 

He did point out that past studies, such as LUNG-MAP S1800A and ImPower150, have suggested the benefits of combining VEGF inhibition with PD-1 blockade, "but not to this striking extent that we're seeing, at least in terms of progression-free survival, in this study." The difference in the extent of benefit raises the question as to whether there's a specific advantage with a bispecific antibody like ivonescimab or if patients would do just as well with the combination of a VEGF inhibitor and a PD-1 inhibitor. "We don't know the answer to this definitively, but it is a possibility," Heymach said, suggesting based on preliminary data that VEGF can promote cooperative binding of ivonescimab to PD-1, leading to enhancement of PD-1 suppression. "So, it is possible that this is greater than just VEGF plus PD-1 itself," he noted. 

In Heymach's view, the overall survival readout will be key to determining ivonescimab's real benefit, as will additional studies with patient populations outside China. "This study highlights the potential benefits of VEGF and PD-1 blockade together," he said. "If these benefits are confirmed, it is possible that our therapeutic 'harmony' we've had in this first-line space may finally come to an end. That's a 'disharmony' that we all should be rooting for." 

In the meantime, Zhou predicted that the compound will likely be approved in the first-line PD-L1-positive NSCLC setting in China soon. Ivonescimab is already approved in China for EGFR-mutated, locally advanced or metastatic non-squamous NSCLC patients who have progressed after EGFR tyrosine kinase inhibitors. Last month, China's National Medical Products Administration granted priority review to Akeso's supplemental new drug application seeking approval for ivonescimab as first-line treatment of PD-L1 positive locally advanced or metastatic NSCLC based on the HARMONi-2 data. 

The makers of this bispecific antibody are already taking steps to expand its used beyond NSCLC. In July, Akeso's partner Summit Therapeutics, which has rights to develop ivonescimab in most territories outside China, inked a deal with MD Anderson Cancer Center to jointly study ivonescimab in tumor types that Summit isn't already studying.