Zongertinib

About a year after Bayer's Hyrnuo (sevabertinib) was first cleared by the FDA as a second-line treatment for certain adults with non–small-cell lung cancer (NSCLC), the oral, small-molecule tyrosine kinase inhibitor (TKI) has now been greenlit for the frontline setting. The US regulator on Wednesday handed Hyrnuo accelerated approval as a first-line treatment for locally advanced or metastatic non-squamous NSCLC in patients whose tumours have HER2 TK domain activating mutations. The FDA nod sets Hyrnuo up to better compete with Boehringer Ingelheim's rival TKI, Hernexeos (zongertinib), which clinched a frontline accelerated approval in February, thanks to a speedy review powered by a Commissioner's National Priority Voucher. Lagging behind Boehringer, Bayer will have to make up commercial ground in the frontline setting — and may also have to dispel some toxicity concerns. When Hyrnuo and Hernexeos were cleared in the post-platinum setting last year based on near-identical efficacy, experts were more impressed by the safety profile of Boehringer's TKI (see – Spotlight On: Boehringer looks to get jump on Bayer in first-line HER2-positive lung cancer race).Both drugs feature warnings for hepatotoxicity, left ventricular dysfunction, interstitial lung disease/pneumonitis, and embryo-fetal toxicity, while Hyrnuo is also associated with ocular toxicity and pancreatic enzyme elevations. Response rate resultsHyrnuo's label expansion was granted based on data from the Phase I/II SOHO-01 trial, which included a cohort of 69 treatment-naïve patients with locally advanced or metastatic HER2-mutant NSCLC, as well as 70 who had received a prior systemic therapy.When given as a first-line treatment, Hyrnuo achieved an overall response rate (ORR) of 75%, with 73% of responders maintaining that status for at least six months. Specifically, 6% of patients had a complete response while 70% were deemed partial responders.In the second-line setting, patients taking the TKI saw a confirmed ORR of 71%, with a median duration of response of 9.2 months.Bayer is running the Phase III SOHO-02 trial to confirm Hyrnuo's benefit in treatment-naïve patients.

Jazz Pharmaceuticals’ bispecific antibody Ziihera has gained FDA approval for first-line HER2-positive stomach cancer, unlocking another market as the company builds toward a $2 billion-plus peak sales target. The latest green light allows Ziihera to be used in addition to chemotherapy, with or without BeOne Medicines’ Tevimbra, in previously untreated, HER2-positive advanced gastroesophageal adenocarcinoma (GEA). The approval permits Jazz to challenge more than a decade of practice, in which trastuzumab (Herceptin) has been the standard HER2 agent used alongside platinum-based chemotherapy—with or without a PD-1 inhibitor—as first-line therapy for these stomach cancer patients. Backing Jazz’s case, the combination of Ziihera, Tevimbra and chemo significantly reduced the risk of death by 28% versus trastuzumab-chemo in the phase 3 Herizon-Gea-01 trial. The Ziihera combo extended patients’ median overall survival (OS) by 7.2 months to 26.4 months. When the data were presented in January, doctors and analysts called the Ziihera regimens practice-changing in first-line GEA. Prior to the FDA’s latest nod, Merck & Co.’s PD-1 inhibitor Keytruda has been approved to treat HER2-positive stomach cancer, but only in tumors that express PD-L1. According to a subgroup analysis of Herizon-Gea-01, overall survival was prolonged in both PD-L1-positive and -negative patients for Ziihera-Tevimbra-chemo versus the control arm, with an even bigger benefit observed among PD-L1-negative patients. In PD-L1-negative patients, as defined by a tumor area positivity (TAP) score below 1, the triplet extended median OS by 13.9 months to 29.7 months. Ziihera, or zanidatamab, is a bispecific antibody that binds to extracellular domains 2 and 4 of the HER2 receptor, which are targets of Herceptin and Roche’s other HER2 drug, Perjeta. As the same antibody can’t bind the two locations on the same receptor because of physical chemical positioning, one antibody has to bind two different receptors, effectively pulling them together to create “receptor clustering,” Rob Iannone, M.D., Jazz’s R&D head, explained in an interview with Fierce ahead of the approval. That dual-binding mechanism of Ziihera promotes immunogenic cell death, providing synergy with PD-1 inhibition even in PD-L1-negative tumors. “What’s meaningful is, [this is the] first time we’re seeing over two years [of] median survival in this pretty poor prognosis disease and broad activity irrespective of PD-L1 status,” Iannone said. Meanwhile, the Ziihera-chemo arm has yet to show a statistically significant OS benefit—only a preliminary favorable trend suggesting a 20% improvement—versus trastuzumab-chemo at the first interim analysis of Herizon-Gea-01. But this sans-PD-1 Ziihera combo still significantly improved progression-free survival by 35%. The PD-1-inclusive triplet delivered a PFS advantage of 37% over control. For both Ziihera arms, patients had a median of 12.4 months without disease worsening, versus 8.1 months in the comparator group. Jazz expects it will accrue enough events to conduct a second interim OS analysis for the doublet regimen by the end of September. Compared with Ziihera’s first FDA nod in previously treated HER2-positive biliary tract cancer, HER2-positive GEA, which includes cancers of the stomach, gastroesophageal junction and esophagus, represents a much larger market. In GEA, which is the fifth most common cancer worldwide, approximately 20% of all cases are HER2-positive, according to Jazz’s estimate. Following the Herizon-Gea-01 data revelation, Jefferies analysts put Ziihera’s peak sales at $1.5 billion in GEA alone. For its part, Jazz has projected Ziihera peak sales at $2 billion across indications. Jazz is considering studying Ziihera for early-stage gastric cancer, where there’s no approved HER2 treatment, Iannone said. Besides a front-line study meant to serve as the confirmatory trial for Ziihera’s biliary tract cancer label, Jazz is testing the bispecific in breast cancer for patients who’ve failed prior HER2 therapies, including AstraZeneca and Daiichi Sankyo’s star antibody-drug conjugate Enhertu. A pan-tumor basket trial is exploring Ziihera’s efficacy across multiple cancers, and according to Iannone, Jazz plans to continue its discussion with the FDA around a potential path to approval in colorectal cancer. Jazz licensed Ziihera from Zymeworks for $50 million upfront in 2022. Today, the Dublin-headquartered company has partnered with Boehringer Ingelheim and AI-driven Iambic Therapeutics to test the bispecific in combination with HER2 tyrosine kinase inhibitors Hernexeos (zongertinib) and IAM1363, respectively, in HER2-positive breast cancer. Such combinations could be synergistic, Iannone said. “There’s evidence that HER2 TKIs upregulate receptor expression, and zanidatamab potentially could work even more effectively with higher density receptors.”