Can a TKI Boost Anti-PD-L1 Activity in NSCLC?

Can adding a TKI that targets programmed death ligand 1 (PD-L1) to a monoclonal antibody that also targets PD-L1 improve outcomes over the monoclonal antibody alone in locally advanced, unresectable non-small cell lung cancer (NSCLC)? Researchers in China have come in with a qualified yes.
The authors of the new study found that a combination of anlotinib, an oral small-molecule TKI, and benmelstobart (TQB2450), a humanized immunoglobulin G subclass 1 (IgG1) monoclonal antibody that targets PD-L1, improved progression-free survival (PFS) compared with benmelstobart alone after concurrent/sequential chemoradiotherapy (60 Gray ± 10%).
A downside of taking the TKI was a significant increase in side effects, Ming Chen, MD, PhD, lead investigator of the R-ALPS trial, reported at American Society of Clinical Oncology (ASCO) 2025.
Study Results
'Our key finding demonstrated significant improvement in median PFS with the combination of benmelstobart plus anlotinib, with a median PFS of 15.1 months compared to 9.7 months with benmelstobart alone and 4.2 months with placebo,' said Chen, while presenting the abstract at the meeting. PFS was the primary endpoint of the study.
Ming Chen, MD, PhD
'This translated into a reduced risk of disease progression with a hazard ratio of 0.49 for the combination arm and 0.53 for benmelstobart alone,' vs placebo, said Chen, who is director of Radiation Oncology at the Sun Yat-sen University Cancer Center in Guangzhou, China. The P values for both were less than .0001.
Chen reported results of an interim analysis of the phase 3 R-ALPS study, which randomized 553 patients to one of three treatment groups after all received concurrent/sequential chemoradiotherapy: Benmelstobart alone, benmelstobart plus anlotinib, or placebo.
Twelve-month PFS rates were 54.9% in the combination group, 45.7% in the benmelstobart alone group, and 26.4% in the placebo group. The data analysis of overall survival rates has not been completed, Chen said.
Among secondary endpoints, overall response rates were 25.6% ( P = .01), 23.3 ( P = .0318), and 12.9% for the combination, benmelstobart alone, and placebo groups, respectively. The disease control rates were 84.5% ( P = .0067) and 86.1% ( P = .0023) for the combination and benmelstobart alone groups, respectively, and was 70.5% for the placebo group.
Safety Profile 'Manageable' or 'Significant'?
The combination group had consistently higher rates of adverse events than the other two groups.
Chen said the safety profile of adding anlotinib to benmelstobart was 'manageable,' while Shankar Siva, PhD, MBBS, a discussant at the oral abstracts session, characterized the toxicity profile of the study as 'significant.'
Shankar Siva, PhD, MBBS
Overall, the rates of grade 3-5 treatment-related adverse events (TRAEs) were 50% in the combination group, 32% in the benmelstobart alone group, and 21% in the placebo group. The rates of serious TRAEs were 38.3%, 33% and 26.5%, respectively.
Hematologic toxicities were not significantly different across the three groups, Chen said, but the following four biochemical measures were significantly elevated in the combination group: Antistreptokinase, creatine phosphokinase, thyroid-stimulating hormone, and amylase.
Among the grade 3-5 non-hematologic TRAEs, rates of infectious pneumonia, hypertension, and hemoptysis were significantly higher in the combination group: 8.1%, 8.6%, and 2.4%, respectively, vs 4.7%, 0.9%, and 0.5% in the benmelstobart alone group and 5.3%, 1.8%, and 0.8% in the placebo group.
Chen added that the rates of radiation pneumonitis and immune pneumonitis 'were very mild in all three arms,' with rates below 3%.
Elaborating on his different take on the combination treatment's safety profile from Chen's, Siva said the incidence of high-grade adverse events in this study was notable.
'More targeted or bispecific TKIs' might be worth exploring in a combination treatment after chemoradiotherapy for NSCLC to improve the safety profile, he said, during the session.
Knowing biomarkers of benefit and potential toxicity would also be important for using multitarget TKIs in combination therapies after chemoradiotherapy for NSCLS, noted Siva, who is a radiation oncologist at Peter MacCallum Cancer Centre in Melbourne, Australia.
One of the limitations of the study was that all patients were Chinese, Chen said.
Anlotinib was approved for advanced NSCLC in China in 2019.
Chia Tai TianQing Pharmaceutical Group funded the study. Chen reported having no relevant financial relationships. Siva reported having financial relationships with AstraZeneca, Bayer, Bristol Myers Squibb, Merck Sharp & Dohme, and Varian Medical Systems.

Try Our AI Features

Explore what Daily8 AI can do for you:

Learn with AIFact CheckingText to SpeechAI Summary

Related Articles

Yahoo

an hour ago

• Yahoo

Gan & Lee Pharmaceuticals Presented Multiple Results in Novel Diabetes Therapies at the American Diabetes Association's 85th Scientific Sessions

In a Phase 2a clinical trial, the GLP-1 RA bofanglutide injection demonstrated a favorable safety and tolerability profile after 23 weeks of once weekly treatment in patients with type 2 diabetes mellitus (T2DM), with significant HbA1c reductions alongside comprehensive benefits for body weight, blood pressure and blood lipid profiles. In a Phase 2b clinical trial, the bofanglutide injection showed superior HbA1c and body weight reduction than semaglutide (Ozempic®) after 24 weeks of bi-weekly treatment in patients with T2DM, along with an acceptable safety and tolerability profile. In a Phase 2 clinical trial, the once-weekly insulin GZR4 injection demonstrated comparable efficacy and safety profiles in patients with T2DM after 16 weeks of treatment. Notably, GZR4 injection achieved superior HbA1c reduction in patients with inadequate glycemic control on prior basal insulin therapy compared to once-daily insulin degludec (Tresiba®). BEIJING and BRIDGEWATER, N.J., June 21, 2025 /PRNewswire/ -- Gan & Lee Pharmaceuticals (Gan & Lee, stock code: announced that the company presented multiple Phase 2 clinical study results of ultra-long-acting GLP-1 receptor agonist (GLP-1 RA) bofanglutide (research code: GZR18) injection and once-weekly basal insulin analog GZR4 injection during a poster presentation at the American Diabetes Association (ADA)'s 85th Scientific Sessions. Statement: Bofanglutide injection and GZR4 injection are investigational drugs that have not yet been launched in any country. Gan & Lee Pharmaceuticals does not recommend the use of any unapproved drugs/indications. Bofanglutide injection: A Multicenter, Randomized, Double-blind, Placebo-controlled Phase 2a Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Efficacy of Bofanglutide (GZR18) Injection in Chinese Patients with Type 2 Diabetes Mellitus (T2DM) In this Phase 2a clinical trial (NCT06256523), 36 adults with T2DM who had inadequate glycemic control through diet and exercise and/or irregular use of antidiabetic medications, were randomized to receive either bofanglutide injection (N=27) or placebo (N=9) once weekly (QW) for 23 weeks, with a dose escalating from 1.5 mg to 13 mg. The key efficacy endpoint was HbA1c change from baseline to week 23. After 23 weeks of treatment, the mean HbA1c change from baseline in the bofanglutide groups was -1.81% compared to 0.12% in the placebo group, with an estimated treatment difference of -1.93% points*. The proportion of participants achieving an HbA1c target of <7.0% and ≤6.5% was 57.7% and 46.2%, respectively, compared to zero in the placebo group. In terms of weight management, participants treated with bofanglutide experienced a mean reduction in body weight of 6.92 kg from baseline, corresponding to a 9.3% decrease, compared to a minimal reduction of 1.2% in the placebo group. Furthermore, bofanglutide showed comprehensive improvements over placebo in multiple metabolic parameters, including fasting plasma glucose (FPG), glycated albumin (GA), waist circumference (WC), blood pressure, and lipid profiles. In terms of safety, bofanglutide was well tolerated in patients with T2DM. Consistent with known GLP-1 RAs, the most common adverse events were gastrointestinal-related, primarily observed during the early dose-escalation period with mostly mild to moderate in severity. No hypoglycemic events or investigational product-related serious adverse events were reported during the study. Bofanglutide injection: A Multicenter, Randomized, Open-label, Active comparator-controlled Phase 2 Clinical Trial to Evaluate the Efficacy and Safety of bofanglutide Injection versus Semaglutide (Ozempic®) in Chinese Patients with T2DM In this Phase 2b clinical trial (NCT06256549), a total of 272 eligible Chinese patients with T2DM, who had inadequate glycemic control either after lifestyle intervention or despite stable use of oral antidiabetic drugs (OADs) for at least 3 months, were randomized to receive bi-weekly (Q2W) 12 mg (N=55), 18 mg (N=54), 24 mg (N=55) bofanglutide injections, or once-weekly (QW) 24 mg (N=54) bofanglutide injections, or 1 mg semaglutide (Ozempic®, N=54) for 24 weeks of treatment, including the dose-escalation period. The primary endpoint was HbA1c change from baseline to week 24. After 24 weeks of treatment, the mean reductions in HbA1c from baseline were 1.87%, 2.28%, and 1.94% in the bofanglutide groups at 12 mg, 18 mg, and 24 mg Q2W, respectively, and -2.32% in the 24 mg QW group. All these treatment regimens showed greater HbA1c reductions compared to the semaglutide group (-1.60%), with the 18 mg Q2W and 24 mg QW bofanglutide groups demonstrating statistically significant superiority (p<0.001)*. Among drug-naïve patients with inadequate glycemic control despite lifestyle interventions, the 18 mg Q2W bofanglutide group achieved a mean HbA1c reduction of 2.98%, which was significantly greater than that observed with semaglutide (-2.04%; p<0.001)*. The proportions of patients achieving HbA1c target of <7.0% were 63.0% to 73.6% in the Q2W bofanglutide group, 75.0% in the QW bofanglutide group, and 70.0% in the semaglutide group. For the HbA1c ≤6.5% target, the corresponding proportions were 58.2% to 67.9%, 69.2%, and 62.0%, respectively. Furthermore, the mean change in body weight for all bofanglutide groups from baseline to week 24 ranged from -4.26 to -6.54 kg, compared to -3.25 kg in the semaglutide group*. Bofanglutide also greatly improved FPG, blood pressure, lipid profiles, and other metabolic parameters. In this study, bofanglutide was generally well tolerated, with safety and tolerability consistent with other known GLP-1 RAs. The most common adverse events were gastrointestinal-related, mostly mild to moderate in severity, and no severe hypoglycemic events were observed. GZR4 injection: A Multicenter, Randomized, Open-label, Active-controlled, Treat-to-target Phase 2 Clinical Study Comparing the Efficacy and Safety of GZR4 Injection Versus Insulin degludec (IDeg, Tresiba®) in Chinese patients with T2DM This Phase 2 clinical study (NCT06202079) enrolled a total of 83 Chinese patients with T2DM who had inadequate glycemic control on OADs (Part A), and 96 patients with inadequate control on OADs combined with basal insulin therapy (Part B). Participants were randomized to receive QW GZR4 injection (Part A: N=42; Part B: N=41) or once-daily IDeg (Tresiba®) injection (Part A: N=48; Part B: N=48) for 16 weeks of treatment. The primary efficacy endpoint was the change in HbA1c from baseline to week 16. After 16 weeks of treatment, in patients from Part A, the mean change in HbA1c was comparable between GZR4 groups and IDeg groups (−1.50% versus -1.48%, p = 0.90). The proportion of participants achieving HbA1c target of <7.0% was 59.5% in the GZR4 group and 70.7% in the IDeg group, while the proportion achieving HbA1c target of ≤6.5% was 38.1% and 29.3%, respectively. In patients from Part B, GZR4 demonstrated significantly greater HbA1c reduction compared to IDeg (-1.26% vs -0.87%; p<0.01), with a higher proportion of patients achieving HbA1c targets of <7.0% and ≤6.5% (52.1% vs 29.2%; 25.0% vs 10.4%). In addition, improvements from baseline in FPG and time in range (TIR) were comparable between the GZR4 group and IDeg group. GZR4 achieved effective glycemic control without the need for a loading dose at the first administration, while the total weekly insulin dosage (mole) for GZR4 was approximately 40–50% of that for IDeg (p<0.001). In terms of safety, the incidence of adverse events was similar between the two groups. No severe hypoglycemic events or investigational product-related serious adverse events were reported during the study. * The clinical data were presented as mean (SE) value. The detailed results of the above Phase 2 clinical study will be published in a peer-reviewed journal. Conclusion and Future Direction The latest clinical results presented at this year's ADA conference highlight Gan & Lee Pharmaceuticals' leading position in the development of long-acting antidiabetic therapies. Building on these positive outcomes, the company will continue to advance the research and development of innovative treatments for diabetes. Currently, Gan & Lee has initiated and is accelerating large-scale Phase 3 clinical programs in China for bofanglutide injection and GZR4 injections for the treatment of type 2 diabetes, aiming to provide more effective treatment options for patients with diabetes. Forward-looking statements Forward-looking statements are based on our expectations and assumptions as of the date of the statements. Actual results may differ materially from those expressed in these forward-looking statements due to a variety of factors, and we can give no assurance that such results will be achieved in the future. We undertake no obligation to update or revise any forward-looking statements, whether as a result of new information, future events, or otherwise. About Gan & Lee Gan & Lee Pharmaceuticals developed the first Chinese domestic insulin analog. Currently, Gan & Lee has six core insulin products, including five insulin analog varieties: long-acting glargine injection (Basalin®), fast-acting lispro injection (Prandilin™), fast-acting aspart injection (Rapilin®), mixed protamine zinc lispro injection (25R) (Prandilin™25), aspart 30 injection (Rapilin®30), and one human insulin injection - mixed protamine human insulin injection (30R) (Similin®30). The company has two approved medical devices in China, namely reusable insulin injection pen (GanleePen), and disposable pen needle (GanleeFine®). In China's 2024 National Insulin-Specific Centralized Procurement, Gan & Lee Pharmaceuticals ranked first among all selected companies in terms of procurement demand for insulin analogs. The company is also making strides in international markets, with the disposable pen needle (GanleeFine®) approved by the US Food and Drug Administration (FDA) in 2020 and received GMP inspection approval from the European Medicines Agency (EMA) in 2024. These achievements significantly boost Gan & Lee's competitiveness in both international and domestic markets. In the future, Gan & Lee will strive for comprehensive coverage in diabetes treatment. Moving forward with its mission to become a world-class pharmaceutical company, Gan & Lee will also actively develop new chemical entities and biological drugs, focusing on treatments for metabolic diseases, cardiovascular diseases, and other therapeutic areas. SOURCE Gan & Lee Pharmaceuticals

WIRED

an hour ago

• WIRED

Methane Pollution Has Cheap, Effective Solutions That Aren't Being Used

Jun 21, 2025 7:00 AM The International Energy Agency estimates that 70 percent of the fossil fuel sector's methane emissions could be cut with existing technologies—many of which would save polluters money. Photograph: TheThis story originally appeared on Vox and is part of the Climate Desk collaboration. Odorless and colorless, methane is a gas that is easy to miss—but it's one of the most important contributors to global warming. It can trap up to 84 times as much heat as carbon dioxide in the atmosphere, though it breaks down much faster. Measured over 100 years, its warming effect is about 30 times that of an equivalent amount of carbon dioxide. That means that over the course of decades, it takes smaller amounts of methane than carbon dioxide to heat up the planet to the same level. Nearly a third of the increase in global average temperatures since the Industrial Revolution is due to methane, and about two-thirds of those methane emissions comes from human activity like energy production and cattle farming. It's one of the biggest and fastest ways that human beings are warming the Earth. But the flip side of that math is that cutting methane emissions is one of the most effective ways to limit climate change. In 2021, more than 100 countries including the United States committed to reducing their methane pollution by at least 30 percent below 2020 levels by 2030. But some of the largest methane emitters like Russia and China still haven't signed on, and according to a new report from the International Energy Agency, global methane emissions from energy production are still rising. Yet the tracking of exactly how much methane is reaching the atmosphere isn't as precise as it is for carbon dioxide. 'Little or no measurement-based data is used to report methane emissions in most parts of the world,' according to the IEA. 'This is a major issue because measured emissions tend to be higher than reported emissions.' It's also hard to trace methane to specific sources—whether from natural sources like swamps, or from human activities like fossil fuel extraction, farming, or deforestation. Researchers are gaining a better understanding of where methane is coming from, surveilling potential sources from the ground, from the sky, and from space. It turns out a lot of methane is coming from underappreciated sources, including coal mines and small oil and gas production facilities. The report also notes that while there are plenty of low-cost tools available to halt much of this methane from reaching the atmosphere, they're largely going unused. The United States, the world's third largest methane-emitting country, has seen its methane emissions slowly decline over the past 30 years. However, the Trump administration is pushing for more fossil fuel development while rolling back some of the best bang-for-buck programs for mitigating climate change, which will likely lead to even more methane reaching the atmosphere if left unchecked. Where Is All This Methane Coming From? Methane is the dominant component of natural gas, which provides more than a third of US energy. It's also found in oil formations. During the drilling process, it can escape wells and pipelines, but it can also leak as it's transported and at the power plants and furnaces where it's consumed. The oil and gas industry says that methane is a salable product, so they have a built-in incentive to track it, capture it, and limit its leaks. But oil developers often flare methane, meaning burn it off, because it's not cost-effective to contain it. That burned methane forms carbon dioxide, so the overall climate impact is lower than just letting the methane go free. And because methane is invisible and odorless, it can be difficult and expensive to monitor it and prevent it from getting out. As a result, researchers and environmental activists say the industry is likely releasing far more than official government estimates show. Methane also seeps out from coal mines—more methane, actually, than is released during the production of natural gas, which after all is mostly methane. Ember, a clean-energy think tank, put together this great visual interactive showing how this happens. The short version is that methane is embedded in coal deposits, and as miners dig to expose coal seams, the gas escapes, and continues to do so long after a coal mine reaches the end of its operating life. Since coal miners are focused on extracting coal, they don't often keep track of how much methane they're letting out, nor do regulators pay much attention. According to Ember, methane emissions from coal mines could be 60 percent higher than official tallies. Abandoned coal mines are especially noxious, emitting more than abandoned oil and gas wells. Added up, methane emitted from coal mines around the world each year has the same warming effect on the climate as the total annual carbon dioxide emissions of India. Alarmed by the gaps in the data, some nonprofits have taken it upon themselves to try to get a better picture of methane emissions at a global scale using ground-based sensors, aerial monitors, and even satellites. In 2024, the Environmental Defense Fund launched MethaneSAT, which carries instruments that can measure methane output from small, discrete sources over a wide area. Ritesh Gautam, the lead scientist for MethaneSAT, explained that the project revealed some major overlooked methane emitters. Since launching, MethaneSAT has found that in the US, the bulk of methane emissions doesn't just come from a few big oil and gas drilling sites, but from many small wells that emit less than 100 kilograms per hour. 'Marginal wells only produce 6 to 7 percent of [oil and gas] in the US, but they disproportionately account for almost 50 percent of the US oil and gas production-related emissions,' Gautam said. 'These facilities only produce less than 15 barrels of oil equivalent per day, but then there are more than half a million of these just scattered around the US.' There Are Ways to Stop Methane Emissions, but We're Not Using Them The good news is that many of the tools for containing methane from the energy industry are already available. 'Around 70 percent of methane emissions from the fossil fuel sector could be avoided with existing technologies, often at a low cost,' according to the IEA methane report. For the oil and gas industry, that could mean something as simple as using better fittings in pipelines to limit leaks and installing methane capture systems. And since methane is a fuel, the sale of the saved methane can offset the cost of upgrading hardware. Letting it go into the atmosphere is a waste of money and a contributor to warming. Capturing or destroying methane from coal mines isn't so straightforward. Common techniques to separate methane from other gases require heating air, which is not exactly the safest thing to do around a coal mine—it can increase the risk of fire or explosion. But safer alternatives have been developed. 'There are catalytic and other approaches available today that don't require such high temperatures,' said Robert Jackson, a professor of earth system science at Stanford University, in an email. However, these methods to limit methane from fossil fuels are vastly underused. Only about 5 percent of active oil and gas production facilities around the world deploy systems to zero out their methane pollution. In the US, there are also millions of oil and gas wells and tens of thousands of abandoned coal mines whose operators have long since vanished, leaving no one accountable for their continued methane emissions. 'If there isn't a regulatory mandate to treat the methane, or put a price on it, many companies continue to do nothing,' Jackson said. And while recovering methane is ultimately profitable over time, the margins aren't often big enough to make the up-front investment of better pipes, monitoring equipment, or scrubbers worthwhile for them. 'They want to make 10 to 15 percent on their money (at least), not save a few percent,' he added. And rather than getting stronger, regulations on methane are poised to get weaker. The Trump administration has approved more than $119 million to help communities reclaim abandoned coal mines. However, the White House has also halted funding for plugging abandoned oil and gas wells and is limiting environmental reviews for new fossil fuel projects. Congressional Republicans are also working to undo a fee on methane emissions that was part of the 2022 Inflation Reduction Act. With weaker incentives to track and limit methane, it's likely emissions will continue to rise in the United States. That will push the world further off course from climate goals and contribute to a hotter planet.

Bloomberg

2 hours ago

• Bloomberg

US Climate-Data Retreat Gives China a New Opportunity

The economic and political importance of monitoring the weather — or at least the effects of weather — was clear to the ancient Egyptians. They came up with the ' nilometer,' a device measuring Nile River flooding that could predict agricultural (and thus tax) yields. It also was likely clear to foreign intelligence agents breaching Australia's Bureau of Meteorology in 2015 (China denied any involvement). From farmers to insurers to homeowners, understanding the weather, how it's changed and what it may do next is of vital economic importance. But in the US, with polarized views on the proven science of climate change, even collecting data has become a partisan issue. The Trump administration for example has cut swathes of spending and personnel tied to the National Oceanic and Atmospheric Administration, or NOAA.