Author: admin

Brad Pitt’s F1 Movie Opens to $55.6M as Liberty Eyes New Rights Pact

As Formula 1 continues to have discussions about the future of its U.S. media rights, the racing property is hoping the strong opening for a new feature film starring Brad Pitt may be just the thing to help push those talks over the finish line.

F1: The Movie took in some $55.6 million in its domestic rollout, which is quite a haul for a non-sequel, adult-oriented film that isn’t constructed around superhero IP. Produced by Jerry Bruckheimer, the Apple Original Films offering stars the septuagenarian Pitt in the unlikely role as a washed-up racer who breaks back onto the circuit after a 30-year layoff.

The film booked another $88.4 million overseas, although it will have to generate a much greater windfall if it is to earn back an estimated $300 million in production and marketing expenses. The stateside summer release calendar may put the kibosh on a profit, however, as this weekend marks the launch of yet another Jurassic Park sequel—the seventh release in the series arrives on the heels of 2022’s $1 billion blockbuster Jurassic World: Dominion—while Warner Bros.’ Superman hits the multiplex on July 11.

If the F1 flick continues to draw a crowd here in the U.S., that enthusiasm could spill over to the televised racing product. While ABC’s broadcast of the Miami Grand Prix delivered the third-largest domestic F1 audience with 2.17 million viewers, that marked a 29% decline from the year-ago race (3.07 million), which was boosted by a lead-in from Game 7 of the Magic-Cavaliers NBA playoff series (4.32 million).

Oscar Piastri’s win in Miami also trailed a competing NASCAR Cup Series race on FS1, a basic-cable network that reaches approximately 30 million fewer homes than ABC. Despite the relatively restricted delivery system, the May 4 race at Texas Motor Superspeedway averaged 2.56 million viewers.

As much as F1 ratings zoomed to previously unimagined heights during its first few years as a Disney media partner, the TV growth effectively maxed out in 2022, when ESPN and its broadcast sibling averaged 1.21 million viewers per race. The following year saw F1’s deliveries slip 8.5% to 1.11 million viewers, an average delivery that carried over to the 2024 season. By way of comparison, NASCAR served up 2.9 million viewers per race over the course of its two most recent seasons.

The fact that NASCAR draws an audience that is two-and-a-half times the size of the F1 crowd likely goes a long way toward explaining why the latter group is getting pushback in its talks with prospective media partners. F1’s parent company, Liberty Media, is looking to double the value of its current $90 million/year deal with Disney, and that big ask has prompted the Mouse House to allow its exclusive negotiating window to lapse without a renewal. (ESPN chairman Jimmy Pitaro has demonstrated his unwillingness to overpay for even a Big Four league, opting out of the final two years of the company’s legacy $550 million/year MLB deal in February.)

While Apple is among the list of digital disruptors said to be kicking the tires on an F1 rights pact, a paywall will all but certainly prevent F1 from achieving the sort of rapid growth it enjoyed on cable and broadcast TV. (Disney’s ratings nearly doubled between 2018, the first year of its F1 stewardship, and 2022.) As illustrated by the 10-year, $2.5 billion Apple-MLS deal, all the money in the world can’t buy a bigger audience when fans have to shell out $99.99 for a season pass.

F1 still has plenty of time to work out the particulars of a new U.S. rights deal (its ESPN contract expires when the 2025 season runs out in December), and there’s an outside chance enthusiasm for the feature film might help boost the televised product just as the talks start heating up. ESPN will carry three F1 races between now and early August, with the British Grand Prix set to roar into view on July 6.

The 2024 race averaged 1.29 million viewers, which should provide a solid baseline for any post-theatrical comparisons when the holiday-delayed official Nielsen data for this year’s event drops on July 9.

Continue Reading

June 30, 2025
Naseeruddin Shah bats for Diljit Dosanjh amid cross-border collaboration row

He added that Diljit’s global recognition made him a target, while the director remained unknown. Shah praised Diljit for agreeing to the casting decision, stating his “mind is not poisoned”.

He further asserted, “What these goons want is to put an end to personal interaction between the people of India and Pakistan.”

Naseeruddin Shah also expressed affection for his “close friends and relatives” in Pakistan.

He wrote, “I have close relatives and some dear friends there and no one can stop me from meeting them or sending them love whenever I feel like it.” He defiantly concluded his statement to those who might tell him to “Go to Pakistan” with, “GO TO KAILASA.”

Naseeruddin Shah is known for not shying away from statements critiquing government policies or societal issues in India.

He has, for instance, expressed concerns about safety in India, described Anupam Kher as a “clown” for endorsing the BJP government, and made contentious remarks on Mughal history.

The core reason for the backlash against Hania (and by extension, Diljit and the film) is that she allegedly made remarks against India’s Operation Sindoor and Armed forces.

Diljit and the film’s co-producer, Gunbir Singh Sidhu, have stated that Sardaar Ji 3 wrapped production during a stable political situation. The film hit theatres internationally, except for those in India.

Continue Reading

June 30, 2025
WTA celebrates Yanina Wickmayer as she retires from professional tennis

ST. PETERSBURG — Belgium’s Yanina Wickmayer, a five-time WTA singles champion and former World No.12, played the last singles match of her professional tennis career Monday at Wimbledon. After announcing in May that The Championships would be her final tournament, the 35-year-old bowed out in the first round against Renata Zarazua of Mexico. She remains in doubles contention, alongside Latvia’s Anastasija Sevastova.

Wickmayer made her WTA qualifying debut on home soil at Hasselt in 2004. She rose to prominence in 2009, the year she captured her first two singles titles (Estoril, Linz) and advanced to the semifinals of the US Open, where Caroline Wozniacki ended her run. She was the recipient of that season’s WTA Most Improved Player award and went on to attain her career-high ranking on April 19, 2010.

Contesting 11 Tour-level singles finals overall — across all surfaces — Wickmayer’s subsequent titles came at Auckland in 2010, Tokyo [Japan Open] in 2015 and Washington, DC in 2016. She also won three doubles titles, most recently at Warsaw in 2023, partnering Heather Watson — and as the mother of a daughter, Luana, who was born in April, 2021.

Among other highlights, Wickmayer posted nine successive Top 100 seasons (2008-16), registered five wins over Top 10 opponents (including Grand Slam winners Li Na, Petra Kvitova and Marion Bartoli) and holds the Belgian record (jointly with Sabine Appelmans) for most singles wins in Billie Jean King Cup play (25-10).

She leaves the game with a singles win-loss record of 535-373 (all levels) and career prize of more than $6 million.

Click here for more on Wickmayer’s distinguished career.

Continue Reading

June 30, 2025
Great Britain to attempt to synthesize human genome • Mezha.Media

A five-year research project called Synthetic Human Genome (SynHG) has been launched in the UK, in which researchers plan to create large fragments of human DNA in the laboratory, The Guardian reports.

The goal of the research is to gain a deeper understanding of how the genome functions and lay the foundation for new treatments for complex diseases, including autoimmune diseases and viral organ damage.

The project is led by Professor Jason Chin from the Medical Research Council’s Laboratory of Molecular Biology (LMB) in Cambridge. The team also includes scientists from the universities of Cambridge, Kent, Manchester, Oxford and Imperial College London. The first stage involves the synthesis of individual sections of chromosomes, which the researchers will insert into human skin cells to observe their behaviour.

This is the first large-scale attempt to rewrite the human genome from the bottom up, from molecule to cell. Previous experience synthesizing the complete genome of E. coli has prepared Chin’s team for the human genome, which is almost a thousand times larger, at over 3 billion base pairs.

Researchers are paying particular attention to the so-called “dark matter of the genome” – sections of DNA whose function remains poorly understood. Their analysis may provide new answers about gene regulation, epigenetics, and the occurrence of hereditary diseases.

Working alongside the scientific team will be an ethics team, led by Professor Joy Zhang from the University of Kent, to examine the social implications and potential risks of the research, including concerns about the use of the technology to create “designer babies” or modified organisms for domestic or industrial purposes.

Bioethicists are also considering using synthetic mitochondria to prevent maternally transmitted diseases, a solution that could reduce the need for donors and simplify IVF procedures.

Share:

Посилання скопійовано

Continue Reading

June 30, 2025
‘Starvation’ Days Over As Cyclists Prepare To Gorge On Tour de France 2025

Not so long ago, cyclists heading into the Tour de France were skinny string beans weighing and measuring every grain of rice that entered their body – but that image has not just gone, it’s taken a seismic shift in the other direction.

This year’s riders will be gorging themselves like never before, taking on board the equivalent of a large plate of pasta per hour and even training their stomachs to cope with this influx of food.

“Intake has doubled,” Julien Louis, nutritionist for the Decathlon-AG2R team, told AFP.

In fact, it’s a 180-degree turnaround from the 2010s and the “low carb” fad popularized by four-time Tour de France winner Chris Froome’s Sky team.

This method consisted of depriving the body of sugars during training in order to lose weight and encourage the body to use fat for energy.

“Two eggs for breakfast and we were off for five-six hours of training, with water in the bottles. We were exhausted the whole time,” recalls British veteran Simon Yates, winner of the last Giro.

Climber Pavel Sivakov paints an even more dramatic picture.

“Mentally, it was very hard,” he says. “We were starving, with no energy, tapping into our fat.”

Those days are gone.

“When there’s nothing left in the tank the runner switches to using fat,” explains Louis, who used to work for English Premier League side Liverpool.

“It works but it’s much less effective than carbohydrates.”

‘Never Eaten So Much’ – The Modern Calorie Load

One look at the map for the Tour de France – which runs 3,338 kilometers over three weeks from Lille, all the way down south and back up to Paris for the finish – is a giveaway when it comes to a rider’s nutritional needs.

He will burn through roughly 7,000 calories on one of the lung-busting, muscle-crunching mountain stages.

“You have to eat four times as much as a normal person,” says Cofidis rider Simon Carr. “We’ve never eaten so much on a bike.”

Most riders now take in up to 120 grams of carbohydrates per hour while racing, in some cases even more, which is enormous.

“It’s the equivalent of six bananas or around 200 grams of dried pasta per hour,” says Louis.

Until recently, eating such large quantities – mainly in the form of gels and energy drinks – was unimaginable, as it would lead to too much intestinal distress.

“Up until five years ago, 120g of carbohydrates per hour was impossible,” Tadej Pogacar explained in a podcast in September, adding such an intake would have had him in dire need of a trip to the toilet.

‘Gut Training’ – The Hidden Factor Behind Performance

Since then, great progress has been made with energy products, which now contain a combination of two types of carbohydrate.

“For a long time, we thought there was only one kind of carbohydrate transporter in the intestine,” explains Louis.

“Then we discovered that there was a second type that could transport fructose. As a result, by using these two pathways at the same time, we can push through twice as much sugar.”

According to all the parties interviewed by AFP, these advances in nutrition, along with developments in equipment and training methods, help to explain the increasingly high levels of performance in cycling – a sport which has often been associated with doping.

Although products are now better tolerated by the body, making this revolution possible, riders still have to train their stomachs to cope with such quantities.

“Otherwise you can’t digest when you’re asked to eat six gels an hour. Your body just can’t cope,” says Pauline Ferrand-Prevot, this year’s winner of the women’s Paris-Roubaix and gold medalist in the cross-country mountain bike at the Paris Olympics.

She found this out the hard way when she gave up, ill, during the World Championships in September, unused to the longer distances after her switch from mountain bikes.

During winter training, the riders now do “at least one session a week of intestinal training, or ‘gut training’,” says Louis.

“At the very beginning, there may be a little discomfort,” he adds. “But without it, you’re at a huge disadvantage. It’s as if you’re not running on the same fuel.”

Continue Reading

June 30, 2025
Using Discrete Choice Data to Support Personalized Pharmacy Counseling in ALK+ NSCLC

Understanding what patients and caregivers value most in cancer treatment is increasingly essential for delivering personalized and patient-centered care, particularly in the context of high-cost, long-term oral targeted therapies such as ALK inhibitors for non–small cell lung cancer (NSCLC). At the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois, Christopher Danes, PhD, scientific director of Global Medical Affairs Oncology at Takeda in Boston, Massachusetts, presented findings from a discrete choice experiment that explored the trade-offs patients with ALK-positive (ALK+) NSCLC and their caregivers are willing to make when evaluating treatment options.

In this interview with Pharmacy Times®, Danes discusses how the study’s insights can inform pharmacist-led shared decision-making, improve adherence strategies, and support value-based care planning by highlighting the nuanced preferences that shape treatment decisions in real-world oncology practice.

Pharmacy Times: How might the findings from this discrete choice experiment inform shared decision-making in pharmacy practice, particularly in patient counseling for ALK+ NSCLC treatments?

Christopher Danes, PhD, is scientific director, Global Medical Affairs Oncology at Takeda n Boston, Massachusetts. Chris joined Takeda nearly 15 years ago as a medical science liaison and has been instrumental in shaping the lung cancer franchise through his strategic vision and leadership. In his current role, Chris spearheads the global medical affairs strategy for Takeda’s lung cancer portfolio, managing and overseeing activities that are critical to understanding the science and disease state, as well as facilitating cross-functional support for designated products/programs. Prior to joining Takeda, Chris served as a research assistant and research fellow at renowned organizations, including the MD Anderson Cancer Center. Chris holds a BS from the University of Buffalo and a PhD in cancer biology from the University of Texas.

Christopher Danes, PhD: Our findings highlight that both patients and caregivers place the greatest value on maximizing 3-year progression-free survival (PFS) but are also willing to make trade-offs for reduced risk of certain adverse events (AEs) when considering potential treatment options for ALK+ NSCLC. The results shed light on the differences in treatment preferences between these groups and underscore the importance of engaging both patients and caregivers in open, individualized conversations about what matters most to them. Pharmacists should use this evidence to frame discussions with patients and caregivers, helping them understand the clinical benefits and potential risks of treatment and guiding shared decision-making that aligns with their preferences.

Pharmacy Times: The study showed that both patients and caregivers prioritized 3-year PFS but were also willing to trade some PFS to reduce certain risks. How should pharmacists help navigate those trade-offs during clinical consults?

Danes: Our data suggest that while most value PFS highly, many are open to trading some PFS for improvements in quality of life. Pharmacists can use these insights to tailor counseling, ensuring discussions about treatment options explicitly address both efficacy and AE profiles and helping support patients and caregivers in making choices that reflect their unique priorities. This is especially important for people living with ALK+ NSCLC, who are often still working or caring for children and may be on therapy for extended periods of time.

As a next step, we will be conducting additional analyses to gain clarity on distinct populations, including how they value tradeoffs and how preferences differ from group to group.

Pharmacy Times: Which specific AEs had the greatest impact on patient vs caregiver willingness to trade PFS, and how might that influence supportive care strategies?

Microscopic view of non–small cell lung cancer cells. Image Credit: © Keopaserth – stock.adobe.com

Danes: According to our results from the full population of participants, both patients and caregivers were most willing to trade PFS to reduce the risk of any grade cognitive/mood effects, grade III or higher abnormal lab results, and grade III or higher lung complications. Interestingly, patients, but not caregivers, also valued reducing grade III or higher weight gain and any grade myalgia. This suggests supportive care strategies should prioritize early identification and management of cognitive/mood disturbances and serious lab or lung complications.

Notably, there were sub-populations of both patients and caregivers that were willing to accept any burden of AEs for improved efficacy, however, there were similar sized sub-populations of patients and caregivers that preferred a more balanced clinical profile. We are conducting further analyses on these populations to better understand what drives these preferences, which we hope to share in the future.

Pharmacy Times: Did the preferences differ significantly between patients with and without brain metastases? How might this subgroup variation affect treatment selection discussions?

Danes: We did evaluate the difference in attribute values in patients with or without brain metastases. Patients with brain metastases were willing to trade 3-year PFS more than others, which was interesting. We are doing further evaluation to assess why this might be and hope to share insights in the future.

Pharmacy Times: What role do you see pharmacists playing in eliciting and documenting patient and caregiver treatment preferences, especially in oral targeted therapy regimens such as ALK inhibitors?

Danes: Pharmacists are essential in eliciting, documenting, and communicating patient and caregiver preferences—particularly for oral ALK inhibitors that require ongoing adherence and monitoring. By routinely asking about patient goals, prior experiences with AEs, and personal values, pharmacists can ensure these preferences are incorporated into the care plan and communicated to the broader care team.

Pharmacy Times: Were there any surprises in the data about what risks patients and caregivers were most willing—or unwilling—to accept in exchange for longer PFS?

Danes: The importance of abnormal laboratory values was surprising, as it often can have little clinical manifestation. We investigated a little more and realized that patients and caregivers were concerned that abnormal laboratory values would lead to dose modifications, which in turn, could affect efficacy. This can induce anxiety for both patients and caregivers and underscores the importance of setting expectations for patients and caregivers at the onset of treatment.

In addition, there were a few differences between how patients and caregivers weighed certain attributes that we found interesting. For example, there was a subset of caregivers who were unwilling to trade any PFS for reduced toxicity, reflecting a strong focus on extending the life of their loved one regardless of AEs. Additionally, while patients were willing to trade a reduction in PFS to reduce risk of grade III or higher weight gain or any grade myalgia, caregivers were not. This makes sense when you think about it from the individual perspectives—significant weight gain and muscle soreness could have a significant impact on a patient’s daily life and self-esteem but may be viewed as only minor concerns by their caregivers, who would rather prioritize extending PFS. These nuances reinforce the importance of individualized discussions with both parties when making treatment decisions.

Pharmacy Times: Given that a subset of caregivers were unwilling to trade any PFS for reduced toxicity, how can pharmacists mediate potential differences in priorities between patients and their caregivers?

Danes: In partnership with health care providers, pharmacists can help serve as neutral facilitators, ensuring both patient and caregiver perspectives are heard. By providing balanced, evidence-based information and encouraging open dialogue, pharmacists can help identify shared goals or clarify areas of divergence, supporting consensus-building or compromise when needed.

Pharmacy Times: How can pharmacy teams use tools like discrete choice experiments to better tailor education and adherence support for long-term users of ALK inhibitors?

Danes: Discrete choice experiments can help us provide actionable insights into what patients and caregivers value most when evaluating potential treatment options. A discrete approach also allows you to avoid potential biases surrounding available treatment options by focusing on attributes vs brand names. Pharmacy teams can use these findings to proactively address the AEs that matter most to patients, personalize education materials, and design adherence interventions that reflect patient concerns and priorities.

Pharmacy Times: The study included patients recruited through an advocacy group—do you think these findings are generalizable to broader populations, and how might that influence pharmacist interpretation of these data?

Danes: While recruiting through an advocacy group may introduce some selection bias, our sample included a range of patients and caregivers representative of the ALK+ NSCLC community. However, pharmacists should interpret the findings with some caution, recognizing that preferences may vary in broader or more diverse populations and should always individualize discussions.

Pharmacy Times: How do these preference data inform value-based decision-making for specialty pharmacy services or formulary management when dealing with high-cost ALK inhibitors?

Danes: Our results suggest that value in ALK+ NSCLC treatments goes beyond survival outcomes and should also account for quality of life and patient/caregiver preferences about AEs. Specialty pharmacy services and formulary decisions should consider these dimensions to ensure access to therapies that best align with what patients and caregivers value most.

Continue Reading

June 30, 2025
Hornets Acquire The Draft Rights To Liam McNeeley And A Future First-Round Draft Pick From Phoenix – NBA
1. Hornets Acquire The Draft Rights To Liam McNeeley And A Future First-Round Draft Pick From Phoenix NBA
2. ‘A cool feeling’: Hornets introduce 2025 NBA Draft picks in Charlotte Charlotte Observer
3. No. 29 pick instant reaction The New York Times
4. Breaking down Liam McNeeley’s fit with the Charlotte Hornets Yahoo Sports
5. Dom Amore: Liam McNeeley, UConn waited for the NBA’s call, and it came just in time Saratogian
Continue Reading
June 30, 2025
Israel acknowledges Palestinian civilians harmed at Gaza aid sites, says 'lessons learned' – Reuters
1. Israel acknowledges Palestinian civilians harmed at Gaza aid sites, says ‘lessons learned’ Reuters
2. US-Israeli backed Gaza aid group must be shut down, say 130 charities BBC
3. Over 170 NGOs call for end to deadly GHF aid distribution system in Gaza Dawn
4. In Gaza, the Israelis are staging Hunger Games Al Jazeera
5. ‘It’s a Killing Field’: IDF Soldiers Ordered to Shoot Deliberately at Unarmed Gazans Waiting for Humanitarian Aid Haaretz
Continue Reading
June 30, 2025
De Minaur’s British summer: Wimbledon goals, Boulter by his side – ATP Tour
1. De Minaur’s British summer: Wimbledon goals, Boulter by his side ATP Tour
2. Katie Boulter reveals the one ‘rarity’ putting her at an advantage this Wimbledon Yahoo
3. Katie Boulter’s age, net worth, height, boyfriend and Instagram revealed Heart
4. Alex de Minaur reveals all on his wedding plans with Katie Boulter Daily Mail
5. De Minaur and Boulter’s life off court during Wimbledon as Aussie ‘sneaks’ around house Daily Express
Continue Reading
June 30, 2025
Study of Combined TIGIT/PD-1 Blockade Signals Potential Shift in Gastric Cancer Management
As the first phase 3 trial to investigate an Fc-silent, anti-TIGIT agent in patients with solid tumors, the STAR-221 study (NCT05568095) may further clarify the therapeutic role of domvanalimab plus zimberelimab (Sepalizumab) and chemotherapy in patients with gastric cancers, potentially reshaping first-line treatment paradigms, particularly for PD-L1–positive disease, according to Kohei Shitara, MD.

STAR-221 is investigating the combination of the TIGIT monoclonal antibody domvanalimab, the PD-1 inhibitor zimberelimab, and FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin) vs nivolumab (Opdivo) plus FOLFOX or CAPOX in the first-line setting for patients with locally advanced unresectable or metastatic gastric, gastroesophageal junction (GEJ), and esophageal adenocarcinoma.¹ Overall survival (OS) serves as the primary end point. Secondary end points include progression-free survival (PFS), overall response rate (ORR), duration of response (DOR), safety, and quality of life outcomes.

The initiation of STAR-221 is based on positive findings from the phase 2 EDGE-Gastric trial (NCT05329766).² Updated findings from arm A1 of the study showed that in all evaluable patients with first-line, locally advanced unresectable or metastatic gastric/GEJ/esophageal adenocarcinoma (n = 41), at a median follow-up of 13.9 months, the confirmed ORR with domvanalimab plus zimberelimab and FOLFOX was 59% (95% CI, 42%-74%). Among patients with a PD-L1 tumor activity positivity (TAP) score of at least 5% (n = 16), this rate was 69% (95% CI, 41%-89%). Among those with a TAP score of less than 5%, the ORR was 50% (95% CI, 29%-71%).

“Maybe the benefit [will be limited to] patients in the PD-L1–high population, but we should see the actual data [from STAR-221],” Shitara said in an interview with OncLive®. “If we have positive findings, this may give us important insight about the structure of the antibody and whether Fc-silent or Fc-activated [agents] give us different stories [in the context of] past negative trials.”

In the interview, Shitara discussed the mechanism of action and clinical activity of the TIGIT-targeted agent domvanalimab; preclinical and phase 2 data that support the continued investigation of domvanalimab plus zimberelimab and chemotherapy in patients with gastric/GEJ/esophageal cancers; and the potential clinical implications of results from STAR-221, which may be influenced by PD-L1 status.

Shitara is the director of the Department of Gastrointestinal Oncology at the National Cancer Center Hospital East in Kashiwa, Japan.

OncLive: How do domvanalimab and zimberelimab work alongside chemotherapy to elicit antitumor responses?

Shitara: The important target molecule is TIGIT, especially for this combination. TIGIT is an inhibitory checkpoint receptor expressed on various types of immune cells, especially exhausted CD8 cells and regulatory T cells [Tregs], where it usually competes with activating molecules, such as CD20 and CD26, for binding its ligands. If there is TIGIT expression, this usually leads to inhibition of a specific immunophenotype like T cells, Tregs, and natural killer cells. Importantly, [TIGIT] is usually observed with other immune checkpoint molecules, such as PD-1 and LAG-3 [inhibitors]. It is expressed at a relatively later stage of exhaustion. That’s why blocking TIGIT has emerged as an attractive strategy in cancer immunotherapy. This is usually combined with anti–PD-1 and –PD-L1 agents.

An important aspect [of some] TIGIT antibodies is [the] Fc-maintained or Fc-activated [state, which] retains Fc receptor binding capabilities, leading to antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity to deplete TIGIT-expressing immune cells. For example, an Fc-maintained IgG1 antibody may deplete Tregs. This may be good for antitumor response, but it may also increase autoimmune toxicity because of the depletion of Tregs.

Another class of agents is the Fc-silent TIGIT antibody, which is engineered to lack Fc receptor engagement. It doesn’t deplete Tregs—instead, it [mainly] enhances the expansion of effector cells. On the other hand, if Fc is maintained, there is also a risk of depletion of activated effector cells. There are always pros and cons for this kind of structure.

In preclinical studies, there’s a good paper for both classification of Fc-silent and Fc-maintained antibodies. This was published in Cancer Research and supports that Fc-silent IgG1 antibodies for TIGIT may be better compared with Fc-maintained [agents]. However, another group published a different paper in Nature that supports that Fc-activated TIGIT antibodies are better, especially regarding depletion of immunosuppressive cells, like Tregs.

Based on these preclinical studies, TIGIT inhibition is attractive. However, there are 2 types of anti-TIGIT antibodies. Domvanalimab is mainly an Fc-silent IgG1 antibody. This may not deplete inhibitory cells, but [it may] mainly activate exhausted effector cells. Because of its lack of depletion of Tregs, the toxicity profile is expected to be feasible. This is usually combined with the anti–PD-1 [agent] zimberelimab. Zimberelimab is an IgG4 monoclonal antibody [with a mechanism of action] similar to that of nivolumab and pembrolizumab [Keytruda]. This combination has been tested in various clinical trials.

What phase 2 data contributed to the rationale for STAR-221?

This combination’s development is further supported by results from the ongoing EDGE-Gastric trial. This is a first-line gastric cancer trial [planning] to enroll approximately 40 patients to test domvanalimab and zimberelimab in combination with a cytotoxic FOLFOX regimen. Initial data were presented at the 2024 ASCO Annual Meeting and showed an ORR of 59% in the entire population, with a median PFS of 12.9 months. Although the small sample size is a relatively major limitation of the study, [the findings], in direct comparison with [those from] previous pivotal trials like the phase 3 CheckMate 649 [NCT02872116] and KEYNOTE-859 [NCT03675737] studies, suggested an increased ORR and longer median PFS.

The subgroup analysis [data] also support [population] enrichment by PD-L1 status. This TIGIT-directed domvanalimab/zimberelimab/chemotherapy combination seemed to work better in patients with high PD-L1 expression, such as a combined positive score [CPS] or TAP score of 5% or higher. This is in line with our expectations, because TIGIT is usually co-expressed with other checkpoints like PD-1 [T] effector cells. Additionally, the safety profile looks manageable; because of a lack of Treg depletion, autoimmune reactions seem to not be increased.

The phase 3 STAR-221 trial is ongoing to test domvanalimab/zimberelimab in combination with first-line FOLFOX or CAPOX vs the current standard of chemotherapy plus nivolumab in the first-line setting. We needed to test PD-L1 status before patient enrollment. Patients could be enrolled regardless of PD-L1 status, but stratification by PD-L1 status was important, considering the mode of action [of the combination demonstrated in] the subgroup analysis of the phase 2 study. That’s why PD-L1 TAP score was included as one of the stratification factors for the primary end point for OS in this study. Subgroups will also be tested according to TAP score or CPS status. Enrollment [to STAR-221] is completed, and we are waiting for survival follow-up and analysis.

Concerning the current other trials for TIGIT-targeted therapy, unfortunately, no phase 3 trial has shown the benefit of TIGIT inhibitors in any solid tumors. For example, there were negative trials in melanoma, gynecological cancer, and lung cancer. The lung cancer trial showed a borderline benefit of TIGIT inhibition, especially in the PD-L1–positive population.

Although all trials [with TIGIT inhibition] have been negative, there [are opportunities to use TIGIT inhibitors with] different modes of action, especially [regarding] the Fc portion. Previously reported phase 3 trials have almost always applied Fc-maintained or Fc-activated TIGIT inhibitors. STAR-221 is the first study to test an Fc-silent anti-TIGIT antibody. [Therefore], we may observe a difference [in outcomes from this trial] compared with previous negative trials.

How might positive results from STAR-221 affect the development of domvanalimab and the placement of the investigational combination among current chemoimmunotherapy regimens for gastric cancers?

It should depend on the result. If [domvanalimab/zimberelimab/chemotherapy] shows an OS benefit compared with chemotherapy plus nivolumab, it should be at least the standard in some populations. However, this depends on the subgroup analysis [where patients are stratified] by PD-L1 status. If it only shows a benefit in the PD-L1–high population, it should be the treatment used for that population [only].

However, if [the combination] shows an [OS] benefit regardless of PD-L1 status, this is also attractive, because usually patients with low PD-L1 status achieve limited benefit with chemotherapy plus a PD-[L]1 inhibitor. If this trial turns out to be positive, why not test this agent in other types of tumors [beyond those] where previous anti-TIGIT therapy failed to show a survival benefit? It should be interesting.

Chemotherapy/nivolumab is standard, especially for patients with a PD-L1 CPS of 1 or higher. [In patients with a] CPS less than 1, [this combination] didn’t show benefit, but there’s no detrimental effect. The [STAR-221] trial was started before the FDA’s Oncologic Drugs Advisory Committee meeting about the restriction of [frontline PD-1 inhibitors to patients with HER2-negative, microsatellite-stable gastric/GEJ adenocarcinoma with a PD-L1 CPS greater than 1]. I don’t expect any large barriers or any differences in this [trial] population compared with the general gastric cancer population regarding CPS frequency.

Additionally, the main objective in this study is to see the treatment effect, especially in patients with a CPS or a TAP score of 5% or higher. [CPS] is being monitored during the trial. It does not seem different from the usual frequency [seen in this population], but the exact results should be reported after the analysis.

References
1. A clinical trial of a new combination treatment, domvanalimab and zimberelimab, plus chemotherapy, for people with an upper gastrointestinal tract cancer that cannot be removed with surgery that has spread to other parts of the body (STAR-221). ClinicalTrials.gov. Updated June 26, 2025. Accessed June 30, 2025. https://www.clinicaltrials.gov/study/NCT05568095
2. Janjigian Y, Oh D, Pelster M, et al. Updates on abstract 433248: EDGE-Gastric arm a1: phase 2 study of domvanalimab, zimberelimab, and FOLFOX in first-line (1l) advanced gastroesophageal cancer. Presented at: 2024 ASCO Annual Meeting. May 31-June 4, 2024. Chicago, IL.
Continue Reading
June 30, 2025