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Gastrointestinal stromal tumors (GISTs) are driven primarily by oncogenic KIT mutations, and breakthroughs such as imatinib, sunitinib, and ripretinib have transformed the disease’s management. Yet resistance emerges almost universally, driven by secondary KIT mutations—particularly those occurring in the activation loop at exon 17/18, a region historically difficult to inhibit. Patients whose tumors harbor these mutations often progress rapidly, with few effective therapeutic options beyond later-line ripretinib.

The PEAK Phase 3 trial of bezuclastinib, a highly selective, next-generation KIT inhibitor from Cogent Biosciences, addresses this critical unmet need. The company’s announcement of positive topline results positions bezuclastinib as a potentially transformative therapy for patients with KIT activation-loop–mutant GIST.

Read About Gastrointestinal Stromal Tumor on OncoDaily

A Next-Generation KIT Inhibitor Designed for Precision and Selectivity

Bezuclastinib is an orally administered, highly selective KIT inhibitor engineered to target the activation loop—specifically the exon 17/18 mutations that drive resistance to imatinib, sunitinib, regorafenib, and even many newer TKIs. Unlike broad-spectrum inhibitors with multi-kinase off-target effects, bezuclastinib was designed for clean, potent inhibition of KIT with minimal activity against PDGFRα, VEGFR, or other kinases, potentially offering enhanced tolerability and fewer dose-limiting adverse events.

Preclinical evaluations demonstrated strong inhibition of KIT D816V and analogous activation loop mutations, deep suppression of downstream signaling pathways such as MAPK and PI3K/AKT, and robust tumor shrinkage in xenograft models. Clinically, early-phase studies showed promising activity across heavily pretreated GIST populations, supporting advancement into the PEAK Phase 3 trial.

The PEAK Phase 3 Trial: Study Overview

PEAK is a global, randomized Phase 3 trial evaluating bezuclastinib in combination with sunitinib versus sunitinib alone in patients with advanced GIST who have progressed on or are intolerant to imatinib. The trial specifically enrolled patients whose tumors harbor KIT exon 17/18 mutations, reflecting the subgroup most likely to benefit from activation-loop inhibition.

The trial was designed to evaluate whether bezuclastinib could overcome sunitinib resistance by directly targeting the activation loop mutations responsible for disease progression. Progression-free survival, overall response rate, duration of response, and safety formed the primary and secondary outcomes assessed in this study.

Topline Results: A Clinically Meaningful Improvement

According to Cogent Biosciences’ announcement, the PEAK trial met its primary endpoint, demonstrating a statistically significant and clinically meaningful improvement in progression-free survival for the bezuclastinib combination compared with sunitinib alone. The magnitude of benefit was consistent with the drug’s targeted mechanism, showing pronounced activity in tumors driven by KIT exon 17/18 mutations.

Initial analyses also revealed favorable trends in overall response rate and depth of response. Patients receiving the bezuclastinib combination exhibited higher rates of tumor shrinkage, delayed progression, and more durable responses than those in the control arm. Although full survival data will mature over time, early signals indicate that the addition of bezuclastinib may meaningfully alter the trajectory of resistant GIST.

One notable observation is that bezuclastinib’s benefit occurred without compromising tolerability. Reported adverse events were consistent with expectations for sunitinib, and no new safety signals attributable to bezuclastinib were identified. The drug’s clean selectivity profile may allow prolonged dosing and better adherence, important considerations for the chronic management of GIST.

Why These Results Matter for GIST Treatment

While first-line imatinib continues to provide long-term benefit for many patients, resistance develops through clonal evolution, most commonly involving mutations in KIT exons 13/14 (ATP-binding pocket) or exons 17/18 (activation loop). Sunitinib and regorafenib offer partial control of ATP-pocket mutations, but activation loop mutations remain highly resistant to almost all approved TKIs.

Bezuclastinib directly addresses this resistance mechanism. By selectively targeting the activation loop, it attacks the mutational drivers responsible for disease progression at a molecular level traditional TKIs cannot reach. The positive PEAK results therefore mark one of the most meaningful advancements in the sequential TKI strategy for GIST since ripretinib entered the landscape.

For clinicians, this means the potential for a more precise, biomarker-driven approach: identifying patients with KIT exon 17/18 mutations and offering them therapy specifically designed to neutralize the resistant clone.

Safety Profile and Clinical Considerations

The safety data emerging from the PEAK study align with bezuclastinib’s design principles. The drug appears to maintain a favorable tolerability profile without introducing the broad off-target toxicities often associated with multi-kinase inhibitors. The lack of new safety concerns in combination with sunitinib is encouraging, as combination TKIs can sometimes amplify adverse effects.

The cleaner profile may make bezuclastinib particularly advantageous for patients who experience dose-limiting complications with less selective TKIs, providing an opportunity for sustained treatment exposure necessary for durable disease control.

Implications for Clinical Practice and Future Development

If the PEAK results are supported by full data presentation and regulatory review, bezuclastinib may soon become the preferred treatment option for KIT exon 17/18 mutant GIST after imatinib failure. The drug’s specificity, tolerability, and clear clinical benefit position it to reshape the treatment sequence in a mutation-guided manner.

Beyond PEAK, bezuclastinib is also in development for systemic mastocytosis—another KIT activation loop–driven disease—illustrating the drug’s broad potential across KIT-dependent malignancies. Its success in GIST underscores the value of highly selective inhibitors capable of countering resistance mechanisms that have limited the durability of existing TKIs.

Conclusion

The positive results from the PEAK Phase 3 trial highlight bezuclastinib as a promising and potentially practice-changing therapy for patients with KIT exon 17/18 mutant gastrointestinal stromal tumors. By addressing one of the most formidable resistance mechanisms in GIST biology, bezuclastinib fills a long-standing therapeutic gap and offers clinicians a new pathway toward sustained disease control in a population with limited options.

Pending further analyses and regulatory submissions, bezuclastinib has the potential to become a new standard of care for this genetically defined subset of GIST, bringing precision oncology one step closer to everyday practice.

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Written by Armen Gevorgyan, MD

Thursday began with a massive rally with the Dow Jones Industrial Average up 700 points, regaining some ground after an earlier AI-related selloff. Upbeat results from retail giant Walmart helped too.

But the market suddenly turned lower, and the Dow lost 300 points, leaving Wall Street wondering what the heck happened.

Some commentators pointed to persistent worries about an AI bust, while others cited the mixed September jobs report that showed strong payroll gains but an uptick in the unemployment rate to the highest level in four years.

Meanwhile, Federal Reserve policymakers have been sounding increasingly hawkish, putting a rate cut next month in doubt.

Market veteran Ed Yardeni, cited these factors in a note late Thursday along with the selloff in the world’s leading cryptocurrency.

“We attribute some of today’s stock market selloff to the ongoing plunge in bitcoin’s price,” he wrote. “There has been a strong correlation between it and the price of TQQQ, an ETF that seeks to achieve daily investment results that correspond to three times (3x) the daily performance of the Nasdaq-100 Index.”

Yardeni blamed bitcoin’s slide on the GENIUS Act, which was enacted on July 18, saying that the regulatory framework it established for stablecoins eliminated bitcoin’s transactional role in the monetary system.

“It’s possible that the rout in bitcoin is forcing some investors to sell stocks that they own,” he added.

Bitcoin has tumbled more than 30% from earlier highs, suffering its worst slump since 2022. Traders who used leverage to make crypto bets would need to liquidate positions in the event of margin calls.

Steve Sosnick, chief strategist at Interactive Brokers, also said bitcoin could swing the entire stock market, pointing out that it’s become a proxy for speculation.

“As a long-time systematic trader, it tells me that algorithms are acting upon the relationship between stocks and bitcoin,” he wrote in a note on Thursday. “Traders have always sought to find relationships between asset classes, and there are teams of skilled quants who pore through data, both long- and short-term, seeking inputs that guide their decisions. We called them ‘leads.’”

And in recent days, Sosnick added, bitcoin has become one of the most reliable leads. 

Tom Lee, Fundstrat Global Advisors’ head of research, linked crypto with the AI trade in particular, noting that investors with big holdings in AI-related stocks also tend to own bitcoin. 

“I think crypto, bitcoin and ethereum are in some ways a leading indicator for equities because of that unwind and now this sort of limping and weakened liquidity,” he told CNBC on Thursday.

Pakistan has reached another major milestone in its digital expansion with the onboarding of the SEA-ME-WE 6 submarine cable, its third international cable system in a year. Federal IT and Telecom Minister Shaza Fatima confirmed the development on LinkedIn, calling it a significant step toward strengthening global connectivity and increasing national internet capacity.

The new system follows the recent arrivals of the Africa-1 and 2Africa cables, marking one of the fastest periods of growth in Pakistan’s subsea infrastructure. Transworld Associates (TWA), the landing partner for SEA-ME-WE 6, will initially add 4 terabits per second (Tbps) of capacity, expanding Pakistan’s current 13.2 Tbps bandwidth by about 40 percent.

Stretching 21,700 kilometres, SEA-ME-WE 6 connects Pakistan to countries between Singapore and France. It is one of the most advanced high-capacity networks in the world, with a minimum design capacity of 132 Tbps across 10 fiber pairs. This system is built to support large-scale data flows needed for Pakistan’s digital economy, international business, and cloud-based platforms.

Alongside this subsea investment, TWA is building a Tier III certified data centre in Karachi. The facility will connect directly to major subsea systems, including SMW-6, SMW-5, TW1, and 2Africa. It will also be Pakistan’s first data centre designed to support high-density racks for AI workloads, offering scalable and secure hosting for critical national and international operations.

The data centre is scheduled to open in January 2026. It will serve businesses both inside and outside Pakistan, strengthening cloud infrastructure, enterprise networks, and content delivery services. Its Tier III certification ensures redundancy, high availability, and fault tolerance, positioning it as a key part of Pakistan’s growing digital and AI-focused ecosystem.

By Isabel Wang

Friday’s market rebound was ‘not built on anything solid but something very ephemeral,’ says strategist

Recent rallies in stocks haven’t been built on anything solid, says Steve Sosnick, chief strategist at Interactive Brokers.

Volatility on Wall Street this week was a reminder of just how frail conviction around the stock market has been: Every bounce was sold, every selloff spiraled and investors still were skeptical if it had bottomed.

Then came Friday – almost on cue, buyers finally stepped in, raising the question of whether the sudden rebound in stocks was the start of an actual bargain-hunting spree or just another end-of-week buying blitz in an otherwise fragile stock market.

“Every dip could be a buying opportunity, but what I’m seeing this week has morphed from dip buying to rally chasing,” said Steve Sosnick, chief strategist at Interactive Brokers. “We’ve become so enamored with chasing the momentum that I think it creates the opportunity for ‘air pockets,’ because those rallies are not built on anything solid but something very ephemeral, and that also means that they can reverse themselves very quickly.”

U.S. stocks on Friday came off an extremely turbulent ride on Wall Street. The Dow Jones Industrial Average DJIA and the S&P 500 SPX logged a four-day losing streak earlier this week before Nvidia Corp.’s (NVDA) robust earnings report sparked a strong rally in the stock market on Thursday morning. But that surge quickly flipped into the biggest intraday selloff for the S&P 500 since April as worries grew that the Federal reserve would stand pat in December on interest rates, before stocks reversed again on Friday with a sharp rebound.

Even with Friday’s moves, the Dow and the S&P 500 still logged their worst week since Oct. 10, with each losing nearly 2%. The Nasdaq Composite COMP tumbled over 2.7% this week, according to Dow Jones Market Data.

Sosnick told MarketWatch that the wild swings in the stock market this week underscore how fragile investor confidence has become, with Friday’s rally also appearing fleeting as the market’s underlying fundamentals have barely changed. That could spell trouble for the days ahead.

“When you get this rally chasing, it could really put you on a very precarious footing in the market,” he said. “People buy dips only when they legitimately think stocks are ‘on sale’ for fundamental or technical reasons, but now they are doing it simply because stocks are getting more expensive, and they think they will be able to flip it to someone else who will pay more for that.”

Ben Fulton, chief executive officer at WEBs Investments, said the stock rebound on Friday suggests traders are “still resilient as the rising sun” as they show up for “the early Black Friday sales in the stock market.” However, the problem is that the market recovery can be short-lived if early profit-taking is experienced when the markets rebound quicker than expected, he told MarketWatch on Friday.

See: Crypto, the dollar, stocks and credit are telling the Fed it needs to cut, popular strategist says

This week’s market action also saw investors rotate into some of the traditional defensive corners on the stock market, as riskier assets such as megacap tech stocks and bitcoin (BTCUSD) came under pressure.

The S&P 500’s consumer-staples XX:SP500.30 and healthcare XX:SP500.35 sectors were among the few areas on the large-cap benchmark index to close the week higher. For the month, these two sectors have surged 2.2% and 7.1%, respectively, compared with the 3.5% decline in the S&P 500 in the same period, according to FactSet data.

Consumer staples and healthcare are traditionally viewed as defensive plays during periods of elevated market volatility. Gold prices (GC00) fell off their peak but have still risen 2.4% so far in November, according to FactSet.

Jim Baird, chief investment officer at Plante Moran Financial Advisors, said the sector rotation is driven more by valuations and less about a classic “flight to safety” trade – with money moving out of stretched megacap technology names and into cheaper parts of the market – rather than a response to stress in the U.S. economy.

“As valuations look pretty stretched in those big-cap tech names, investors are starting to look for other ways to improve their portfolio diversification and be a little less tied to the AI story and position themselves in a more diversified manner,” he said.

“Taking a little bit of those winnings off the table, particularly during periods of uncertainty, can help you sleep at night,” Baird added.

-Isabel Wang

This content was created by MarketWatch, which is operated by Dow Jones & Co. MarketWatch is published independently from Dow Jones Newswires and The Wall Street Journal.

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Remember when America Online CDs carpeted America and “You’ve got mail” felt like the future? The internet did transform work—but not the way 1998 thought. The surprises weren’t just CEOs in hoodies and legions of coders. They were barbers with booking links, nurses on telehealth, and delivery jobs by the hundreds of thousands.

Looking back at that time isn’t just an exercise in nostalgia. What we imagined then, and how the internet actually changed jobs—sometimes loudly, often quietly—suggests a lot about today’s artificial-intelligence moment.

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Canada Post and the union representing some 55,000 postal workers have reached a tentative deal to end a strike which has disrupted mail deliveries across the country.

The details of the deal were not released, but the Canadian Union of Postal Workers (CUPW) said all parties “have agreed on the main points” and strike action had been suspended.

“We need to agree on the contractual language that will form the collective agreements that would be put to a vote by the members,” the union said, adding that it will “retain the right to strike”.

A nationwide mail strike began on 25 September, before switching to a rolling strike amid an ongoing dispute over postal worker’s pay and benefits.

Canada Post also confirmed that a deal had been reached, pending a union vote, saying: “While this is being done, it has been agreed that all strike or lockout activities are suspended.”

The union and the postal service have been negotiating for nearly two years.

In September, the strike was launched hours after the federal government announced it was authorising significant changes at Canada Post.

The proposed new measures included ending door-to-door mail delivery to about four million homes, allowing non-urgent letter mail to be moved by ground instead of air, shutting some formerly rural post offices, and giving the service more flexibility to raise prices.

The government argues that the changes are necessary to stop Canada Post from losing so much money. Canada Post lost C$1bn ($717; £535m) last year and is on track to lose C$1.5bn this year, according to government figures.

The Canadian postal service – like the UK’s Royal Mail and the United States Postal Service – has seen sharp declines in letter mail delivery over the past decades and subsequent financial shortfalls.

Its three primary revenue streams – letter mail, direct-marketing mail and parcel mail – are all in decline, either through lack of demand or through stiff competition from other courier services.

Previously postal workers went on strike in November 2024 over pay and working conditions.

Last December, ahead of the busy holiday season, the Canadian government ordered the postal workers back to work.

By Michael Sincere

Linda Raschke shares the secrets behind playing to win and her successful trading career

“You are going to lose money,” says stock trader Linda Raschke. “It’s the tuition that every trader ends up paying.”

‘If trading were easy, it wouldn’t exist, because everybody would be a winner.’Linda Raschke

Linda Raschke first learned about the stock market from a book in her father’s library: “A Treasury of Wall Street Wisdom,” edited by Harry D. Shultz. A copy still sits on her shelf. Raschke began her investing career at the Pacific Coast Stock Exchange before moving to the Philadelphia Stock Exchange, where she gained experience in making markets in equity options.

After becoming a commodity trading advisor, or CTA, Raschke launched LBR Group and LBR Asset Management. She founded the Granat hedge fund, ranked by Barclay Hedge as No. 17 out of 4,500 hedge funds for best five-year return. She was also officer of several technical societies and lectured on technical analysis around the world. Raschke offered some of her findings in “Street Smarts,” a book written in collaboration with Larry Connors.

Raschke is known for swing trading for shorter durations – anywhere from an hour to two months. After 45 years, she remains a profitable trader, which she attributes to daily preparation. Raschke was the first woman to be included in Jack Schwager’s book, “The New Market Wizards,” which elevated her credibility, and fame, among traders.

Raschke is the author of “Trading Sardines: Lessons in the Market from a Lifelong Trader,” an account of what she’s learned in decades of market experience. Her trading is built around robust technical set-ups that she has modeled across all markets. Raschke refers to them as “principles of price behavior.” She acknowledges that decades of tape reading, and market experience, make a big difference.

In this recent interview, edited for length and clarity, Raschke discusses what traders need to do to be profitable, how to minimize losing money, and the set-ups she looks for when trading.

MarketWatch: What advice would you give new traders?

Raschke: Start with a very small account size because you are going to lose money. It’s the tuition that every trader ends up paying. People think they’re smart, but they are not savvy, yet, to different market environments and context. It’s much more than just learning technical analysis.

MarketWatch: What do traders need to understand before they can become consistently profitable?

Raschke: When to use leverage but, even more important, understanding the bad habits that are costing you money. No one can teach you how to trade. You need to step up, find your own style, and keep trying different methods. Most people underestimate the learning curve. There is an initial period that can last for a few years to a lifetime when the learning is haphazard and disorganized. During this stage, you are accumulating experiences. At some point, the trader becomes more deliberate about their development, figuring out what kind of trader they will be. This is the hard part. If you are just starting, it’s helpful to have a lot of money tucked away that you can live off of without the pressure of having to make money.

‘Many traders underestimate the number of hours that they need to devote each day to trading. It is not a part-time job.’

MarketWatch: Why do so many traders struggle with discipline?

Raschke: Many people don’t give it enough time. If they’re not successful on a trade immediately, they often move too quickly to the next trade. Every time they click, it’s a dopamine hit. It’s very addictive. It’s like gambling. It goes to the same part of the brain that gambling goes to, which is why some people click far too often. Most don’t recognize their own cognitive biases, either.

MarketWatch: What separates the small percentage of traders who succeed from the majority who don’t?

Raschke: First is awareness or self-actualization. If trading were easy, it wouldn’t exist, because everybody would be a winner. Several studies have concluded that very few traders’ accounts were profitable at the end of the year. If you are a trader with an account size of less than $30,000, 5% are going to be profitable at the end of the year. Do you want to be a professional tennis player, golfer, or rock ‘n’ roll star? There’s only so much room at the top in most fields.

MarketWatch: How do you approach the markets each day?

Raschke: Every single day, I have a game plan. Let’s say I have an existing position in gold (GC00). Will I add to an existing position because it’s in a strong uptrend? Am I going to move my stop? Or am I going to take partial profits and trade against the core position. This is part of my game plan, which is all I care about. My business is to see if there are any arbitrage opportunities during the day. If a security gaps up, will it retrace back below its 7 a.m. CST reading by noontime? Technical analysis ignores the news and ignores the fundamentals, and focuses instead on the chart to gauge how fast prices are moving, among other things.

‘I always take on a position with the intention of holding it overnight. I make most of my money holding overnight.’

MarketWatch: How would you describe your trading style and time frame?

Raschke: I’m not a day trader. I always take on a position with the intention of holding it overnight. I make most of my money holding overnight. Whether that happens or not is another story. The market is similar to bending over and picking up a dollar bill on the sidewalk. It’s like 31 flavors. There are many beautifully moving markets, but they won’t benefit you unless you prepare and do your homework.

MarketWatch: How do you approach setting up a trade in something such as the S&P 500 SPX?

Raschke: You look at the price opening today relative to the previous day’s range. You decide whether to trade off the opening price, and where support should be if the market is in an uptrend, but it may want to sell off first thing in the morning. A lot involves making a note of how price acts at those levels. For example, let’s say the market has had four consecutive down bars, which is rare in the S&P 500. The next morning, I may consider buying, since the market is oversold, but I may not hold it for too long unless it makes a “V” or builds a small base.

MarketWatch: What do most people misunderstand about what it really takes to become a successful trader?

Raschke: Many traders underestimate the number of hours that they need to devote each day to trading. It is not a part-time job. It is a 12- to 14-hour-a-day job when you’re starting. They underestimate the homework, preparation and studying, and being ready for two or three different scenarios the next day. Once you’ve done that, you have to do it day after day to get a feel for your Achilles’ heel. It is not about swinging for the fences, getting rich, buying bitcoin and hoping it goes to a billion dollars. Each day has its own playbook, and you go in there and you make your plays.

MarketWatch: Why is it so hard for most traders to capture the big winning trades?

‘The way to win this game is to stay in it. Most people will not. They will make big errors. They will get frustrated. They will spin their wheels.’

Raschke: Statistically speaking, four days out of the year could make 80% of your profits. Understanding how to capture those fat tails is really what trading is all about. Sometimes systems will keep you in those fat tails, which is the idea behind trend following. However, this approach is not appropriate for new traders, as they often lack the capital and fortitude to execute it correctly. It’s nice to talk about staying with a trade, but trend following has some 40% drawdowns if you are trading it appropriately. New traders won’t be able to handle that.

MarketWatch: How do you develop and test the trading patterns that you use?

Raschke: I have lots of fabulous little patterns that I like to trade, but they may occur only twice a month. You have to do modeling, which involves asking questions. For example, what happens if the price remains above the opening price throughout the day, only to drop below it at noon? What percentage of the time will it close on its low? What percentage of time does it come back up? People need to spend a lot more time doing this basic modeling, which is not a mechanical system.

MarketWatch: Can traders predict major market moves or outlier events in advance?

Raschke: No. The whole point is that you can’t predict these things in advance. You couldn’t predict in advance that Russia was going to invade Ukraine, and wheat went skyrocketing higher. You can’t predict these outliers. You need to understand when they start to unfold and learn what the market is telling you.

MarketWatch: Once an outlier move begins, how should traders respond?

Raschke: You want to trade in the same direction as the outlier. I don’t want to step in front of a freight train and play mean reversion at the same time that something’s exploding. Hell no. When that freight train leaves the station, you want to jump onboard, especially when it’s starting to pick up speed.

MarketWatch: What’s the most important factor in becoming a successful trader over the long run?

Raschke: The way to win this game is to stay in it. Most people will not. They will make big errors. They will get frustrated. They will spin their wheels. They don’t understand capital preservation. They will trade on margin, but the way to win in the long run is to stay in it, as this allows you to accumulate experience.

Michael Sincere is the author of several books, including “Understanding Stocks,” “Understanding Options,” and “Help Your Child Build Wealth.”

More: Stocks near all-time highs. Consumer sentiment near-record lows. So what gives?

Also read: How $5,000 became $31 billion: 5 market lessons from the greatest trader ever

-Michael Sincere

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