Category: 3. Business

LEAP-012 trial investigates pembrolizumab (KEYTRUDA®) plus lenvatinib (LENVIMA®) in combination with transarterial chemoembolization (TACE) versus TACE alone for patients with unresectable, non-metastatic hepatocellular carcinoma (HCC).

HCC remains among the most lethal cancers worldwide, and while TACE has long been the standard of care for intermediate-stage disease, progression within a year is common due to angiogenic and immunosuppressive escape mechanisms. Preclinical and early clinical data have suggested that combining immunotherapy, VEGF inhibition, and locoregional therapy may produce synergistic antitumor effects by enhancing antigen release, promoting vascular normalization, and strengthening immune activation.

Study Design and Methods

LEAP-012 was a multicenter, double-blind, randomized Phase 3 study enrolling 480 patients with unresectable, non-metastatic HCC not previously treated with systemic therapy.
Patients were randomized 1:1 to receive:

• Experimental arm: Pembrolizumab (400 mg IV every 6 weeks) + Lenvatinib (12 mg or 8 mg daily based on body weight) + TACE
• Control arm: Dual placebo + TACE

TACE was performed using chemotherapeutic and embolic agents delivered via the hepatic artery, beginning 2–4 weeks after initiation of systemic therapy.

Primary endpoints

• Progression-Free Survival (PFS) by blinded independent central review (BICR) per RECIST v1.1
• Overall Survival (OS)

Secondary endpoints: Objective response rate (ORR), duration of response (DOR), disease control rate (DCR), and safety.

Results

At the pre-specified interim analysis, KEYTRUDA + LENVIMA + TACE met the primary endpoint of PFS, demonstrating a statistically significant and clinically meaningful improvement compared to TACE alone. These findings, presented at ESMO 2024 and published in The Lancet, confirmed the biological synergy between immune checkpoint blockade, VEGF inhibition, and locoregional therapy.
However, the combination did not achieve statistical significance for overall survival (OS) compared with TACE alone. After internal review, Merck and Eisai determined that the probability of reaching the OS threshold at future analyses was low, leading to early study termination.

• PFS: Statistically significant improvement with the combination regimen versus TACE alone (per BICR; p < 0.001).
• OS: Did not reach protocol-defined significance; trial closed early for futility.
• Safety: Adverse events were consistent with known profiles of pembrolizumab and lenvatinib; no new safety signals were observed.

Interpretation

The LEAP-012 trial reinforces the biologic rationale of combining immunotherapy and VEGF blockade with TACE but highlights the challenge of translating radiographic progression benefits into survival advantage in intermediate-stage HCC.
Although PFS improvement was robust and reproducible, the lack of OS benefit suggests that earlier immune modulation may not meaningfully alter long-term outcomes in this disease stage, possibly due to the limited duration of systemic exposure and competing post-progression treatments.
Nonetheless, the findings contribute valuable insights into the integration of systemic and locoregional therapies and underscore the need for patient stratification, biomarker-driven selection, and optimization of treatment sequencingin HCC.

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Regulatory Context

Despite the global trial closure, in June 2025, China’s National Medical Products Administration (NMPA) approved KEYTRUDA + LENVIMA + TACE for unresectable, non-metastatic HCC based on PFS benefit and clinical relevance in local patient populations.
The results do not affect existing approvals of the pembrolizumab–lenvatinib combination for advanced RCC, endometrial carcinoma, or HCC monotherapy indications.

Key Takeaway Messages

• LEAP-012 met its PFS endpoint but failed to show a statistically significant overall survival benefit versus TACE alone.
• Trial discontinued early based on low probability of meeting OS threshold at later analyses.
• Safety profile consistent with known pembrolizumab + lenvatinib experience; no new toxicities observed.
• Findings highlight the translational gap between improved tumor control and extended survival in intermediate-stage HCC.
• Reinforces need for rational combinations, biomarker-guided selection, and optimized systemic-locoregional sequencing in liver cancer management.

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Google’s Gmail security is changing.

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Whilst millions of Gmail passwords have not suddenly leaked, despite multiple reports, Google warns compromised security credentials are giving hackers access to accounts. Its advice is clear — if you have not done so already, make this account change now.

For the second time in just a few weeks, Google hit back as reports (1,2) suggested a massive new password leak. “Reports of a ‘Gmail security breach impacting millions of users’ are false. Gmail’s defenses are strong, and users remain protected.”

But just because the breach is not new does not mean it’s not dangerous. Google says users should “reset passwords when they are found in large batches like this.” In reality, don’t wait for a breach to turn up, while regularly changing passwords is no longer considered best practice, ensuring passwords are strong and unique certainly is.

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But passwords will always be vulnerable to being leaked or stolen. “Attackers are intensifying their phishing and credential theft methods, which drive 37% of successful intrusions,” Google warns, and “an exponential rise in cookie and authentication token theft as a preferred method for attackers, with an 84% increase in infostealers.”

That’s why Google tells users that “adopting passkeys as a stronger and safer alternative to passwords” stops account password compromises.

And on that note, with these latest “Gmail security breach” headlines still swirling, there was some quieter, better news for Google and its billions of Gmail account holders.

“Google commands half of all passkey authentication activity,” Dashlane confirmed in its latest passkey adoption report. “A scale so dominant that including it in our top 20 would distort the competitive landscape for other services.” According to the password manager, “Google’s sheer volume dwarfs that of other platforms.”

This, it says, was driven “by a pivotal product decision: In October 2023, Google made passkeys the default login option for personal Google Accounts. This move effectively exposed hundreds of millions of users to passwordless authentication, creating the largest real-world deployment of passkeys to date.”

The result: “Google passkey authentications exploded by 352% over the past year.”

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Unlike Microsoft, Google is not yet advocating for the complete deletion of passwords. But it does say that defaulting to passkeys means users can create complex passwords and multi-factor authentication options that don’t need to be as convenient as SMS.

As such, while adopting passkeys is the solution, it only works if you stop using your password — even if a password remains on the account (with MFA) as a back-up.

“Google’s approach demonstrates the power of defaults,” Dashlane says. “By making passkeys the path of least resistance rather than an opt-in security feature, Google transformed passkey adoption from a trickle into a flood.”

A decade-old vulnerability in the Linux kernel has reemerged as a powerful weapon for ransomware groups, according to warnings issued by the Cybersecurity and Infrastructure Security Agency (CISA). Tracked as CVE 2024 1086, the flaw resides in the netfilter nf_tables component and enables local privilege escalation (LPE), allowing attackers with initial access to elevate their permissions to root and take full control of a system.

Originally introduced in the kernel’s codebase in 2014, the bug affects Linux versions from 3.15 through 6.8 rc1, impacting major distributions including Debian, Ubuntu, Fedora, and Red Hat. The vulnerability stems from a use after free (UAF) condition in the nft_verdict_init() and nf_hook_slow() functions, which improperly handle packet filtering verdicts. This flaw can lead to double free memory corruption, providing attackers a pathway to execute arbitrary code in the kernel space and gain persistent access.

Although a patch was released in January 2024 and the issue was added to CISA’s Known Exploited Vulnerabilities (KEV) Catalog by May 2024, researchers now confirm that it is being actively weaponized in ransomware campaigns. Security firm CrowdStrike first detected exploitation attempts in April 2024, later escalating the risk rating to “Critical” after public exploit code surfaced online.

Privilege escalation flaws such as CVE 2024 1086 are particularly valuable to ransomware operators. By obtaining root privileges, attackers can disable endpoint protections, encrypt files, delete backups, and move laterally across networks. Even a low privileged user account can become a launchpad for full system compromise, making this bug a prime catalyst for large scale ransomware incidents.

Organizations that rely on Linux for cloud workloads, enterprise servers, or operational technology should treat this vulnerability as actively exploited in the wild and assume exposure until verified otherwise. Especially at a time when security breaches of cloud systems are at their highest.

Islanders are being encouraged to reuse and recycle pumpkins after Halloween.

Guernsey Waste said a “scary amount” of waste was produced at the end of October every year.

It said the pieces of flesh removed when carving pumpkins could be used in recipes such as pumpkin lasagne, spicy pumpkin soup and autumnal pumpkin tart.

The company said the more fibrous flesh from around the seeds could be home composted or put into the food waste caddy, along with the carved pumpkin.

Waste minimisation and sustainability officer Douglas Button said islanders bought thousands of pumpkins each year to carve or for decoration.

But h said the “best – and tastiest- parts of the pumpkin” were often forgotten and ended up being thrown away.

Islanders are also being asked to think about the number of single-use plastics they consume during Halloween, from sweet wrappers to costume items.

Mr Button said decorations and costumes could be reused in following years which also helped to save money.

He added: “Through a few small steps, people can have fun at Halloween while limiting any negative impacts on the environment.

“It’s all about trying to reduce, reuse and recycle as much as we can.”

Industrial production decreased by 0.1% quarter-on-quarter in the third quarter, primarily due to reductions in output related to US tariffs. Transportation equipment and iron/steel output declined in September, likely due to the lingering effects of US tariffs. Still, the recent easing of tariff tensions in several countries should support Japan’s production rebound in the coming months. Semiconductor equipment sales rose for a second consecutive month, suggesting that strong global chip demand continued. Meanwhile, retail sales rebounded 0.3% MoM in September, but missed the market consensus of 0.8%.

Both IP and retail sales fell in Q3, indicating a GDP contraction for 3Q25. However, a rebound in September points to a gradual economic recovery in the current quarter.

The BoJ cited trade uncertainty as the reason for pausing rate hikes yesterday. However, today’s data indicates a possible economic recovery that could support future rate hikes.

Today’s data supports our view that the BoJ is likely to hike rates in December.

Following yesterday’s regional GDP data, today brings the release of Poland’s October inflation figures, as always, the first inflation print from the CEE region. Our economists expect a slight increase from 2.9% to 3.0% YoY, in line with market expectations, while core inflation should remain unchanged at 3.2% YoY. Today’s figure could decide whether the National Bank of Poland cuts rates again next week. We believe that it will take a break, but a surprise to the downside could push the decision back towards a rate cut.

Yesterday’s GDP data in the Czech Republic and Hungary confirmed our bias and more divergence in economic performance in the region. While the Czech GDP surprised up, with a growth of 2.7% YoY, the Hungarian economy surprised down by 0.6% YoY, both roughly in line with our expectations. Although the market impact was almost invisible given the strong global story, in the longer term, this is clearly a story worth following.

Next week, we will see the meeting of the Czech National Bank, which will also publish a new forecast. Although headline inflation may give the impression that the central bank may be relaxed and may return to rate cuts one day, the economic data shows that the CNB needs to be cautious as we look ahead. The economy is growing at its fastest pace since the Covid rebound, and at the same time, wages are showing upside, which will keep core inflation higher. On the other hand, the Hungarian economy has confirmed its weak performance, and we believe that the market will push more dovish bets even though the NBH remains hawkish. This should gradually start to undermine the HUF in the medium term.

For now, the strong rate reaction in the CEE region to Wednesday’s hawkish Fed should offset the impact of a stronger US dollar, and we expect EUR/HUF and EUR/CZK to stabilise at current levels, while PLN will follow inflation figures.

Chris Turner

China’s decision to impose export controls on rare earths was a “mistake” and drew attention to Beijing’s ability to use them as a coercive tool, US Treasury Secretary Scott Bessent said in an interview published Saturday.

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