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  • Red Dead Redemption 2 NPC Feature Continues To Impress Years After Launch

    Red Dead Redemption 2 is a game best known for the little details that give it character and soul.

    For many Red Dead Redemption 2 has ruined gaming as Rockstar Games’ attention to detail makes other open-world titles look simple in comparison….

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  • FIA post-Sprint press conference – 2025 United States Grand Prix

    FIA post-Sprint press conference – 2025 United States Grand Prix

    DRIVERS

    1 – Max VERSTAPPEN (Red Bull Racing), 2 – George RUSSELL (Mercedes), 3 – Carlos SAINZ (Williams)

    TRACK INTERVIEWS
    (Conducted by Jenson Button)

    Q: Max Verstappen, once again the winner of the Sprint race here in Austin. I mean, it…

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  • As Andrew gives up titles, what difference will it really make?

    As Andrew gives up titles, what difference will it really make?

    Sean CoughlanRoyal correspondent

    PA Media The Duke of York departs Westminster Abbey, London, following the Coronation of King Charles IIIPA Media

    We’re unlikely to see Prince Andrew at a royal public event now for at least six months. And then maybe only once or twice a year.

    Banned from royal Christmas celebrations at Sandringham he won’t be on the…

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  • Addressing Drug Resistance in Lung Cancer

    Addressing Drug Resistance in Lung Cancer

    Drug resistance remains one of the greatest challenges in the treatment of advanced lung cancer, particularly in patients with tumors harboring monogenic alterations. Despite significant progress in targeted therapies, resistance ultimately limits the effectiveness of treatment, underscoring the need for new strategies to overcome both intrinsic and acquired resistance mechanisms.

    At the European Society for Medical Oncology 2025 Congress in Berlin, Germany, Pasi A. Jänne, MD, senior vice president for Translational Medicine and David M. Livingston, MD chair at Dana-Farber Cancer Institute, a professor of medicine at Harvard Medical School, discussed the underlying mechanisms of resistance, how to prevent resistance, and the role of antibody drug conjugates (ADCs) in overcoming barriers to optimal treatment response.

    Understanding the Origins of Resistance

    Resistance in lung cancer arises primarily through 2 mechanisms: pre-existing resistant clones and drug tolerance states. Pre-existing clones are subpopulations of tumor cells that harbor inherent resistance mechanisms before therapy begins. In contrast, the drug tolerance state emerges when tumor cells survive initial targeted therapy, entering a reversible, persistent state. These cells maintain some sensitivity to therapy but can eventually acquire multiple resistance mechanisms over time.

    Targeted therapy resistance is highly heterogeneous. In individual patients, multiple resistance pathways may develop simultaneously, including secondary mutations, bypass signaling pathways, and histologic transformation. For example, EGFR-mutant lung cancers can develop compound mutations, downstream pathway activation, or transform into small cell or squamous histology, each representing a distinct resistance mechanism. This complexity makes designing effective treatment strategies particularly challenging.

    “”Cancer is heterogeneous, and multiple resistance mechanisms can develop simultaneously,” explained Jänne, “which makes it challenging to determine the best therapeutic strategy.”

    Preventing Resistance Through Combination Therapies and Advanced Inhibitors

    One approach to managing resistance is the development of more potent inhibitors capable of overcoming resistance to earlier-generation drugs. For instance, osimertinib (Tagrisso; AstraZeneca) was designed to inhibit EGFR T790M mutations, while lorlatinib (Lorbrena; Pfizer Inc) targets resistance mutations arising after prior-generation ALK inhibitors.

    Combination therapy also plays a critical role. Clinical studies have shown that pairing targeted inhibitors with additional agents can improve response rates and delay the emergence of resistance. In EGFR-mutant lung cancer, trials combining osimertinib with MET inhibitors—such as capmatinib (Tabrecta; Novartis Pharmaceuticals Corporation) or savolitinib (Orpathys; HUTCHMED; AstraZeneca)—demonstrated higher response rates in patients with MET amplification or high MET expression. These biomarker-driven approaches illustrate the potential of combination strategies to preemptively circumvent specific resistance pathways.

    Targeting Drug-Tolerant, Persistent Cancer

    A challenging subset of lung cancer involves drug-tolerant, persistent tumor cells. These cells survive initial targeted therapy, often displaying stem cell-like properties, slow cycling, epithelial-mesenchymal transition (EMT) characteristics, and epigenetic modulation. Local therapies, such as consolidated radiation to residual lesions, have shown potential controlling these populations. Small studies demonstrate improved progression-free survival (PFS) and overall survival (OS) when radiation is combined with ongoing targeted therapy.

    “This drug-tolerant persistent state represents a therapeutic opportunity,” said Jänne. “If we can eliminate this intermediate population [cells that survive therapy but aren’t fully resistant], we may extend the benefit of first-line targeted therapy and delay resistance.”

    Preclinical models have further illustrated the potential of targeting this drug-tolerant state. In a mouse model of EGFR-mutant lung cancer, chimeric antigen receptor (CAR) T-cell therapy cured 4 out of 10 mice with durable responses, whereas treatment with osimertinib alone or with ADCs failed to produce long-term cures. These findings suggest that novel systemic therapies, including cellular therapies, may effectively eliminate residual resistant populations and extend the duration of benefit from first-line targeted therapy.

    Addressing Acquired Resistance

    Acquired resistance occurs when tumors initially respond to therapy but later progress. The pattern of progression—whether systemic or focal—guides subsequent treatment decisions. For localized progression, clinicians may employ targeted local therapies such as radiation, while continuing systemic targeted therapy. For systemic progression, tissue biopsies, often combined with liquid biopsies, provide critical insights into the mechanisms of resistance, which can then inform tailored treatment approaches.

    For example, EGFR-mutant tumors that acquire MET amplification can respond to combination therapy with osimertinib and MET inhibitors, showing response rates up to 58% compared with 34% for chemotherapy. Similarly, resistance mechanisms involving RET or ALK rearrangements can be addressed with combination strategies targeting the specific alterations. However, the heterogeneity of resistance mechanisms in individual tumors means that a single approach rarely addresses all pathways simultaneously.

    Small Cell Transformation and Novel Therapeutics

    Another mechanism of resistance in EGFR-mutant NSCLC is transformation into small cell lung cancer (SCLC). These transformed tumors are treated according to standard SCLC protocols, typically platinum-etoposide chemotherapy. Novel approaches, including tarlatamab (Imdelltra; Amgen) and ADCs, are being evaluated for efficacy in transformed SCLC. Early evidence suggests that combining targeted therapy with chemotherapy may enhance responses in this context, and ongoing trials will clarify the role of immune checkpoint inhibitors and ADCs in these transformed tumors.

    The Role of ADCs and Broader Therapeutic Approaches

    ADCs are emerging as a promising therapeutic option in resistant lung cancers, including those with EGFR mutations. ADCs can target a broad range of resistance mechanisms independent of the specific mutation, providing a more universal approach for patients lacking identifiable targetable alterations. For example, data from trials of troponin-2 ADCs and datopotamab deruxtecan-dlnk (Datroway;_Daiichi Sankyo, Inc) show response rates of approximately 40% in EGFR-mutant lung cancer, with some durable responses. These agents offer hope for patients whose tumors exhibit complex or polyclonal resistance mechanisms.

    The Need for Biomarkers

    Despite these advances, a major limitation in treating resistant lung cancers is the lack of predictive biomarkers. Biomarkers are essential for identifying which patients are most likely to benefit from combination therapy, local interventions, ADCs, or novel cellular approaches. Ongoing research aims to discover robust markers to guide treatment decisions and maximize therapeutic benefit while minimizing unnecessary toxicity.

    “Careful biomarker-driven strategies will be key to tailoring treatments and improving patient outcomes in resistant lung cancers,” Jänne said.

    Conclusion

    Drug resistance remains a formidable challenge in advanced lung cancer, but evolving strategies offer new hope. By understanding the origins of resistance—from pre-existing clones to drug-tolerant persistent states—clinicians can better tailor therapy to individual patients. Combination therapies, local interventions, ADCs, and CAR T cells all provide promising avenues to overcome resistance, while ongoing research into biomarkers will be crucial for guiding these approaches.

    REFERENCES
    Wolf J, Jänne P, Leighl N. Targeting oncogenes in NSCLC. Presented at: European Society for Medical Oncology 2025 Congress. October 17, 2025, to October 21, 2025. Berlin, Germany.

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  • Exclusive: US returning Caribbean strike survivors to Colombia and Ecuador, Trump says – Reuters

    1. Exclusive: US returning Caribbean strike survivors to Colombia and Ecuador, Trump says  Reuters
    2. Trump confirms ‘submarine’ attack in Caribbean, amid reports of survivors  Al Jazeera
    3. A war on drugs or a war on terror? Trump’s military pressure…

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  • New study sheds light on why GLP-1s could mitigate alcohol abuse

    New study sheds light on why GLP-1s could mitigate alcohol abuse

    Back in May, a study was published suggesting that popular weight-loss drugs such as Ozempic and Wegovy could curb alcohol cravings by as much as 70%. At the time, researchers weren’t entirely sure why the GLP-1s had such a profound effect on…

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  • Israel returns 15 Palestinian bodies to Gaza: health ministry

    Israel returns 15 Palestinian bodies to Gaza: health ministry



    Ghada Musbeh holds her phone showing a photo of her husband, trying to identify him among…

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  • Max Verstappen targets improved race trim for United States GP to fend off unknown pace of McLaren

    Max Verstappen targets improved race trim for United States GP to fend off unknown pace of McLaren

    Max Verstappen has targeted improvements for Sunday’s United States Grand Prix, to ward off the unknown of McLaren’s race pace, despite controlling Saturday’s Sprint as he claimed another victory.

    Verstappen closed to within 55 points of the…

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  • Perioperative Enfortumab Vedotin Plus Pembrolizumab May Represent New SOC in Cisplatin-Ineligible MIBC

    Perioperative Enfortumab Vedotin Plus Pembrolizumab May Represent New SOC in Cisplatin-Ineligible MIBC

    Perioperative enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) with radical cystectomy and standard pelvic lymph node dissection (RC + PLND) significantly improved event-free survival (EFS), overall survival (OS), and pathologic complete response (pCR) rate vs RC + PLND followed by observation alone in patients with muscle-invasive bladder cancer (MIBC) who were not eligible for or refused cisplatin-based chemotherapy, according to data from the phase 3 KEYNOTE-905 study (NCT03924895).1

    The data, which were shared during the 2025 ESMO Congress as part of a late-breaking session, showed that enfortumab vedotin plus pembrolizumab (n = 170) led to a median EFS that was not reached (NR; 95% CI, 37.3-NR) vs 15.7 months (95% CI, 10.3-20.5) with the control (n = 174; HR, 0.40; 95% CI, 0.28-0.57; 1-sided P < .0001). The 12-month EFS rates in the respective arms were 77.8% and 55.1%; the 24-month rates were 74.7% and 39.4%.

    Top Takeaways from KEYNOTE-905:

    • Perioperative enfortumab vedotin plus pembrolizumab plus RC + PLND significantly improved EFS (HR, 0.40), OS (HR, 0.50), and pCR (57.1% vs 8.6%) vs RC + PLND alone in cisplatin-ineligible or -refusing patients with MIBC.
    • Consistent benefit with the addition of enfortumab vedotin plus pembrolizumab to RC + PLND was seen across subgroups: Improvements in EFS and OS were observed regardless of age, ECOG performance status, PD-L1 expression, or tumor stage, supporting broad applicability across patient subsets.
    • AEs were consistent with known toxicities of enfortumab vedotin and pembrolizumab, with no new safety signals identified.
    • The combination could represent a new standard of care in this high-need population.

    Moreover, the median OS with enfortumab vedotin plus pembrolizumab was also NR (95% CI, NR-NR) vs 41.7 months (95% CI, 31.8-NR) with the control (HR, 0.50; 95% CI, 0.33-0.74; 1-sided P = .0002). The 12- and 24-month OS rates in the enfortumab arm were 86.3% and 79.7%, respectively; in the control arm, these rates were 75.7% and 63.1%. The pCR rate with enfortumab plus pembrolizumab was 57.1% (95% CI, 49.3%-64.6%) vs 8.6% (95% CI, 4.9%-13.8%) with the control, translating to an estimated difference of 48.3% (95% CI, 39.5%-56.5%) between arms (1-sided P < .000001).

    “KEYNOTE-905 is the first phase 3 study to show improved efficacy outcomes with perioperative therapy relative to surgery for patients with MIBC who are ineligible for cisplatin-based chemotherapy,” Christof Vulsteke, MD, PhD, of the Integrated Cancer Center Ghent, AZ Maria Middelares, in Belgium, and the Center for Oncological Research at Antwerp University in Belgium, said in a presentation. “Perioperative enfortumab vedotin plus pembrolizumab added to RC + PLND may represent a new standard of care in this population with high unmet clinical need.”

    Topline data from KEYNOTE-905 were previously announced in August 2025.2

    What Did the KEYNOTE-905 Study Evaluate?

    The trial enrolled adult patients with MIBC who had an ECOG performance status ranging from 0 to 2, clinical stage T2 to T4aN0M0 or T1 to T4aN1M0 disease by central assessment, and at least 50% urothelial histology.1 Patients were either ineligible to receive cisplatin per Galsky criteria, or they had refused it.

    Patients (n = 344) were randomly assigned 1:1 to receive pembrolizumab at 200 mg every 3 weeks (Q3W) for 3 cycles with enfortumab vedotin at 1.25 mg/kg on days 1 and 8 Q3W, then RC + PLND followed by adjuvant pembrolizumab at 200 mg Q3W for 14 cycles plus enfortumab vedotin at 1.25 mg/kg on days 1 and 8 Q3W (n = 170) or RC + PLND followed by observation (n = 174). They were stratified based on cisplatin ineligibility (ineligible vs eligible but declining), clinical stage (T2N0 vs T3/T4aN0 vs T1 to 4aN1), and region (United States vs European Union vs most of world).

    The primary end point of the study was EFS by blinded independent central review, and key secondary end points were OS and pCR by central pathologist review. Investigators also evaluated safety and EFS by pCR status.

    In 2019, the study launched with 2 treatment arms, where patients were randomly assigned 1:1 to receive perioperative pembrolizumab with RC + PLND vs RC + PLND alone. A year later, in 2020, the third treatment arm, perioperative enfortumab vedotin plus pembrolizumab with RC + PLND, was added; patients were then randomly assigned 1:1:1 between the 3 arms. In 2022, investigators expanded the inclusion criteria to include patients who were eligible for cisplatin but refused cisplatin-based treatment. In the same year, they stopped randomly assigning patients to receive pembrolizumab plus RC + PLND and updated the trial enrollment to a 1:1 randomization for the enfortumab vedotin and control arms. They allowed patients in the control arm to receive adjuvant nivolumab (Opdivo) when indicated and available.

    The efficacy of enfortumab vedotin plus pembrolizumab and RC + PLND was compared with the control and evaluated in all concurrently randomly assigned patients; these patients comprised the intention-to-treat (ITT) population. Investigators evaluated safety in all patients who had received at least 1 dose of treatment, including surgery. KEYNOTE-905 will continue to examine additional hypotheses for the perioperative pembrolizumab arm, Vulsteke said.

    What Were the Baseline Characteristics of Patients Enrolled to KEYNOTE-905?

    The median patient age was 74.0 years (range, 47-87) in the enfortumab vedotin arm vs 72.5 years (range, 46-87) in the control arm. Most patients were male (80.6% vs 75.3%), had an ECOG performance status of 0 (60.0% vs 54.6%), and were from the European Union (45.9% vs 44.3%) or most of the world (41.8% vs 42.5%). The majority of patients were not eligible for cisplatin (83.5% vs 79.9%), although 16.5% vs 20.1% of patients were eligible but refused cisplatin-based treatment. In the enfortumab vedotin arm, 17.6% of patients had T2N0 (17.6%), T3/T4aN0 (78.2%), and T1 to 4aN1 (4.1%) disease; in the control arm, these rates were 18.4%, 75.9%, and 5.7%, respectively.

    What Additional Data From KEYNOTE-905 Are Important to Know?

    In the enfortumab vedotin arm, 167 patients started neoadjuvant treatment, and 144 patients completed it; 149 patients underwent surgery, and 147 patients had complete resection. Those who did not undergo surgery did not because of withdrawal from the trial (n = 10), toxicity (n = 7), disease progression (n = 3), or physician decision (n = 1). A total of 100 patients began the adjuvant phase. In the control arm, 156 patients underwent surgery, and 149 patients had complete resection. In the 18 patients who did not undergo surgery, reasons included withdrawal (n = 13), adverse effect (AE; n = 3), loss to follow-up (n = 1), and physician decision (n = 1).

    The median follow-up from randomization to the data cutoff date of June 6, 2025, was 25.6 months (range, 11.8-53.7).

    “PFS benefit was consistent across subgroups, including age, ECOG performance status, PD-L1 [expression,] and tumor stage,” Vulsteke said. “The OS benefit was [also] consistent across the subgroups, including age, ECOG performance status, and PD-L1 [expression].”

    An exploratory analysis of EFS by pCR status was conducted in the ITT population. In those who received enfortumab vedotin plus pembrolizumab and achieved a pCR (n = 97), the median EFS was NR (95% CI, NR-NR) vs 41.2 months (95% CI, 12.7-NR) in those in the control arm who achieved pCR (n = 15; HR, 0.43; 95% CI, 0.16-1.16). In those in the enfortumab vedotin arm who did not achieve a pCR (n = 73), the median EFS was 26.1 months (95% CI, 10.1-41.2) vs 14.2 months (95% CI, 10.1-19.5) for those in the control arm who did not have a pCR (n = 159; HR, 0.76; 95% CI, 0.51-1.14).

    “EFS benefits [were seen with] enfortumab vedotin plus pembrolizumab, irrespective of pCR,” he noted. “But when we look at the pCR, it’s a bad prognostic factor, but also the patients with a pCR in the control arm seem at risk and stay as a high unmet medical need.”

    What Was the Safety Profile of Enfortumab Vedotin Plus Pembrolizumab in KEYNOTE-905?

    Any-grade treatment-emergent AEs (TEAEs) occurred in all safety-evaluable patients in the enfortumab vedotin arm (n = 167) and 64.8% of those in the control arm (n = 159); these TEAEs were grade 3 or higher for 71.3% and 45.9% of patients, respectively. Serious TEAEs occurred in 58.1% of those in the enfortumab vedotin arm and 40.9% of those in the control arm. AEs led to surgery delay for 4.0% of patients in the enfortumab vedotin arm and 0.6% of those in the control arm. Toxicities led to dose reduction or discontinuation of enfortumab vedotin for 16.8% and 41.3% of patients; they led to discontinuation of pembrolizumab for 34.1% of patients; and they proved fatal for 7.8% of those in the enfortumab vedotin arm and 5.7% of those in the control arm.

    The most common TEAEs experienced in all phases of treatment with enfortumab vedotin plus pembrolizumab included pruritus (47.3%), alopecia (34.7%), diarrhea (34.1%), fatigue (32.3%), anemia (30.5%), decreased appetite (28.1%), dysgeusia (28.1%), constipation (27.5%), nausea (25.7%), rash (25.1%), increased aspartate aminotransferase level (24.0%), urinary tract infection (24.0%), weight decrease (19.8%), increased alanine aminotransferase level (19.2%), asthenia (17.4%), maculopapular rash (16.2%), and dry skin (15.0%). During the surgery phase, the most common TEAEs experienced in the enfortumab vedotin arm were anemia (13.7%), prostate cancer (11.6%), and urinary tract infection (8.9%).

    Enfortumab vedotin–related AEs of special interest included skin reactions (57.5%), peripheral neuropathy (36.5%), ocular disorders (17.4%), hyperglycemia (9.6%), and infusion-related reactions (1.2%). AEs of special interest associated with pembrolizumab included hypothyroidism (14.4%), severe skin reactions (13.8%), hyperthyroidism (4.8%), pneumonitis (3.6%), hepatitis (3.6%), thyroiditis (3.0%), colitis (2.4%), gastritis (2.4%), nephritis (2.4%), adrenal insufficiency (0.6%), myasthenic syndrome (0.6%), myocarditis (0.6%), and myositis (0.6%).

    “The safety profile of perioperative enfortumab vedotin plus pembrolizumab was manageable and consistent with prior reports of this regimen in the locally advanced or metastatic urothelial carcinoma setting,” Vulsteke concluded. “No new safety signals were observed.”

    Disclosures: Vulsteke disclosed receipt of research funding and medical writing support from Merck Sharp & Dohme LLC for the present work. He serves on the advisory board for MSD, Janssens-Cilag, GSK, Astellas Pharma, BMS, Leo Pharma, Bayer, AstraZeneca, Pfizer, Merck, and Atheneum Partners. Research grant to the institution was provided by MSD.

    References

    1. Vulsteke C, Kaimakliotis HZ, Danchaivijitr P, et al. Perioperative enfortumab vedotin plus pembrolizumab in participants with muscle-invasive bladder cancer who are cisplatin-ineligible: phase 3 KEYNOTE-905 study. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA2.
    2. Keytruda (pembrolizumab) plus Padcev (enfortumab vedotin-ejfv) significantly improved event-free and overall survival and pathologic complete response rate for certain patients with muscle-invasive bladder cancer when given before and after surgery. News release. Merck. August 12, 2025. Accessed October 18, 2025. https://www.merck.com/news/keytruda-pembrolizumab-plus-padcev-enfortumab-vedotin-ejfv-significantly-improved-event-free-and-overall-survival-and-pathologic-complete-response-rate-for-certain-patients-with-muscle/

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  • Arrow Electronics says that US trade curbs on its Chinese affiliates are being reversed – Reuters

    1. Arrow Electronics says that US trade curbs on its Chinese affiliates are being reversed  Reuters
    2. What Makes Arrow Electronics (ARW) a New Strong Buy Stock  Yahoo Finance
    3. Chip Firm Arrow Says Its Units To Be Removed from US Blacklist  Bloomberg.com
    4. Is Arrow Electronics Stock a Bargain After Recent 12% Slide in 2025?  Yahoo Finance

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