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

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

    By Karen Freifeld

    (Reuters) -U.S.-based electronic components distributor Arrow Electronics said on Saturday the U.S. government was reversing trade restrictions placed on Arrow’s China-based affiliates for facilitating the sale of U.S. components found in weaponized drones used by Iran-backed groups like the Houthis.

    Arrow (China) Electronics Trading Co and another Arrow entity with six aliases in Hong Kong were added to the Commerce Department’s Entity List on October 8 in a Federal Register posting.

    Licenses are required to export goods and technology to companies on the list and are likely to be denied. Firms are placed on the list over U.S. national security or foreign policy interests.

    On October 8, Commerce said that drones operated by Iran-backed groups and their debris recovered in the Middle East since 2017 had U.S. components traced to sales tied to these Arrow-related entities.

    Arrow said on Saturday the Commerce Department told it the department would soon publish the reversal in the U.S. Federal Register and sent a letter Friday removing the restrictions in the meantime.

    “We have received official communication from the U.S. Commerce Department,” Arrow spokesman John Hourigan said in an email. “Arrow is authorized to resume shipping to and from these entities under the same conditions that applied prior to October 8.”

    Asked about the matter, a spokesperson for the U.S. Department of Commerce’s Bureau of Industry and Security said in an email: “BIS is committed to ensuring that export restrictions are appropriately targeted to protect national security.”

    Hourigan said the company operates in compliance with all laws and regulations. Centennial, Colorado-based Arrow Electronics had global 2024 sales of $28 billion.

    Hourigan said that Arrow Electronics (Hong Kong) Co. Ltd, which he described as a subsidiary when it was added to the Entity List, was not actually affiliated with Arrow Electronics.

    However, the six aliases tied to the Hong Kong company in the Federal Register posting are affiliated with Arrow and, the company said, would be removed from the Entity List.

    (Reporting by Karen Freifeld; Editing by Cynthia Osterman)

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  • Is TSMC Still a Bargain After 46% Rally and Soaring AI Chip Demand in 2025?

    Is TSMC Still a Bargain After 46% Rally and Soaring AI Chip Demand in 2025?

    Feeling hesitant about Taiwan Semiconductor Manufacturing stock? You are not alone. With its meteoric rise of 46.4% year-to-date and an astonishing 381.3% return over the last three years, it is only natural to wonder whether it is the moment to buy in, hold tight, or take some profits off the table. Over just the past week, the stock notched up another 5.1%, and in the past month alone, it surged 12.3%. Long-term investors have been handsomely rewarded, as a 257.2% gain in the last five years shows. These impressive moves are not just random luck, either.

    TSMC’s performance seems closely tied to rising optimism across global semiconductor markets. With surging demand for advanced chips and recent headlines about supply chain investment, investors appear convinced that the company remains at the center of technological innovation. This has reshaped risk perceptions and fueled buying enthusiasm, making the price climb seem more than justified in the eyes of some market watchers.

    Still, growth is only one piece of the puzzle. If you are weighing the next step, valuation is key. On a 6-point scorecard measuring undervaluation across several financial checks, TSMC lands a score of 3. So, by about half the usual measures, the stock still looks undervalued despite its run. The trick is understanding which approaches tell the real story. There is a smarter way to judge TSMC’s true value that we will get to by the end of this article. But first, let’s dig into the major valuation methods one by one.

    Taiwan Semiconductor Manufacturing delivered 48.6% returns over the last year. See how this stacks up to the rest of the Semiconductor industry.

    The Discounted Cash Flow (DCF) model estimates a company’s true worth by projecting its future free cash flows and then discounting those back to today’s values. This approach aims to capture the business’s underlying earning power, regardless of day-to-day stock price swings.

    For Taiwan Semiconductor Manufacturing, the latest trailing twelve months Free Cash Flow stands at approximately NT$804.8 Billion. Analysts provide detailed projections for the next five years, anticipating significant annual growth in free cash flows. For example, estimates suggest Free Cash Flow could rise to around NT$2,774.8 Billion in 2029, with further growth extrapolated beyond that point. These figures are all quoted in New Taiwan Dollars (NT$), reflecting the company’s reporting currency.

    Based on the 2 Stage Free Cash Flow to Equity model, the estimated intrinsic value for TSMC’s shares is NT$291.97. Compared to the current share price, the implied intrinsic discount indicates the stock is about 1.1% overvalued. This puts it very close to fair value using today’s long-term cash flow outlook.

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  • Neoadjuvant T-DXd Plus THP Yields pCR Benefit in High-Risk, HER2+ Early Breast Cancer

    Neoadjuvant T-DXd Plus THP Yields pCR Benefit in High-Risk, HER2+ Early Breast Cancer

    Neoadjuvant treatment with fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) followed by paclitaxel, trastuzumab (Herceptin), and pertuzumab (Perjeta; THP) led to an improvement in pathologic complete response (pCR) rate compared with dose-dense doxorubicin and cyclophosphamide plus THP (ddAC-THP) in patients with high-risk, HER2-positive early breast cancer, according to data from the phase 3 DESTINY-Breast11 trial (NCT05113251).1

    Findings presented at the 2025 ESMO Congress demonstrated that patients treated with T-DXd followed by THP (n = 321) experienced a pCR rate of 67.3% compared with 56.3% for those given ddAC-THP (n = 320; difference, 11.2%; 95% CI, 4.0%-18.3%; P = .003). Notably, the pCR benefit was observed in the hormone receptor–positive population, where the pCR rate was 61.4% in the T-DXd arm (n = 236) vs 52.3% in the ddAC-THP arm (n = 235; difference, 9.1%; 95% CI, 0.2%-17.9%), as well as the hormone receptor–negative population, where the respective pCR rates for the T-DXd arm (n = 83) and ddAC-THP arm (n = 85) were 83.1% and 67.1% (difference, 16.1%; 95% CI, 3.0%-28.8%).

    “DESTINY-Breast11 showed the highest reported pCR rate in HER2-positive early breast cancer for a registrational study in the neoadjuvant setting, despite—if you want to do cross-trial comparisons—a high prevalence of hormone receptor–positive disease and a high-risk population,” lead study author Nadia Harbeck, MD, PhD, said in a presentation of the data.

    DestinyBreast-11 Highlights

    • Neoadjuvant T-DXd followed by THP generated a pCR benefit vs ddAC-THP in patients with high-risk, HER2-positive early breast cancer, with the experimental regimen generating an 11.2% pCR rate improvement.
    • The FDA is reviewing a supplemental biologics license application seeking the approval of neoadjuvant T-DXd plus THP in this patient population.
    • The T-DXd monotherapy arm in DESTINY-Breast11 was closed early following a recommendation from the trial’s independent data monitoring committee.

    Harbeck is director of the Breast Center and chair for Conservative Oncology at the Department of OB&GYN at LMU University Hospital in Munich, Germany.

    How Was the DESTINY-Breast11 Trial Designed?

    Harbeck noted that current neoadjuvant standard-of-care (SOC) regimens for HER2-positive early breast cancer have remained unchanged for more than a decade. As such, investigators sought to evaluate T-DXd–based treatment in this population with the goal of improving efficacy and safety vs the current SOC.

    The randomized, global, multicenter, open-label study enrolled patients with previously untreated HER2-positive early breast cancer who had high-risk disease, defined as ≥cT3 and N0-3 or cT0-4 and N1-3; or inflammatory breast cancer. Patients were allowed to enroll, irrespective of hormone receptor status.

    Patients were randomly assigned in a 1:1:1 fashion to receive T-DXd followed by THP; ddAC-THP; or T-DXd alone, followed by surgery in all arms. In the first arm, patients received 4 cycles of T-DXd followed by 4 cycles of THP. In the second, ddAC was administered for 4 cycles, followed by 4 cycles of THP. In the final arm, patients received T-DXd alone for 8 cycles.

    Notably, the T-DXd monotherapy arm was closed in March 2024, following a recommendation from the study’s independent data monitoring committee.

    After surgery, study protocols called for the following treatments, irrespective of arm:

    • pCR: radiotherapy and concomitant trastuzumab with or without pertuzumab for up to 1 year
    • Non-pCR: radiotherapy and ado-trastuzumab emtansine (Kadcyla) for up to 14 cycles
    • Hormone receptor–positive disease: endocrine therapy

    The study’s primary end point was pCR rate (ypT0/Tis ypN0) per blinded independent central review (BICR) assessment. Secondary end points included BICR-assessed pCR rate (ypT0 ypN0), event-free survival (EFS), safety, pharmacokinetics, invasive disease-free survival, overall survival, and health-related quality of life. Residual cancer burden (RCB) was an additional outcome measured during the study.

    At data cutoff, 16.9% of patients in the T-DXd plus THP arm discontinued a study drug, including T-DXd (2.8%), paclitaxel (14.4%), trastuzumab (2.2%), and pertuzumab (2.2%); 97.2% of patients in this arm proceeded to surgery. In the ddAC-THP arm, 13.8% of patients had discontinued any study treatment, including AC (2.9%), paclitaxel (12.0%), trastuzumab (3.0%), and pertuzumab (3.7%); 93.8% of patients in this arm underwent surgery. In the T-DXd monotherapy arm (n = 286), 18.4% of patients discontinued study treatment, and 95.8% underwent surgery.

    Regarding post-neoadjuvant treatments, 99.1% of evaluable patients in the T-DXd arm who achieved a pCR (n = 226) underwent any adjuvant therapy, comprising any cytotoxic chemotherapy regimen (5.8%), any T-DM1–containing regimen (1.8%), and any trastuzumab-containing regimen (94.2%). In the ddAC-THP, 98.4% of patients who achieved a pCR (n = 190) underwent any adjuvant therapy, including any cytotoxic chemotherapy regimen (5.8%), any T-DM1–containing regimen (2.1%), and any trastuzumab-containing regimen (91.6%).

    For patients who did not achieve a pCR, any adjuvant therapy was administered to 89.5% of patients in the T-DXd plus THP arm (n = 95) and 82.3% of patients in the ddAC-THP arm (n = 130). In the experimental group, adjuvant therapies included any cytotoxic chemotherapy regimen (10.5%), any T-DM1–containing regimen (52.6%), and any trastuzumab-containing regimen (38.9%). These respective rates were 9.2%, 56.9%, and 26.2% in the control group.

    In the T-DXd plus THP and ddAC-THP arms, the median age was 50 years (range, 25-82) and 50 years (range, 23-79), respectively. All patients in both arms were female. The highest proportion of patients in each arm was from Asia (T-DXd plus THP, 47.4%; ddAC-THP, 47.5%) and were Asian (49.8%; 49.1%). Most patients had an ECOG performance status of 0 (86.6%; 87.5%), had immunohistochemistry 3+ HER2-positive disease (87.2%; 88.4%), had cT0-2 tumors (54.8%; 58.8%), and had positive lymph nodes (89.4%; 87.8%).

    What Were the Other Efficacy Outcomes for T-DXd Plus THP vs ddAC-THP?

    Findings also showed that 81.3% of patients in the T-DXd plus THP arm had no RCB (RCB-0) or minimal RCB (RCB-1) in resected breast or lymph node tissue compared with 69.1% in the ddAC-THP arm (difference, 12.2%). In the hormone receptor–positive population, the RCB-0 plus RCB-1 rates were 78.0% for T-DXd plus THP vs 64.7% for ddAC-THP; these respective rates were 90.4% and 81.2% in the hormone receptor–negative population.

    Investigators also reported an EFS trend favoring T-DXd plus THP, with data at 4.5% maturity (HR, 0.56; 95% CI, 0.26-1.17). Maturity for the data cutoff of the trial’s final analysis is predicted at approximately 10%. The 24-month EFS rates were 96.9% (95% CI, 93.5%-98.6%) in the T-DXd plus THP arm vs 93.1% (95% CI, 88.7%-95.8%) in the ddAC-THP arm.

    What Is the Safety Profile of T-DXd Plus THP?

    Any-grade adverse effects (AEs) occurred in 98.1% of patients in the T-DXd plus THP arm compared with 98.7% of patients in the ddAC-THP arm. The respective rates of grade 3 or higher AEs were 37.5% and 55.8%. Any-grade serious AEs were reported in 10.6% and 20.2% of patients, respectively.

    In the T-DXd plus THP arm, AEs led to dose any dose reduction, any drug interruption, and any treatment discontinuation in 18.1%, 37.8%, and 14.1% of patients, respectively. In the ddAC-THP group, these rates were 19.2%, 54.5%, and 9.9%, respectively. AEs led to death in 0.6% of patients in both arms. AEs led to delays in surgery in 3.4% of patients in the experimental arm vs 2.6% of patients in the control arm.

    Regarding AEs of special interest, any-grade drug-related adjudicated interstitial lung disease (ILD) was 4.4% in the T-DXd plus THP arm vs 5.1% in the ddAC-THP arm. The rates of grade 3 or higher ILD were 0.6% and 1.9%, respectively. Grade 5 ILD occurred in 1 patient (0.3%) in both groups. Any-grade left ventricular dysfunction occurred in 1.3% of patients in the experimental arm vs 6.1% of patients in the control arm. The rates of grade 3 or higher left ventricular dysfunction were 0.3% and 1.9%, respectively, although no grade 5 events were reported in either group.

    Any-grade treatment-emergent AEs reported in at least 20% of patients in either arm included nausea (T-DXd plus THP, 64.7%; ddAC-THP, 51.6%), diarrhea (58.8%; 54.2%), alopecia (47.5%; 49.0%), fatigue (41.3%; 54.8%), increased transaminase levels (34.4%; 33.7%), neutropenia (29.1%; 44.2%), constipation (29.1%; 24.4%), vomiting (28.8%; 21.2%), peripheral neuropathy (25.9%; 20.8%), anemia (22.8%; 49.7%), stomatitis (18.4%; 27.9%), and leukopenia (17.2%; 23.4%).

    What Data Were Reported for T-DXd Monotherapy in HER2+ Early Breast Cancer?

    When the T-DXd monotherapy arm, patients were allowed to remain on therapy or immediately switch to local SOC. If patients switched therapy, they were classified as having a non-pCR.

    Findings from the monotherapy arm showed that patients (n = 286) achieved a pCR rate of 43.0% at the primary analysis and 51.4% at a prespecified supplementary analysis. EFS data were similar between T-DXd monotherapy and ddAC-THP (HR, 0.82; 95% CI, 0.41-1.62), and the 24-month EFS rate in the T-DXd monotherapy group was 94.4% (95% CI, 90.5%-98.7%).

    Regarding safety, 97.5% of patients treated with T-DXd alone (n = 283) experienced any-grade AEs, 22.6% had grade 3 or higher AEs, and 10.2% had any-grade serious AEs. AEs led to dose reduction, drug interruption, and treatment discontinuation in 6.7%, 18.0%, and 7.8% of patients, respectively. One patient (0.4%) experienced an AE that led to death. AEs led to surgical delay in 6.4% of patients.

    The rate of any-grade, drug-related adjudicated ILD was 4.9% in the T-DXd monotherapy arm, although all instances were grade 1 or 2. Left ventricular dysfunction occurred in 0.7% of patients, all at grade 1 or 2.

    What’s Next for T-DXd Plus THP?

    Based on data from DESTINY-Breast11, the FDA accepted a supplemental biologics license application seeking the approval of neoadjuvant T-DXd followed THP for the treatment of adult patients with high-risk, HER2-positive (IHC 3+ or in situ hybridization–positive), stage II/III breast cancer.2

    The FDA has assigned a target action date of May 18, 2026, under the Prescription Drug User Fee Act.

    “DESTINY-Breast11 results support T-DXd [plus] THP as a more effective and less toxic neoadjuvant treatment compared with ddAC-THP, and it may become the preferred regimen for patients with high-risk, HER2-positive early breast cancer,” Harbeck concluded in her presentation.1

    Disclosures: Harbeck reported receiving honoraria from AstraZeneca, Daiichi Sankyo, Gilead, Lilly, Menarini Stemline, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Viatris, and Zuellig Pharma; serving as a consultant or advisor for Exact Sciences, Gilead, Pfizer, Roche, and Sandoz; having an institutional site contract with AstraZeneca; serving as a data safety monitoring board or advisory board member for Gilead, IQVIA, and Roche; and having ownership interested in the West German Study Group.

    References

    1. Harbeck N, Modi S, Pusztai L, et al. DESTINY-Breast11: neoadjuvant trastuzumab deruxtecan alone (T-DXd) or followed by paclitaxel + trastuzumab + pertuzumab (T-DXd-THP) vs SOC for high-risk HER2+ early breast cancer (eBC). Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract 291O.
    2. Enhertu followed by THP supplemental biologics license application accepted in the U.S. for patients with high-risk HER2 positive early-stage breast cancer prior to surgery. News release. Daiichi Sankyo. October 1, 2025. Accessed October 18, 2025. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202510/20251001_E.pdf

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  • Is silver the new gold? Prices surge as demand outpaces supply – NPR

    Is silver the new gold? Prices surge as demand outpaces supply – NPR

    1. Is silver the new gold? Prices surge as demand outpaces supply  NPR
    2. Dhanteras 2025: How much will gold & silver prices rise by Dhanteras next year & should you buy this Diwa  Times of India
    3. Gold hits US$4,000/oz – trend or turning point?  World Gold Council
    4. Sold Out in India, Panic in London: How the Silver Market Broke  Bloomberg.com
    5. Silver’s Secret Surge: The Forces Behind the Precious Metal’s Unseen Ascent  kurdistan24.net

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  • From Mutation to Medicine: Targeted Therapies in Lung Cancer

    From Mutation to Medicine: Targeted Therapies in Lung Cancer

    Decades of clinical research has led to the discovery of key biomarkers, development of novel agents, and the subsequent improvement in patient survival outcomes.

    At the European Society for Medical Oncology 2025 Congress, Jürgen Wolf, MD, medical director at the Center for Integrated Oncology, and chair of the Lung Cancer Program at Center for Integrated Oncology at the University Hospital of Cologne, shared key updates in non-small cell lung cancer (NSCLC) treatment. He discussed novel drugs and emphasized the crucial role of molecular diagnostics in guiding treatment decisions to ensure every patient receives the right therapy at the right time.

    Lung cancer represents the second most common cancer in the United States, with over 260,000 new cases in 2025. NSCLC is the most prevalent type of lung cancer, representing roughly 80% to 85% of cases. Pivotal advancements in drug development have significantly improved survival rates for patients over the past 40 years—12.4% in the mid-1970s to 26.7% by 2020. Various investigational and FDA approved agents are responsible—from tyrosine kinase inhibitors (TKIs) to other targeted therapies.1-3

    However, mutations present continued obstacles to optimal outcomes. In NSCLC, there are various mutations not limited to EGFR, ALK fusion, ROS1, BRAF V600E, HER2, and KRAS. Wolf discussed the benefit of molecular diagnostic testing even prior to initiation of therapy for NSCLC. Liquid biopsy has a high specificity but limited sensitivity. He establishes tissue biopsy as the continuing gold standard for molecular diagnostics.4

    “Molecular diagnostics remains the foundation of personalized care in [NSCLC],” Wolf said. “Comprehensive testing before first line therapy should include all guideline recommended markers. RNA next-generation sequencing is essential for sensitive fusion detection.”4

    EGFR

    EGFR mutations are the most common in NSCLC—representing 10% to 15% of lung adenocarcinomas. It is more prevalent and in nonsmokers, women, and Asian populations, with exon 19 deletion and exon 21 L858R being the most frequent mutations. In the adjuvant setting following surgery, osimertinib (Tagrisso; AstraZeneca), a TKI, is the standard of care with proven overall survival (OS) benefit in resected early-stage NSCLC.4,5

    Osimertinib’s successfully secured multiple FDA approvals, supported by data showing its efficacy in adjuvant and neoadjuvant settings. The first approval was supported by data from the randomized, double-blind, placebo-controlled ADAURA trial (NCT02511106). Four years later, the FDA granted osimertinib another approval in the adjuvant setting supported by data from the double blind, randomized, placebo-controlled LAURA trial (NCT03521154).6-9

    Wolf highlights the FLAURA-2 and MARIPOSA trials (NCT04035486; NCT04487080), which is exploring osimertinib as a monotherapy. Both trials had a primary end point of progression-free survival (PFS) and OS and showed osimertinib’s superiority over other available TKIs. OS was favorable and similar between both trials at 60% vs 51% (for combination vs monotherapy) in MARIPOSA and 63% vs 51% (for combination vs monotherapy) in FLAURA-2. The researchers report an approximate 10 to 12 months improvement with a hazard ratio of 0.75 for both trials.4,10,11

    Compared with combination therapies, osimertinib as a monotherapy was associated with less toxicity. Combination therapies yielded more severe adverse events (AEs) and higher rates of treatment interruption. Patients in FLAURA-2 experienced chemotherapy-associated side effects, while MARIPOSA patients had painful infusion reactions such as rash and pulmonary embolism.4

    “However, this improved efficacy comes at the cost… combination therapies are significantly more toxic than monotherapy,” explained Wolf. “But I think it’s fair enough to say that toxicity management has improved substantially with prophylactic skincare, subcutaneous formulation and anti-coagulation. Nevertheless, they remain challenging in clinical routine.”4

    However, osimertinib shows additional efficacy across as a neoadjuvant treatment. Wolf highlights the NEOADURA trial (NCT04351555), a randomized phase 2 trial comparing osimertinib to placebo. The primary end point was major pathological response, which showed a clear advantage for osimertinib.4,12

    “I think this is really an attractive option for these patients, and should be considered and discussed in the tumor growth.”4

    ALK Fusion

    ALK fusions are detected in approximately 1% to 4% of lung cancers, most often in adenocarcinomas. These alterations tend to occur in younger patients and those with minimal smoking history. Alectinib (Alecensa; Genentech) is the current standard-of-care therapy for ALK-positive NSCLC and received FDA approval in 2024 for adjuvant use following tumor resection.2,4

    Wolf highlights other approved agents in this setting including lorlatinib (Lorbrena; Pfizer Inc) and crizotinib (Xalkori; Pfizer), which were compared head-to-head in the CROWN trial (NCT03052608).4,13

    “Lorlatinib has been tested in a phase 3 study against crizotinib, which has already shown progression-free survival benefits in use,” said Wolf, “and it’s a better drug—65% versus around 40% with the second-generation inhibitors.”4

    CROWN results showed a 5-year PFS of 60% in lorlatinib with favorable brain activity. In patients without initial brain metastases, the data showed a hazard ratio of 0.05 for central nervous system progression.Permanent discontinuation rates were 11% vs 7%.4

    “However, there are still a lot of reservations against this drug, and this is based on new side effects, such as hydrochlorist weight gain and, in particular, neurologic AEs,” Wolf explained. “There were also some reservations from patients about stem cell use, but when we look at the permanent discontinuation rates from the trial—11% versus 7%—it’s not necessarily more toxic. There’s a learning curve involved.”4

    ROS1

    ROS1 rearrangements account for 1% to 2% of NSCLC cases with an estimated 10,000 to 15,000 new cases every year around the world. Although relatively uncommon in comparison to other mutations. Patients with ROS1 mutations are younger with a history of light smoking; however, some diagnosed patients have no history of smoking.14

    ROS1 mutated lung cancers exhibit clinical similarities to ALK-rearranged NSCLC, though ROS1, EGFR, and ALK rearrangements are generally mutually exclusive. After exposure to TKIs, a subset of ROS1-positive tumors acquires secondary driver mutations, predominantly in KRAS or EGFR.4

    “For ROS1 fusions, we have active TKIs approved in the first line—entrectinib (Rozlytrek; Genentech), crizotinib, and epotrectinib (Augtyro; Bristol Myers Squibb)—entering for resistant fusions,” said Wolf. “In this field, we already have a next-generation agent approved now after TKI failure.”4

    HER2

    HER2 mutations are seen across cancer types. In lung cancer, they are rarer than ROS1 and ALK fusions, occurring in approximately 0.2% of patients. Wolf highlights datopotamab deruxtecan-dlnk (Datroway;_Daiichi Sankyo, Inc) and zongertinib (Hernexeos; Boehringer Ingelheim Pharmaceuticals, Inc), which are both FDA approved for treatment of patients with NSCLC as of 2025. D-DXd is approved for adults with locally advanced or metastatic EGFR-mutated NSCLC who received prior EGFR-directed therapy and platinum-based chemotherapy.4,15

    Zongertinib is the most recent approval for adults with unresectable or metastatic nonsquamous NSCLC whose tumors have HER2 mutations based on positive data from the Beamion LUNG-1 trial (NCT04886804).16,17

    Beamion LUNG-1 is an open-label, phase 1 dose escalation trial evaluating zongertinib as a monotherapy in patients with unresectable or metastatic, nonsquamous NSCLC with HER2 TKD mutations. The overall response rate was about 75% (95% CI, 63–83), with 58% experiencing a duration of response of 6 months or longer.18

    KRAS

    KRAS G12C mutations represent one of the most significant oncogenic drivers in lung cancer, though therapeutic progress in this space has historically been limited. Currently, only two targeted therapies—sotorasib (Lumakras; Amgen) and adagrasib (Krazati; Mirati Therapeutics)—have received FDA approval, both indicated for second-line treatment following chemotherapy.4

    Despite these advances, clinical benefit remains modest, with disease-free survival rates around 30% and a median duration of response of approximately 5 to 6 months. Although both agents have demonstrated improvements compared with docetaxel, outcomes underscore the ongoing need for more durable and effective options.4

    The field of KRAS inhibition is rapidly evolving, with multiple next-generation agents currently in clinical development. Ongoing studies are exploring monotherapy and combination approaches, as well as agents that target the GDP-bound (inactive) form of KRAS and emerging pan-KRAS inhibitors designed to address resistance and broader mutation coverage.4

    Conclusion

    The evolution of molecularly targeted therapies has transformed the treatment landscape of NSCLC, turning what was once a fatal disease into one defined by precision and personalization. As highlighted by Wolf, the continued integration of comprehensive molecular diagnostics remains essential to ensuring that each patient receives the most effective therapy for their unique tumor profile. According to Wolf:

    “Continuous innovation demands not only better products, but also better data, smarter networks and genuine partnership with our patients to guide everyday decisions”

    REFERENCES
    1. Key Statistics for lung cancer. American Cancer Society. Updated January 16, 2025. Accessed October 18, 2025. https://www.cancer.org/cancer/types/lung-cancer/about/key-statistics.html
    2. Gerlach A. Zongertinib receives breakthrough therapy designation for patients with HER2 non-small cell lung cancer. Pharmacy Times. September 4, 2025. Accessed October 18, 2025. https://www.pharmacytimes.com/view/zongertinib-receives-breakthrough-therapy-designation-for-patients-with-her2-non-small-cell-lung-cancer
    3. Eldridge L. Lung cancer survival rates by type, age, and stage. Very Well Health. Updated April 14, 2025. Accessed October 18, 2025. https://www.verywellhealth.com/lung-cancer-survival-rates-by-type-and-stage-2249401#:~:text=The%20survival%20rate%20for%20lung,also%20contribute%20to%20your%20survival.
    4. 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.
    5. Gerlach A. Navigating EGFR mutations and ALK fusions in early-stage non-small cell lung cancer. Pharmacy Times. July 19, 2025. Accessed October 18, 2025. https://www.pharmacytimes.com/view/navigating-egfr-mutations-and-alk-fusions-in-early-stage-non-small-cell-lung-cancer
    6. FDA approves osimertinib as adjuvant therapy for non-small cell lung cancer with EGFR mutations. FDA. December 18, 2024. Accessed October 18, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-osimertinib-adjuvant-therapy-non-small-cell-lung-cancer-egfr-mutations
    7. AZD9291 versus placebo in patients with stage IB-IIIA non-small cell lung carcinoma, following complete tumour resection with or without adjuvant chemotherapy. (ADAURA). Clinicaltrials.gov. August 28, 2025. Accessed October 18, 2025. https://clinicaltrials.gov/study/NCT02511106
    8. FDA approves osimertinib for locally advanced, unresectable (stage III) non-small cell lung cancer following chemoradiation therapy. FDA. September 25, 2024. Accessed October 18, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-osimertinib-locally-advanced-unresectable-stage-iii-non-small-cell-lung-cancer
    9. A Global Study to Assess the Effects of Osimertinib Following Chemoradiation in Patients With Stage III Unresectable Non-small Cell Lung Cancer (LAURA) (LAURA). Clinicaltrials.gov. October 16, 2025. Accessed October 18, 2025. https://clinicaltrials.gov/study/NCT03521154
    10. A study of osimertinib with or without chemotherapy as 1st line treatment in patients with mutated epidermal growth factor receptor non-small cell lung cancer (FLAURA2) (FLAURA2). Clinicaltrials.gov. October 10, 2025. Accessed October 18, 2025. https://clinicaltrials.gov/study/NCT04035486
    11. A study of amivantamab and lazertinib combination therapy versus osimertinib in locally advanced or metastatic non-small cell lung cancer (MARIPOSA). Clinicaltrials.gov. September 15, 2025. Accessed October 18, 2025. https://clinicaltrials.gov/study/NCT04487080
    12. A study of osimertinib with or without chemotherapy versus chemotherapy alone as neoadjuvant therapy for patients with eGFRm positive resectable non-small cell lung cancer (NeoADAURA). Clinicaltrials.gov. May 23, 2025. Accessed October 18, 2025. https://www.clinicaltrials.gov/study/NCT04351555
    13. A study of lorlatinib versus crizotinib in first line treatment of patients with ALK-positive NSCLC. Clinicaltrials.gov. December 24, 2024. Accessed October 18, 2025. https://clinicaltrials.gov/study/NCT03052608
    14. D’Angelo A, Sobhani N, Chapman R, et a;. Focus on ROS1-Positive Non-Small Cell Lung Cancer (NSCLC): Crizotinib, Resistance Mechanisms and the Newer Generation of Targeted Therapies. Cancers (Basel). November 6, 2020. doi: 10.3390/cancers12113293. PMID: 33172113
    15. FDA grants accelerated approval to datopotamab deruxtecan-dlnk for EGFR-mutated non-small cell lung cancer. FDA. June 23, 2025. Accessed October 18, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-datopotamab-deruxtecan-dlnk-egfr-mutated-non-small-cell-lung-cancer
    16. FDA grants accelerated approval to zongertinib for non-squamous NSCLC with HER2 TKD activating mutations. FDA. August 8, 2025. Accessed October 18, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zongertinib-non-squamous-nsclc-her2-tkd-activating-mutations
    17. Beamion LUNG-1: a study to test different doses of zongertinib in people with different types of advanced cancer (solid tumours with changes in the HER2 Gene). Updated July 28, 2025. Accessed October 18, 2025. https://clinicaltrials.gov/study/NCT04886804#study-overview
    18. Gerlach A. Zongertinib receives breakthrough therapy designation for patients with HER2 non-small cell lung cancer. Pharmacy Times. September 4, 2025. Accessed October 18, 2025. https://www.pharmacytimes.com/view/zongertinib-receives-breakthrough-therapy-designation-for-patients-with-her2-non-small-cell-lung-cancer

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  • KEYTRUDA® (pembrolizumab) Plus Padcev® (enfortumab vedotin-ejfv) Reduced Risk of Event-Free Survival Events by 60% and Risk of Death by 50% for Certain Patients with Muscle-Invasive Bladder Cancer When Given Before and after Surgery – UroToday

    1. KEYTRUDA® (pembrolizumab) Plus Padcev® (enfortumab vedotin-ejfv) Reduced Risk of Event-Free Survival Events by 60% and Risk of Death by 50% for Certain Patients with Muscle-Invasive Bladder Cancer When Given Before and after Surgery  UroToday
    2. Pfizer and Astellas announce positive results from phase 3ev-303 clinical trial for Padcev in combination with Keytruda  TradingView
    3. Enfortumab Vedotin Plus Pembro Cuts Risk of Disease Progression, Death 60% for Patients With MIBC Who Can’t Have Chemo With Bladder Removal  The American Journal of Managed Care® (AJMC®)
    4. ESMO25: Padcev, Keytruda regimen given before, after surgery shines in bladder cancer  FirstWord Pharma
    5. KEYNOTE-905: EV/pembrolizumab emerges as new option for cisplatin-ineligible MIBC  Urology Times

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  • Trump’s Crypto Fortune Soars Amid Policy Shift and Mar

    Trump’s Crypto Fortune Soars Amid Policy Shift and Mar

    This article first appeared on GuruFocus.

    Following the October 11 market correction, risk-off sentiment swept across global crypto markets. Yet, within days, the Trump family’s digital-asset ecosystem including the WLFI platform, the USD1 stablecoin, and American Bitcoin (ABTC) delivered substantial gains. Independent estimates suggest roughly $1.3 billion in new wealth creation, pushing the family’s total net worth to around $7.7 billion. Supporters hail the momentum as a sign of market recovery, while critics warn of regulatory capture and conflicts of interest. The convergence of policy and capital has become a defining feature of this new policy-driven market.

    Policy-Capital Feedback Loop:

    Since Donald Trump’s inauguration, regulatory posture has softened and pending litigation settlements have accelerated. Liquidity has flowed back into crypto markets, lifting correlated assets tied to the Trump ecosystem.

    Two Primary Growth Engines:

    • WLFI: Governance-token unlock and institutional accumulation.

    • USD1: After the federal compliance framework (Genius Act) took effect, the reserve-based model began generating significant interest income and network expansion.

    Industrial Backbone:American Bitcoin (ABTC) went public via merger and Nasdaq listing, seeing sharp intraday volatility and rapid valuation gains.

    Core Controversy:The boundary between regulator and regulated remains blurred. The role of offshore capital introduces national-security and governance-integrity concerns.

    • Jan 2025: SEC leadership reshuffle ? enforcement pivot.

    • Mar Aug 2025: ABTC formed and completed merger with a listed entity.

    • Jul 2025: Federal Stablecoin Framework (Genius Act) signed into law.

    • Aug 2025: Alt5 Sigma announces $1.5 billion allocation to WLFI.

    • Sept 1 2025: WLFI lists publicly ? peak valuation ? $7 billion.

    • Sept 3 2025: ABTC debuts on Nasdaq ? intraday valuation ? $13.2 billion.

    1. WLFI Governance Token: Market debut and institutional buying boosted capitalization and liquidity.

    2. USD1 Stablecoin: Interest income from reserve assets and ecosystem integration magnified cashflow.

    3. ABTC Equity Holdings: Public-market repricing increased book value.

    Across multiple independent reports, the Trump family’s paper and realized gains for Q3 2025 are estimated around $1.3 billion, with aggregate net worth now near $7.7 billion, including unrealized holdings.

    • Policy Reversal: Mid-term politics and regulatory realignment could drive valuation retracement.

    • Governance & Ethics: Potential conflicts of interest and offshore funding influence demand greater audit transparency.

    • Market Volatility: Post-October 11 secondary sell-offs suggest liquidity recovery remains incomplete.

    This case illustrates how policy markets precede fundamentals.Investors should watch for early signals of capital rotation such as:

    • Rising political donations ? policy commitments ? fast-track implementation ? market inflows. Asset selection should focus on sustainable cashflow, audited transparency, policy resilience, and liquidity management.

    Amid heightened volatility, some investors have shifted from price speculation toward cashflow anchoring.NB HASH, a global digital-income platform established in 2019, offers a regulated and automated pathway for generating daily returns through transparent digital-asset contracts positioning itself as a potential cashflow buffer during high-volatility cycles.

    Highlights:

    • Stable distribution: Daily settlements with real-time dashboard visibility.

    • Low entry threshold: Starting from $20, suited for varying risk profiles.

    • Flexible compounding: Withdraw anytime or auto-reinvest for long-term growth.

    • Free Fund Experience: Trial program allows users to validate mechanisms at zero cost.

    Use Cases: education funding, retirement supplements, or household secondary cashflow.More information is available at nbhash.cominfo@nbhash.com

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  • Tiragolumab Plus Atezolizumab Fails to Improve Outcomes as Consolidation in NSCLC | Targeted Oncology

    Tiragolumab Plus Atezolizumab Fails to Improve Outcomes as Consolidation in NSCLC | Targeted Oncology

    Consolidation therapy with tiragolumab plus atezolizumab (Tecentriq) failed to meet the primary end point of improving independent review facility (IRF)-assessed progression-free survival (PFS) vs standard durvalumab (Imfinzi) in patients with locally advanced, unresectable, stage III non–small cell lung cancer (NSCLC) that has not progressed after platinum-based concurrent chemoradiation (cCRT), according to findings from the phase 3 SKYSCRAPER-03 trial presented at the 2025 ESMO Congress.1

    At a median follow-up of 30.7 months, the median IRF-PFS in the overall population was 14.2 month (95% CI, 12.6-19.2) in patients receiving the combination vs 13.8 months (95% CI, 10.9-17.0) in patients treated with durvalumab (HR, 1.00; 95% CI, 0.84-1.19). The 24-month PFS event-free rates were 39.0% and 38.5%, respectively. The median overall survival (OS) was 45.6 months (95% CI, 37.1–not evaluable [NE]) vs 45.8 months (95% CI, 36.9-NE), respectively (HR, 0.98; 95% CI, 0.80-1.20). The 24-month OS event-free rates were 67.0% vs 66.3%, respectively.

    The primary end point was also missed in PD-L1–positive patients (Tumor Cell [TC] score ≥1%) with a median IRF-PFS of 19.4 months vs 16.6 months in patients treated with the combination vs durvalumab, respectively (HR, 0.96; 95% CI, 0.75-1.23; P = .7586). The median OS in these patients was NE vs 54.8 months, respectively (HR, 0.99; 95% CI, 0.73-1.34). The 24-month PFS and OS event-free survival rates were 46.1% vs 42.9% and 72.2% vs 69.2%, respectively.

    “SKYSCRAPER-03 did not meet its primary end point of IRF-PFS. There were no new or unexpected [safety] findings,” said first study author Rafal Dziadziuszko, MD, PhD, department of oncology and radiotherapy of the Medical University of Gdansk, Poland.

    What Was the Safety Profile of the Combination and Monotherapy Arms in the SKYSCRAPER-03 trial?

    “Tiragolumab plus atezolizumab demonstrated a tolerable safety profile, consistent with previous observations for the combination,” said Dziadziuszko.

    Grade 3/4 treatment-related adverse events (TRAEs) occurred in 13.8% of patients in the combination arm, with serious TRAEs experienced by 11.5%. There were 2 patient deaths considered to be related to the combination treatment. In the durvalumab arm, grade 3/4 TRAEs and serious TRAEs each occurred in 10.7% of patients. There were 7 patient deaths considered to be related to durvalumab treatment.

    What Was the Study Rationale and Design for the SKYSCRAPER-03 trial?

    Regarding the rationale for the study, Dziadziuszko explained, “Consolidation durvalumab is the standard of care for patients with unresectable, stage III NSCLC that has not progressed following cCRT; however, disease recurrence [still] represents an unmet need.”

    He added that the immune checkpoint target TIGIT has a role in cancer immune evasion and the study hypothesis was that tiragolumab, an anti-TIGIT monoclonal antibody, could potentially augment antitumor activity when used in combination with immunotherapies such atezolizumab.

    The open-label phase 3 SKYSCRAPER-03 trial was launched to test this hypothesis in patients with newly diagnosed, unresectable, stage III NSCLC whose disease has not progressed following at least 2 cycles of definitive platinum-based cCRT. Patients had to have known PD-L1 status, and an ECOG performance status of 0 or 1. Patients with EGFR– or ALK-positive tumors were not eligible for enrollment.

    At 1 to 42 days post cCRT, patients were randomized in a 1 to 1 ratio to combination therapy with tiragolumab (840 mg IV every 4 weeks) plus atezolizumab (1680 mg IV every 4 weeks) or single-agent durvalumab (10 mg/kg IV every 2 weeks or 1500 mg IV every 4 weeks). Patient could receive up to 13 cycles of treatment (28-day cycles).

    The primary end point was PFS assessed by an independent review facility in patients with PD-L1–positive (Tumor Cell [TC] score ≥1%) as well as PD-L1 all-comers. Secondary end points included OS, duration of response, objective response rate, patient-reported outcomes, and safety.

    What Were the Patient Characteristics in the SKYSCRAPER-03 trial?

    Patient characteristics were well balanced between the 2 study arms. The median age was 64 years (range, 35-84) in the combination arm vs 65 years (range, 41-86) in the durvalumab arm. About half of patients in each arm were aged less than 65 years at 50.8% and 47.4%, respectively. About 80% of patients in each arm were male, about 60% were White, and about 35% were Asian. Patients’ ECOG performance status was mostly split evenly between 0 and 1, with a slightly higher number of patients in each arm at ECOG 1 status. About 75% of patients in each arm were former tobacco users and about 20% were current tobacco users.

    About 50% of patients in each arm had a PD-L1 TC score of <1%, with about 25% of patients having a score of 1%-49%, and the remaining patients having a score of ≥50%. Tumor staging prior to definitive cCRT showed that 41.1% of patients receiving the combination had stage IIIA tumors vs 39.6% of patients in the single-agent arm. Rates of stage IIIB and stage IIIC tumors were 47.4% vs 44.4% and 11.4% vs 16.0%, respectively. About 60% of patients in each arm had squamous histology and about 40% had non-squamous histology. Best response to concurrent chemoradiotherapy in the combination vs durvalumab arms was complete response (0.5% in each arm), partial response (59.7% vs 61.4%), and stable disease (39.8% vs 38.1%).

    In his concluding remarks, Dziadziuszko did not report any next steps for the combination of tiragolumab plus atezolizumab in this setting.

    Disclosures

    Dziadziuszko disclosed relationships with AstraZeneca, Boehringer Ingelheim, BMS, Pfizer, Takeda, Eli Lilly, BioNTech, Novartis, and Roche.

    Reference

    1. Dziadziuszko R, Ahn M-J, Bradley JD, et al. SKYSCRAPER-03: Phase III, open-label, randomised study of atezolizumab (atezo) + tiragolumab (tira) vs durvalumab (durva) in locally advanced, unresectable, stage III non-small cell lung cancer (NSCLC) after platinum-based concurrent chemoradiation (cCRT). Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA69.

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