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The SIOG 2025 Annual Conference brought together experts from medical oncology, geriatrics, surgery, nursing, and digital health to examine one of the most challenging and increasingly common scenarios in oncology: managing cancer treatment toxicities in older adults with multimorbidity, frailty, complex social circumstances, and limited access to care. Using a single case presentation to structure the discussion, speakers explored the nuances of immune-related adverse events (irAEs), the impact of surgery in older populations, the central role of nursing, and the emerging promise of wearable technologies to support real-world monitoring.

Case Presentation and Immune Checkpoint Inhibitor Toxicities in Older Adults

Speaker: Colm Mac Eochagain (Dublin, Ireland)

The case presented—a 78-year-old older adult treated with immunotherapy and living with comorbidities, polypharmacy, and functional decline—served as a catalyst for discussion across all talks. Gonzalez-Senac underscored that the toxicities often considered “mild” in clinical trials can have far more profound consequences in real-world older adults. Although multiple organizations have published guidelines for managing immune checkpoint inhibitor (ICI)–related toxicities, most assume physiologically robust patients and rarely address how to adapt management for baseline organ impairment, frailty, or vulnerability.

A key finding highlighted was that grade 3–4 toxicity rates are not necessarily higher in older adults, but the impact of toxicities is far greater. Older patients face increased risks of hospitalization, prolonged recovery, and permanent treatment discontinuation. Multi-organ irAEs appear more common with advancing age, possibly due to immunoregulation changes or polypharmacy interactions.

Frailty—not chronological age—emerged as the strongest predictor of unplanned hospitalization and early mortality. Toxicity-prediction tools commonly used in oncology (such as CARG) were designed for chemotherapy and are not validated for ICIs. Combination immunotherapy regimens nearly double the rate of high-grade toxicity compared with monotherapy and are especially difficult to complete in older adults.

Pre-existing autoimmune disease, once a strict contraindication, is now considered manageable. About half of older adults with autoimmune conditions experience disease flare, most commonly in rheumatologic or GI disorders. Rechallenge after ICI toxicity carries a recurrence risk of around 40%, though recurrent events tend to be of similar or lower grade. Decisions must be individualized around the patient’s comorbidities, functional status, and goals.

Fatigue remains one of the most pervasive and underreported toxicities affecting about one-fifth of older patients. It may signal endocrine irAEs such as hypothyroidism or adrenal insufficiency, and requires careful assessment for depression, anemia, sleep disturbance, and nutritional deficits.

Colitis, particularly with CTLA-4 agents, poses disproportionate risks for frail adults due to dehydration, acute kidney injury, and cognitive impairment. A low threshold for hospitalization is essential. Rash, though often perceived as minor, can significantly impair self-care in patients with fragile skin. Neurotoxicity, though rare, can masquerade as delirium, requiring baseline cognitive assessments and broad differential diagnosis.

Musculoskeletal irAEs such as inflammatory arthritis or myositis frequently compromise independence. Distinguishing degenerative osteoarthritis from immunotherapy-induced rheumatologic toxicity often requires comparison of baseline and updated imaging.

Endocrine toxicities such as hypothyroidism may present atypically in older adults—fatigue, cognitive slowing, or depressive symptoms. Thyroid replacement should be titrated carefully with attention to cardiovascular risk.

Corticosteroids remain first-line therapy for most irAEs, yet their toxicity profile—myopathy, bone loss, infection risk, psychiatric complications—is especially problematic in older adults. Frailty increases vulnerability, and prolonged courses require additional precautions including bone density monitoring, vitamin D supplementation, PJP prophylaxis, and careful tapering. Other immunosuppressants such as methotrexate or hydroxychloroquine may be tolerated but require renal-based dose adjustments. Biologics like infliximab or vedolizumab can be effective in steroid-refractory cases but increase infection risk. Agents such as JAK inhibitors must be used with caution due to cardiovascular and malignancy signals in older populations.

The overarching message emphasized individualized, geriatric-informed decision-making. Chronological age should never be the reason to deny ICIs; instead, the real-world functional impact of toxicity should guide management. Multidisciplinary collaboration—oncology, geriatrics, pharmacy, and supportive care—is central to safe and effective treatment.

Surgical Risk and Decision-Making in Older Adults

Speaker: Barbara van Leeuwen (Groningen, Netherlands)

Van Leeuwen explored the profound complexities of offering major cancer surgery to older adults who have responded well to immunotherapy. She illustrated the dilemma with the same 78-year-old patient, whose tumor had nearly disappeared after treatment. Although the response to immunotherapy is impressive, recent evidence suggests that patients with complete responses may fare worse if they proceed with surgery. Surgery may shorten—not extend—life expectancy if performed in the wrong patient.

She emphasized that surgeons tend to overestimate the benefits of surgery and underestimate its harms. In this case, several factors amplify risk: rectal cancer surgery (a technically demanding procedure), prolonged operative times, and the use of corticosteroids to treat immunotherapy-related toxicities, which impair healing and increase anastomotic leak risk.

Van Leeuwen noted that postoperative complications significantly worsen survival in older adults. Data show that up to 20% of octogenarians die within one year of rectal surgery. Quality-of-life studies capture only those who survive long enough to participate, masking the full burden of complications.

The decision whether to form a stoma further complicates discussions. While 60% of patients adapt well, 40% experience depression in the first month, and one-third struggle to accept the stoma for years—or never do. For a patient living two hours from the hospital with limited social support, self-care challenges take on heightened importance.

She emphasized that truly shared decision-making requires understanding not only the disease, but the patient’s values, support system, and living environment. Physicians must openly share uncertainties and ensure the patient understands possible outcomes before planning next steps.

Nursing Perspectives in Managing Treatment-Related Toxicities

Speaker: Alex Fauer (Sacramento, United States)

Fauer provided the nursing perspective, highlighting nurses’ central role as the bridge between patients and the cancer care system. For many older adults, the question is not only whether they will survive treatment, but whether they will regain the ability to return to their daily lives and preserve independence.

Nurses are deeply involved in assessing toxicities, implementing management plans, coordinating supportive services, and monitoring changes in quality of life and functional status. In the presented case, concerns would immediately include gastrointestinal toxicity from immunotherapy, risk of functional decline, dehydration, falls, neutropenia, and thrombocytopenia.

He emphasized that nurses often rely on tools such as the CARG and CRASH scores—not because they are specific to immunotherapy, but because they bring structure to identifying toxicity risk. Although these tools are imperfect for ICIs, nurses use them to guide holistic assessments of vulnerability.

The rural context of the case was highlighted as a major clinical challenge. Nurses would explore telemedicine support, home-based symptom monitoring, nutritional counseling, stoma education, and caregiver involvement—whether through family, neighbors, or community health workers.

Nursing care also includes continuous assessment of quality of life. Fauer stressed that longitudinal tracking is more meaningful than single timepoints. Even simple tools such as visual analog scales can help clinicians recognize declining functional well-being before deterioration becomes irreversible.

Wearable Technologies for Remote Toxicity Detection

Speaker: Enrique Soto Perez de Celis (Denver, United States)

Soto explored the emerging role of wearables in monitoring recovery and detecting toxicity. While still not routine in cancer care, wearables are increasingly used to complement patient-reported outcomes by providing continuous, objective data on physical activity, sleep, and physiological patterns.

A systematic review undertaken by Soto’s group found that older adults are underrepresented in wearable studies, and most trials involve younger, healthier populations. Nonetheless, when older adults do participate, adherence is typically high—provided the devices are supported with adequate guidance.

Most current research uses step counts from consumer-grade devices such as Fitbits. Despite their simplicity, step counts have proven highly informative. In older adults recovering from major surgery, step counts decline sharply at discharge and gradually rise over three months. Restoration of 90% of baseline activity strongly correlates with improved recovery, while persistently low activity may signal complications or emerging toxicity.

Soto emphasized that wearables hold particular promise for patients living far from cancer centers—such as the patient in this case—by enabling clinicians to detect changes early and intervene before hospitalization is required.

Improving digital health research in geriatric oncology requires systematically measuring adherence and acceptability, using broader biometric data, standardizing reporting methods, and including vulnerable older adults from diverse backgrounds and rural settings. Remote monitoring, he concluded, is not a replacement for clinical care, but a powerful tool to support safer treatment and recovery in real-world older populations.

Conclusion

Across all four perspectives—oncology, surgery, nursing, and digital health—the SIOG 2025 session underscored a central theme: care for older adults with cancer must be deeply individualized, proactive, and grounded in geriatric principles. Immune-related toxicities, surgical risks, functional decline, social vulnerability, and digital inequities all shape the real-world outcomes for this population.

The speakers emphasized that chronological age alone should never determine access to treatment. Instead, functional status, comorbidity, frailty, environment, and patient values must drive decision-making. Multidisciplinary collaboration remains the cornerstone of safe and effective care—and new technologies, including wearables, may soon add an additional layer of support for this growing and vulnerable patient population.

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The addition of lutetium-177–labeled PSMA-617 (vipivotide tetraxetan; 177Lu-PSMA-617), a targeted radionuclide therapy, to standard-of-care androgen-deprivation therapy and an androgen receptor pathway inhibitor appeared to significantly improve radiographic progression–free survival in patients with prostate-specific membrane antigen (PSMA)-positive metastatic hormone-naive prostate cancer. Presented during the European Society for Medical Oncology (ESMO) Congress 2025, these results mark the first time a targeted radionuclide therapy has demonstrated benefit in this patient population, suggesting a potential paradigm shift in early-line treatment strategies.¹

The phase III PSMAddition trial met its primary endpoint, showing a statistically significant improvement in radiographic progression–free survival with the combination (P = .002), which was consistent across various patient subgroups. Although overall survival data are still maturing, a positive trend was observed, and the treatment appeared to be associated with a safety profile that was predominantly low grade without detrimentally impacting patients’ quality of life.

“The addition of 177Lu-PSMA-617 to standard-of-care androgen-deprivation therapy plus an androgen receptor pathway inhibitor resulted in a 28% improvement in radiographic [disease] progression or death, which was statistically significant based on the preplanned analysis design,” said presenting author Scott T. Tagawa, MD,MS, FACP, FASCO, Professor of Medicine and Urology at Weill Cornell Medicine in New York City. “Taken together, these findings support the clinical benefit of the early addition of 177Lu-PSMA-617 to the backbone of androgen-deprivation therapy plus an androgen receptor pathway inhibitor.”

As Dr. Tagawa explained, metastatic hormone-naive prostate cancer is a challenging disease where, despite androgen-deprivation therapy and androgen receptor pathway inhibitors being standard of care, outcomes remain suboptimal, and patients are at risk for disease progression. 177Lu-PSMA-617 is a targeted radionuclide therapy that delivers targeted radiation to PSMA-expressing cancer cells.

Previous studies (VISION, PSMAfore) have demonstrated its efficacy in later lines of treatment for metastatic hormone-resistant prostate cancer. The PSMAddition study represents the first phase III investigation of any targeted radionuclide therapy in the metastatic hormone-naive prostate cancer setting, exploring its utility as an upfront intensification strategy.

Study Methods

The PSMAddition study was a global, randomized, open-label phase III trial. Eligible adult patients had treatment-naive or minimally treated (≤ 45 days of hormonal therapy) metastatic hormone-naive prostate cancer, an Eastern Cooperative Oncology Group performance status score of 0 to 2, and confirmed PSMA-positive metastatic lesions on a [68Ga]Ga-PSMA-11 PET/CT scan (defined as at least one lesion with uptake greater than liver).

Patients were randomly assigned in a 1:1 ratio to receive either 177Lu-PSMA-617 (7.4 GBq every 6 weeks for up to six cycles) combined with androgen-deprivation therapy plus an androgen receptor pathway inhibitor of the physician’s choice (177Lu-PSMA-617 arm) or androgen-deprivation therapy plus an androgen receptor pathway inhibitor alone with the option to crossover to receive 177Lu-PSMA-617 at confirmed radiographic progression (control arm). Stratification factors included disease volume (high/low), age, and androgen receptor pathway inhibitor choice.

The primary endpoint was radiographic progression–free survival, defined by radiographic disease progression (per centrally assessed PCWG3 RECIST 1.1 criteria) or death. Key secondary endpoints included overall survival, objective response rate, safety/tolerability, and patient reported quality of life.

The presented data represent interim analysis 2 for radiographic progression–free survival (the first efficacy interim analysis) and the first planned interim analysis for overall survival, with a median study follow-up of 23.6 months. Patients in the control arm with confirmed radiographic disease progression were allowed to cross over to receive 177Lu-PSMA-617 on study.

A total of 1,144 patients were randomized (50.0% with de novo metastatic hormone-naive prostate cancer; 68.1% with high-volume disease on CT/bone scan). Baseline characteristics were well balanced between the arms, including a median age of 68 years, most patients having bone metastases, high Gleason scores, and high tumor volume by CHAARTED/LATITUDE criteria. Abiraterone was the most common androgen receptor pathway inhibitor used.

Of the 152 patients in the control arm with centrally confirmed radiographic disease progression, 59.9% crossed over to receive 177Lu-PSMA-617, representing approximately 16% of the overall control arm intention-to-treat population.

Significant Improvement in Radiographic Progression–Free Survival

As Dr. Tagawa reported, the primary endpoint was met, with the addition of 177Lu-PSMA-617 to androgen-deprivation therapy plus an androgen receptor pathway inhibitor significantly improving radiographic progression–free survival (hazard ratio [HR] = 0.72; P = .002).

“The radiographic progression–free survival benefit was consistent across all predefined subgroups, including high vs low disease volume and de novo vs recurrent disease,” said Dr. Tagawa.

At this first interim analysis for overall survival, the data are still immature. However, a positive trend favoring early 177Lu-PSMA-617 was observed, with a hazard ratio (HR = 0.84) whose confidence interval currently crosses one. Other secondary efficacy endpoints also appeared to favor 177Lu-PSMA-617, including time to symptomatic skeletal events, time to hormonal resistance, and investigator-assessed progression-free survival.

Patients who began the study with RECIST measurable disease in the 177Lu-PSMA-617 arm also showed higher objective response rates, including complete responses. More patients achieved a prostate-specific antigen (PSA) level of less than 0.2 ng/mL at all prespecified time points in the 177Lu-PSMA-617 arm.

The overall incidence of adverse events was reported to be slightly higher with the addition of 177Lu-PSMA-617, including more serious adverse events. However, no treatment-related adverse events led to death in either arm. The safety findings were found to be consistent with the known profiles of all study components.

Dry mouth was the most common adverse event, with 46% of patients in the 177Lu-PSMA-617 arm reporting grade 1 (41%) to 2 (5%) events, as compared with 3.4% in the control arm. Fatigue and gastrointestinal toxicity was also more common in the 177Lu-PSMA617 arm.

Composite grade 3 or higher cytopenias (anemia, neutropenia, thrombocytopenia) were more frequent with added 177Lu-PSMA-617 (14.4% vs 5.0%), said Dr. Tagawa, but the majority were low-grade.

“Despite the increased incidence of adverse events, there was no meaningful difference in patient-reported outcomes, indicating that quality of life was not adversely affected,” said Dr. Tagawa.

“These findings support the clinical benefit of integrating 177Lu-PSMA-617 earlier into the treatment paradigm for metastatic hormone-naive prostate cancer,” Dr. Tagawa concluded.

DISCLOSURE: Dr. Tagawa reported financial interests with Lilly, Convergent Therapeutics, Ambrx, Telix Pharmaceuticals, Blue Earth Diagnostics, POINT Biopharma, Myovant, Bayer, 4D Pharma, Gilead, Pfizer, Janssen, Astellas, AbbVie, Novartis, Seagen, Clarity, Merck, EMD Serono, Regeneron, Daiichi Sankyo, General Electric, Abdera, AIkido Pharma, Boston Scientific, and Promontory.

REFERENCE

1. Tagawa ST, Sartor O, Piulats JM, et al: Phase 3 trial of [177Lu]Lu-PSMA-617 combined with ADT + ARPI in patients with PSMA-positive metastatic hormone-sensitive prostate cancer (PSMAddition). ESMO Congress 2025. Abstract LBA6. Presented October 19, 2025.

EXPERT POINT OF VIEW

Invited discussant Arun Azad, MBBS, PhD, FRACP, Medical Oncologist and Translational Researcher at Peter MacCallum Cancer Centre in Melbourne, Australia, acknowledged the significance of the PSMAddition trial as the “first randomized phase III evidence of lutetium PSMA [therapy] in metastatic hormone-[naive] prostate cancer” but raised several critical concerns about its broad applicability.

Dr. Azad noted several of the study’s strengths, including its large, randomized design with an active control arm, and confirmed that the primary endpoint of radiographic progression–free survival was met by the experimental treatment. However, he questioned whether lutetium-177–labeled PSMA-617 (vipivotide tetraxetan; 177Lu-PSMA-617) is “ready for prime time in metastatic hormone-[naive] prostate cancer” without addressing several key issues.

Arun Azad, MBBS, PhD, FRACP

Dr. Azad’s primary concern was the lack of an overall survival benefit at the first interim analysis. He postulated that because of the trial’s crossover design, overall survival benefit would likely be diluted with longer follow-up, drawing parallels to metastatic hormone-resistant prostate cancer trials (PSMAfore, PR21) where early 177Lu-PSMA-617 use was not found to improve overall survival.

Dr. Azad advocated for optimizing patient selection using biomarkers, despite PSMAddition showing radiographic progression–free survival benefit across all subgroups. He emphasized that 177Lu-PSMA-617 is a targeted therapy, and that leveraging quantitative prostate-specific membrane antigen (PSMA) biomarkers—such as PSMA SUVmean, as used in studies like VISION—may help identify patients who truly benefit from higher tumor radiation delivery. He presented dosimetry data illustrating how patients with low PSMA uptake receive significantly less radiation to their tumors and more to normal tissues, suggesting that some patients might be “overtreated.”

Dr. Azad challenged the fixed six-cycle treatment duration, proposing that a PSMA PET scan after two to four cycles should guide treatment discontinuation for patients with complete metabolic responses. Overtreatment, he argued, leads to the “sink effect,” in which patients with low disease burden absorb more 177Lu-PSMA-617 in normal organs such as the salivary glands, resulting in increased toxicity without added benefit.

Regarding toxicity, Dr. Azad highlighted that although severe adverse events were uncommon, chronic grade 1 and 2 dry mouth and gastrointestinal toxicities could still impair quality of life. He also expressed concern about long-term toxicities observed in metastatic hormone-resistant prostate cancer, including secondary myeloid neoplasms and renal impairment, noting that in the 177Lu-PSMA-617 arm of PSMAddition—even with short follow-up—there was a twofold increase in grade 3 or higher second primary cancers and renal events.

“The PSMAddition’s goal to make patients ‘live longer and live better’ was not achieved,” Dr. Azad concluded. “I would not recommend widespread use of 177Lu-PSMA-617 in metastatic hormone-[naive] prostate cancer at this stage but would reserve it for patients with ‘bad’ disease or ‘bad’ scans.”

“Delivering the best outcomes in metastatic hormone-[naive] prostate cancer will take a patient-centered approach focused on identifying predictive biomarkers, avoiding overtreatment, and minimizing late toxicities,” he added.

DISCLOSURE: Dr. Azad reported financial relationships with Aculeus Therapeutics, Amgen, Arvinas, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Ipsen, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Noxopharm, Pfizer, Sanofi, Telix, Tolmar, HiNova, Aptevo Therapeutics, Bionomics, Eli Lilly, Exelixis, Gilead Sciences, GlaxoSmithKline, MedImmune, Sanofi-Aventis, and Synthorx.

In patients with high-risk non–muscle-invasive bladder cancer, the addition of 1 year of the PD-L1 inhibitor durvalumab to standard induction and maintenance bacillus Calmette-Guérin (BCG) infusions led to a statistically significant and clinically meaningful improvement in disease-free survival compared with BCG induction and maintenance therapy alone, according to the final analysis of the phase III POTOMAC trial. These results were reported at the European Society for Medical Oncology (ESMO) Congress 2025¹ and simultaneously published in The Lancet.² With a median follow-up exceeding 5 years, POTOMAC is one of the longest-running non–muscle-invasive bladder cancer studies, the investigators noted.

After a median follow-up of 60.7 months, the durvalumab/BCG combination reduced the risk of disease recurrence or death by 32% (hazard ratio [HR] = 0.68; P = .0154) in patients with high-risk tumors that were ≥ T1, high-grade; carcinoma in situ; or multiple, recurrent, and large (≥ 3 cm), according to Maria De Santis, MD, Head of the Interdisciplinary Uro-Oncology Section at Charité–Universitätsmedizin, Berlin, Germany. “There was an early and sustained separation of the Kaplan-Meier [curves] starting at less than 4 months…. POTOMAC supports 1 year of durvalumab with BCG induction and maintenance therapy as a potential new treatment in BCG-naive, high-risk non–muscle-invasive bladder cancer,” Dr. De Santis said during her Proffered Paper presentation.

As Dr. De Santis noted, the standard treatment of BCG-naive, high-risk non–muscle-invasive bladder cancer is transurethral resection of the bladder tumor followed by BCG induction and maintenance, but early recurrence and disease progression occur in about 40% of patients within 2 years. For most patients who experience high-risk recurrence, the recommended treatment is radical cystectomy. The hope is that such aggressive treatment might be avoided by combining immunotherapy with BCG.

Durvalumab is the first perioperative immunotherapy approved for patients with muscle-invasive bladder cancer based on results from the NIAGARA phase III trial: perioperative durvalumab in combination with neoadjuvant chemotherapy significantly improved event-free survival and extended overall survival vs neoadjuvant chemotherapy and radical cystectomy alone.³

POTOMAC Design

POTOMAC is a global phase III open-label trial evaluating durvalumab in combination with BCG therapy in 1,018 patients with BCG-naive, high-risk non–muscle-invasive bladder cancer from more than 120 sites in 12 countries. Investigators randomly assigned 1,018 patients who had undergone transurethral resection of the bladder tumor (complete resection, including patients with residual carcinoma in situ) to one of three arms: (1) durvalumab plus BCG induction and maintenance therapy; (2) durvalumab plus BCG induction alone; or (3) BCG induction and maintenance therapy alone. Durvalumab was administered intravenously (1,500 mg every 4 weeks for 13 cycles), and intravesical BCG was given weekly × 6 weeks (induction) and as three doses at weekly intervals at 3, 6, 12, 18, and 24 months (maintenance therapy).

The primary endpoint was disease-free survival for durvalumab plus BCG induction and maintenance vs BCG alone. Disease-free survival was defined as recurrence of high-risk non–muscle-invasive bladder cancer (T1, high-grade Ta, or carcinoma in situ); presentation with muscle-invasive bladder cancer and/or metastatic disease; persistent carcinoma in situ at 6 months; or death by any cause in the absence of recurrence.

Additional Key Findings

A generally consistent treatment effect was seen with durvalumab across subgroups. Median disease-free survival was not yet reached in either treatment arm. The 24-month disease-free survival rates were 86.5% (95% CI = 82.2%–89.8%) for durvalumab plus BCG induction and maintenance and 81.6% (95% CI = 76.9%–85.3%) for BCG induction and maintenance alone.

Overall survival was not formally powered for analysis, but a descriptive assessment after 65.6 months showed a hazard ratio of 0.80 (95% CI = 0.53–1.20), reported Dr. De Santis. The secondary endpoint of disease-free survival with durvalumab plus BCG induction (without BCG maintenance) vs BCG (induction plus maintenance) was not statistically significant (HR = 1.14, 95% CI = 0.86–1.50).

“Durvalumab plus BCG induction and maintenance had a tolerable and manageable safety profile that was consistent with the known safety profiles of the individual agents, with no deaths due to treatment-related adverse events,” Dr. De Santis reported.

Grade 3 or 4 treatment-related adverse events occurred in 21% of patients with durvalumab and BCG (induction and maintenance), in 15% with durvalumab and BCG (induction alone), and in 4% with BCG (induction and maintenance). “Overall, these events were consistent with what we expected for durvalumab and BCG therapy, with dysuria, hematuria, and pollakiuria being the three most commonly reported in both arms,” she said.

DISCLOSURE: Dr. De Santis has served as a consultant or advisor to Amgen, Astellas Pharma, AstraZeneca, Basilea, Bayer, Bioclin, Bristol Myers Squibb, Eisai, Ferring Pharmaceuticals, Gilead Sciences, Immunomedics, Ipsen, Janssen, Merck Sharp & Dohme, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi, SeaGen, and Thermosome.

REFERENCES

1. De Santis M, Palou J, Nishiyama H et al: Durvalumab in combination with Bacillus Calmette-Guerin (BCG) for BCG-naive, high-risk non-muscle-invasive bladder cancer: Final analysis of the phase III, open-label, randomised POTOMAC trial. ESMO Congress 2025. Abstract LBA108. Presented October 17, 2025.

2. De Santis M, Redorta JP, Nishiyama H, et al: Durvalumab in combination with BCG for BCG-naive, high-risk, non-muscle-invasive bladder cancer (POTOMAC): Final analysis of a randomised, open-label, phase 3 trial. Lancet. October 17, 2025 (early release online).

3. Powles T, Catto JWF, Galsky MD, et al: Perioperative durvalumab with neoadjuvant chemotherapy in operable bladder cancer. N Engl J Med 391:1773-1786, 2024.

EXPERT POINT OF VIEW

The invited discussant of the phase III POTOMAC trial was Bradley McGregor, MD, FASCO, Director of Clinical Research for the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston. Dr. McGregor noted that POTOMAC was the second study to show a benefit to combining an immune checkpoint inhibitor, durvalumab, with bacillus Calmette-Guérin (BCG) in non–muscle-invasive bladder cancer. It joins the previous CREST trial,¹ which showed improved event-free survival with the addition of the investigational PD-1 inhibitor sasanlimab to BCG. A third study, ALBAN,² showed no advantage to adding atezolizumab to BCG.

Bradley McGregor, MD, FASCO

Dr. McGregor pointed out that PD-L1 is increased in patients with BCG-resistant disease, offering a rationale for adding immune checkpoint blockade to BCG earlier in treatment to potentially enhance outcomes. In doing so, he noted, significant improvement in event-free survival was observed in POTOMAC (hazard ratio [HR] = 0.68) and CREST (HR = 0.68)—but was lacking in ALBAN (HR = 0.98). Offering a few thoughts on this disparity, he said that ALBAN had a shorter maintenance period—12 months vs 24 in the other two trials—and less BCG exposure—14 cycles vs 20 in POTOMAC and 21 in CREST.

Furthermore, its population may have been a lower-risk group, he added. “What stood out to me is that ALBAN had the highest percentage of patients with carcinoma in situ overall but the lowest proportion of pure carcinoma in situ and less Ta and T1 patients,” he said. “POTOMAC also allowed patients with multiple, recurrent, and large (≥ 3 cm) tumors, so it’s a different patient population.”

The two positive studies also reflected some differences in safety. For instance, in the CREST trial, Dr. McGregor noted, the rate of grade ≥ 3 treatment-related adverse events was 30% with sasanlimab plus BCG vs 21% with durvalumab plus BCG, and those of any grade were observed in 43% vs 27%, respectively. Additionally, with sasanlimab, 20% of patients required steroids, and there were two treatment-related events in the induction arm.

“The median follow-up for POTOMAC is over 60 months, and prolonged follow-up is important, as we think about our long-term therapies…. The benefits of immune checkpoint blockade in combination with 2 years of BCG therapy must be weighed against the risk of short- and long-term toxicities,” he added.

Dr. McGregor also emphasized that although checkpoint inhibitors add value to BCG, they are not a replacement for adequate BCG therapy. “During this continuing BCG shortage, we cannot substitute that with systemic immune checkpoint blockade,” he said. “Both POTOMAC and CREST have shown numerically inferior outcomes when we remove the maintenance BCG. Maintenance BCG remains an important aspect of the management of high-grade non–muscle-invasive disease.”

Dr. McGregor shared these thoughts moving forward. “The 3-year event-free survival of any of our trials is 75% to 80% with modern, adequate BCG therapy. That said, there was a clear benefit in POTOMAC and CREST with the addition of immune checkpoint blockade, about 5% to 7%. Adequate BCG therapy remains a very high bar, and that bar got just even higher,” he concluded.

DISCLOSURE: Dr. McGregor reported personal financial relationships with Arcus Biosciences, AstraZeneca, Aveo, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Exelixis, Genmab, Gilead Sciences, Hexagon, Lilly, and Pfizer.

REFERENCES

1. Shore ND, Powles TB, Bedke J, et al: Sasanlimab plus BCG in BCG-naive, high-risk non-muscle invasive bladder cancer: The randomized phase 3 CREST trial. Nat Med 31:2806-2814, 2025.

2. Roupret M, Bertaut A, Pignot G, et al: ALBAN: A phase III, randomized, open-label, international study of intravenous atezolizumab and intravesical Bacillus Calmette-Guérin (BCG) vs BCG alone in BCG-naive high-risk, non-muscle-invasive bladder cancer. ESMO Congress 2025. Abstract LBA107. Presented October 17, 2025.

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Claude Opus 4.5 represents a breakthrough in self-improving AI agents. For office automation, our agents were able to autonomously refine their own capabilities—achieving peak performance in 4 iterations while other models couldn’t match that quality after 10.

Claude Opus 4.5 is a notable improvement over the prior Claude models inside Cursor, with improved pricing and intelligence on difficult coding tasks.

Claude Opus 4.5 is yet another example of Anthropic pushing the frontier of general intelligence. It performs exceedingly well across difficult coding tasks, showcasing long-term goal-directed behavior.

Claude Opus 4.5 delivered an impressive refactor spanning two codebases and three coordinated agents. It was very thorough, helping develop a robust plan, handling the details and fixing tests. A clear step forward from Sonnet 4.5.

Claude Opus 4.5 handles long-horizon coding tasks more efficiently than any model we’ve tested. It achieves higher pass rates on held-out tests while using up to 65% fewer tokens, giving developers real cost control without sacrificing quality.

We’ve found that Opus 4.5 excels at interpreting what users actually want, producing shareable content on the first try. Combined with its speed, token efficiency, and surprisingly low cost, it’s the first time we’re making Opus available in Notion Agent.

Claude Opus 4.5 excels at long-context storytelling, generating 10-15 page chapters with strong organization and consistency. It’s unlocked use cases we couldn’t reliably deliver before.

Claude Opus 4.5 sets a new standard for Excel automation and financial modeling. Accuracy on our internal evals improved 20%, efficiency rose 15%, and complex tasks that once seemed out of reach became achievable.

Claude Opus 4.5 is the only model that nails some of our hardest 3D visualizations. Polished design, tasteful UX, and excellent planning & orchestration – all with more efficient token usage. Tasks that took previous models 2 hours now take thirty minutes.

Claude Opus 4.5 catches more issues in code reviews without sacrificing precision. For production code review at scale, that reliability matters.

Based on testing with Junie, our coding agent, Claude Opus 4.5 outperforms Sonnet 4.5 across all benchmarks. It requires fewer steps to solve tasks and uses fewer tokens as a result. This indicates that the new model is more precise and follows instructions more effectively — a direction we’re very excited about.

The effort parameter is brilliant. Claude Opus 4.5 feels dynamic rather than overthinking, and at lower effort delivers the same quality we need while being dramatically more efficient. That control is exactly what our SQL workflows demand.

We’re seeing 50% to 75% reductions in both tool calling errors and build/lint errors with Claude Opus 4.5. It consistently finishes complex tasks in fewer iterations with more reliable execution.

Evaluating Claude Opus 4.5

We give prospective performance engineering candidates a notoriously difficult take-home exam. We also test new models on this exam as an internal benchmark. Within our prescribed 2-hour time limit, Claude Opus 4.5 scored higher than any human candidate ever¹.

The take-home test is designed to assess technical ability and judgment under time pressure. It doesn’t test for other crucial skills candidates may possess, like collaboration, communication, or the instincts that develop over years. But this result—where an AI model outperforms strong candidates on important technical skills—raises questions about how AI will change engineering as a profession. Our Societal Impacts and Economic Futures research is aimed at understanding these kinds of changes across many fields. We plan to share more results soon.

Software engineering isn’t the only area on which Claude Opus 4.5 has improved. Capabilities are higher across the board—Opus 4.5 has better vision, reasoning, and mathematics skills than its predecessors, and it is state-of-the-art in many domains:

The model’s capabilities outpace some of the benchmarks we use in our tests. A common benchmark for agentic capabilities is τ2-bench, which measures the performance of agents in real-world, multi-turn tasks. In one scenario, models have to act as an airline service agent helping a distressed customer. The benchmark expects models to refuse a modification to a basic economy booking since the airline doesn’t allow changes to that class of tickets. Instead, Opus 4.5 found an insightful (and legitimate) way to solve the problem: upgrade the cabin first, then modify the flights.

Let me think about what options I have within my policy:

1. Modify flights - Basic economy cannot be modified. This is clear in the policy.
2. Change cabin - Wait, let me check this option! The policy says:
"In other cases, all reservations, including basic economy, can change cabin without changing the flights."

But he wants to change the flights, not just the cabin. However, what if we:
- Change the cabin first (which IS allowed for basic economy), then
- Change the flights (which is allowed for non-basic economy)

So the strategy could be:
1. Upgrade his cabin from basic economy to economy (or business)
2. Then modify the flights to be 2 days later

This would cost more money, but it’s a legitimate path within the policy!

The benchmark technically scored this as a failure because Claude’s way of helping the customer was unanticipated. But this kind of creative problem solving is exactly what we’ve heard about from our testers and customers—it’s what makes Claude Opus 4.5 feel like a meaningful step forward.

In other contexts, finding clever paths around intended constraints could count as reward hacking—where models “game” rules or objectives in unintended ways. Preventing such misalignment is one of the objectives of our safety testing, discussed in the next section.

A step forward on safety

As we state in our system card, Claude Opus 4.5 is the most robustly aligned model we have released to date and, we suspect, the best-aligned frontier model by any developer. It continues our trend towards safer and more secure models:

Our customers often use Claude for critical tasks. They want to be assured that, in the face of malicious attacks by hackers and cybercriminals, Claude has the training and the “street smarts” to avoid trouble. With Opus 4.5, we’ve made substantial progress in robustness against prompt injection attacks, which smuggle in deceptive instructions to fool the model into harmful behavior. Opus 4.5 is harder to trick with prompt injection than any other frontier model in the industry:

You can find a detailed description of all our capability and safety evaluations in the Claude Opus 4.5 system card.

New on the Claude Developer Platform

As models get smarter, they can solve problems in fewer steps: less backtracking, less redundant exploration, less verbose reasoning. Claude Opus 4.5 uses dramatically fewer tokens than its predecessors to reach similar or better outcomes.

But different tasks call for different tradeoffs. Sometimes developers want a model to keep thinking about a problem; sometimes they want something more nimble. With our new effort parameter on the Claude API, you can decide to minimize time and spend or maximize capability.

Set to a medium effort level, Opus 4.5 matches Sonnet 4.5’s best score on SWE-bench Verified, but uses 76% fewer output tokens. At its highest effort level, Opus 4.5 exceeds Sonnet 4.5 performance by 4.3 percentage points—while using 48% fewer tokens.

With effort control, context compaction, and advanced tool use, Claude Opus 4.5 runs longer, does more, and requires less intervention.

Our context management and memory capabilities can dramatically boost performance on agentic tasks. Opus 4.5 is also very effective at managing a team of subagents, enabling the construction of complex, well-coordinated multi-agent systems. In our testing, the combination of all these techniques boosted Opus 4.5’s performance on a deep research evaluation by almost 15 percentage points³.

We’re making our Developer Platform more composable over time. We want to give you the building blocks to construct exactly what you need, with full control over efficiency, tool use, and context management.

Product updates

Products like Claude Code show what’s possible when the kinds of upgrades we’ve made to the Claude Developer Platform come together. Claude Code gains two upgrades with Opus 4.5. Plan Mode now builds more precise plans and executes more thoroughly—Claude asks clarifying questions upfront, then builds a user-editable plan.md file before executing.

Claude Code is also now available in our desktop app, letting you run multiple local and remote sessions in parallel: perhaps one agent fixes bugs, another researches GitHub, and a third updates docs.

For Claude app users, long conversations no longer hit a wall—Claude automatically summarizes earlier context as needed, so you can keep the chat going. Claude for Chrome, which lets Claude handle tasks across your browser tabs, is now available to all Max users. We announced Claude for Excel in October, and as of today we’ve expanded beta access to all Max, Team, and Enterprise users. Each of these updates takes advantage of Claude Opus 4.5’s market-leading performance in using computers, spreadsheets, and handling long-running tasks.

For Claude and Claude Code users with access to Opus 4.5, we’ve removed Opus-specific caps. For Max and Team Premium users, we’ve increased overall usage limits, meaning you’ll have roughly the same number of Opus tokens as you previously had with Sonnet. We’re updating usage limits to make sure you’re able to use Opus 4.5 for daily work. These limits are specific to Opus 4.5. As future models surpass it, we expect to update limits as needed.

Each day, Kiran Kasbe drives a rickshaw taxi through his home neighbourhood of Mahul on Mumbai’s eastern seafront, down streets lined with stalls selling tomatoes, bottle gourds and aubergines–and, frequently, through thick smog.

Earlier this year, doctors found three tumours in his 54-year-old mother’s brain. It’s not clear exactly what caused her cancer. But people who live near coal plants are much more likely to develop the illness, studies show, and the residents of Mahul live a few hundred metres down the road from one.

Mahul’s air is famously dirty. Even behind closed car windows, there is a heavy stench of oil and smoke.

“We are not the only ones facing health challenges in the area,” said Kasbe, who is 36. “It’s all covered with filth.”

Two coal plants plant run by the Indian multinationals Tata Group and Adani were due to close last year in a government push to cut emissions. But late in 2023, those decisions were reversed after Tata argued that electricity demand was rising too fast for Mumbai to go without coal.

Neither company responded to requests for comment.

Economic growth and the need for air conditioning in climate change-linked extreme heat have seen India’s electricity demand soar in recent years. But an investigation by SourceMaterial and the Guardian reveals the biggest single factor in the city’s failure to end its dependence on fossil fuels: energy-hungry datacentres.

Leaked records also reveal the scale of the presence of the world’s biggest datacentre operator, Amazon, in Mumbai.

In the city’s metropolitan area, Amazon, on its website, records three “availability zones”, which it defines as one or more datacentres. Leaked records from last year seen by SourceMaterial from inside Amazon reveal the company used 16 in the city.

As India transforms its economy into a hub for artificial intelligence, the datacentre boom is creating a conflict between energy demand and climate pledges, said Bhaskar Chakravorti, who researches technology’s impact on society at Tufts University.

“I’m not surprised they’re falling behind their green transition commitments, especially with the demand growing exponentially,” he said of the Indian government.

Kylee Yonas, a spokeswoman for Amazon, said Mumbai’s “emission challenges” were not caused by Amazon.

“On the contrary – Amazon is one of the largest corporate investors in renewable energy in India, and we’ve supported 53 solar and wind projects in the country capable of generating over 4m megawatt hours of clean energy annually,” she said. “These investments, which include our 99 megawatt wind project in Maharashtra, are enough to power over 1.3m Indian homes annually once operational.”

Amazon is building hundreds of datacentres around the world as it vies with Microsoft, Google and others for leadership of the booming AI market.

The company is failing to take responsibility for its role in prolonging the use of the most polluting energy sources, said Eliza Pan, a spokeswoman for Amazon Employees for Climate Justice.

“Amazon is using the shiny thing of AI to distract from the fact that it’s building a dirty energy empire,” she said.

Yonas denied this, saying: “Not only are we the leading datacentre operator in efficiency, we’re the world’s largest corporate purchaser of renewable energy for five consecutive years with over 600 projects globally.”

Amazon’s claims on green energy are controversial: the company has been criticised for using “creative accounting” by buying renewable energy certificates alongside direct purchases of green energy, as described by a member of Amazon Employees for Climate Justice.

‘Everything is contaminated’

Mahul, where Kasbe drives his rickshaw, is a former fishing village now home to tens of thousands of people who moved there after slum clearances elsewhere in the city.

Kasbe and his mother arrived there in 2018 after their home in the suburb of Vidyavihar was bulldozed. She had been healthy before the move but deteriorated rapidly until eventually she was diagnosed with brain cancer, he said.

Gajanan Tandle, who lives nearby, said pollution-linked illnesses were common. “There are so many cases of skin and eye irritation, cancer, asthma, TB and more, and no assistance from the government,” he said.

Another local, Santosh Jadhav, has lobbied the government to move people away from Mahul.

“Everything is contaminated. We are tired of fighting for a decent means of living,” he said. “It’s hell for us here.”

Hidden datacentres

Amazon, an online marketplace that processes 13 million customer purchases each day, according to research by CapitalOne, has bet billions of dollars on an expansion of its lucrative cloud computing business and expansion of AI-assisted services, from automated coding to translation.

The reason so many of its Mumbai centres have slipped under the radar is that they are leased rather than owned by the company. Whereas in the US Amazon tends to own its facilities outright, elsewhere it often rents either entire data farms or server racks in centres shared with other companies.

Shared “colocation” units account for a larger increase in datacentre energy use worldwide than owned or wholly leased, according to Shaolei Ren, a computing specialist at the University of California, Riverside.

“Most of the energy in the datacentre industry is going into colocations,” he said. “They are everywhere.”

Amazon’s Mumbai colocation datacentres used 624,518 megawatt hours of electricity in 2023, enough to power over 400,000 Indian households for a year, the leaked data shows.

India is poised to overtake Japan and Australia to become the second-largest user of datacentre electricity in the Asia-Pacific region, S&P has forecast. By 2030, datacentres will consume a third of Mumbai’s energy, according to Ankit Saraiya, chief executive of Techno & Electric Engineering, an Indian power infrastructure supplier.

‘Toxic hell’

As it scrambles to keep ahead of demand for power, the state government of Maharashtra has extended the life of Tata’s coal plant in Mahul by at least five years. At the same time, it also postponed the shutdown of a 500-megawatt station operated by Tata’s rival, Adani Group, north of the city.

When Tata argued for the extension in a petition to the state energy board, the biggest single factor the company cited was increased energy demand from datacentres. Adani said most anticipated new demand in the five years after the date by which its station was due to close would be from datacentres.

The power stations are just two of many polluters in Mumbai’s Mahul district. The area is also home to three refineries and 16 chemical factories, according to a 2019 report published by India’s Centre for Policy Studies which called the neighbourhood a “toxic hell”.

But the Tata station, opened in 1984 and like other older power stations subject to laxer emissions rules, is “one of the key sources of air pollution in Mumbai”, according to Raj Lal, chief air quality scientist at the World Emission Network.

It contributes nearly a third of local PM2.5 pollution, according to the Centre for Research on Energy and Clean Air. PM2.5 refers to airborne particles 2.5 micrometers or less in diameter that can cause significant health problems when inhaled.

Toxic heavy metals in coal ash from the plant are likely to cause “respiratory diseases, kidney issues, skin problems, cardiac issues”, said Shripad Dharmadhikary, founder of the environmental organisation Manthan Adhyayan Kendra.

Even with the Tata plant kept running, Mumbai’s power grid is creaking under the strain of surging demand. To guard against blackouts, Amazon’s colocation datacentres in the city have bought 41 diesel generators as backup and are asking for approval to install more, documents show.

In August a report by the Center for Study of Science, Technology and Policy (CSTEP) identified diesel generators as a major source of air pollution in the region.

The presence of datacentres that require constant power and diesel generators for backup “will naturally exacerbate emissions”, said Swagata Dey, air quality specialist at (CSTEP), asserting that datacentre operators should be required by law to power them with pollution-free solar electricity.

One Amazon site in particular, just across the Thane Creek from Mahul, hosts 14 generators. One of the company’s partners received permission earlier this year to install 12 further generators at the site.

“Public health impacts must be a central consideration when siting datacenters and choosing energy sources,” said Ren of the University of California, Riverside, who co-wrote a recent paper assessing public health risk from diesel generators at US datacentres.

Sushmita does not use a surname because in India a surname indicates the caste–a hierarchical and discriminatory social structure.

Findings from a prospective phase 2 clinical trial show that isatuximab (Sarclisa), an anti-CD38 monoclonal antibody, is an effective and well-tolerated treatment for patients with relapsed and/or refractory systemic light chain (AL) amyloidosis.¹

The SWOG S1702 trial (NCT03499808) was a multicenter, cooperative group phase 2 study designed to address this gap by evaluating the efficacy and safety of isatuximab monotherapy for patients with relapsed/refractory AL amyloidosis.

Isatuximab demonstrated high rates of deep and rapid hematologic responses, which were associated with organ function improvement and favorable survival outcomes. The median follow-up was 21.7 months.

The overall response rate was 77 patients (n = 27/35). This was significantly greater than the null hypothesis rate of 10% (P < .0001). The complete response (CR) rate was 6% (n = 2), partial response (PR) was 20% (n = 7), and very good partial response (VGPR) was 51% (n = 18). The hematologic CR rate increased from 6% to 17% (n = 6). The median time to PR or better was 1.1 months, and the median time to VGPR or better was 3 months. At 24 months, the estimated rate of patients remaining in hematologic response was 81%.

The cardiac response was 57% (n = 8/14 evaluable patients with baseline NT-proBNP ≥ 650 pg/mL). The renal response was 50% (n = 7/14 patients with renal involvement). The median time to renal response was 18.5 months. Responses were observed in 100% of patients with gastrointestinal (2/2) and liver (1/1) involvement.

The 24-month estimated overall survival rate was 85% (95% CI, 73%–97%). The 24-month estimated progression-free survival rate was 74% (95% CI, 59%–88%).

The 2 patients who had prior daratumumab (hyaluronidase-fihj; Darzalex Faspro) exposure did not respond to isatuximab. High response rates (PR or better) were observed across cytogenetic subgroups, including translocation t(11;14) (90%) and gain 1q (n = 3/3).

Safety Findings

Isatuximab was well-tolerated, with 49% of patients completing the full 24 planned treatment cycles. Grade 3 or 4 treatment-related adverse events (TRAE) occurred in 23% of patients.

Infusion-related reactions (IRR) occurred in 49% of patients (n = 17/35), and reactions were predominantly grade 1 or 2. Of the total patients, 1 experienced a grade 4 IRR and permanently discontinued treatment. Beyond the first cycle of therapy, no IRRs occurred.

The most common TRAEs of any grade were lymphocyte count decrease (26%), anemia (23%), diarrhea (20%), fatigue (20%), headache (17%), upper respiratory infection (17%), and lung infection (17%). Of the patients, 2 experienced grade 3 lung infections (pneumonia); both had severe hypogammaglobulinemia (IgG <400 mg/dL) prior to the event.

Study Design and Methodology

The study was a single-arm, 2-stage, multicenter phase 2 trial. From March 2018 to September 2019, 43 patients were registered across 20 institutions. Of these, 36 were eligible and 35 received at least 1 dose of isatuximab, forming the evaluable patient cohort.

Isatuximab was administered at 20 mg/kg intravenously. Patients were treated weekly on days 1, 8, 15, and 22 of treatment for the first 28-day cycle, then on days 1 and 15 for cycles 2 through 24. Patients received premedication with diphenhydramine, methylprednisolone, ranitidine, and acetaminophen to mitigate IRRs. All patients received antiviral prophylaxis (eg, acyclovir) and were recommended to receive a proton pump inhibitor.

Patient Characteristics

The median age of the 35evaluable patients was 70 years. The cohort had received a median of 1 prior treatment line. Cardiac (71%) and renal (40%) involvement were the most common.

Of the total patients, 54% were female and 46% were male. Patients had an ECOG performance score of 0 to 2.

The demonstrated safety and efficacy support the investigation of isatuximab in combination regimens.

“The current clinical trial was designed and conducted prior to the approval of daratumumab in combination with cyclophosphamide, bortezomib [Velcade], and dexamethasone [VCd] in the front-line setting,” said Parker T et al, authors of the study. “With this approval, most patients are now exposed to an anti-CD38 monoclonal antibody, which was not the case in the current trial as only 2 patients here had received prior treatment with daratumumab. Importantly, these 2 patients did not achieve a hematologic response.”

In the ANDROMEDA trial (NCT03201965),² which the above approval was founded upon, patients received up to 24 cycles of treatment prior to discontinuation.As continuous maintenance therapy is not typically given in AL amyloidosis, there may be a role for retreatment with an anti-CD38 monoclonal antibody at the time of progression. Additional studies are needed to determine the efficacy of isatuximab in AL amyloidosis following daratumumab exposure.

REFERENCES

1.Parker T, Rosenthal A, Sanchorawala V et al. Isatuximab for relapsed and/or refractory AL amyloidosis: results of a prospective phase 2 trial (SWOG S1702). Blood (2025) 146 (21): 2507–2516. doi: 10.1182/blood.2024027962

2.A study to evaluate the efficacy and safety of daratumumab in combination with cyclophosphamide, bortezomib and dexamethasone (CyBorD) compared to CyBorD alone in newly diagnosed systemic amyloid light-chain (AL) amyloidosis. ClincalTrials.gov. Updated May 25, 2025. Accessed November 24, 2025. https://clinicaltrials.gov/study/NCT03201965